A Phase 3 Randomized Clinical Trial of Nivolumab Alone, Nivolumab in Combination With Ipilimumab, or Investigator's Choice Chemotherapy in Participants With Microsatellite Instability High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer
Phase: PHASE3
Conditions: Metastatic Colorectal Cancer
Sponsor: Bristol-Myers Squibb

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Page:
1
Protocol Number:
CA2098HW
IND Number:
119,381
EU CT Number:
2023-503956-29
Date:
03-Apr-2018
Revised Date:
01-Jul-2024
CLINICAL PROTOCOL CA2098HW
A Phase 3 Randomized Clinical Trial of Nivolumab alone, Nivolumab in Combination with 
Ipilimumab, or Investigator’s Choice Chemotherapy in Participants with Microsatellite Instability 
High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer 
(CheckMate 8HW: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 8HW)
Protocol Amendment: 10
Clinical Scientist
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 
Clinical Trial Physician/Medical Monitor
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office): 
24-hr Emergency Telephone Number
USA: 1-866-470-2267
International: +1-248-844-7390
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium
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 
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BMS-936558
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Protocol Amendment No.: 10
Date: 01-Jul-2024
2
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).
© 2024 Bristol-Myers Squibb Company
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Clinical Protocol
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BMS-936558
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Protocol Amendment No.: 10
Date: 01-Jul-2024
3
DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol Amendment 
10
01-Jul-2024
Due to the delay of progression-free survival (PFS) events for the 
comparison of Arms B vs A all lines, the pre-planned, study-wise 
final analysis for overall survival (OS), planned to occur around
5-years from the first participant randomized (which is around 
Aug-2024), is no longer feasible because it will deviate from the 
study testing strategy. In order to maintain the testing strategy in the 
pre-planned analysis around Aug-2024, the study-wise final analysis 
for OS at the 5-year mark is removed and an interim analysis of 
PFS B vs A in all lines is added to occur at this time. If PFS B vs A in 
all lines meets its pre-specified statistical significance in this interim 
analysis (IA), the secondary endpoints including OS (IA) are allowed 
to be tested following the testing strategy. PFS final analysis time is 
updated to occur at approximately the 2-year minimum follow-up of 
all randomized participants. Overall survival final analysis time is 
updated to occur at approximately the 3-year minimum follow-up of 
all randomized participants. 
Protocol Amendment 
09
01-Jun-2023
Given the heterogeneity of patient populations (first-line [1L] and all 
lines) and different mode of action of study drugs (chemotherapy and 
immuno-oncology [I-O] therapy) the progression-free survival (PFS) 
event accumulation may not align for the 2 primary endpoints (PFS 
Arm B vs Arm C 1L and PFS Arm B vs Arm A all lines). The 
protocol is being amended to allow the option to trigger the interim 
analysis (IA) for each primary endpoint independently if the projected 
number of PFS events do not occur in close proximity to each other. 
In this case separate database locks (DBLs) may be conducted for IA 
of each primary endpoint.
Administrative Letter 
04
05-Jan-2023
The purpose of this administrative letter is to inform you of updated 
language corresponding to the collection of plasma samples (for 
ctDNA analysis) to correct a typo in the protocol.
Protocol Amendment 
08
04-Aug-2022
The purpose of this amendment is to specify that the data monitoring 
committee (DMC) will be utilized for the assessment of the study 
interim data and it will be providing recommendation to Bristol-
Myers Squibb (BMS) on the next steps with regards to the study 
conduct.
Protocol Amendment 
07
10-May-2022
The main objective of Protocol Amendment 07 was to update the 
statistical analyses schedule to reflect new enrollment timelines for 
Part 2. In addition, the projection of the number of randomized 
participants based on local mismatch repair deficient/microsatellite 
instability high (dMMR/MSI-H) status has been revised to reflect 
higher than initially assumed discordance rate between central and 
local dMMR/MSI-H testing results. Other changes made to comply 
with Health Authorities’ requests to include additional safety 
language around oxaliplatin use and clarification on contraception 
requirements for study participants. 
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Protocol Amendment No.: 10
Date: 01-Jul-2024
4
Document
Date of Issue
Summary of Change
Protocol Amendment 
06
01-Oct-2021
The protocol was revised to update the statistical testing strategy for 
study primary endpoints. Frequency of the tumor assessments has 
been reduced after the first 2 years from randomization. In addition, 
other minor clarifying updates were included.
Administrative Letter 
03
09-Jun-2021
Study acknowledgement page was corrected.
Administrative Letter 
02
11-Jan-2021
Noted changes to HIV testing for participants in Italy.
Protocol Amendment
05
18-Nov-2020
The protocol was updated to include dose modification criteria for
immuno-oncology (I-O) therapy and I-O-related AE management 
algorithms based on version 5 of common terminology criteria
(CTCAE v5). Program level updates were incorporated, including 
new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
study requirements, male contraception requirements in connection 
with I-O therapy. Additional safety requirements for oxaliplatin 
included.
Revised Protocol 04
17-Jul-2020
The study design was amended to expand enrollment of participants 
who have not received prior therapy for metastatic disease. Second 
primary endpoint (comparison of PFS between nivolumab plus 
ipilimumab arm and chemotherapy arm in participants who have not 
received prior therapy) was also added. Updated study rationale to 
reflect recent internal and external data in dMMR/MSI-H mCRC 
patients. Modified objectives and statistical analyses. Additional 
editorial or formatting changes, where appropriate were made.
Revised Protocol 03
28-Mar-2019
The study design was amended to include the standard of care (SOC) 
Arm that will allow for comparison of efficacy and safety of 
immunotherapy vs chemotherapy in 1L and 2L settings in a 
prospective randomized study. 
Revised Protocol 02
20-Dec-2018
Modified to become a randomized controlled trial (RCT) to compare 
nivolumab monotherapy to combination (nivolumab +ipilimumab) 
therapy in participants with and without prior treatment for metastatic 
disease.
Revised Protocol 01
16-May-2018
Modified inclusion criteria in order to extend eligibility to the 
subgroup of patients who received first line chemotherapy as a triplet 
chemotherapy combination (FOLFOXIRI).
Original Protocol
03-Apr-2018
Not applicable
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OVERALL RATIONALE FOR PROTOCOL AMENDMENT 10:
Due to the delay of progression-free survival (PFS) events for the comparison of Arms B vs A all 
lines, the pre-planned, study-wise final analysis for overall survival (OS), planned to occur around 
5-years from the first participant randomized (which is around Aug-2024), is no longer feasible 
because it will deviate from the study testing strategy. In order to maintain the testing strategy in 
the pre-planned analysis around Aug-2024, the study-wise final analysis for OS at the 5-year mark
is removed and an interim analysis of PFS B vs A in all lines is added to occur at this time. If 
PFS B vs A in all lines meets its pre-specified statistical significance in this interim analysis (IA), 
the secondary endpoints including OS (IA) are allowed to be tested following the testing strategy.
PFS final analysis time is updated to occur at approximately the 2-year minimum follow-up of all 
randomized participants. Overall survival final analysis time is updated to occur at approximately
the 3-year minimum follow-up of all randomized participants.
The protocol synopsis was updated to reflect changes in the protocol.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 10
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated “EUDRACT Number” to “EU CT 
Number.”
The term "EudraCT" is obsolete, 
as it refers to the previous 
legislation shortening the 
number per Clinical Trial 
Regulation (CTR) minimum 
requirements.
Updated the European Union (EU) Clinical 
Trial (CT) number.
Section 5.1: Overall Design
Figure 5.1-1: Study Design 
Schematic
Updated to include that Part 2 randomization 
was completed in Apr-2023.
To reflect the most recent study 
status.
Section 9.2.4: Regulatory 
Reporting Requirements for 
SAEs
Appendix 2: Study 
Governance Considerations
Replacement of Directive 2001/20/EC by 
Regulation 536/2014.
Update the legal framework of 
the trial after transition to 
EU-CTR.
Section 10.1.1: Sample Size 
Determination of Primary 
Endpoints
Removed the study-wise final analysis (OS 
final analyses) and added an interim analysis 
of PFS B vs A in all lines at the pre-planned 
analysis at 5-year from first participant 
randomized.
To fulfill the testing strategy
which would allow testing of the 
secondary endpoints including 
OS IA in this pre-planned 
analysis, therefore maintaining 
the testing strategy.
Updated the timing of the final analysis (FA)
for PFS B vs A in all lines will occur at 
approximately the 2-year minimum follow-up 
of all randomized participants.
To mitigate risk of significant 
delay of readout due to limited 
accumulation of PFS events 
beyond the 2-year minimum 
follow-up for all randomized 
participants.
Section 10.1.1: Sample Size 
Determination of Primary 
Endpoints
Updated to include that PFS B vs C in 1L has 
been tested at its IA and met the pre-specified 
statistical criteria.
To confirm the alpha passing 
based on PFS B vs C in 1L 
interim analysis result, which is 
a basis of updated statistical 
testing parameters.
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SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 10
Section Number & Title
Description of Change
Brief Rationale
Section 10.1.2: Power 
Calculation of Secondary 
Endpoints
Section 10.1.2: Power 
Calculation of Secondary 
Endpoints
Updated the projected percentage of the total 
number of PFS events of arm B vs arm A in 
1L that will be observed from 90% to 75% 
and updated the approximate number of 
events from 140 to 117.
To update analysis parameters 
aligning with the updated 
schedule of PFS analyses.
Added language in regard to when PFS B vs 
A in 1L interim analysis will be conducted or 
skipped. 
To align with the updated 
schedule of PFS analyses. 
Added: “Final analysis of PFS B vs A in 1L 
will be conducted when approximately 
156 events are observed or 2 years after the 
last participant from Part 2 enrollment was 
randomized, whichever occurs first.”
To mitigate risk of significant 
delay of readout due to potential
limited accumulation of PFS 
events beyond the 2-year 
minimum follow-up for all 
randomized participants.
Updated the timing of the final OS analyses.
To allow extended follow-up for 
survival data collection mitigate 
risk of significant delay of 
readout 
due 
to 
potential 
significant delay in OS events 
accumulation.
Section 10.3.11: Interim 
Analyses
Updated the language for the study-wise IAs 
planned for primary and secondary endpoints  
prior to the FA of OS endpoints.
To align with updates in 
Section 10.1.
Updated the timing of the final OS analyses.
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TABLE OF CONTENTS 
 
 
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3.1.1 Research Hypothesis ................................................................................ 
 
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3.2.1 Metastatic Colorectal Cancer .................................................................. 
 
3.2.2 Microsatellite Instability and Metastatic Colorectal Cancer .................. 
 
3.2.3 Chemotherapy and Targeted Agents in dMMR/MSI-H Metastatic 
Colorectal Cancer ....................................................................................... 
 
3.2.4 Immunotherapy in dMMR/MSI-H Metastatic Colorectal Cancer: Check-
Mate-142 Study and Other Data ................................................................. 
 
3.2.5 Nivolumab Mechanism of Action ............................................................. 
 
3.2.6 Ipilimumab Mechanism of Action ............................................................ 
 
3.2.7 Nivolumab Combined with Ipilimumab: Clinical Activity Across Different 
Tumor Types................................................................................................ 
 
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5.1.1 Data Monitoring Committee and Other External Committees ................ 
 
5.1.1.1 Data Monitoring Committee ........................................................... 
 
5.1.1.2 Blinded Independent Central Review (BICR) ................................. 
 
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5.4.1 Rationale for Treatment Setting ............................................................... 
 
5.4.2 Rationale for Investigator’s Choice Treatment and PFS assumptions in 
Chemotherapy Arm ..................................................................................... 
 
5.4.3 Rationale for Nivolumab Monotherapy ................................................... 
 
5.4.4 Rationale for Nivolumab and Ipilimumab Combination ......................... 
 
5.4.5 Rationale for Optional Crossover from Chemotherapy Arm ................... 
 
5.4.6 Rationale for Choice of Primary Endpoints ............................................ 
 
5.4.7 Clinical Validation of Companion Diagnostics ....................................... 
 
5.4.8 Rationale for Tissue Requirements .......................................................... 
 
5.4.9 Rationale for Duration of Study Treatment ............................................. 
 
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6.5.1 Retesting During Screening or Lead-In Period ....................................... 
 
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7.1.1 Study Treatment Duration ....................................................................... 
 
7.1.2 Treatment Schedules ................................................................................ 
 
7.1.2.1 Arm A - Nivolumab Monotherapy ................................................... 
 
7.1.2.2 Arm B - Nivolumab Plus Ipilimumab (Q3W x 4) ............................ 
 
7.1.2.3 Arm C - Investigator’s Choice Chemotherapy................................ 
 
7.1.2.4 Crossover Cohort - Nivolumab Plus Ipilimumab (Q6W 
continuously) ......................................................................................... 
 
7.1.3 Antiemetic Premedications ...................................................................... 
 
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7.2.1 Initial Treatment Assignment ................................................................... 
 
7.2.2 Crossover Cohort Treatment Assignment ................................................ 
 
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7.4.1 Dose Delay Criteria ................................................................................. 
 
7.4.1.1 Dose Delay Criteria for Nivolumab and/or Ipilimumab................. 
 
7.4.1.2 Dose Delay Criteria for Investigator’s Choice of Chemotherapy .. 
 
7.4.2 Dose Reductions....................................................................................... 
 
7.4.2.1 Dose Reduction for Nivolumab and/or Ipilimumab ........................ 
 
7.4.2.2 Dose Reductions for Investigator’s Choice Chemotherapy ............ 
 
7.4.3 Criteria to Resume Treatment .................................................................. 
 
7.4.3.1 Criteria to Resume Treatment in Arm A, Arm B or Crossover 
Cohort ................................................................................................... 
 
7.4.4 Management Algorithms for Nivolumab and Ipilimumab ....................... 
 
7.4.5 Criteria to Resume Treatment in Arm C .................................................. 
 
7.4.6 Treatment of Treatment-related Infusion Reactions ................................ 
 
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7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
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7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.3 Surgical Resection Following Initial Response ....................................... 
 
7.7.4 Permitted Therapies ................................................................................. 
 
7.7.5 Palliative Local Therapy.......................................................................... 
 
7.7.6 Imaging Restriction and Precautions ...................................................... 
 
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8.1.1 Nivolumab and/or Ipilimumab Dose Discontinuation (Arm A, B or 
Crossover Cohort) ...................................................................................... 
 
8.1.2 Investigator’s Choice Chemotherapy Dose Discontinuation (Arm C) .... 
 
8.1.3 Treatment Beyond Progression for Participants in the Arms A, B or 
Crossover Cohort ........................................................................................ 
 
8.1.4 Post Study Treatment Study Follow-up.................................................... 
 
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9.1.1 Imaging Assessment for the Study............................................................ 
 
9.1.1.1 Methods of Measurement ................................................................ 
 
9.1.1.2 BICR Assessment of Progression .................................................... 
 
9.1.1.3 Imaging and Clinical Assessment ................................................... 
 
9.1.2 Patient-Reported Outcomes ..................................................................... 
 
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9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
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9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 Electrocardiograms ................................................................................. 
 
9.4.4 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.5 Imaging Safety Assessment ...................................................................... 
 
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9.8.1 Tissue biomarkers .................................................................................... 
 
9.8.2 Peripheral Blood ...................................................................................... 
 
9.8.3 Soluble Biomarkers .................................................................................. 
 
9.8.3.1 Immunophenotyping ........................................................................ 
 
9.8.3.2 Whole Blood for Germline DNA ..................................................... 
 
9.8.3.3 Myeloid Derived Suppressor Cells ................................................. 
 
9.8.3.4 Circulating Tumor DNA Analysis (Plasma) Biomarkers................ 
 
9.8.4 Stool Sample Collection ........................................................................... 
 
9.8.5 Additional Research Collection ............................................................... 
 
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10.1.1 Sample Size Determination of Primary Endpoints ................................ 
 
10.1.2 Power Calculation of Secondary Endpoints .......................................... 
 
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10.3.1 General Considerations ......................................................................... 
 
10.3.2 Efficacy Analyses ................................................................................... 
 
10.3.3 Safety Analyses....................................................................................... 
 
10.3.4 Analyses of Crossover Cohort Treated Participants ............................. 
 
10.3.5 Pharmacokinetic Analyses ..................................................................... 
 
10.3.6 Immunogenicity ...................................................................................... 
 
10.3.7 Biomarker Analyses ............................................................................... 
 
10.3.8 Outcomes Research Analyses ................................................................ 
 
10.3.8.1 EORTC QLQ-C30 and QLQ-CR29 .............................................. 
 
10.3.8.2 EQ-5D-3L ..................................................................................... 
 
10.3.9 Other Analyses ....................................................................................... 
 
10.3.10 Strong Control of Type I Error ............................................................ 
 
10.3.11 Interim Analyses................................................................................... 
 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
1
SYNOPSIS
Protocol Title:
A Phase 3 Randomized Clinical Trial of Nivolumab alone, Nivolumab in Combination with 
Ipilimumab, or Investigator’s Choice Chemotherapy in Participants with Microsatellite Instability 
High (MSI-H) or Mismatch Repair Deficient (dMMR) Metastatic Colorectal Cancer 
Short Title:
A study of nivolumab, nivolumab plus ipilimumab, or investigator’s choice chemotherapy for the 
treatment of patients with dMMR/MSI-H metastatic colorectal cancer (mCRC).
Study Phase: 3
Rationale:
CA2098HW 
(CHECKpoint 
pathway 
and 
nivoluMAb 
clinical 
Trial 
Evaluation 
[CHECKMATE]-8HW) is a Phase 3, randomized, open-label, multi-center 3-arm clinical trial of 
nivolumab monotherapy, nivolumab plus ipilimumab combination therapy or standard 
chemotherapy in recurrent or metastatic dMMR/MSI-H CRC across lines of therapy. 
Results from non-randomized cohort study CA209142 led to the accelerated approval of 
nivolumab single agent or in combination with ipilimumab for dMMR/MSI-H metastatic CRC 
(mCRC) patients who progressed after fluoropyrimidine, oxaliplatin, and irinotecan treatment. 
Although both nivolumab monotherapy and nivolumab plus ipilimumab combination therapy 
demonstrated strong clinical activity, indirect comparisons suggested improved clinical benefit of 
combination therapy vs monotherapy. The CA2098HW is designed to confirm these findings and 
directly compare the clinical benefit, as measured by progression-free survival (PFS), objective 
response rate (ORR), and overall survival (OS), achieved by nivolumab in combination with 
ipilimumab or by nivolumab monotherapy.
It is generally accepted that patients with dMMR/MSI-H metastatic CRC are less responsive to 
conventional chemotherapy and may have a poorer prognosis than patients with mismatch repair-
proficient (pMMR) or MSS mCRC. Studies comparing single agent immunotherapy vs 
chemotherapy in patients who have not received prior treatment are currently ongoing, however 
there are no randomized studies evaluating combination of immunotherapies vs chemotherapy. 
Recently presented data from a randomized phase 3 study comparing pembrolizumab with 
standard chemotherapy in front-line setting (Keynote-177 study) confirmed superior antitumor 
activity as reflected by PFS and ORR achieved by anti-PD1 single agent vs chemotherapy in MSI-
H mCRC patients. In the CA209142 study, nivolumab plus ipilimumab combination in previously 
untreated dMMR/MSI-H mCRC patients demonstrated high ORR and durable responses which 
translated into improvement of PFS and OS. Also, this combination showed favorable safety 
profile. Promising activity of nivolumab plus ipilimumab combination as 1L treatment in 
dMMR/MSI-H mCRC patients requires further evaluation, including direct comparison vs current 
chemotherapy standard of care. This will be evaluated in the CA2098HW study.  
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
The CA2098HW study also includes a pharmacodiagnostic component as part of a post-approval 
commitment in the US. The study data will be utilized to support the analytical and clinical 
validation of an immunohistochemistry-based and a nucleic acid-based in vitro diagnostic device 
that is essential to the safe and effective use of nivolumab and/or nivolumab plus ipilimumab 
combination therapy for patients with tumors that are dMMR/MSI-H.
Study Population:
Male and female participants ≥ 18 years of age, with recurrent or metastatic dMMR/MSI-H CRC 
not amenable to surgery.
Key Inclusion Criteria: 
•
Histologically confirmed recurrent or metastatic CRC irrespective of prior treatment history 
with chemotherapy and/or targeted agents not amenable to surgery. This inclusion criterion is 
applicable only during Part 1* enrollment of the study.
•
Known tumor MSI-H or dMMR status per local standard of practice. 
•
All participants must have measurable disease by CT or MRI per RECIST 1.1 criteria. 
•
Adequate tumor tissue available. Tumor tissue specimens, either a FFPE tissue block
(preferred) or unstained tumor tissue sections (minimum of 30 positively charged slides) from 
primary or metastatic site, must be submitted to the central laboratory. Central laboratory must 
provide IRT with confirmation of receipt of evaluable tumor tissue prior to randomization. 
Tumor tissue specimen must meet either of the criteria below:
−
Obtained within 3 months of enrollment with no intervening systemic anti-cancer treatment 
between time of acquisition and randomization AND this must be the same tissue sample 
as was used for local MMR/MSI testing; 
OR
−
If above is not available, archival tissue can be accepted if the same tissue was used for 
MMR/MSI testing.
Biopsy should be excisional, incisional or core needle. Fine needle aspiration is unacceptable 
for submission. Biopsies of bone lesions that do not have a soft tissue component or decalcified 
bone samples are also unacceptable for submission.
•
ECOG Performance Status ≤1 
•
Histologically confirmed recurrent or metastatic CRC with no prior treatment history with 
chemotherapy and/or targeted agents for metastatic disease and not amenable to surgery. 
Participants treated with adjuvant chemotherapy are eligible if disease progression occurred 
later than 6 months (≥ 6 months) after completion of chemotherapy. This inclusion criterion is 
applicable during Part 2* enrollment of the study.
*Refer to Overall Design section for details
Key exclusion criteria: 
•
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 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory 
antitumor agents.
•
Participants with an active, known or suspected autoimmune disease. 
•
History of interstitial lung disease or pneumonitis.
•
Known history of positive test for HIV or known AIDS. 
•
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune disease.
•
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 
results. 
•
Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency. Systematic 
screening for DPD deficiency has to be performed at sites where mandated locally.
Additional exclusion criteria for participants who have not received prior systemic therapy or 
who have received one prior line of systemic therapy.
•
Prior major surgery, open biopsy or significant traumatic injury within 28 days prior to 
randomization. Any wound-related AE(s) must have resolved prior to randomization.
•
Clinically significant cardiovascular disease, including but not limited to congenital long QT 
syndrome. Pre-existing hypertension should be adequately controlled.
•
Clinically significant bleeding diathesis or coagulopathy.
•
Myocardial infarction, arterial thrombosis or cerebrovascular accident within 6 months prior 
to enrollment.
•
History of gastrointestinal perforation or abscess within 6 month prior to enrollment.
•
Persistence of toxicities related to first-line chemotherapy Grade > 1 (CTCAE v5.0) (except 
alopecia, fatigue or peripheral sensory neuropathy which can be Grade 2) 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Objectives and Endpoints:
The study includes two target populations and objectives are set up according to the populations. 
The randomized participants regardless of prior lines of therapy will refer to ‘All lines’ and the 
randomized participants who have not received prior therapy for metastatic disease will refer to 
‘1L’.
Primary Objective
Endpoint
•
All lines
To compare the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm 
PFS by BICR (arm B vs A)
•
1L
To compare the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or chemotherapy arm
PFS by BICR (arm B vs C)
Secondary Objective
Endpoint
•
All lines
To compare the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm
ORR by BICR (arm B vs A) 
To compare the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC and randomized to nivolumab plus ipilimumab combination therapy 
arm or nivolumab monotherapy arm
OS (arm B vs A)
To estimate the Investigator-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm
PFS by Investigator assessment
(arm A and B)
To estimate the BICR-assessed PFS of participants with dMMR/MSI-H 
mCRC per local testing who were randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm
PFS by BICR among all 
randomized participants (arm A 
and B) 
•
1L
To compare the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or nivolumab monotherapy arm
PFS by BICR (arm B vs A)
To compare the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or chemotherapy arm
ORR by BICR (arm B vs C) 
To compare the BICR -assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or nivolumab monotherapy arm
ORR by BICR (arm B vs A) 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Secondary Objective
Endpoint
To compare the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC who have not received prior therapy and randomized to nivolumab 
plus ipilimumab combination therapy arm or nivolumab monotherapy arm
OS (arm B vs A)
To estimate the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab monotherapy arm or 
chemotherapy arm
PFS by BICR (arm A and C)
To estimate the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC who have not received prior therapy and randomized to nivolumab 
plus ipilimumab combination therapy arm or chemotherapy arm
OS (arm B and C)
To estimate the BICR assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab monotherapy arm or 
chemotherapy arm
ORR by BICR (arm A and C) 
To estimate the BICR-assessed PFS of participants with dMMR/MSI-H 
mCRC per local testing who have not received prior treatment and 
randomized to nivolumab plus ipilimumab combination therapy arm or 
chemotherapy arm
PFS by BICR among all 
randomized participants who 
have not received prior treatment 
(arm B and C) 
To estimate the BICR-assessed PFS of participants with dMMR/MSI-H 
mCRC per local testing who have not received prior treatment and 
randomized to nivolumab plus ipilimumab combination therapy arm or 
nivolumab monotherapy arm
PFS by BICR among all 
randomized participants who 
have not received prior treatment 
(arm A and B) 
•
CDx (All lines and 1L)
To estimate the BICR-assessed PFS of participants with confirmed 
dMMR/MSI-H status by each central test who have not received prior 
therapy and randomized to nivolumab plus ipilimumab combination 
therapy arm or chemotherapy arm
PFS by BICR (arm B and C)
To estimate the BICR-assessed PFS of participants with confirmed 
dMMR/MSI-H status by each central test and randomized to nivolumab 
plus ipilimumab combination therapy arm or nivolumab monotherapy arm
PFS by BICR (arm B and A)
•
Crossover Cohort
To estimate the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC treated in the crossover cohort 
PFS by BICR 
To estimate the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC treated in the crossover cohort
ORR by BICR
Overall Design:
CA2098HW is a Phase 3, randomized, 3-arm open-label study of nivolumab monotherapy (arm 
A), nivolumab plus ipilimumab combination therapy (arm B) or investigator’s choice 
chemotherapy (arm C) for treatment of participants with recurrent or metastatic dMMR/MSI-H 
CRC. In protocol revision 04, the study expanded to include additional participants in 1L setting. 
Therefore, the study enrollment includes 2 sequential parts. Part 1 enrollment is open to 
participants across all lines of therapy, and Part 2 enrollment is open only to participants who have 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
not received prior therapy for metastatic disease (1L). Part 2 enrollment starts immediately after 
completion of part 1 enrollment. 
After confirmation of eligibility criteria participants will be randomized to arms A, B or C in a 
2:2:1 ratio. Randomization to arm C will be restricted to participants who have received no more 
than 1 prior line of systemic therapy (0 or 1 line). Part 1 enrollment continues to allow 
randomization of approximately 442 participants across lines of therapy with centrally confirmed 
dMMR/MSI-H mCRC as per protocol revision 03.
Approximately 230 additional participants who have not received prior therapy for metastatic 
disease (1L) with centrally confirmed dMMR/MSI-H mCRC will be randomized during part 2 
enrollment. 
A continuous evaluation of the discordance rate between local and central testing during the study 
conduct suggests that approximately 15% of the samples have discordant dMMR/MSI-H results. 
The observed discordance rate is higher than the initially assumed rate of 10% used for sample 
size calculation for randomization per local testing. Additionally, poor tissue quality led to the 
absence of valid central test results in some instances; ie, no confirmation of dMMR/MSI-H status 
by either central test. Therefore, while the projected number of randomized participants per central 
testing have not changed, the number of participants per local testing is revised to reflect higher 
than initially assumed discordance rate. 
Part 1 enrollment was completed as of Revised Protocol 06. Part 2 randomization was completed 
in Apr-2023.
Stratification factors
CA2098HW study participants will be stratified by tumor location (right vs left) and by the number 
of prior treatments for metastatic disease (none, one, two or more). Stratification by tumor 
sidedness will continue during Part 2 enrollment, however stratification by line of therapy will not 
be applicable since enrollment will be open only for participants who have not received prior 
therapy. Study specific definition of tumor sidedness and line of therapy (number of prior systemic 
treatments for metastatic disease) are provided in the Appendices 12 and 10, respectively.
Crossover Cohort
Participants assigned to arm C who experience documented progression of disease (PD) per 
RECIST 1.1 by Blinded Independent Central Review (BICR) will have an option to crossover to 
nivolumab plus ipilimumab therapy (Crossover Cohort) provided that they complete at least 
Follow Up Visit 1 within the Follow Up phase and meet all other crossover criteria outlined in the 
protocol. Crossover Cohort participants will receive treatment until progression, toxicity, 
discontinuation for other reasons, or reaching maximum treatment duration. After study treatment 
discontinuation, they will also enter the Follow Up phase (second treatment Follow Up) and will 
follow the assessment schedules. The Crossover Cohort starts when participants begins nivolumab 
plus ipilimumab combination therapy.
The study design schematic is presented in Figure 1.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Figure 1
Study Design Schematic
Abbreviations: BICR, Blinded Independent Central Review; CRC, colorectal cancer; IC, informed consent, MSI-H, microsatellite 
instability high; dMMR, deficient mismatch repair; PD, progressive disease; PFS, progression free survival
1L, 2L, ≥3L – subgroups of participants within each study arm for whom study treatment is a 1st line (0 prior lines of 
systemic therapy), 2nd line (1 prior line of systemic therapy) or 3rd line and beyond (2 or more prior lines of systemic 
therapy), respectively.
# Line of therapy is not a stratification factor during Part 2 enrollment.
* Participants with ≥2 prior lines are randomized only to arm A or B during Part 1; only participants with 0 prior lines 
are randomized during Part 2 enrollment.
** Optional Crossover for arm C with Nivo + Ipi q6w dosing
*** Part 1 enrollment continues to allow randomization of approximately 560 participants across lines of therapy with 
locally confirmed dMMR/MSI-H mCRC. Part 2 enrollment continues to allow randomization of approximately 271 
additional participants with locally confirmed dMMR/MSI-H status who have not received prior therapy for metastatic 
disease (1L). Part 2 randomization was completed in Apr-2023.
^ max treatment duration is not applicable for arm C participants
Number of Participants: 
It is expected that approximately 831 participants with dMMR/MSI-H mCRC determined by local 
testing will be randomized to study, including approximately 560 and 271 during part 1 and part 2 
enrollment, respectively. These correspond to randomization of approximately 442 participants 
across lines of therapy and 230 participants who have not received prior treatment with centrally 
confirmed dMMR/MSI-H status during part 1 and part 2 enrollment, respectively. These 
estimations are based on the number of participants with centrally confirmed dMMR/MSI-H status 
required for evaluation of each primary endpoint and on assumption of discordance rate between 
local and central testing of 15%. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Treatment Arms and Duration:
Arm A (Nivolumab monotherapy): Nivolumab 240 mg administered every 2 weeks (Q2W) for up 
to 6 doses (2 cycles), followed by nivolumab 480 mg administered every 4 weeks (Q4W) until 
disease progression, unacceptable toxicity, withdrawal of consent, or until reaching maximum 
treatment duration.a
Arm B (Nivolumab plus ipilimumab): Nivolumab 240 mg plus ipilimumab 1 mg/kg both 
administered every 3 weeks (Q3W) for up to 4 doses (2 cycles), followed by nivolumab 480 mg 
administered every 4 weeks (Q4W) until disease progression, unacceptable toxicity, withdrawal 
of consent, or until reaching maximum treatment duration.a
Arm C (Investigator’s Choice Chemotherapy): One of 6 Investigator’s choice chemotherapy 
regimens (mFOLFOX6; mFOLFOX6 + bevacizumab; mFOLFOX6 + cetuximab; FOLFIRI; 
FOLFIRI + bevacizumab; FOLFIRI + cetuximab) administered every 2 weeks (Q2W) until disease 
progression, unacceptable toxicity, withdrawal of consent.
In addition, arm C participants that experience BICR-documented progression on or after 
treatment, will have the option to enroll in the Crossover Cohort to receive nivolumab in 
combination with ipilimumab. 
Crossover Cohort (Nivolumab plus ipilimumab): Nivolumab 240 mg administered every 2 weeks 
(Q2W), for up to 6 doses (2 cycles), followed by nivolumab 480 mg administered every 4 weeks 
(Q4W) thereafter. Ipilimumab will be administered at a dose of 1 mg/kg every 6 weeks 
continuously (Q6W). Both nivolumab and ipilimumab will be administered until disease 
progression, unacceptable toxicity, withdrawal of consent, or until reaching maximum treatment 
duration.b 
amaximum treatment duration for arm A or arm B will be 2 years from the first dose of study 
treatment 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 includes treatment beyond progression. 
bParticipants enrolled to Crossover Cohort may have maximum treatment duration, including 
treatment beyond progression, of 2 years from the first dose in Crossover Cohort.
Study treatment: 
Study Drug for CA2098HW
Medication
Potency
IP/Non-IP
Nivolumab
(BMS-936558-01)
Solution for Injection
100 mg (10 mg/mL) and 40 mg (10 mg/mL)
IP
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Study Drug for CA2098HW
Medication
Potency
IP/Non-IP
Ipilimumab Solution for Injection
200 mg (5 mg/mL)
and 50 mg (5 mg/mL)
IP
Oxaliplatina,b
various strengths
IP
Leucovorin (folinic acid)a,b
various strengths
IP
Fluorouracila,b
various strengths
IP
Irinotecana,b
various strengths
IP
Bevacizumaba,b
various strengths
IP
Cetuximaba,b
various strengths
IP
a These products may be obtained by the investigational sites as local commercial products in certain countries if 
allowed by local regulations. In these cases, products may be in a different pack size/potency/pharmaceutical form 
than listed in the table. These products should be prepared/stored/administered in accordance with the package 
inserts or summaries of product characteristics. 
b Potency, packaging, and storage conditions may vary for China. Storage conditions will be indicated on the label.
Data Monitoring Committee: Yes
Sample Size Determination: 
During part 1 enrollment, participants who have received no more than 1 prior line of systemic 
therapy (0 or 1) will be randomized to nivolumab monotherapy arm (arm A), nivolumab plus 
ipilimumab combination therapy arm (arm B) or investigator’s choice of chemotherapy arm (arm 
C) at a 2:2:1 ratio. Participants who have received 2 or more prior lines of systemic therapy will 
be randomized to arm A or to arm B at a 1:1 ratio. Among all randomized participants it is expected 
that the proportion of those who have had 0 prior line of systemic therapy (1L) will be 
approximately 35%, those who had 1 prior line of systemic therapy (2L) will be approximately 
35%, and those who have had a least 2 lines of systemic therapy (3L+) will be approximately 30%. 
Part 2 enrollment was added in protocol revision 04, in order to provide appropriate power for PFS 
comparison among 1L participants between arms B vs C and arms B vs A. Only participants who 
have no prior line of systemic therapy (ie, participants for whom study treatment is a 1L therapy) 
will be randomized at 2:2:1 ratio to arms A, B and C during Part 2.  
Comparisons of an efficacy endpoint (eg, PFS, ORR, or OS) between given two arms will be based 
on concurrently randomized participants to the corresponding two arms, except when otherwise 
specified.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Participants will be enrolled based on local evaluation of their dMMR/MSI-H status but the 
primary efficacy population will consist of participants with centrally confirmed dMMR/MSI-H 
mCRC by either central test (IHC or PCR-based). It is expected that approximately 15% of the 
participants may not have their local dMMR/MSI-H mCRC confirmed centrally. The sample size 
calculation is based on randomized participants with dMMR/MSI-H status confirmed by central 
tests. Unless otherwise specified, “participants” of Study CA2098HW mentioned in this section 
refer to “randomized participants with dMMR/MSI-H status confirmed by central tests”; clinical 
outcomes (e.g., “event,” “response,” etc) of Study CA2098HW mentioned in this section refer to 
those observed among randomized participants with dMMR/MSI-H status confirmed by central 
tests.
The sample size of this study will be driven by the comparison of the two primary endpoints and 
the secondary endpoint of PFS comparison between 1L participants randomized to arm B and arm 
A: 
1. PFS comparison between participants randomized to arm B and arm A during Part 1 and 
Part 2 enrollment, hereafter denoted as ‘PFS B vs A in all lines’
2. PFS comparison between participants who have not received prior line of systemic therapy 
and randomized to arm B and arm C during Part 1 and Part 2 enrollment, hereafter denoted 
as ‘PFS B vs C in 1L’. 
3. PFS comparison between participants who have not received prior line of systemic therapy 
and randomized to arm B and arm A during Part 1 and Part 2 enrollment, hereafter denoted 
as ‘PFS B vs A in 1L’. 
In order to control the overall type I error at 5%, for the purpose of sample size calculation, the 
alpha is initially split between the two primary endpoints, with 0.6% for PFS B vs A in all lines 
and 4.4% for PFS B vs C in 1L. The secondary endpoint of PFS B vs A in 1L will be tested 
hierarchically. The testing procedure for the other secondary endpoints is provided in the protocol. 
PFS comparison in all lines between arm B vs arm A
Prior to the revised protocol 04, based on the observed PFS curve and rates at different time points 
in the nivolumab monotherapy cohorts of CA209142 (data on file, results from August 2018 
database lock), the PFS distribution for nivolumab monotherapy (arm A) was assumed to be 
piecewise exponential.
Since both arm A and arm B are immunotherapies, no delayed separation of PFS KM curves will 
be expected. 
Initially a constant hazard ratio (HR) of 0.65 for arm B compared with arm A is assumed which 
therefore translates to piecewise exponential distribution of PFS in arm B. Under these 
assumptions, the median estimates for PFS is 6 months and 27 months for monotherapy and 
combination therapy arms, respectively. 
Approximately 354 PFS events will provide about 90% power to detect a HR of 0.65 with an 
overall type 1 error of 0.006 (two-sided). Under the assumption of a staggered enrollment, it is 
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13.0
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
required to randomize approximately 564 participants to both arm A and B during Part 1 and Part 
2 enrollment. 
This initial design accounts for one PFS interim look when approximately 80% of the total number 
of events are observed (approximately 283 events). It is projected that Part 1 enrollment will take 
approximately 16 months and Part 2 enrollment will take approximately 14 months. The timing of 
final analysis is projected to be 49 months from the date of first participant being randomized 
during Part 1 enrollment.
At the time of protocol revision 04 development, the updated data from CA209142 and published 
data from Keynote-177 suggested updated assumptions on PFS rates of arm A and HR of arm B 
vs arm A in all lines. Based on the updated assumptions, approximately 319 events will provide 
about 90% power to detect a HR of 0.635 with an overall type 1 error of 0.006 (two-sided). The 
final analysis of the primary endpoint of PFS B vs A in all lines will be conducted when at least 
319 PFS events are observed, which is projected to be approximately 50 months after the first 
participant is randomized during Part 1 enrollment. An interim analysis will be conducted when 
approximately 85% of the total number of events are observed (approximately 271 events) and 
after the last participant is randomized during Part 2 enrollment.
If PFS B vs C in 1L meets the pre-specified statistical criteria at the interim or final analysis and 
0.024 alpha is passed to PFS B vs A in all lines, 319 PFS events will provide approximately 96.8% 
power with two-sided alpha of 0.03 for HR of 0.635.
Due to the delay of PFS events, the pre-planned, study-wise final analysis (OS final analyses, 
planned to occur around 5 years from the first participant’s randomization, which is around 
Aug-2024) is no longer feasible because it will deviate from the testing strategy. In order to 
maintain the testing strategy in the pre-planned analysis around Aug-2024, the study-wise final 
analysis for OS at the 5-year mark is removed and an interim analysis of PFS B vs A in all lines is 
added at this time. It is projected that the PFS events for Arm B vs A in all lines will reach 
approximately 240 events (~75% of the total number of events) around Aug-2024. If PFS B vs A 
in all lines meets its pre-specified statistical significance in this IA, the secondary endpoints 
including OS (IA) are allowed to be tested following the testing strategy. The originally planned 
PFS IA B vs A in all lines at approximately 271 events will be the second IA after the one around 
Aug-2024. The target number of events for the PFS FA B vs A in all lines (approximately 319 
events) remain unchanged. The final analysis of PFS B vs A in all lines will be conducted when 
approximately 319 events are observed or 2 years after the last participant from Part 2 enrollment 
was randomized, whichever occurs first.
Therefore, PFS B vs A in all lines will have 2 IAs (1 at approximately 240 events with a data 
cut-off in around Aug-2024 [newly added] and 1 at approximately 271 events [previously 
planned]) and a FA (previously planned, but with updated timing: when approximately 319 events 
are observed or 2 years after the last participant from Part 2 enrollment was randomized, whichever 
occurs first). The 2nd IA will be skipped if the projected time of the 2nd PFS IA B vs A in all lines 
is too close to the proposed PFS FA time (eg, less than 6 months apart), or it is projected to be 
after the proposed PFS FA time.
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13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
The significance level for the PFS IA(s) will be determined based on the observed information 
fraction of the planned total number of 319 events. If the second IA is skipped, no alpha will be 
spent for the second IA and the remaining alpha level after the first IA will be used at the FA. The 
significance level for the PFS FA will be calculated according to the actual alpha(s) spent at IA(s). 
If less than 319 events are observed, the significance level will be based on the planned 319 events 
without further adjustment for the actual total number of PFS events. 
PFS in 1L for comparison between arm B vs arm C
The sample size for the PFS B vs C in 1L is determined with the following additional assumptions:
•
The distribution of PFS in arm A in 1L is assumed based on observed data in Keynote-177. 
The PFS rates in arm B in 1L are assumed on the basis of a constant HR of 0.6 vs arm A 
in 1L.
•
The distribution of PFS in arm C in 1L follows an exponential distribution with median 
PFS of 9 months.
Based on simulations, approximately 125 PFS events will provide about 99% power to detect an 
average HR of 0.55 with an overall type 1 error of 0.044 (two-sided). Under the assumption of a 
staggered enrollment, it is required to randomize approximately 230 1L participants to arms B and 
C during Part 1 and Part 2 enrollment at 2:1 ratio. 
This design accounts for one PFS interim look when 85% of the total number of events are 
observed (approximately 106 events) and after the last participant is randomized during Part 2 
enrollment. The final analysis is projected to be approximately 47 months, from the date of first 
participant being randomized during Part 1 enrollment.
To ensure the sample size is sufficient for both of the primary endpoints as discussed above, Part 
1 randomization will be closed when approximately 442 participants are randomized with central 
lab confirmed dMMR/MSI-H. This translates to an approximate number of participants in arm A 
(N=190), B (N=190) and C (N=62 as arm C will only randomize participants who received 0 or 1 
prior lines of therapy). During Part 2 enrollment approximately 230 1L participants with central 
lab confirmed dMMR/MSI-H will be randomized. This translates to an approximate number of 
participants in arm A (N=92), B (N=92) and C (N=46). 
PFS B vs C in 1L has been tested at its interim analysis (Data cut-off date: 12-Oct-2023; 
DBL: 15-Nov-2023) and met the pre-specified statistical criteria. Therefore, PFS B vs C in 1L is 
concluded and will not be tested again in a final analysis.  
Power calculation for PFS in 1L for comparison between arms B vs A 
The PFS comparison between arm B vs arm A for 1L participants is the first secondary endpoint. 
Using the sample size as determined for the primary endpoints, the power calculation for PFS B 
vs A in 1L is calculated under the following assumptions:
•
The PFS KM curve in arm A 1L follows the piece-wise exponential distribution 
•
A constant HR of 0.6 is assumed for PFS in 1L arm B vs arm A
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13.0
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
•
The concurrent randomization ratio of arm B vs arm A is 1:1. Based on the sample size 
determined by the primary endpoints, it is estimated that a total of 308 1L participants will be 
concurrently randomized to arms A and B
•
One interim analysis of PFS of arm B vs arm A in 1L is planned. PFS B vs C in 1L has been 
tested at its interim analysis (Data cut-off date: 12-Oct-2023; DBL: 15-Nov-2023) and met the 
pre-specified statistical criteria. If PFS B vs A in all lines meets its pre-specified statistical 
criteria at its first interim analysis with the data cut-off in around Aug-2024, interim analysis 
of PFS B vs A in 1L will be conducted at the same time. It is projected that approximately 75%
of the total number of PFS events of arm B vs arm A in 1L will be observed (approximately 
117 events) in around Aug-2024. If PFS B vs A in all lines does not meet the pre-specified 
statistical criteria at its first interim analysis, PFS B vs A in 1L interim analysis will be skipped 
and the endpoint will be tested at its final analysis. Details on the testing procedure is described 
in Section 10.3.10. 
•
Under the above assumptions, a total of 156 PFS events will provide approximately 87% power 
with two-sided alpha of 0.044 to demonstrate statistical significance of arm B vs arm A in 1L. 
If PFS B vs A in all lines does not meet the pre-specified statistical criteria in the final analysis 
and PFS B vs A in 1L is tested with alpha of 0.02 passed only from PFS B vs C in 1L, 156 PFS 
events will provide approximately 79.5% power. Final analysis of PFS B vs A in 1L will be 
conducted when approximately 156 events are observed or 2 years after the last participant
from Part 2 enrollment was randomized, whichever occurs first.
Primary Endpoints and Statistical Analyses
The primary efficacy population will be the “Confirmed dMMR/MSI-H” participants. Appropriate 
analyses will be performed for “Confirmed dMMR/MSI-H by IHC” and “Confirmed dMMR/MSI-
H by PCR” to demonstrate comparable efficacy based on dMMR/MSI-H by one of the central 
tests. These analyses will support the clinical utility of the IVD for each of the central test. The 
SAP will document further details. The endpoint defined below will apply to both “All 
participants” and “1L participants,” unless otherwise specified.
Endpoint 
Statistical Analysis Methods
Primary
BICR-assessed Progression-free survival (PFS) is 
defined as the time from the randomization 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.
•
Participants who die without a reported prior 
progression and without initiation of subsequent 
anti-cancer therapy will be considered to have 
progressed on the date of their death.
The distribution of PFS will be 
compared via a two-sided, log-rank 
test 
stratified 
by 
randomization 
stratification factors of line of therapy 
(not applicable to PFS in 1L) and 
tumor sidedness recorded in IRT at the 
allocated significance level at IA and 
FA. 1L endpoints, stratified analyses 
will exclude ‘lines of therapy’ as a 
stratification factor.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Endpoint 
Statistical Analysis Methods
•
Participants who did not progress or die will be 
censored on the date of their last tumor assessment 
•
Participants who did not have any on study tumor 
assessments and did not die will be censored on the 
randomization date. 
•
Participants who started any subsequent anti-cancer 
therapy without a prior reported progression or 
prior to death will be censored at the last tumor 
assessment prior to initiation of the subsequent anti-
cancer therapy.
•
Further explanation for various censoring scenarios 
for PFS will be specified in SAP.
The hazard ratio (HR) and the 
corresponding 
100x 
(1-adjusted 
alpha) % confidence interval (CI) will 
be estimated in a stratified Cox 
proportional hazards model using the 
randomized arm as a single covariate, 
stratified by line of therapy and tumor 
sidedness as recorded in IRT. 
PFS curves will be estimated using 
Kaplan-Meier (KM) product-limit 
methodology. Median PFS with two-
sided 95% confidence interval (CI) 
using the Brookmeyer and Crowley 
method (with log-log transformation) 
will be computed. 
In addition, PFS rates at a specific 
time point (eg, 6, 12, 24 months) with 
two-sided 95% CI using the log-log 
transformation will be computed.
Interim Analyses 
The DMC will be utilized to provide an independent evaluation of the study interim data. An 
independent statistical group will be utilized to conduct unblinded monitoring of pooled events of 
the two corresponding arms of each comparison in order to track the number of events by each 
comparison. 
Study-wise, there are two interim analyses (IA) planned for primary and secondary endpoints prior 
to the final analysis of OS endpoints. 
•
The first interim analysis of the study is planned for the interim analysis for both the 
primary endpoints of PFS. Considering the variability of the enrollment assumptions from 
the actual enrollment rate and differences of the shape of PFS curves in arms A, B, and C, 
this study plans to have the interim analysis of PFS for the 2 primary endpoints at the same 
time when the latest of the targeted number of events of each endpoint is observed and after 
the last participant is randomized during Part 2 enrollment. In other words, the first interim 
analysis of the study was planned to be triggered when at least 85% of the total number of 
events were observed for both PFS primary endpoints and after the last participant 
randomized during Part 2 enrollment. Separate database locks for IA PFS B vs C in 1L and 
IA PFS B vs A in all lines may be conducted if the locks are expected to occur at least 3 
months apart from each other. As of Protocol Amendment 10, PFS B vs C in 1L has been 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
tested at its interim analysis (Data cut-off date: 12-Oct-2023; DBL: 15-Nov-2023) and met 
the pre-specified statistical criteria. Interim analysis of PFS B vs A in all lines will be 
conducted in a separate DBL with a data cut-off in around Aug-2024 (“PFS B vs A all lines
IA1 DBL”). If PFS B vs A in all lines does not meet the pre-specified statistical criteria in 
this first interim look, a second interim look (“PFS B vs A all lines IA2 DBL”) may be 
conducted if the projected time between the second interim look and final look is more than
6 months. The interim analysis of the secondary endpoint PFS B vs A in 1L will be 
conducted when PFS B vs A in all lines meets the pre-specified statistical criteria at its 
interim analysis. The stopping boundaries at the interim analysis for each of the PFS 
endpoints will be derived based on the exact number of events observed in the locked 
database using Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. 
For any PFS endpoint, if the timing of interim analysis based on this trigger is too close to 
the projected time of its final analysis (eg, within 6 months), the interim analysis of this 
specific PFS endpoint may be skipped and the endpoint will be tested at the final analysis.
•
Since PFS B vs C in 1L has been concluded, the second interim analysis of the study will 
be the final analysis of PFS B vs A in all lines and PFS B vs A in 1L, which will be 
conducted when the required number of total events are observed or 2 years after the last 
participant from Part 2 enrollment was randomized, whichever occurs first.
•
The final analysis of this study will include the final OS analysis for arm B vs arm A in all 
lines, Arm B vs Arm C in 1L, and Arm B vs Arm A in 1L, which will be conducted 3 years 
after the last participant in Part 2 enrollment was randomized. 
•
As described above, these interim and final analyses may be triggered by more than one 
endpoint and therefore all the events observed in the two arms for the corresponding 
comparisons will be used for the analyses. For a given endpoint, the stopping boundaries 
(alpha allocation) at the interim analysis will be derived based on the exact number of 
events observed in the locked database (vs target number of events at final analysis) using 
Lan-DeMets alpha spending function with O’Brien-Fleming boundaries. In the scenario 
that the final analysis of an endpoint is event-driven and the locked database has more 
events than planned, the final allocation of alpha will be adjusted based on actual number 
of events observed at the final analysis.   
Once one of the primary endpoints of PFS meets the pre-specified statistical criteria at the interim 
or final analyses, the secondary and exploratory endpoints in the same set of participants will be 
analyzed. Secondary endpoints (to be tested under the testing procedure) which have not met the 
pre-specified statistical significance level may not be reported in an aggregated fashion and be 
analyzed at the final analysis.
In addition, an ad hoc interim analysis of ORR estimation in arm A, B and arm C for 1L participants 
may be conducted to support potential 1L regulatory submission requirements. No statistical 
comparison will be made among arms. Should such an interim analysis occur, the SAP will specify 
the details, including the timing, and number of participants to be used, prior to the database lock.
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES 
Table 2-1:
Screening Procedural Outline (CA2098HW)
Procedure
Screening
Visita
Notes
Eligibility Assessments
Informed Consent
X
Must be obtained prior to performing any screening procedures. 
Register in IRT to obtain participant number. If participant meets criteria for re-enrollment, (see 
Section 6.5.1), the participant must be re-consented and assigned a new participant number via IRT.
Inclusion/Exclusion Criteria
X
Assessed during screening period (and re-enrollment, if applicable).
Must be confirmed prior to randomization.
Medical History
X
All medical history relevant to the disease under study.
Includes: concomitant medications, smoking history (including electronic cigarettes) and alcohol history.
Review previous anti-cancer 
treatment
X
As applicable. 
Please refer to Appendix 10 for study specific definition of the line of therapy (number of prior systemic 
treatments for metastatic disease) that is required for proper stratification and randomization of 
participants.
Tumor Tissue Sample
X
Either a FFPE tissue block (preferred) or unstained tumor tissue sections (minimum of 30 positively charged 
slides), from primary or metastatic site, meeting either of the following criteria must be submitted to the 
central laboratory: 
1)
Obtained within 3 months of enrollment with no intervening systemic anti-cancer treatment between 
time of acquisition and randomization AND this must be the same tissue sample as was used for local 
MMR/MSI testing; 
•
OR
2)
If above is not available, archival tissue can be accepted if the same tissue was used for MMR/MSI 
testing.
Central lab must provide IRT with confirmation of receipt of evaluable tumor tissue prior to 
randomization. Tumor tissue should be excisional, incisional or core needle biopsies or surgical 
specimens. Fine needle biopsies are not acceptable. Biopsies of bone lesions that do not have a soft tissue 
component or decalcified bone samples are also not acceptable.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2098HW)
Procedure
Screening
Visita
Notes
MMR/Microsatellite Status per 
local testing
X
Sites must submit and document prior MMR/MSI testing and results. 
Confirm availability of pathology report for MMR or microsatellite-testing results. Report should also 
contain specific results of markers tested by IHC or PCR-based method. Refer to Inclusion criteria (see 
Section 6.1) and Appendix 8 for details.
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 randomization. See Section 9.1.1.1.
Brain Imaging
X
MRI of the brain with and without contrast is required if participant is symptomatic or has a history of 
brain metastasis, and has not had brain imaging within 30 days of anticipated randomization. CT of the 
Brain (with and without contrast) can be performed if MRI is contraindicated. See Section 9.1.1.1.
Other Imaging (eg, Bone Scan)
X
As clinically indicated per local standards. See Section 9.1.1.
Safety Assessments
Physical Examination, 
Measurements, Vital Signs and 
ECOG Performance Status
X
Must be collected within 14 days prior to randomization. 
Height, weight, BP, HR, temperature and Performance Status (see Appendix 6) must be obtained. 
Assessment of Signs and Symptoms
X
Within 14 days prior to randomization.
Concomitant Medication Use and 
Vaccination
X
Within 14 days prior to randomization. Record vaccine use within 30 days prior to randomization.
SAE Assessment
X
SAEs from time of consent. See Section 9.2, and Appendix 3
All AEs (SAEs or non-serious AEs) associated with SARS-CoV-2 infection collected from time of 
consent.
ECG
X
Within 14 days prior to randomization. 12-lead ECG is required.
Laboratory Tests
Laboratory Tests (CBC 
w/differential, Chemistry, 
Endocrine, Viral)
X
CBC with differential, chemistry, urinalysis, and endocrine testing must be performed within 14 days 
prior to randomization. 
Viral testing to be performed within 28 days prior to randomization.
For HIV: testing at sites where locally mandated; see Appendix 9 for country-specific requirements.
3URWRFRO$PHQGPHQW1R
'DWH-XO
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2098HW)
Procedure
Screening
Visita
Notes
Where locally required testing for Dihydropyrimidine dehydrogenase (DPD) deficiency should be done at 
any time during screening. If testing for DPD-deficiency was done prior to study entry and the medical 
documentation is available there is no need to repeat testing. See Appendix 9 for country-specific 
requirements.
For full list of assessments to be performed, see Section 9.4.4. 
History of determination of tumor 
gene status for RAS and BRAF
X
RAS mutation status (KRAS and NRAS), BRAF mutation status, and history of Lynch syndrome (genetic 
testing results) if available.
CEA and CA19-9 Assessment
X
CEA and CA19-9 tumor markers to be assessed at any time during screening. If CEA is within normal 
limits and CA19-9 is elevated, this patient will be followed with both the CEA and CA19-9 tumor 
markers. However, if the CA19-9 is within normal limits, this patient will be followed with CEA tumor 
marker only.
Urinalysisb
X
At screening and must be performed within 14 days prior to randomization. See Section 9.4.4
Stool Samples for Microbiome 
Analysis
X
Stool sample to be collected within 7 days prior to first dose. 
SARS-CoV-2 Serology
X
Serum collected to be used for potential future measurements of anti-SARS-CoV-2 serology (anti-SARS-
CoV-2 total or IgG [see Section 9.8.3])
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) to be done at 
screening visit and 24 hours prior to first dose of study treatment. For females under the age of 55, FSH 
> 40 mIU/mL is required to confirm menopause. See Appendix 4.
a 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.
b Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required. If urine 
protein is ≥ 2+ from urine dipstick or equivalent from random urinalysis, results from a 24-hour urine collection or urine protein to creatinine ratio (UPCR) are 
required to determine eligibility (refer to exclusion criteria).
Abbreviations: BP, blood pressure; CA19-9, cancer antigen 19-9; CBC, complete blood count; CEA, carcino embryonic antigen; CT, computed tomography; 
ECOG, Eastern Cooperative Oncology Group; FFPE, formalin-fixed paraffin-embedded; HCG, human chorionic gonadotropin; HR, heart rate; IgG, 
immunoglobulin G; IHC, immunohistochemistry; IRT, Interactive Response system; MMR, mismatch repair; MRI, magnetic resonance imaging; MSI, 
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
microsatellite instability; PCR, polymerase chain reaction; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WOCBP, 
women of child bearing potential.
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
Safety Assessments
Targeted Physical 
Examination, Physical 
Measurements, Vital Signs, 
ECOG Performance Status
X
X
X
X
X
Weight, BP, HR, temperature and Performance 
Status (see Appendix 6). Obtain prior to each dose.
Review of Concomitant 
Medications and Vaccination 
Continuously
X
Record at each visit.
AE Assessment (including 
SAE Assessment)
Continuously
X
Record at each visit. 
All AEs (SAEs or non-serious AEs), must be 
collected continuously during the treatment period.
Clinical Laboratory Tests 
(CBC w/differential, 
Chemistry)
X
X
X
X
On site/ local laboratory testing should be done 
within 72 hours prior to each dose. Screening labs 
are acceptable if performed within the previous 72 
hours and results are available. For full list of 
assessments to be performed, see Section 9.4.4
Endocrine function testing
X
X (see note) 
Thyroid function testing should be done every 6 
weeks for the first 24 weeks, and then every 8 
weeks until completion of study treatment. C4D15
testing falls where there is no corresponding 
dosing and can be performed at the preceding 
dosing visit (C4D1). If clinically indicated 
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
additional tests (ACTH, cortisol) to be performed 
per local requirements. See Section 9.4.4
CEA and CA19-9 Assessment
X
X (see note)
X
CEA alone or CEA and CA19-9 will be assessed 
prior to each restaging (every 6 weeks (± 7 days) 
for the first 24 weeks, and every 8 weeks (± 7 
days) thereafter). Sample collection can be 
obtained at the corresponding dosing visit. C4D15
testing falls where there is no corresponding 
dosing and can be performed at the preceding 
dosing visit (C4D1).
Pregnancy Test (WOCBP 
only)
X
C1D29
C2D15
X
Serum or urine within 24 hours prior to first dose 
and then every 4 weeks (± 1 week) regardless of 
dosing schedule.
Health Outcomes 
EORTC QLQ-C30 
Questionnaire 
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, 
and then every other cycle (Q8W) thereafter. 
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 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
delayed, the administration of the patient-reported 
outcome measures scheduled for that same time 
point should also be delayed to coincide with when 
that time point’s dosing actually occurs
EORTC QLQ-CR29 
Questionnaire
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, 
and then every other cycle (Q8W) thereafter. 
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 patient-reported 
outcome measures scheduled for that same time 
point should also be delayed to coincide with when 
that time point’s dosing actually occurs
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
EQ-5D-3L Questionnaire
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1 
and then every other cycle (Q8W) thereafter. 
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 patient-reported 
outcome measures scheduled for that same time 
point should also be delayed to coincide with when 
that time point’s dosing actually occurs
Efficacy Assessments
Tumor assessmentsd
See note 
During first 96 weeks from randomization 
(Year 1 and 2)
Tumor assessment should occur every 6 weeks (±
7 days) from randomization for the first 24 weeks, 
and every 8 weeks (± 7 days) thereafter, until 
BICR confirmed progression, and treatment 
discontinuation (including treatment beyond 
progression), whichever occurs later. This schedule 
should be followed even if treatment delay 
occurs. See Section 9.1.1 for further details.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
During week 97 - 144 from randomization 
(Year 3)
Tumor assessment should occur every 16 weeks (±
7 days) until BICR confirmed progression. See 
Section 9.1.1 for further details.
Beyond week 144 from randomization (Year 4 
and beyond)
Tumor assessment should occur every 24 weeks (±
14 days) until BICR confirmed progression. See 
Section 9.1.1 for further details.
Brain Imaging
See note
Participants with a history of brain metastasis 
should have surveillance MRI per standard of care 
(approximately every 12 weeks, or sooner if 
clinically indicated). See Section 9.1.1 for further 
details.
Other Imaging (eg, Bone Scan)
See note
As clinically indicated per local standards. See 
Section 9.1.1 for further details.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
Pharmacokinetic /Immunogenicity Assessments
PK and Immunogenicity 
samples
X
See note
See Table 9.5-1 for time points of collection.
Biomarker Assessments
Exploratory Plasma 
Biomarkers, Whole Blood 
DNA, MDSC, PBMC, Serum 
X
X (See note)
X (see note)
See Table 9.8-1 for time points of collection. 
SARS-CoV-2 Serologye
X (See note)
Serum collected approximately every 6 cycles 
during study treatment to be used for potential 
future measurements of anti-SARS-CoV-2 serology 
(anti-SARS-CoV-2 total or IgG [see Section 9.8.3]). 
Stool samples for microbiome 
analysis
C2D1
X (see note)
See Table 9.8-1 for time points of collection. 
Samples may collected within 3 days prior to 
dosing.
3URWRFRO$PHQGPHQW1R
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
13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
Collection of tumor tissue for 
biomarker research on-
treatment and upon disease 
progression
C1D22-28 
(1 week after 2nd dosing and before the 3rd dosing)
X (see note)
Tumor tissue submission while on-treatment (1 
week after 2nd dosing and before the 3rd dosing, 
i.e. between Day 22-28 of Cycle 1) and upon 
progression (PD + 14 days) is optional but strongly 
recommended to understand the 
response/resistance to nivolumab treatment. See 
Table 9.8-1 for time points of collection.
If biopsy or surgical resection is performed per 
protocol while on treatment or at progression, a 
tumor sample (block [preferred] or slides) should 
be submitted to central laboratory. If 
biopsies/surgical resection are done at any other 
time on treatment, tissue samples should be 
submitted as well.
Clinical Drug Supplies
Randomization
X
IRT Drug Vial Assignment
Participant must receive the first dose of study 
medication within 3 days after randomization.
3URWRFRO$PHQGPHQW1R
'DWH-XO
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-2:
On Treatment Procedural Outline (CA2098HW) Arm A (Nivolumab Monotherapy)
Cycles 1 and 2 
(cycle =6 weeks)
Cycle 3 to 
EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 
days)
C3D1 and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks)
(± 3 days)
Nivolumab 240 mg flat dose 
IV
X
X
X
Nivolumab 480 mg flat dose 
IV
X
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b 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.
c Treatment to progression, unacceptable toxicity, withdrawal of consent, or maximum treatment duration as specified in Section 7.1.1
d Any additional imaging, including unscheduled timepoints, that may demonstrate tumor response/progression should be submitted to BICR.
e Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection.
Abbreviations: AE, adverse event; BICR, Blinded Independent Central Review; BP, blood pressure; CA19-9, cancer antigen 19-9; CBC, complete blood count; 
CEA, carcino embryonic antigen ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-CR29 Questionnaire, European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire-Core 29; EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30; EOT, end of treatment; EQ-5D-3L Questionnaire, EuroQol Five-Dimensional Questionnaire, Three-Level Questionnaire; HR, heart rate; 
IgG, immunoglobulin G; IRT, Interactive Response system; MDSC, myeloid-derived suppressor cell, MRI, magnetic resonance imaging; PBMC, peripheral blood 
mononuclear cell; PK, pharmacokinetic; PD, progressive disease; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; 
WOCBP, women of child bearing potential.
3URWRFRO$PHQGPHQW1R
'DWH-XO
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline (CA2098HW) Arm B (Nivolumab + Ipilimumab Combination)
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D22
(± 3 
days)
C2D1 and 
C2D22 
(± 3 days)
C3D1 and Day 1 
of each 
subsequent 
Cycle to EOTc
(every 4 weeks)
(± 3 days)
Safety Assessments
Targeted Physical Examination, 
Physical Measurements, Vital 
Signs, ECOG Performance 
Status
X
X
X
X
X
Weight, BP, HR, temperature and Performance Status 
(see Appendix 6). Obtain prior to each dose.
Review of Concomitant 
Medications and Vaccination 
Continuously
X
Record at each visit.
Adverse Events Assessment 
(including SAE Assessment)
Continuously
X
Record at each visit. 
All AEs (SAEs or non-serious AEs) must be collected 
continuously during the treatment period.
Clinical Laboratory Tests (CBC 
w/differential, Chemistry)
X
X
X
X
On site/ local laboratory testing should be done within 
72 hours prior to each dose. Screening labs are 
acceptable if performed within the previous 72 hours 
and results are available. For full list of assessments to 
be performed, see Section 9.4.4
Endocrine function testing
X
X (see note) 
Thyroid function testing should be done every 6 
weeks for the first 24 weeks, and then every 8 weeks 
until completion of study treatment. C4D15 testing 
falls where there is no corresponding dosing and can 
be performed at the preceding dosing visit (C4D1). If 
clinically indicated additional tests (ACTH, cortisol) 
to be performed per local requirements. See Section 
9.4.4
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline (CA2098HW) Arm B (Nivolumab + Ipilimumab Combination)
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D22
(± 3 
days)
C2D1 and 
C2D22 
(± 3 days)
C3D1 and Day 1 
of each 
subsequent 
Cycle to EOTc
(every 4 weeks)
(± 3 days)
CEA and CA19-9 Assessment
X
X (see note)
X
CEA alone or CEA and CA19-9 will be assessed prior 
to each restaging (every 6 weeks (± 7 days) for the 
first 24 weeks, and every 8 weeks (± 7 days) 
thereafter). Sample collection can be obtained at the 
corresponding dosing visit. C4D15 testing falls where 
there is no corresponding dosing and can be 
performed at the preceding dosing visit (C4D1).
Pregnancy Test (WOCBP only)
X
X
X
X
Serum or urine within 24 hours prior to first dose and 
then every 4 weeks (± 1 week) regardless of dosing 
schedule.
Health Outcomes 
EORTC QLQ-C30 
Questionnaire
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, and 
then every other cycle (Q8W) thereafter. 
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 patient-reported outcome measures scheduled 
for that same time point should also be delayed to 
coincide with when that time point’s dosing actually 
occurs.
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline (CA2098HW) Arm B (Nivolumab + Ipilimumab Combination)
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D22
(± 3 
days)
C2D1 and 
C2D22 
(± 3 days)
C3D1 and Day 1 
of each 
subsequent 
Cycle to EOTc
(every 4 weeks)
(± 3 days)
EORTC QLQ-CR29
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, and 
then every other cycle (Q8W) thereafter. 
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 patient-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
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, and 
then every other cycle (Q8W) thereafter. 
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 patient-reported outcome measures scheduled 
for that same time point should also be delayed to 
coincide with when that time point’s dosing actually 
occurs.
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline (CA2098HW) Arm B (Nivolumab + Ipilimumab Combination)
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D22
(± 3 
days)
C2D1 and 
C2D22 
(± 3 days)
C3D1 and Day 1 
of each 
subsequent 
Cycle to EOTc
(every 4 weeks)
(± 3 days)
Efficacy Assessments
Tumor assessmentsd
See note 
During first 96 weeks from randomization (Year 1 
and 2)
Tumor assessment should occur every 6 weeks (± 7 
days) from randomization for the first 24 weeks, and 
every 8 weeks (± 7 days) thereafter, until BICR 
confirmed progression, and treatment discontinuation 
(including treatment beyond progression), whichever 
occurs later. This schedule should be followed even if 
treatment delay occurs. See Section 9.1.1 for further 
details. 
During week 97 - 144 from randomization (Year 3)
Tumor assessment should occur every 16 weeks (± 7 
days) until BICR confirmed progression. See Section 
9.1.1 for further details.
Beyond week 144 from randomization (Year 4 and 
beyond)
Tumor assessment should occur every 24 weeks (± 14 
days) until BICR confirmed progression. See Section 
9.1.1 for further details.
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline (CA2098HW) Arm B (Nivolumab + Ipilimumab Combination)
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D22
(± 3 
days)
C2D1 and 
C2D22 
(± 3 days)
C3D1 and Day 1 
of each 
subsequent 
Cycle to EOTc
(every 4 weeks)
(± 3 days)
Brain Imaging
See note
Participants with a history of brain metastasis should 
have surveillance MRI per standard of care 
(approximately every 12 weeks, or sooner if clinically 
indicated). See Section 9.1.1 for further details.
Other Imaging (eg, Bone Scan)
See note
As clinically indicated per local standards. See 
Section 9.1.1 for further details.
Pharmacokinetic /Immunogenicity Assessments
PK and Immunogenicity 
samples
X
See note
See Table 9.5-2 for time points of collection.
Biomarker Assessments
Exploratory Plasma 
Biomarkers, Whole Blood 
DNA, MDSC, PBMC, Serum 
X
See note
X (see 
note)
See Table 9.8-2 for time points of collection. 
SARS-CoV-2 Serologye
X (See note)
Serum collected approximately every 6 cycles during 
study treatment to be used for potential future 
measurements of anti-SARS-CoV-2 serology (anti-
SARS-CoV-2 total or IgG [see Section 9.8.3]). 
Stool samples for microbiome 
analysis
C2D1
X (see 
note)
See Table 9.8-2 for time points of collection. Samples 
may be collected within 3 days prior to dosing.
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-3:
On Treatment Procedural Outline (CA2098HW) Arm B (Nivolumab + Ipilimumab Combination)
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 
weeks)
Upon PD
Notes
Procedurea,b
C1D1
C1D22
(± 3 
days)
C2D1 and 
C2D22 
(± 3 days)
C3D1 and Day 1 
of each 
subsequent 
Cycle to EOTc
(every 4 weeks)
(± 3 days)
Collection of tumor tissue for 
biomarker research on-
treatment and upon disease 
progression 
C1D29-35 
(1 week after 2nd dosing and before the 3rd dosing)
X (see 
note)
Tumor tissue submission while on-treatment (1 week 
after 2nd dosing and before the 3rd dosing, i.e. 
between Day 29-35 of Cycle 1) and upon progression 
(PD + 14 days) is optional but strongly recommended 
to understand the response/resistance to nivolumab 
plus ipilimumab treatment. See Table 9.8-2 for time 
points of collection.
If biopsy or surgical resection is performed per 
protocol while on treatment or at progression (PD + 
14 days), a tumor sample (block [preferred] or slides) 
should be submitted to central laboratory. If biopsies/ 
surgical resection are done at any other time on 
treatment, tissue samples should be submitted as well.
Clinical Drug Supplies
Randomization
X 
IRT Drug Vial Assignment
Participant must receive the first dose of study 
medication within 3 days after randomization.
Nivolumab 240 mg flat dose IV
X
X
X
Ipilimumab (1 mg/kg) IV 
X
X
X
Nivolumab 480 mg flat dose IV
X
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b 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.
c Treatment to progression, unacceptable toxicity, withdrawal of consent, or maximum treatment duration as specified in Section 7.1.1
d Any additional imaging, including unscheduled timepoints, that may demonstrate tumor response/progression should be submitted to BICR.
e Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection.
Abbreviations: AE, adverse event; BICR, Blinded Independent Central Review, BP, blood pressure; CA19-9, cancer antigen 19-9; CBC, complete blood count; 
CEA, carcino embryonic antigen; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-CR29 Questionnaire, European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 29; EORTC QLQ-C30, European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire-Core 30; EOT, end of treatment; EQ-5D-3L Questionnaire, EuroQol Five-Dimensional Questionnaire, Three-Level 
Questionnaire; FFPE, formalin-fixed paraffin-embedded; HCG, human chorionic gonadotropin; HR, heart rate; IgG, immunoglobulin G; IHC, 
immunohistochemistry; IRT, Interactive Response system; MDSC, myeloid-derived suppressor cell; MMR, mismatch repair; MRI, magnetic resonance imaging; 
MSI, microsatellite instability; PBMC, peripheral blood mononuclear cell, PCR, polymerase chain reaction; PK, pharmacokinetic; PD, progressive disease; SAE, 
serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WOCBP, women of child bearing potential.
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
Safety
Targeted Physical 
Examination, Physical 
Measurements, Vital 
Signs, ECOG 
Performance Status
X
X
X
X
X
X
Weight, BP, HR, temperature and 
Performance Status (see Appendix 6). Obtain 
prior to each dose.
Review of Concomitant 
Medications and 
Vaccination 
Continuously
X
Record at each visit.
AE Assessment 
(including SAE 
Assessment)
Continuously
X
Record at each visit. 
All AEs (SAEs or non-serious AEs) must be 
collected continuously during the treatment 
period.
Clinical Laboratory 
Tests (CBC 
w/differential, 
Chemistry)
X
X
X
X
X
On site/ local laboratory testing should be 
done within 72 hours prior to each dose. 
Screening labs are acceptable if performed 
within the previous 72 hours and results are 
available. For full list of assessments to be 
performed, see Section 9.4.4
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
Urinalysis
Xd
Xd
Xd
Xd
Xd
For participants assigned to receive 
bevacizumab-containing regimens only.
CEA and CA19-9 
Assessment
X
X (see note)
X
CEA alone or CEA and CA19-9 will be 
assessed prior to each restaging (every 6 
weeks (± 7 days) for the first 24 weeks, and 
every 8 weeks (± 7 days) thereafter). Sample 
collection can be obtained at the 
corresponding dosing visit. 
Pregnancy Test 
(WOCBP only)
X
C1D29
C2D15
X (see note)
Serum or urine within 24 hours prior to first 
dose and then every 4 weeks (± 1 week) 
regardless of dosing schedule.
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
Health Outcomes 
EORTC QLQ-C30 
Questionnaire 
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, 
C3D1, and then every other cycle (Q8W) 
thereafter. 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 patient-reported 
outcome measures scheduled for that same 
time point should also be delayed to coincide 
with when that time point’s dosing actually 
occurs
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
EORTC QLQ-CR29
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, 
C3D1, and then every other cycle (Q8W) 
thereafter. 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 patient-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
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, 
C3D1 and then every other cycle (Q8W) 
thereafter. 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 patient-reported 
outcome measures scheduled for that same 
time point should also be delayed to coincide 
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
with when that time point’s dosing actually 
occurs
Efficacy Assessments
Tumor assessmentse
See note 
During first 96 weeks from randomization 
(Year 1 and 2)
Tumor assessment should occur every 6 
weeks (± 7 days) from randomization for the 
first 24 weeks, and every 8 weeks (± 7 days) 
thereafter, until BICR confirmed progression, 
and treatment discontinuation (including 
treatment beyond progression), whichever 
occurs later. This schedule should be 
followed even if treatment delay occurs. See 
Section 9.1.1 for further details. 
During week 97 - 144 from randomization 
(Year 3)
Tumor assessment should occur every 16 
weeks (± 7 days) until BICR confirmed 
progression. See Section 9.1.1 for further 
details.
Beyond week 144 from randomization 
(Year 4 and beyond)
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
Tumor assessment should occur every 24 
weeks (± 14 days) until BICR confirmed 
progression. See Section 9.1.1 for further 
details.
Brain Imaging
See note
Participants with a history of brain metastasis 
should have surveillance MRI per standard of 
care (approximately every 12 weeks, or 
sooner if clinically indicated). See Section 
9.1.1 for further details.
Other Imaging (eg, 
Bone Scan)
See note
As clinically indicated per local standards. 
See Section 9.1.1 for further details.
Biomarker Assessments
Exploratory Plasma 
Biomarkers, Whole 
Blood DNA, MDSC, 
PBMC, Serum 
X
X (see note)
X (see 
note)
See Table 9.8-1 for time points of collection. 
3URWRFRO$PHQGPHQW1R
'DWH-XO

13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
SARS-CoV-2 Serologyf
X (See note)
Serum collected approximately every 6 
cycles during study treatment to be used for 
potential future measurements of anti-SARS-
CoV-2 serology (anti-SARS-CoV-2 total or 
IgG [see Section 9.8.3]). 
Stool samples for 
microbiome analysis
C2D1 
X (see 
note)
See Table 9.8-1 for time points of collection. 
Samples may collected within 3 days prior to 
dosing.
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13.0
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930125433
13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
Collection of tumor 
tissue for biomarker 
research on-treatment 
C1D22-28 
(1 week after 2nd dosing and before the 3rd dosing)
X (see 
note)
Tumor tissue submission while on-treatment 
(1 week after 2nd dosing and before the 3rd 
dosing, i.e. between Day 22-28 of Cycle 1) 
and upon progression (PD + 14 days) is 
optional but strongly recommended to 
understand the response/resistance to 
nivolumab treatment. See Table 9.8-1 for 
time points of collection.
Tumor tissue collection upon progression 
(PD + 14 days) is mandatory if medically 
feasible for enrolment to Crossover Cohort. 
If biopsy or surgical resection is performed 
per protocol while on treatment or at 
progression, a tumor sample (block 
[preferred] or slides) should be submitted to 
central laboratory. If biopsies/ surgical 
resection are done at any other time on 
treatment, tissue samples should be 
submitted as well.
Clinical Drug Supplies
Randomization
X
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-4:
On Treatment Procedural Outline (CA2098HW) Arm C (Investigator’s Choice Chemotherapy)
Cycles 1 and 2
(cycle =6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15 
and 
C1D29
(± 3 
days)
C2D1, 
C2D15, 
and 
C2D29
(± 3 days)
C3D1, and 
Day 1 of each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) 
(± 3 days)
C3D15, and 
Day 15 of 
each 
subsequent 
Cycle to 
EOTc (every 
4 weeks) (± 3 
days)
IRT Drug Vial 
Assignment
Participant must receive the first dose of 
study medication within 3 days after 
randomization.
Oxaliplatin, 85 mg/m2
X (see note)
Chemotherapy drugs will be administered 
every 2 weeks per local standards. See 
Section 7.1.2 for details. 
Leucovorin, 400 mg/m2  
Fluorouracil bolus, 400 
mg/m2  
Fluorouracil infusion, 
2400 mg/m2
Irinotecan, 180 mg/m2
Bevacizumab, 5 mg/kg
Cetuximab, 500 mg/m2
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b 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.
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13.0
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
c Treatment to progression, unacceptable toxicity, withdrawal of consent, or maximum treatment duration as specified in Section 7.1.1
d If urine protein is ≥ 2+ from urine dipstick or equivalent from random urinalysis a 24 hour urine collection or UPCR should be performed and results obtained 
before the next treatment with bevacizumab. See Sections 7.4.1.2 (Dose Delay), 7.4.2.2 (Dose Reductions), and 7.4.5 (Criteria to Resume Treatment) for 
bevacizumab dose modification criteria.
e Any additional imaging, including unscheduled timepoints, that may demonstrate tumor response/progression should be submitted to BICR.
f Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection.
Abbreviations: AE, adverse event; BICR, Blinded Independent Central Review, BP, blood pressure; CA19-9, cancer antigen 19-9; CBC, complete blood count; 
CEA, carcino embryonic antigen; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-CR29 Questionnaire, European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 29; EORTC QLQ-C30, European Organization for Research and Treatment 
of Cancer Quality of Life Questionnaire-Core 30; EOT, end of treatment; EQ-5D-3L Questionnaire, EuroQol Five-Dimensional Questionnaire, Three-Level 
Questionnaire; FFPE, formalin-fixed paraffin-embedded; HCG, human chorionic gonadotropin; HR, heart rate; IgG, immunoglobulin G; IHC, 
immunohistochemistry; IRT, Interactive Response system; MDSC, myeloid-derived suppressor cell; MMR, mismatch repair; MRI, magnetic resonance imaging; 
MSI, microsatellite instability; PBMC, peripheral blood mononuclear cell, PCR, polymerase chain reaction; PD, progressive disease; SAE, serious adverse event; 
SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WOCBP, women of child bearing potential.
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13.0
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-5:
Follow-Up Assessments (CA2098HW)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-
Up Visits b
Notesc
Safety Assessments
Targeted Physical Examination, 
Measurements, Vital Signs, and 
Performance Status
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
*
All AEs to be collected for 100 days after last dose of study treatment. 
Participants in arm C eligible to crossover have to complete at least 
Follow Up Visit 1 before entering the Crossover Cohort.
Participants will be followed for all SAEs, non-serious AEs of special 
interest (as defined in Section 9.2), and all AEs (SAEs and non-serious 
AEs) associated with confirmed or suspected SARS-CoV-2 infection 
until resolution, the condition stabilizes, the event is otherwise explained, 
the event is deemed irreversible, the participant is lost to follow-up (as 
defined in Section 8.3), for suspected cases, until SARS-CoV-2 is ruled 
out.
*In Survival Follow-Up period only to include toxicities from study 
therapy. 
ECG
X
Only at FU1. 12-lead ECG is required.
Review of Concomitant Medication
and Vaccination
X
Only at FU1 except for Vaccination, that should be reviewed at both FU1 
and FU2
Review of Subsequent Cancer 
Therapies
X
X
Additional subsequent cancer therapy details such as regimen, setting of 
the regimen, line of therapy, start date and end date of each regimen, best 
response to the regimen and date of progression after second line therapy 
will be collected.
Laboratory Tests
(CBC w/differential, Chemistry)
X
On site/local laboratory testing. 
To be performed at FU1. To be repeated at FU2 if study drug related 
toxicity persists.
For full list of assessments to be performed, see Section 9.4.4.
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13.0
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930125433
13.0
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Approved
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-5:
Follow-Up Assessments (CA2098HW)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-
Up Visits b
Notesc
Endocrine function testing
X (see note)
Thyroid function testing should be done. Additional tests (e.g. ACTH, 
cortisol, etc.) should be performed if clinically indicated. For participants 
who received nivolumab without or with ipilimumab. See Section 9.4.4
Urinalysisd
X (see note)
For participants who received bevacizumab
Pregnancy Test (WOCBP only)
X (see note)
Serum or urine only for FU1, unless testing is required for a longer 
period, per local regulations.
SARS-CoV-2 serologye
X (see note)
Only at FU1: Serum collected to be used for potential future 
measurements of anti-SARS-CoV-2 serology (anti-SARS-CoV-2 total or 
IgG [see Section 9.8.3])
Efficacy Assessments
Tumor assessmentsf
During first 96 weeks from randomization (Year 1 and 2)
Participants who enter the follow-up period without BICR confirmed tumor progression will continue to have tumor 
imaging assessments as per on-treatment schedule (every 6 weeks [± 7 days] from randomization for the first 24 
weeks, and every 8 weeksg [± 7 days] thereafter, until BICR confirmed disease progression, lost to follow-up, or 
withdrawal of consent, whichever occurs first. See Section 9.1.1 for details on methodology. 
During week 97 - 144 from randomization (Year 3)
Tumor assessment should occur every 16 weeks (± 7 days) until BICR confirmed progression. See Section 9.1.1
for further details.
Beyond week 144 from randomization (Year 4 and beyond)
Tumor assessment should occur every 24 weeks (± 14 days) until BICR confirmed progression. See Section 9.1.1
for further details.
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 9.1.1 for further details.
Other Imaging (eg. Bone Scan)
As clinical indicated per local standards. See Section 9.1.1for further details.
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-5:
Follow-Up Assessments (CA2098HW)
Procedure
Follow Up,
Visits 1 and 2a
Survival Follow-
Up Visits b
Notesc
TSST/PFS2 assessment
X
X
Following first progression, participants will continue to be followed 
during the safety and survival visits. Timing of second progression per 
Investigator’s assessment will be documented.
Outcomes Research Assessment 
EQ-5D-3L Questionnaire
X
X
Can be collected either during a clinic visit or by telephone.
EORTC QLQ-C30 
X
EORTC QLQ-CR29
X
Participant Status
Survival Statusband Subsequent 
Therapy Information
X
X
Every 3 months after safety follow-up Visit 2; may be accomplished by 
visit, phone contact or email, to assess subsequent anti-cancer therapy 
after completing safety follow up visit. Additional subsequent cancer 
therapy details such as regimen, setting of the regimen, line of therapy, 
start date and end date of each regimen, best response to the regimen and 
date of progression after subsequent line therapy will be collected.
# Follow Up assessments are applicable for participants entering the Follow Up phase from arms A, B and C (first treatment Follow Up), and from the 
Crossover Cohort (second treatment Follow Up). Follow Up visits 1 (FU1) and 2 (FU2) are in-clinic visits. 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 42 days after last dose, Follow-
up visit 2 (FU2) occurs approximately 100 days (± 7 days) from last dose. Both Follow Up visits should be conducted in person.
a All participants must be followed for at least 100 days after last dose of study treatment with the exception of participants from arm C that experience PD on 
treatment AND who enter the Crossover Cohort. These participants are required to complete at least Follow Up Visit 1 following EOT in arm C. 
b Survival Follow Up Visits may be conducted in clinic or via telephone contact: Every 3 Months (± 7 days) from FU2. BMS may request that survival data be 
collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant will be contacted to determine their 
survival status unless the participant has withdrawn consent for all contact.
c 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.
3URWRFRO$PHQGPHQW1R
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
d Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required. If urine 
protein is ≥ 2+ from urine dipstick or equivalent from random urinalysis, 24-hour urine collection or UPCR may be performed if deemed clinically indicated by 
the investigator.
e Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection.
f Any additional imaging, including unscheduled timepoints, that may demonstrate tumor response/progression should be submitted to BICR.
g Every 12 weeks for participants who enter Follow Up from the Crossover Cohort.
Abbreviations: AE, adverse event; BP, blood pressure; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC QLQ-CR29 Questionnaire, 
European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 29; EORTC QLQ-C30, European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT, end of treatment; EQ-5D-3L Questionnaire, EuroQol Five-Dimensional Questionnaire, 
Three-Level Questionnaire; HR, heart rate; IgG, immunoglobulin G; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cell; PFS2, time 
from randomization to second disease progression or death; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TSST, 
time from randomization to second subsequent therapy or death; WOCBP, women of child bearing potential.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
Eligibility 
assessment 
Informed consent
X
Eligibility criteria
X
Participants must have completed Follow-Up Visit 1 
on arm C, meet all eligibility criteria for crossover to 
nivolumab plus ipilimumab therapy (See Section 6.3), 
and have had a tumor biopsy upon progression on arm 
C, if medically feasible.  
Safety Assessments
Targeted Physical 
Examination, 
Physical 
Measurements, 
Vital Signs, ECOG 
Performance Status
X
X
X
X
X
X**
X
Baseline visit: Must be collected within 14 days prior 
to vial assignment. 
Weight, BP, HR, temperature and Performance Status 
(see Appendix 6). Obtain prior to each dose.
**Only on days when ipilimumab is administered. 
ECG
X
Within 14 days prior to vial assignment. 12-lead ECG 
is required. 
Review of 
Concomitant 
X
Continuously
X
Record at each visit.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
Medications and 
Vaccination 
Adverse Events 
Assessment 
(including SAE 
Assessment)
X
Continuously
X
Record at each visit.
Clinical Laboratory 
Tests (CBC 
w/differential, 
Chemistry, Viral)
X
(See note)
X
X
X
X
X**
Baseline visit: CBC with differential, chemistry must 
be performed within 14 days prior to vial assignment. 
Viral testing to be performed within 28 days prior to 
vial assignment. See Section 9.4.4 for the details.
On treatment visits: On site/ local laboratory testing 
for CBC with differential and chemistry should be 
done within 72 hours prior to each dose. Baseline labs 
are acceptable if performed within the previous 72 
hours and results are available. For full list of 
assessments to be performed, see Section 9.4.4
**Only on days when ipilimumab is administered.
Urinalysis
X
(See note)
Testing must be performed within 14 days prior to vial 
assignment. See Section 9.4.4
Endocrine function 
testing
X
(See note)
X
X (see note) 
Baseline visit: Testing must be performed within 14 
days prior to vial assignment. See Section 9.4.4
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
On-treatment visits: thyroid function testing should be 
done every 6 weeks for the first 24 weeks, and then 
every 8 weeks until completion of study treatment. If 
clinically indicated additional tests (ACTH, cortisol) to 
be performed per local requirements. See Section 9.4.4
CEA and CA19-9 
Assessment
X
X
X (see note)
X
CEA alone or CEA and CA19-9 will be assessed prior 
to each restaging (every 6 weeks (± 7 days) for the first 
24 weeks, and every 12 weeks (± 7 days) thereafter). 
Sample collection can be obtained at the corresponding 
dosing visit. 
Pregnancy Test 
(WOCBP only)
X
X
X
X
X
Serum or urine pregnancy test (minimum sensitivity 25 
IU/L or equivalent units of HCG) to be done at 
baseline visit and within 24 hours prior to first dose 
and then every 4 weeks (± 1 week) regardless of dosing 
schedule.
Health Outcomes 
EORTC QLQ-C30 
Questionnaire
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, and 
then every other cycle (Q8W) thereafter. 
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 
3URWRFRO$PHQGPHQW1R
'DWH-XO
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
visit). If a dose is delayed, the administration of the 
patient-reported outcome measures scheduled for that 
same time point should also be delayed to coincide 
with when that time point’s dosing actually occurs.
EORTC QLQ-CR29 
Questionnaire
X
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, and 
then every other cycle (Q8W) thereafter. 
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 
patient-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
C2D1
See note
Assessed prior to dosing on C1D1, C2D1, C3D1, and 
then every other cycle (Q8W) thereafter. 
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 
patient-reported outcome measures scheduled for that 
same time point should also be delayed to coincide 
with when that time point’s dosing actually occurs.
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
Efficacy 
Assessments
Tumor assessmentsd
X 
(see note)
See note 
Baseline: The participant will be re-baselined based on 
the investigator’s assessment of the scans with which 
BICR progression was determined.
During first 96 weeks from start of treatment in 
Crossover cohort (Year 1 and 2)
On treatment: Tumor assessment should occur every 
6 weeks (± 7 days) from vial assignment for the first 24 
weeks, and every 12 weeks (± 7 days) thereafter, until 
BICR confirmed progression, and treatment 
discontinuation (including treatment beyond 
progression), whichever occurs later. This schedule 
should be followed even if treatment delay occurs. See 
Section 9.1.1 for further details. 
During week 97 - 144 from start of treatment in 
Crossover cohort (Year 3)
Tumor assessment should occur every 16 weeks (± 7 
days) until BICR confirmed progression. See Section 
9.1.1 for further details.
3URWRFRO$PHQGPHQW1R
'DWH-XO
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
Beyond week 144 from start of treatment in 
Crossover cohort (Year 4 and beyond)
Tumor assessment should occur every 24 weeks (± 14 
days) until BICR confirmed progression. See Section 
9.1.1 for further details.
Brain Imaging
X
See note
Participants with a history of brain metastasis should 
have surveillance MRI per standard of care 
(approximately every 12 weeks, or sooner if clinically 
indicated). See Section 9.1.1 for further details.
Other Imaging (eg, 
Bone Scan)
X
See note
As clinically indicated per local standards. See Section 
9.1.1 for further details.
Pharmacokinetic /Immunogenicity Assessments
PK and 
Immunogenicity 
samples
X
See note
See Table 9.5-3 for time points of collection.
Biomarker Assessments
Exploratory Plasma 
Biomarkers, Whole 
Blood DNA, 
X
See note
X (See 
note)
See Table 9.8-3 for time points of collection. 
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
MDSC, PBMC, 
Serum 
SARS-CoV-2 
Serologye
X
X (see note)
Baseline: Serum collected to be used for potential 
future measurements of anti-SARS-CoV-2 serology 
(anti-SARS-CoV-2 total or IgG [see Section 9.8.3]).
On treatment:
Serum collected approximately every 6 cycles during 
study treatment to be used for potential future 
measurements of anti-SARS-CoV-2 serology (anti-
SARS-CoV-2 total or IgG [see Section 9.8.3]). 
Stool samples for 
microbiome 
analysis
X 
(See note)
C2D1 (See note)
X (See 
note)
See Table 9.8-3 for time points of collection. 
Baseline visit: Stool sample to be collected within 7 
days prior to first dose. 
On treatment visit: Samples may be collected within
3 days prior to dosing.
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Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
Collection of tumor 
tissue for biomarker 
research on-
treatment and upon 
disease progression 
X
(See note)
C1D22-28 
(1 week after 2nd dosing and before the 3rd dosing)
X (See 
note)
Baseline visit: Tumor biopsy upon progression on or 
after chemotherapy treatment in arm C is mandatory, if 
medically feasible, for enrollment to Crossover Cohort.
On treatment visits: Tumor tissue submission while 
on-treatment (1 week after 2nd dosing and before the 
3rd dosing, i.e. between Day 22-28 of Cycle 1) and 
upon progression (PD + 14 days) is optional but 
strongly recommended to understand the 
response/resistance to nivolumab plus ipilimumab 
treatment. See Table 9.8-3 for time points of collection. 
If biopsy or surgical resection is performed per 
protocol while on treatment or at progression, a tumor 
sample (block [preferred] or slides) should be 
submitted to central laboratory. If biopsies/ surgical 
resection are done at any other time on treatment, 
tissue samples should be submitted as well.
Clinical Drug 
Supplies
IRT 
X
IRT Drug Vial 
Assignment
Participant must receive the first dose of study 
medication within 3 days from drug vial assignment.
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Table 2-6:
On Study (Baseline and on Treatment) Procedural Outline (CA2098HW) Optional Crossover Cohort
Baseline
Cycles 1 and 2 
(cycle = 6 weeks)
Cycle 3 to EOT
(cycle = 4 weeks)
Upon 
PD
Notes
Procedurea,b
C1D1
C1D15
and 
C1D29
(± 3 
days)
C2D1, 
C2D15 
and 
C2D29 
(± 3 
days)
C3D1 
and Day 
1 of each 
cycle to 
EOTc
(± 3 
days)
C3D15 
and Day 
15 of 
each 
cycle to 
EOTc
(± 3 
days)
Nivolumab 240 mg 
flat dose IV
X
X
X
Ipilimumab (1 
mg/kg) IV 
X
C2D1 
only
C3D1, 
C6D1,  
C9D1 
and Day 
1 of 
every 3 
cycles
C4D15, 
C7D15, 
C10D15 
and Day 
15 of 
every 3 
cycles
Nivolumab 480 mg 
flat dose IV
X
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs.
b 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.
c Treatment to progression, unacceptable toxicity, withdrawal of consent, or maximum treatment duration as specified in Section 7.1.1
d Any additional imaging, including unscheduled timepoints, that may demonstrate tumor response/progression should be submitted to BICR.
e Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection.
Abbreviations: AE, adverse event; CA19-9, cancer antigen 19-9; CBC, complete blood count; CEA, carcino embryonic antigen; ECOG, Eastern Cooperative 
Oncology Group; EORTC QLQ-CR29 Questionnaire, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 29;
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EORTC QLQ-C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30; EOT, end of treatment; EQ-5D-3L 
Questionnaire, EuroQol Five-Dimensional Questionnaire, Three-Level Questionnaire; IgG, immunoglobulin G; IRT, Interactive Response system; MDSC, 
myeloid-derived suppressor cell; MRI, magnetic resonance imaging; PBMC, peripheral blood mononuclear cell; PFS2, time from randomization to second disease 
progression or death; SAE, serious adverse event; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TSST, time from randomization to second 
subsequent therapy or death; WOCBP, women of child bearing potential.
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3
INTRODUCTION
3.1
Study Rationale
CA2098HW 
(CHECKpoint 
pathway 
and 
nivoluMAb 
clinical 
Trial 
Evaluation 
[CHECKMATE]-8HW) is a Phase 3, randomized open-label multi-center 3-arm clinical trial of 
nivolumab monotherapy, nivolumab plus ipilimumab combination therapy or standard 
chemotherapy in recurrent or metastatic dMMR/MSI-H (see Appendix 1 for List of Abbreviations) 
CRC across all lines of therapy. 
Results from non-randomized cohort study CA209142 led to the accelerated approval of 
nivolumab single agent or in combination with ipilimumab for dMMR/MSI-H metastatic CRC 
(mCRC) patients who progressed after fluoropyrimidine, oxaliplatin, and irinotecan treatment. 
Although both nivolumab monotherapy and nivolumab plus ipilimumab combination therapy 
demonstrated strong clinical activity, indirect comparisons suggested improved clinical benefit of 
combination therapy versus monotherapy. The CA2098HW is designed to confirm these findings 
and directly compare the clinical benefit, as measured by PFS, ORR and OS, achieved by 
nivolumab in combination with ipilimumab or by nivolumab monotherapy.
It is generally accepted that patients with dMMR/MSI-H metastatic CRC are less responsive to 
conventional chemotherapy and may have a poorer prognosis than patients with mismatch repair-
proficient (pMMR) or MSS mCRC. Studies comparing single agent immunotherapy vs 
chemotherapy in patients who have not received prior treatment are currently ongoing, however 
there are no randomized studies evaluating combination of immunotherapies vs chemotherapy. 
Recently presented data from a randomized phase 3 study comparing pembrolizumab with 
standard chemotherapy in front-line setting (Keynote-177 study) confirmed superior antitumor 
activity as reflected by PFS and ORR achieved by anti-PD1 single agent vs chemotherapy in MSI-
H mCRC patients.1 In the CA209142 study, nivolumab plus ipilimumab combination in previously 
untreated dMMR/MSI-H mCRC patients demonstrated a high ORR and durable responses which 
translated into improvement of PFS and OS. Also, this combination showed favorable safety 
profile. Promising activity of nivolumab plus ipilimumab combination as 1L treatment in
dMMR/MSI-H mCRC patients requires further evaluation, including direct comparison vs 
chemotherapy, a current standard of care. This will be evaluated in CA2098HW study.
The CA2098HW study also includes a pharmacodiagnostic component as part of a post-approval 
commitment in the US. The study data will be utilized to support the analytical and clinical 
validation of an immunohistochemistry-based (IHC) and a nucleic acid-based (PCR) in vitro 
diagnostic device  that is essential to the safe and effective use of nivolumab and/or nivolumab 
plus ipilimumab combination therapy for patients with tumors that are dMMR/MSI-H.2, 3
3.1.1
Research Hypothesis
CA2098HW study will test 3 research hypotheses. The first hypothesis is that nivolumab plus 
ipilimumab combination therapy will improve PFS when compared with nivolumab monotherapy 
in participants with recurrent or metastatic dMMR/MSI-H CRC across all lines of therapy. This 
hypothesis will be evaluated across participants randomized to nivolumab monotherapy or 
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nivolumab plus ipilimumab combination therapy. The second hypothesis is that nivolumab plus 
ipilimumab combination therapy is superior to standard chemotherapy as measured by PFS in 
participants with recurrent or metastatic dMMR/MSI-H CRC who have not received prior 
treatment for metastatic disease. The second hypothesis will be assessed across all study 
participants who have not received prior therapy (1L) and were randomized to nivolumab plus 
ipilimumab combination therapy or standard chemotherapy arms. The third research hypothesis is 
that nivolumab plus ipilimumab combination improves PFS compared with nivolumab 
monotherapy in participants who have not received prior therapy (1L). This hypothesis will be 
tested hierarchically.
3.2
Background
3.2.1
Metastatic Colorectal Cancer
Colorectal cancer is one of the leading causes of cancer-related death worldwide with a 5-year 
survival rate of approximately 14% in patients with metastatic disease.4,5 The active agents in first-
and second-line treatment of mCRC consist of fluoropyrimidines (5-FU, capecitabine), oxaliplatin, 
and irinotecan. Chemotherapy is often combined with a monoclonal antibody inhibiting VEGF 
(bevacizumab or ziv-aflibercept); or EGFR (cetuximab or panitumumab; only indicated in RAS 
wild-type tumors). Despite newer treatment options for mCRC, the benefit of systemic therapy 
after first-line treatment is modest, and complete responses are rare. The multi-targeted tyrosine 
kinase inhibitor, regorafenib, and the oral nucleoside analogue trifluridine/tipiracil (TAS-102) are 
among more recently available options beyond second line. For unselected patients with refractory 
mCRC, accumulating data seem to support the use of these agents prior to considering 
“rechallenge” with a previously used agent.6 Regorafenib and trifluridine/tipiracil seem to have 
similar efficacy in the refractory setting with different toxicity profiles. The OS and DCR are 
improved with both of these agents compared to placebo, however response rates seem to be very 
low (1-4%).7,8,9,10 In the pivotal study of regorafenib vs placebo (CORRECT study) the median 
OS and PFS was 6.4 months and 1.9 months in regorafenib arm, and 5 months and 1.7 months in 
placebo arm, respectively.7 In the Phase 3 study of TAS-102 in refractory mCRC the median OS 
improved from 5.3 months with placebo to 7.1 months with TAS-102. The median PFS improved 
from 1.7 months in placebo arm to 2 months in TAS-102 arm.10
Colorectal cancer is shown to be a heterogeneous disease at the molecular level. 11 A 
comprehensive and globally accepted disease classification system has not yet been established in 
terms of optimizing personalized medicine. However, there are few established biomarkers that 
provide predictive and prognostic information. Clinical practice in many centers have rapidly 
evolved to include assessment of key biomarkers in clinical decision making, including testing for 
KRAS, NRAS, BRAF mutations, and evaluation of MMR or MSI status, by IHC or by PCR, 
respectively. Among these, dMMR/MSI-H status in metastatic CRC has both prognostic and 
predictive value.  Patients with m dMMR/MSI-H CRC have a worse outcome when treated with 
SOC, yet they may have potential durable benefit if treated with checkpoint inhibitors.
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3.2.2
Microsatellite Instability and Metastatic Colorectal Cancer
Microsatellite instability is the molecular fingerprint of a deficient mismatch repair, which is 
involved in CRCs arising in association with Lynch syndrome as well as subgroup of sporadic 
CRC. The term MSI is widely accepted as a surrogate for both dMMR and MSI-H tumors. These 
are characterized by either epigenetic silencing of MLH1 or a germline mutation in one of the 
mismatch repair genes MLH1, MSH2, MSH6, or PMS2.12 There are well established methods to 
detect dMMR/MSI-H that are incorporated into clinical practice. 
Studies have shown that dMMR/MSI-H CRC seems to be clinically distinct from MSS/pMMR 
CRC. Approximately 15% of patients with stage II or stage III CRC have dMMR/MSI-H tumors. 
While patients with stage II dMMR/MSI-H CRC might not benefit from adjuvant 5-FU-based 
adjuvant chemotherapy, overall patients with non-metastatic dMMR/MSI-H CRC seem to have 
better prognosis than non-MSI-H/proficient MMR CRC.13,14 However, patients with metastatic 
dMMR/MSI-H CRC, (approximately 5% of all mCRC), have been reported to have a worse OS, 
and seemingly less benefit from conventional chemotherapy.15,16,17,18
A pooled analysis of four Phase 3 studies in first-line mCRC participants treated with 
chemotherapy demonstrated that median PFS (6.2 months vs 7.6 months) and OS (13.6 months vs 
16.8 months) were significantly worse for patients with dMMR compared with pMMR tumors, 
respectively.16 In later lines of treatment an exploratory retrospective analysis of a small subgroup 
of MSI-H patients treated with regorafenib or placebo on CORRECT trial failed to show an 
interaction between MSI status and regorafenib treatment benefit in OS or PFS, however there was 
less clinical benefit in patients with MSI-H subgroup.19 A recent South Australian registry analysis 
of patient characteristics and survival outcomes compared patients with MSI-H or MSS disease. 
There was a trend towards poorer outcomes in MSI-H mCRC and this was considered to point 
towards the need for alternate treatment approaches. 20
3.2.3
Chemotherapy and Targeted Agents in dMMR/MSI-H Metastatic 
Colorectal Cancer
Current Standard of Care (SOC) for patients with dMMR/MSI-H mCRC who have not received 
any prior systemic therapy (1L) or who have received one prior line of systemic therapy (2L) 
consists of combination of cytotoxic agents that are frequently used together with anti-VEGF or -
anti-EGFR antibodies. These combinations are referred as chemotherapy. Although available first-
line therapies are effective, there remains an unmet need for therapies that will result in durable 
responses and survival. 
Currently there are no randomized prospective studies on the efficacy and safety of chemotherapy 
compared with immunotherapy in dMMR/MSI-H mCRC patients. Currently available data for 
patients with dMMR/MSI-H consist of post-hoc analyses of the randomized clinical studies, meta-
analyses of clinical trials, or retrospective cohort studies conducted on unselected mCRC patients. 
Importantly, in dMMR/MSI-H mCRC tumors the data on efficacy of chemotherapy are primarily 
available for 1L patients and these data are described further. To evaluate the efficacy of 
chemotherapy in dMMR/MSI-H mCRC patients Koopman et al. (2009) conducted a retrospective 
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analysis of CAIRO study to compare the PFS/OS results in patients with dMMR and pMMR 
tumors receiving 1L treatment. The tumor tissues were available from 515 patients with advanced 
mCRC of which 18 had dMMR/MSI-H status. The investigators found a non-significant decrease 
in median OS of 17.9 vs 10.2 months, and in median PFS of 6.9 vs 4.0 months in pMMR vs dMMR 
patients treated with chemotherapy, with a decreased disease control rate of 83 vs 56%, 
respectively. These results were supported by the meta-analysis of the 4 studies that included 
primary tumors from 3,063 patients. The median PFS (6.2 months vs 7.6 months) and OS (13.6 
months vs 16.8 months) was significantly shorter in dMMR/MSI-H patients compared with MSS 
patients treated with chemotherapy.
Recently post-hoc analyses of patients with dMMR/MSI-H mCRC treated with 1L chemotherapy 
on CALBG/SWOG80405 and FIRE-3 studies, were published.18, 21 These data should be 
interpreted with caution considering small number of patients with dMMR/MSI-H mCRC in both 
studies. CALBG/SWOG80405 study compared 1L bevacizumab vs cetuximab co-administered 
with FOLFOX or FOLFIRI, and FIRE-3 trial compared bevacizumab vs cetuximab both co-
administered with FOLFIRI in RAS wild type mCRC. In CALBG/SWOG80405 study mPFS and 
mOS were respectively 9.3 and 30 months in bevacizumab treated; 5.4 and 11.9 in cetuximab 
treated dMMR/MSI-H mCRC patients. These data pose a question on potential resistance of 
dMMR/MSI-H mCRC to Cetuximab. Analysis of FIRE-3 trial by Consensus Molecular Sub-type 
(CMS) showed no difference in PFS or OS for cetuximab vs bevacizumab added to FOLFIRI in 
patients with CMS-1 (data was reported for CMS-1 due to small number of dMMR/MSI-H 
patients). Therefore survival data were combined across both bevacizumab and cetuximab arms. 
In CMS-1 RAS wild type mCRC patients’ mPFS and OS were, respectively, 7.8 and 14.8 month; 
while in CMS-1 RAS mutant mCRC patients’ mPFS and OS were, respectively, 9.6 and 17.4 
month.  
Limited data in second-line setting show shorter PFS in dMMR/MSI-H mCRC patients compared 
to pMMR/MSS patients. The retrospective analysis of the dMMR/MSI-H cohort from 18 centers 
in France reported the mPFS of 3.5 months, and the OS of 15.8 months.22
Some 30-40% of patients with dMMR/MSI-H mCRC harbor BRAF V600E mutation associated 
with poor outcomes. Recently, data from a study for BRAF mutant mCRC (Beacon-CRC study) 
that allowed to enroll patients with dMMR/MSI-H tumors, have been published. Beacon-CRC 
study compared efficacy and safety of encorafenib, binimetinib, and cetuximab (triplet-therapy 
group); encorafenib and cetuximab (doublet-therapy group); or chemotherapy (control group -
cetuximab and irinotecan or cetuximab and FOLFIRI) in mCRC patients who have disease 
progression after one or two previous regimens. Proportion of dMMR/MSI-H patients was low 
across all study groups - 10%, 9% and 5% in triplet, doublet and control group, respectively. The 
ORR were 26% in triplet group, 20% in doublet group and 2% in control group. Duration of 
response at least 6 months was reported in 24% (7/29) of patients in triplet group, 43% (10/23) in 
doublet group and 50% (1/2) in control group. Responses were not durable due to resistance 
development. Median PFS and OS were respectively 4.3 and 9 months with triplet regimen; 4.2 
and 8.4 months with doublet regimen; 1.5 and 5.4 months with chemotherapy. Consistently with 
the overall population, patients with dMMR/MSI-H tumors demonstrated improved survival in 
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triplet therapy group, though confidence interval was broad and crossed 1 (HR = 0.67 (95% CI, 
0.26 to 1.76)). 
3.2.4
Immunotherapy in dMMR/MSI-H Metastatic Colorectal Cancer: Check-
Mate-142 Study and Other Data
The strong local immune reaction observed in dMMR/MSI-H CRC is characterized by peritumoral 
lymphoid nodules (Crohn’s-like reaction) and a dense overall infiltration of the tumor with 
lymphocytes,23 part of which are activated and cytotoxic.24,25 Frameshift mutations encountered 
in dMMR/MSI-H CRC might lead to the generation of tumor-specific antigens. The existence of 
T cell responses directed against multiple tumor antigens in individuals with dMMR/MSI-H CRC 
has been demonstrated in patients.26,27 This observation strongly suggests that antigenic structures 
are generated from coding DNA sequences carrying frameshift mutations in sufficient amounts to 
trigger antigen-specific T cell responses. In study CA209-003, a Phase 1 trial of nivolumab in 
participants with solid tumors, one trial participant with dMMR/MSI-H mCRC had a long-term 
complete response, suggesting the immune-modulatory approach warranted further evaluation.28
These findings led to the CA209142 study in dMMR/MSI-H mCRC.
The initial results of CA209142 showed efficacy of nivolumab monotherapy in a cohort of 74 
patients previously treated with, or intolerant of one or more prior lines of therapy.29 Durable 
clinical benefit and deepening of responses were demonstrated with long term follow up. At a 
median follow up of 21 months (17-40 months), ORR and DCR per BICR was 34% and 62%, 
respectively. The CRs increased to 9% after median follow up of 21 months from 3% reported 
after median follow up period of 12 months30. No new safety signals were reported with long-term 
follow-up. Grade 3 to 4 treatment-related AEs were reported in 20% of patients.
In another cohort of CA209142, safety and efficacy of nivolumab plus ipilimumab combination 
were evaluated in 119 patients with dMMR/MSI-H mCRC. As in the nivolumab monotherapy 
cohort, the nivolumab plus ipilimumab cohort enrolled patients who were previously treated with, 
or intolerant of one or more prior lines of therapy. Patients received nivolumab (3 mg/kg) and 
ipilimumab (1 mg/kg) every 3 weeks for four doses followed by the same dose of nivolumab every 
2 weeks until disease progression or discontinuation for other reasons. At a median follow up of 
13.4 months (range: 9-25 months) the ORR and DCR per BICR were reported in 49% (n=58) and 
81% (n=97), respectively.31 Grade 3 to 4 treatment-related AEs occurred in 32% of patients and 
were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs 
had an ORR (63%) consistent with that of the overall population. 
High rates and durability of responses observed with both nivolumab monotherapy and nivolumab 
plus ipilimumab combination translated into clinical benefit in dMMR/MSI-H mCRC as measured 
by PFS and OS. Median PFS per BICR in the nivolumab monotherapy cohort was 6.6 months, and 
not reached in the nivolumab plus ipilimumab cohort. The OS was not reached in either cohorts. 
Indirect comparisons of the data with similar follow up period, suggest that combined 
immunotherapy using ipilimumab and nivolumab provides improved efficacy over nivolumab 
monotherapy and has a favorable benefit-risk ratio.
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Based on these results, the US FDA granted an accelerated approval for nivolumab monotherapy 
(31-Jul-2017) and nivolumab combination with ipilimumab (10-Jul-2018) in dMMR/MSI-H 
mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and 
irinotecan.
The safety and efficacy of nivolumab plus ipilimumab combination in 1L setting was assessed in 
Cohort 3 of CA209142 study. In a 1L cohort of CA209142 study 45 previously untreated for 
metastatic disease patients with histologically confirmed metastatic or recurrent CRC and 
dMMR/MSI-H status per local laboratory, received nivolumab 3 mg/kg administered every 2 
weeks (Nivo 3 Q2W) plus ipilimumab 1 mg/kg administered every 6 weeks (Ipi 1 Q6W). After 
median follow up of 19.9 months (range: 15.1 - 24.6), BICR-assessed ORR was 58%; 78% of 
patients had disease control for ≥ 12 weeks. Responses were consistent with the overall population 
across evaluated subgroups including age, gender, ECOG performance status, primary tumor 
location, mutation status, and prior adjuvant/neoadjuvant therapy. At 15 months, PFS and OS rates 
(95% CI) per investigator assessment were 75% (59–85) and 84% (70–92), respectively. No new 
safety signals were reported. Overall, 20% of patients had grade 3–4 treatment related adverse 
event (TRAEs). TRAEs of any grade led to discontinuation in 5 (11%) patients.32
Efficacy and safety of pembrolizumab in MSI-H mCRC patients were demonstrated in several 
clinical studies in previously treated patients leading to accelerated approval in the US for MSI-H 
mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and 
irinotecan. Recently, the results of the trial comparing pembrolizumab with chemotherapy as 1L 
treatment have been disclosed. Pembrolizumab demonstrated superior activity as reflected by 
doubling of mPFS (16.5 vs 8.2 months), higher rates of response (43.8% vs 33.1%), and its 
durability (median not reached vs 10.6 months).1
In the US, the NCCN panel recommends nivolumab (alone or in combination with ipilimumab), 
or pembrolizumab as a treatment option in first-line for patients who are not appropriate for 
intensive chemotherapy (category 2B), and for all patients with dMMR/MSI-H mCRC beyond 
first-line (category 2A).33 The NCCN also recommends universal MMR or MSI testing for all 
patients with a personal history of colon or rectal cancer to inform the use of immunotherapy in 
metastatic disease. While such testing is also done in many parts of the world and the importance 
of the checkpoint inhibitor approach for this population is scientifically recognized, nivolumab in 
combination with ipilimumab does not carry this indication in the rest of the world at this time.
3.2.5
Nivolumab Mechanism of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely on immune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. 
Meanwhile, tumor progression may depend upon acquisition of traits that allow cancer cells to 
evade immunosurveillance and escape effective innate and adaptive immune responses.34,35,36
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by mechanisms such as introducing cancer antigens by therapeutic 
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vaccination or by modulating regulatory checkpoints of the immune system. T-cell stimulation is 
a complex process involving the integration of numerous positive as well as negative 
co-stimulatory signals in addition to antigen recognition by the T-cell receptor (TCR). 37
Collectively, these signals govern the balance between T-cell activation and tolerance. 
PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors that also includes CD28, 
CTLA 4, ICOS, and BTLA. 38 PD-1 signaling has been shown to inhibit CD28-mediated 
upregulation of IL-2, IL-10, IL-13, IFN-γ, and Bcl-xL. PD-1 expression has also been noted to 
inhibit T-cell activation, and expansion of previously activated cells. Evidence for a negative 
regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a variety of 
autoimmune phenotypes.39 These results suggest that PD-1 blockade has the potential to activate 
anti-self T-cell responses, but these responses are variable and dependent upon various host genetic 
factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of tolerance to 
self-antigens.
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (HuMab; immunoglobulinG4 [IgG4]-S228P). Nivolumab is expressed in Chinese 
hamster ovary (CHO) cells and is produced using standard mammalian cell cultivation and 
chromatographic purification technologies. In vitro, nivolumab binds to PD-1 with high affinity 
(EC50 0.39-2.62 nM), and inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ±
1nM). Nivolumab binds specifically to PD-1 and not to related members of the CD28 family such 
as CD28, ICOS, CTLA 4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a 
reproducible enhancement of both proliferation and IFN-γ release in the MLR. Using a CMV re-
stimulation assay with PBMC, the effect of nivolumab on antigen specific recall response indicates 
that nivolumab augmented IFN-γ secretion from CMV specific memory T-cells in a dose-
dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine analog 
of nivolumab enhances the anti-tumor immune response and result in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).40
3.2.6
Ipilimumab Mechanism of Action 
CTLA-4, an activation-induced T-cell surface molecule, is a member of the CD28:B7 
immunoglobulin superfamily that competes with CD28 for B7. CTLA-4 mediated signals are 
inhibitory and turn off T cell-dependent immune responses. 41 Ipilimumab (BMS-734016, 
MDX010, MDX-CTLA4) is a fully human monoclonal IgG1κ that binds to the CTLA-4 antigen 
expressed on a subset of T cells from human and nonhuman primates. The proposed mechanism 
of action for ipilimumab is interference of the interaction of CTLA-4 with B7 molecules on APCs, 
with subsequent blockade of the inhibitory modulation of T-cell activation promoted by the CTLA 
4/B7 interaction. 
3.2.7
Nivolumab Combined with Ipilimumab: Clinical Activity Across 
Different Tumor Types 
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules. 
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The following information describes the results of initial early phase clinical studies that were the 
basis for the nivolumab plus ipilimumab combination regimens that have been explored in late 
phase clinical development.
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly 
with ascending doses of ipilimumab in participants with unresectable or metastatic melanoma. In 
each arm in this multi-arm study, ipilimumab was administered once every 3 weeks for 4 doses 
with nivolumab administered once every 3 weeks for 8 doses. Starting at Week 24, ipilimumab 
and nivolumab were administered once every 12 weeks for 8 doses. The three initial dose-
escalation cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg + ipilimumab 3 mg/kg; n = 14), 
Cohort 2 (nivolumab 1.0 g/kg + ipilimumab 3 mg/kg; n = 17) and Cohort 3 (nivolumab 3.0 mg/kg 
+ ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a which evaluated 
nivolumab 3 mg/kg + ipilimumab 1 mg/kg (n = 16). The primary objective was to assess 
safety/tolerability; the secondary objective was to assess preliminary efficacy.
Of the 52 participants evaluable for response as of the 15-Feb-2013 clinical cut-off in CA209004, 
21 participants (40%) had an objective response by modified World Health Organization (mWHO) 
criteria. In an additional 2 participants (4%) there was an unconfirmed objective response. In 
Cohort 1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 14 evaluable participants had an 
objective response by mWHO (21%), including 1 CR and 2 PRs.42 In Cohort 2 (1 mg/kg 
nivolumab + 3 mg/kg ipilimumab), 9 out of 17 (53%) evaluable participants had an objective 
response by mWHO, including 3 CRs (18%) and 6 PRs (35%). In Cohort 2a (3 mg/kg nivolumab 
+ 1 mg/kg ipilimumab), 6 out of 15 (40%) response evaluable participants had an objective 
response by mWHO, including 1 CR (7%) and 5 PRs (33%). In Cohort 3 (3 mg/kg 
nivolumab + 3 mg/kg ipilimumab), 3 out of 6 (50%) evaluable participants had an objective 
response by mWHO, all 3 of which were PRs (50%).
Preliminary analysis revealed 16 of the 52 evaluable participants (31%) had > 80% reduction in 
the size of target tumor lesions by the week 12 evaluation. This is compared to < 2% for 3 mg/kg 
ipilimumab monotherapy based on CA184020 (N = 540) and < 3% for nivolumab monotherapy 
based on CA209003 (N = 94, 0.1-10 mg/kg). 
The following DLTs were observed: in Cohort 1,Grade 3 elevated AST/ALT (1 participant); in
Cohort 2, Grade 3 uveitis (1 participant) and Grade 3 elevated AST/ALT (1 participant) and in 
Cohort 3, Grade 4 elevated lipase (2 participants) and Grade 3 elevated lipase (1 participant). 
Based on these data, Cohort 2 was identified as the maximum tolerated dose (MTD) and Cohort 3 
exceeded the MTD.
A total of 53 melanoma participants were treated with nivolumab combined with ipilimumab in 
CA209004 across Cohorts 1, 2, 2a, and 3. At least 1 AE regardless of causality has been reported 
in 98% of participants treated. The most common (reported at > 10% incidence) treatment related 
AEs (any Grade 93%; Grade 3-4 53%:) are rash (55%; 4%), pruritus (47%; 0%), vitiligo (11%; 
0%), fatigue (38%; 0%), pyrexia (21%, 0%), diarrhea (34%; 6%), nausea (21%, 0%), vomiting
(11%, 2%), ALT increased (21%; 11%), AST increased (21%; 13%), lipase increased (19%; 13%), 
amylase increased (15%, 6%), headache (11%, 0%), and cough (13%, 0%).
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The majority of AEs leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 participants, 21%). Grade 3 events included lipase increased, ALT increased, 
AST increased, troponin I increased, colitis, diverticular perforation, pancreatitis, tachycardia, 
renal failure acute, choroiditis, autoimmune disorder, and pneumonitis. One participant each 
discontinued due to Grade 4 events of blood creatinine increased and AST increased. No drug-
related deaths were reported.42,43
The combination of nivolumab with ipilimumab is being studied in the Phase 1 study CA209016.  
Participants with mRCC (Karnofsky performance status ≥ 80%; untreated or any number of prior 
therapies) were randomized to receive nivolumab 3 mg/kg + ipilimumab 1 mg/kg (arm N3 + I1) 
or nivolumab 1 mg/kg + ipilimumab 3 mg/kg (arm N1 + I3) IV Q3W for 4 doses followed by 
nivolumab 3 mg/kg IV Q2W until progression/toxicity. The primary objective was to assess 
safety/tolerability; secondary objective was to assess antitumor activity. 
Participants were randomized to N3 + I1 (n = 47) and N1 + I3 (n = 47). Approximately half (n = 48; 
51%) had prior systemic therapy (N3 + I1: 22; N1 + I3: 26). After a median follow-up of 22.3 
months, the confirmed ORR per RECIST 1.1 was 40.4% (n = 47) in both arms N3 + I1 and N1 + 
I3; 42.1% (n = 8) and 36.8% (n = 7) had an ongoing response, with a median DOR of 88.7 weeks 
(95% CI: 37.14, NA) and 85.9 weeks (95% CI: 35.14, NA), respectively. Median PFS was 7.7 
months (95% CI: 3.71, 14.29) and 9.4 months (95% CI: 5.62, 18.63) in arms N3 + I1 and N1 + I3, 
respectively. OS at 12 months was 80.9% and 85.0% in arms N3 + I1 and N1 + I3, respectively, 
and at 24 months was 67.3% and 69.6%, respectively.
Treatment-related AEs were seen in 88/94 pts (94%), including 43/47 (92%) in N3 + I1 and
45/47 (96%) in N1 + I3. The most frequently reported drug-related AEs in N3 + I1 included
fatigue (66%), cough (53.2%), and arthralgia (51.1%); the majority were Grade 1- 2. The most 
frequently reported drug-related AEs in N1 + I3 included fatigue (74.5%), nausea (55.3%), and 
diarrhea (53.2%).
The
majority
were Grade 1-2. Treatment-related
AEs
leading
to
discontinuation (31.9% versus 10.6%), and treatment-related SAEs (34% versus 23.4%) occurred
more commonly in participants in the N1 + I3 arm than in the N3 + I1 arm, respectively.44’45
CA209012 was a multi-arm Phase 1b trial evaluating the safety and tolerability of nivolumab in 
patients with chemotherapy-naïve advanced NSCLC, as either a monotherapy or in combination 
with other agents including ipilimumab, at different doses and schedules. The primary endpoint of 
the study was safety with secondary endpoints of ORR per RECIST 1.1 and 24-week PFS. 
Participants were assigned to receive nivolumab 3 mg/kg Q2W + ipilimumab 1mg/kg Q12W 
(n = 38), nivolumab 3mg/kg Q2W + ipilimumab 1 mg/kg Q6W (n = 39) and nivolumab 3mg/kg 
Q2W (n = 52). The confirmed ORR was 47% (N3 Q2W + I1 Q12W), 39% (N3 Q2W + I1 Q6W) 
and 23% (N3 Q2W). The median DOR was not reached in any of these groups. 
The rate of treatment-related AEs in the N+I Q12W (82%) and Q6W (72%) arms were comparable 
to monotherapy (72%). In the study, Grade 3/4 AEs were 37%, 33%, and 19% for the N+I Q12W, 
Q6W and nivolumab monotherapy arms, respectively. Treatment-related Grade 3-4 AEs led to 
discontinuation in 5% and 8% of participants in the Q12W and Q6W cohorts, respectively, and 
were similar to nivolumab monotherapy. There were no treatment-related deaths. The treatment-
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related select AEs in patients administered the optimized dosing schedule (3 mg/kg of nivolumab 
Q2W plus 1 mg/kg of ipilimumab Q6W) were skin related (36%), gastrointestinal (23%), 
endocrine (20%), and pulmonary (5%) and there were  5% treatment related Grade 3 and Grade 4 
AEs per category.46
CA209067 was a Phase 3, randomized, double-blind study of nivolumab monotherapy or 
nivolumab combined with ipilimumab versus ipilimumab monotherapy in first-line melanoma 
patients. In this study, combination of nivolumab 1 mg/kg and ipilimumab 3 mg/kg for 4 doses, 
followed by nivolumab 3 mg/kg, Q2W (N+I), compared with ipilimumab 3 mg/kg, Q3W x4 doses 
(Ipi) demonstrated a significant improvement in OS and PFS. Median OS not reached in the N+I 
group compared with 19.98 months in the Ipi group, and mPFS was 11.7 months in the N+I group 
compared with 2.9 months in the Ipi group. When N+I group was compared to nivolumab 3 mg/kg 
group (Nivo), a numeric difference in OS and improved PFS (mPFS of 11.73 vs 6.87 months) were 
observed in favor of the combination. The ORR in N+I (58.9%) was significantly higher than the 
Ipi group (19.0%) and numerically higher than N group (44.6%). The overall safety profile of N+I 
combination therapy and Nivo monotherapy was consistent with the mechanisms of action of 
nivolumab and ipilimumab. In general, the frequency of AEs was lowest across AE categories in 
the Nivo group and highest in the N+I group. Treatment-related AEs of Grade 3 or 4 occurred in 
59% patients of the N+I group, 21% of the Nivo group and 34% of the Ipi group. Analyses of 
IMAEs showed that most IMAEs were Grade 1-2. The majority of IMAEs in the IMAE categories 
of diarrhea/colitis, and hepatitis were Grade 3-4. The majority of IMAEs resolved and were 
manageable using the recommended treatment guidelines for early evaluation and intervention47.
CA209214 was a Phase 3, randomized, open-label study of nivolumab combined with ipilimumab 
versus sunitinib monotherapy in first line patients with RCC. Among the intermediated/poor-risk 
participants, combination of nivolumab and ipilimumab therapy (N+I, nivolumab 3 mg/kg and 
ipilimumab 1 mg/kg, Q3W for 4 doses then followed by nivolumab 3 mg/kg, Q2W) demonstrated 
a statistically significant higher ORR (41.6%) than sunitinib (26.5%). CR was achieved in 9.4% 
vs 1.2% in N+I and sunitinib groups, respectively. Responses in the N+I group occurred early 
(median TTR of 2.79 months) and were durable (median DOR not reached). In the sunitinib group, 
mTTR (3.04 months) was similar but responses were less durable (18.17 months). N+I 
combination therapy demonstrated statistically significant and superior OS (mOS was not reached) 
compared with sunitinib (mOS of 25.95 months). The overall safety profile of N+I was acceptable. 
Treatment-related AEs occurred in 93% of patients received N+I, and 97% received sunitinib; 
Grade 3 or 4 AEs occurred in 46% and 63%, and treatment-related AEs leading to discontinuation 
occurred in 22% and 12%, respectively. Most IMAEs were Grade 1-2, and the majority of IMAEs 
resolved and were manageable using the recommended treatment guidelines for early evaluation 
and intervention.
3.3
Benefit/Risk Assessment
Extensive details on the safety profile of nivolumab and ipilimumab are available in the 
Investigator Brochures, and will not be repeated herein.
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Overall, the safety profile of nivolumab monotherapy as well as in combination with ipilimumab 
is manageable and generally consistent across completed and ongoing clinical trials with no MTD 
reached at any dose tested up to 10 mg/kg. Most AEs were low-grade (Grade 1 to 2) with relatively 
few related high-grade (Grade 3 to 4) AEs. There was no pattern in the incidence, severity, or 
causality of AEs with respect to nivolumab dose level. Additionally, the on-going CA209142 study 
provides mature efficacy data that confirms the overall positive benefit-risk assessment of both 
nivolumab and nivolumab plus ipilimumab combination in patients with dMMR/MSI-H mCRC.
A pattern of immune-related AEs has been defined, for which management algorithms have been 
developed; these are provided in Appendix 5. Most high-grade events were manageable with the 
use of corticosteroids and hormone replacement therapy, in case of endocrinopathies, as instructed 
in these algorithms. 
Additional details on the safety profile of nivolumab and ipilimumab, including results from other 
clinical studies, are also available in the nivolumab and ipilimumab IBs.
The benefit and risk of front-line and second-line chemotherapy (FOLFOX or FOLFIRI without 
or with bevacizumab or cetuximab) has been well defined in clinical trials. Grade 3 to 5 AEs are 
common (up to 67%) particularly when cytotoxic agents (FOLFOX or FOLFIRI) are combined 
with targeted agents (bevacizumab, cetuximab, other). Most common Grade 3-5 AEs reported for 
chemotherapy + bevacizumab or cetuximab combinations are hematologic adverse events (approx. 
30%), diarrhea (approx. 10%), and sensory neuropathy (approx. 13%). Other Grade 3-4 AEs 
include skin reactions that are commonly observed with cetuximab (up to 26%), while 
bevacizumab-containing regimens are associated with higher rate of bleeding (2%), 
gastrointestinal perforation (2%), and venous thromboembolic events (5%). Toxicities lower than 
grade 3 are distinct between these 2 targeted agents, with acneiform rash (61% vs 8%) 
predominating for cetuximab and hypertension (32% vs 15%) predominating for 
bevacizumab.48,49
4
OBJECTIVES AND ENDPOINTS
The study includes two target populations and objectives are set up according to the populations. 
The randomized participants regardless of prior lines of therapy will refer to ‘All lines’ and the 
randomized participants who have not received prior therapy for metastatic disease will refer to 
‘1L’.
Primary Objective
Endpoint
•
All lines
To compare the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm 
PFS by BICR (arm B vs A)
•
1L
To compare the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or chemotherapy arm
PFS by BICR (arm B vs C)
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Secondary Objective
Endpoint
•
All lines
To compare the BICR assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm
ORR by BICR (arm B vs A)
To compare the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC and randomized to nivolumab plus ipilimumab combination therapy 
arm or nivolumab monotherapy arm
OS (arm B vs A)
To estimate the Investigator-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC and randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm
PFS by Investigator assessment
(arm A and B)
To estimate the BICR-assessed PFS of participants with dMMR/MSI-H 
mCRC per local testing who were randomized to nivolumab plus 
ipilimumab combination therapy arm or nivolumab monotherapy arm
PFS by BICR among all 
randomized participants (arm A 
and B) 
•
1L
To compare the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or nivolumab monotherapy arm
PFS by BICR (arm B vs A)
To compare the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or chemotherapy arm
ORR by BICR (arm B vs C)
To compare the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab plus ipilimumab 
combination therapy arm or nivolumab monotherapy arm
ORR by BICR (arm B vs A)
To compare the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC who have not received prior therapy and randomized to nivolumab 
plus ipilimumab combination therapy arm or nivolumab monotherapy arm
OS (arm B vs A)
To estimate the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab monotherapy arm or 
chemotherapy arm
PFS by BICR (arm A and C)
To estimate the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC who have not received prior therapy and randomized to nivolumab 
plus ipilimumab combination therapy arm or chemotherapy arm
OS (arm B and C)
To estimate the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior treatment for 
metastatic disease and randomized to nivolumab monotherapy arm or 
chemotherapy arm
ORR by BICR (arm A and C)
To estimate the OS of participants with centrally confirmed dMMR/MSI-H 
mCRC who have not received prior therapy and randomized to nivolumab 
monotherapy arm or chemotherapy arm
OS (arm A and C)
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Secondary Objective
Endpoint
To estimate the Investigator-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have not received prior therapy by 
treatment arm
PFS by Investigator (arm A, B 
and C)
To estimate the BICR-assessed PFS of participants with dMMR/MSI-H 
mCRC per local testing who have not received prior treatment and 
randomized to nivolumab plus ipilimumab combination therapy arm or 
chemotherapy arm
PFS by BICR among all 
randomized participants who 
have not received prior treatment 
(arm B and C) 
To estimate the BICR-assessed PFS of participants with dMMR/MSI-H 
mCRC per local testing who have not received prior treatment and 
randomized to nivolumab plus ipilimumab combination therapy arm or 
nivolumab monotherapy arm
PFS by BICR among all 
randomized participants who 
have not received prior treatment 
(arm A and B) 
•
CDx (All lines and 1L)
To estimate the BICR-assessed PFS of participants with confirmed 
dMMR/MSI-H status by each central test who have not received prior 
therapy and randomized to nivolumab plus ipilimumab combination 
therapy arm or chemotherapy arm
PFS by BICR (arm B and C)
To estimate the BICR-assessed PFS of participants with confirmed 
dMMR/MSI-H status by each central test and randomized to nivolumab 
plus ipilimumab combination therapy arm or nivolumab monotherapy arm
PFS by BICR (arm B and A)
•
Crossover Cohort
To estimate the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC treated in the crossover cohort 
PFS by BICR 
To estimate the BICR-assessed ORR of participants with centrally 
confirmed dMMR/MSI-H mCRC treated in the crossover cohort
ORR by BICR
Exploratory Objective
Endpoint
To estimate the BICR-assessed PFS of participants with centrally 
confirmed dMMR/MSI-H mCRC who have received 1 prior line by 
treatment arm
PFS by BICR (arm A, B and C)
To further define the safety and tolerability of study treatment in all treated 
dMMR/MSI-H mCRC participants by treatment arm and line of prior 
therapy
Including but not limited to: 
AEs/SAEs by grade and 
attribution, laboratory 
abnormalities (arm A, B and C)
To estimate the Investigator-assessed PFS during next line of treatment 
(PFS2) in randomized dMMR/MSI-H mCRC participants with centrally 
confirmed dMMR/MSI-H status per treatment arm
PFS2 by Investigator assessment 
(arm A, B and C)
To evaluate participant-reported symptoms, functioning, and quality of life 
in all randomized dMMR/MSI-H mCRC participants by treatment arm and 
line of prior therapy
EORTC QLQ-C30 and QLQ-
CR29 scale and item scores and 
score changes
To evaluate participant-reported health status and utility in all randomized 
dMMR/MSI-H mCRC participants by treatment arm and line of prior 
therapy
EQ-5D-3L visual analog scale 
(VAS) and utility index scores 
and score changes
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Exploratory Objective
Endpoint
To characterize the PK and the immunogenicity of nivolumab plus 
ipilimumab combination therapy and nivolumab monotherapy in all treated 
dMMR/MSI-H mCRC participants in nivolumab plus ipilimumab arm and 
in nivolumab monotherapy arm, respectively
Population PK parameters and 
incidence of immunogenicity for 
ipilimumab combined with 
nivolumab and nivolumab 
monotherapy (arm B and A)
To explore potential biomarkers associated with clinical efficacy in all 
randomized dMMR/MSI-H mCRC participants 
Associations of select 
biomarkers that may include but 
not be limited to PD-L1, TMB 
and serum/plasma/microbiome 
biomarkers with efficacy 
outcomes (eg, OS, PFS and 
ORR)
To assess the time to treatment failure (TTF) across treatment arms in all 
randomized participants with centrally confirmed dMMR/MSI-H mCRC 
TTF by Investigator assessment
To evaluate the recurrence free survival (RFS) after curative surgery by 
Investigator assessment in participants with centrally confirmed 
dMMR/MSI-H mCRC who have not received prior treatment by treatment 
arm
RFS by Investigator assessment 
•
Crossover Cohort
To characterize the efficacy of nivolumab plus ipilimumab combination by 
line of prior therapy in participants treated in the crossover cohort as 
reflected by BICR-assessed ORR and PFS, and Investigator-assessed ORR, 
PFS and OS
ORR, PFS by BICR and 
Investigator assessment
OS
To characterize the safety of nivolumab plus ipilimumab combination in 
participants treated in the Crossover cohort
Including but not limited to: 
AEs/SAEs by grade and 
attribution, laboratory 
abnormalities
To characterize the PK and the immunogenicity of nivolumab and 
ipilimumab in treated dMMR/MSI-H mCRC participants in the Crossover 
cohort
Population PK parameters and 
incidence of immunogenicity for 
ipilimumab combined with 
nivolumab 
Main estimands for the primary and key secondary endpoints are summarized in Table 4-1. 
Table 4-1:
Main Estimands for the Primary and Key Secondary Endpoints
Endpoint
Population
Treatments
Intercurrent 
Events
Summary 
Statistics
PRIMARY OBJECTIVES
PFS by BICR
All participants 
across lines who are 
randomized to Arm 
A and Arm B and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm A
• Death: composite 
variable strategy 
(eg, considered an 
event)
• Start of 
subsequent 
therapy: while-on-
Stratified HR from 
CPH model, with CI
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Table 4-1:
Main Estimands for the Primary and Key Secondary Endpoints
Endpoint
Population
Treatments
Intercurrent 
Events
Summary 
Statistics
PFS by BICR
All participants in 
1L who are 
randomized to Arm 
B and Arm C and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm C
treatment strategy 
(eg, PFS will be 
censored on the 
date of last 
evaluable tumor 
assessment prior 
to or on the same 
date of initiation 
of new anticancer 
therapya)
KEY SECONDARY OBJECTIVES
PFS by BICR
All participants in 
1L who are 
randomized to Arm 
A and Arm B and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm A
• Death: composite 
variable strategy 
(eg, considered an 
event)
• Start of 
subsequent 
therapy: while-on-
treatment strategy 
(eg, PFS will be 
censored on the 
date of last 
evaluable tumor 
assessment prior 
to or on the same 
date of initiation 
of new anticancer 
therapya)
Stratified HR from 
CPH model, with CI
ORR by BICR
All participants 
across lines who are 
randomized to Arm 
A and Arm B and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm A
• Dropout or death 
without disease 
assessment: 
composite 
variable strategy 
(eg, included in 
the ORR analyses 
and categorized as 
nonresponders)
• Start of 
subsequent 
therapy: while-on-
treatment strategy 
(eg, only 
responses before 
the intercurrent 
event will be 
considered)
Difference of 
response rates using 
CMH method of 
weighting, with CI
ORR by BICR
All participants in 
1L who are 
randomized to Arm 
B and Arm C and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm C
ORR by BICR
All participants in 
1L who are 
randomized to Arm 
Arm B vs Arm A
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Table 4-1:
Main Estimands for the Primary and Key Secondary Endpoints
Endpoint
Population
Treatments
Intercurrent 
Events
Summary 
Statistics
A and Arm B and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
OS
All participants 
across lines who are 
randomized to Arm 
A and Arm B and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm A
• Lost to follow up: 
hypothetical 
strategy (eg, 
censor)
• All other 
intercurrent events 
(eg, start of 
subsequent 
therapy) will be 
handled with 
treatment policy 
strategy (eg, OS 
will not be 
censored on the 
date of the 
initiation of 
subsequent 
anticancer 
therapy, assuming 
subsequent 
anticancer 
therapies represent 
clinical practice)
Stratified HR from 
CPH model, with CI
OS
All participants in 
1L who are 
randomized to Arm 
B and Arm C and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm C
OS
All participants in 
1L who are 
randomized to Arm 
A and Arm B and 
with centrally 
confirmed 
dMMR/MSI-H 
mCRC
Arm B vs Arm A
a For the endpoints of PFS per BICR, a supportive analysis will be performed using a treatment policy strategy to 
handle the intercurrent events of start of subsequent therapy. Under this strategy, information after the initiation of 
subsequent therapy will be used as well. Details are listed in statistical analysis plan.
Abbreviations: 1L, first line; BICR: Blinded Independent Central Review; CMH, Cochran-Mantel-Haenszel; CI, 
confidence interval; CPH, Cox proportional hazards; dMMR/MSI-H mCRC, DNA mismatch repair-
deficient/microsatellite instability-high metastatic colorectal cancer; HR, hazard ratio; ORR, overall responses rate; 
OS, overall survival; PFS, progression-free survival.
5
STUDY DESIGN
5.1
Overall Design
CA2098HW is a Phase 3, randomized, 3-arm open-label study of nivolumab monotherapy (arm 
A), nivolumab plus ipilimumab combination therapy (arm B) or an investigator’s choice 
chemotherapy (arm C) for the treatment of participants with recurrent or metastatic dMMR/MSI-
H CRC. In protocol revision 04, the study expanded with additional participants in 1L setting. 
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Therefore, the study enrollment includes 2 sequential parts. Part 1 enrollment is open to 
participants across all lines of therapy, and Part 2 enrollment open only to participants who have 
not received prior therapy for metastatic disease (1L). Part 2 enrollment starts immediately after 
completion of part 1 enrollment. 
After confirmation of eligibility criteria participants will be randomized to arms A, B or C in a 
2:2:1 ratio. Randomization to arm C will be restricted to participants who have received no more 
than 1 prior line of systemic therapy (0 or 1 line). Part 1 enrollment continues to allow 
randomization of approximately 442 participants across lines of therapy with centrally confirmed 
dMMR/MSI-H mCRC as per protocol revision 03. 
Approximately 230 additional participants who have not received prior therapy for metastatic 
disease (1L) with centrally confirmed dMMR/MSI-H mCRC will be randomized during part 2 
enrollment. 
A continuous evaluation of the discordance rate between local and central testing during the study 
conduct suggests that approximately 15% of the samples have discordant dMMR/MSI-H results. 
The observed discordance rate is higher than the initially assumed rate of 10% used for sample 
size calculation for randomization per local testing. Additionally, poor tissue quality led to the 
absence of valid central test results in some instances; ie, no confirmation of dMMR/MSI-H status 
by either central test. Therefore, while the projected number of randomized participants per central 
testing have not changed, the number of participants per local testing is revised to reflect higher 
than initially assumed discordance rate.
Part 1 enrollment was completed as of Revised Protocol 06. Part 2 randomization was completed 
in Apr-2023.
Stratification factors
CA2098HW study participants will be stratified by tumor location (right vs left) and by the number 
of prior treatments for metastatic disease (none, one, two or more). Stratification by tumor 
sidedness will continue during Part 2 enrollment, however stratification by line of therapy will not 
be applicable since enrollment will be open only for participants who have not received prior 
therapy. Study specific definition of tumor sidedness and line of therapy (number of prior systemic 
treatments for metastatic disease) are provided in the Appendices 12 and 10, respectively.
Participants will receive treatment until progression, toxicity, discontinuation for other reasons, or 
reaching maximum treatment duration. Study participants from all three arms that discontinue 
study treatment will enter the Follow Up phase (first treatment Follow Up) and will follow the 
assessment schedules outlined in Table 2-5.
Crossover Cohort
Participants assigned to arm C that experience documented progression of disease (PD) per 
RECIST 1.1 by Blinded Independent Central Review (BICR) will have an option to crossover to 
nivolumab plus ipilimumab therapy (Crossover Cohort) provided that they complete at least 
Follow Up Visit 1 (Table 2-5) within the Follow Up phase and meet all other crossover criteria 
outlined in the protocol Section 6.3. Crossover Cohort participants will receive treatment until 
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progression, toxicity, discontinuation for other reasons, or reaching maximum treatment duration. 
After study treatment discontinuation, they will also enter the Follow Up phase (second treatment 
Follow Up) and will follow the assessment schedules outlined in Table 2-5. The Crossover Cohort 
starts when participants begins nivolumab plus ipilimumab combination therapy.
The study design schematic and study conduct scheme are presented in Figure 5.1-1 and Figure 
5.1-2.
Figure 5.1-1:
Study Design Schematic
1L, 2L, ≥3L – subgroups of participants within each study arm for whom study treatment is a 1st line (0 prior lines of 
systemic therapy), 2nd line (1 prior line of systemic therapy) or 3rd line and beyond (2 or more prior lines of systemic 
therapy), respectively.
# Line of therapy is not a stratification factor during Part 2 enrollment.
* Participants with ≥2 prior lines are randomized only to arm A or B during Part 1 enrollment; only participants with 
0 prior lines are randomized during Part 2 enrollment.
** Optional Crossover for arm C with Nivo + Ipi q6w dosing.
*** Part 1 enrollment continues to allow randomization of approximately 560 participants across lines of therapy with 
locally confirmed dMMR/MSI-H mCRC. Part 2 enrollment continues to allow randomization of approximately 271 
additional participants with locally confirmed dMMR/MSI-H status who have not received prior therapy for metastatic 
disease (1L). Part 2 randomization was completed in Apr-2023.
^ max treatment duration is not applicable for arm C participants.
Abbreviations BICR, Blinded Independent Central Review; CRC, colorectal cancer; IC, informed consent, MSI-H, 
microsatellite instability high; dMMR, deficient mismatch repair; PD, progressive disease; PFS, progression free 
survival.
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Figure 5.1-2:
Study Conduct Scheme
* Line of therapy is not a stratification factor in Part 2 enrollment
Abbreviations: CRC, colorectal cancer; ECOG, Eastern Cooperative Oncology Group IC, informed consent, MSI-H, 
microsatellite instability high; dMMR, deficient mismatch repair 
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China Sub-study
A China extension will be added to allow continued enrollment of participants from China after 
the completion of the enrollment to the global study. All details regarding the study design, sample 
size, and duration of enrollment will be specified in the China-specific protocol. 
5.1.1
Data Monitoring Committee and Other External Committees
5.1.1.1
Data Monitoring Committee
A data monitoring committee (DMC) will be utilized to provide an independent evaluation of the 
study interim data. The DMC charter will describe additional details of the DMC responsibilities 
and procedures related to the committee operations. The Sponsor will have responsibility for the 
overall conduct of the study, including managing the communication of study data.
5.1.1.2
Blinded Independent Central Review (BICR)
A BICR will be utilized in this study for determination of BICR-assessed endpoints. Details of 
BICR 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 9.1.1 Imaging Assessment for the Study 
for further details.
5.2
Number of Participants 
It is expected that approximately 831 participants with dMMR/MSI-H mCRC determined by local 
testing will be randomized to study, including approximately 560 and 271 during part 1 and part 2 
enrollment, respectively. These corresponds to randomization of approximately 442 participants 
across lines of therapy and 230 participants who have not received prior treatment with centrally 
confirmed dMMR/MSI-H status during part 1 and part 2 enrollment, respectively. These 
estimations are based on the number of participants with centrally confirmed dMMR/MSI-H status 
required for evaluation of each primary endpoint and on assumption of discordance rate between 
local and central testing of 15%.50
The study may randomize participants beyond these numbers if 1) discordance rate between local 
and central dMMR/MSI-H testing exceeds 15% or no central confirmation of dMMR/MSI-H 
status is available, 2) distribution across lines of therapy significantly deviates from preliminary 
estimations or 3) increasing number of participants will undergo surgical resection prior to 
progression event (ie, 15% or more).
5.3
End of Study Definition 
The start of the trial is defined as first patient first visit. End of trial is defined as the last visit or 
scheduled procedure shown in the Schedule of Activities (Section 2) for the last participant. Study 
completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
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5.4
Scientific Rationale for Study Design
Both nivolumab monotherapy and nivolumab in combination with ipilimumab have shown highly 
promising activity and durable responses in the treatment of dMMR/MSI-H mCRC beyond first-
line. 
There is growing body of evidence that immunotherapy is effective not only in the refractory 
settings but also in earlier lines of treatment. Recently presented data from a randomized phase 3 
study comparing pembrolizumab with standard chemotherapy in front-line setting (Keynote-177 
study) confirmed superior antitumor activity as reflected by PFS and ORR achieved by anti-PD1 
single agent vs chemotherapy in MSI-H mCRC patients.1
Indirect comparisons suggest that nivolumab (3 mg/kg) + low-dose ipilimumab (1 mg/kg) 
combination therapy provides improved clinical benefit versus nivolumab monotherapy with a 
favorable benefit-risk profile for previously treated patients with dMMR/MSI-H mCRC (≥ 1 prior 
therapy). Extrapolation of the data from the Keynote-177 study extends these assumptions of 
improved PFS and OS of IO-IO combination vs IO monotherapy to 1L setting. Accumulating 
external and internal data in MSI-H mCRC suggest consistent treatment effect in terms of PFS 
improvement with combination vs monotherapy regardless of the line of therapy justifying study 
statistical design. Therefore, the randomized design was chosen to confirm the findings of the 
indirect comparison within the non-randomized study (CA209142) demonstrating superior 
response rates, improved PFS and OS with nivolumab plus ipilimumab combination therapy 
compared with nivolumab monotherapy. Moreover, the randomized design will enable more 
reliable analyses across combination and monotherapy arms between patient and tumor 
characteristics and disease outcomes, from both efficacy and safety perspectives. 
Up to now, no study has reported results on comparative efficacy of dual I-O combination (anti-
CTL-4 + anti-PD1) vs chemotherapy in dMMR/MSI-H mCRC patients, including those who have 
not received prior therapy for metastatic disease or received 1 prior line of therapy. There are 2 
(Keynote-177 and COMMIT) ongoing phase 3 clinical studies evaluating efficacy and safety of 
immunotherapy vs standard of care as 1L therapy in dMMR/MSI-H mCRC patients.51,52 While 
the Keynote-177 study compares pembrolizumab single agent with chemotherapy, and the 
COMMIT study evaluates atezolizumab in combination with chemotherapy vs chemotherapy, no 
study evaluates the combination of two immunotherapies vs chemotherapy as 1L treatment in 
dMMR/MSI-H mCRC patients. In the Keynote-177 study, early detriment in terms of PFS was 
observed with single-agent pembrolizumab compared with chemotherapy leading to the crossing 
of the PFS curves. These data of IO monotherapy as 1L treatment in MSI-H mCRC patient raises 
the question if IO-IO combination is able to overcome or reduce the detriment.
To address these questions the study design expands enrollment for participants who have not 
received prior therapy for metastatic disease. 
5.4.1
Rationale for Treatment Setting 
The goal of treatment is palliative for the majority of patients with mCRC, while a small subset 
may achieve cure (liver and/or lung-limited oligometastatic disease). With modern treatment 
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approaches, median survival can exceed two years for patients who are able to tolerate intensive 
therapy.53 Standard of care for initial therapy for mCRC is combination of cytotoxic chemotherapy 
with biologic agent (anti-VEGF or anti-EGFR). The addition of a biologic agent (anti-VEGF or 
anti-EGFR) to standard chemotherapy has been shown to improve PFS and OS. Combinations of 
chemotherapy (FOLFOX or FOLFIRI) and a biologic agent in the first-line setting achieve 
response rates >40%, and mPFS up to 9-11 months, but toxicities reported such as Grade 3-4 
neutropenia or diarrhea can exceed 40%.54 Furthermore, with aging populations across the globe, 
some patients with mCRC may not be candidates for such intensive therapy. Confirming efficacy 
of checkpoint inhibition and IO-IO combination in earlier lines of treatment for dMMR/MSI-H 
mCRC can allow more patients to benefit from durable response with potentially less persistent 
toxicity. It should be noted that nivolumab monotherapy and nivolumab plus ipilimumab 
combination are listed in the NCCN guidelines among treatment options in first-line and beyond 
for patients who are not appropriate for intensive therapy (category 2B for first line), and for all 
patients with dMMR/MSI-H mCRC beyond first-line (category 2A).33
Immune responses to combination therapy with nivolumab and ipilimumab may be more robust in 
patients who are chemotherapy-naive.55 In dMMR/MSI-H mCRC, long term follow up of the 
monotherapy cohort demonstrated stronger response among patients who had ≤2 standard 
chemotherapies as compared with those who received all three chemotherapies prior to 
nivolumab.31 These observations, taken together with the decreased benefit from cytotoxic 
chemotherapy in the dMMR/MSI-H mCRC population,16 suggest that a rational approach would 
be to offer combined immunotherapy to dMMR/MSI-H patients earlier in the course of their 
disease.
The efficacy and safety of immune check-point inhibitors across all lines of treatment for 
dMMR/MSI-H mCRC are currently under investigation in clinical trials. The preliminary data 
from the treatment-naive cohort (C3 Cohort) in the CA209142 study suggest that nivolumab 
combined with ipilimumab is an active and promising treatment in first-line setting.56 Moreover, 
ongoing studies in first-line dMMR/MSI-H mCRC include pembrolizumab monotherapy vs 
chemotherapy (NCT02563002). The nivolumab monotherapy and combination of nivolumab plus 
ipilimumab provided higher and more durable response compared to historical control in the non-
randomized CA209142 study.29,31 Therefore, extension of the inclusion criteria allowing the 
randomization of patient irrespective of prior treatment history to nivolumab monotherapy versus 
nivolumab and ipilimumab combination provides promisingly effective treatment options even for 
first-line treatment with manageable safety profile to patients whose tumors may not respond to 
chemotherapy to the same extent as MSS tumors.
Front-line chemotherapy in unselected mCRC patients is effective as reflected by high rates of 
ORR (40-60%), mPFS (10-11 months) and mOS (20-30 months).48 The second-line treatment has 
lower efficacy compared to first-line therapy. The reported rates of ORR in second-line setting 
vary significantly from 5 to 20%, with mPFS and mOS reaching approximately 6 months and 11 
months, respectively. 57 Retrospective analyses of several studies suggest that patients with 
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dMMR/MSI-H mCRC may not benefit from chemotherapy to the same extent as patients with 
MSS tumors. These observations have been recently confirmed by the Keynote-177 study results.  
The mPFS for front-line chemotherapy arm was 8.2 months, and 33.1% of participants achieved 
response, including 3.9% complete response.
Availability of such data for front and second-line would allow to optimize dMMR/MSI-H 
patients’ management considering the excellent results from CA209142 study in 1L and chemo-
refractory settings. 
5.4.2
Rationale for Investigator’s Choice Treatment and PFS assumptions in 
Chemotherapy Arm
Chemotherapy is the only approved treatment option for unselected, including dMMR/MSI-H, 
mCRC patients who have not received any prior systemic therapy or who have received one prior 
line of therapy. Since the best way to combine and sequence chemotherapeutic agents is still not 
established the approach for initial and subsequent treatments may vary in terms of choice of 
regimen and inclusion of targeted agents.33,58 Considering that CA2098HW is a global study the 
investigator’s choice standard chemotherapy will include one of 6 SOC regimens (FOLFOX, 
FOLFIRI with or without Bevacizumab or Cetuximab) recommended by guidelines for initial or 
subsequent mCRC treatment. 
Efficacy results of chemotherapy in front- and second line settings are summarized in the Section 
5.4.1. Patients who are refractory to chemotherapy can be treated with regorafenib or TAS-102. 
Both agents provide modest improvement in mOS vs best supportive care (6.4 versus 5 months 
for regorafenib; and 9 versus 6.6 months for TAS-102) at the expense of significant adverse events 
profile.59 On the other hand nivolumab and nivolumab plus ipilimumab that are approved in this 
setting provide robust and durable clinical benefit as reflected by significant improvement of PFS 
and OS in patients with dMMR/MSI-H mCRC.2,3 Therefore only patients without prior systemic 
treatment (1L) or those who have had received one prior line of systemic therapy (2L) will be 
randomized to chemotherapy arm. 
The median PFS in unselected patient population with mCRC treated with 1L doublet 
chemotherapy is approximately 10 months. Reported mPFS in studies with 2L chemotherapy is 
approximately 6-7 months. Taking into account data from post-hoc analyses of randomized studies 
and real-world cohorts suggesting shorter mPFS in patients with dMMR/MSI-H mCRC compared 
to patients with MSS tumors (See Sections 3.2.3 and 5.4.1 for additional details), the mPFS in 
patients with dMMR/MSI-H mCRC who have not received prior systemic therapy (1L) assumed 
9 months, and in patients who have received one prior line of systemic therapy (2L) assumed 5 
months. The mPFS assumptions for 1L chemotherapy has been recently confirmed by the 
Keynote-177 study that reported mPFS of 8.2 months in previously untreated patients who 
received investigators choice chemotherapy.1 During part 1 enrollment, approximately equal 
distribution of 1L and 2L patients in the arm C (this ratio is derived from internal sites feasibility 
assessment) is projected. 
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5.4.3
Rationale for Nivolumab Monotherapy
Nivolumab monotherapy provides clinically meaningful and durable responses in dMMR/MSI-H 
biomarker-selected population beyond second-line, which seem to exceed historical response rates 
remarkably with standard options. In CA209142 study after median follow up of 21 months of 
patients treated with nivolumab monotherapy (n = 74), the median DOR per BICR was not reached 
and the mPFS was 6.6 month (95% CI: 3.0, NE). Landmark PFS rates were 44% (95% CI: 32.6, 
55.3) at both 12 and 18 months. Median OS was not reached (95% CI: 19.6, NE), and the OS rates 
at 12 and 18 months were 72% (95% CI: 60.0-80.9) and 67% (95% CI: 54.9-76.9), respectively.60
These findings in this pretreated population (beyond first-line) demonstrate the durability of 
clinical benefit in some patients and justify further study of nivolumab monotherapy in 
dMMR/MSI-H mCRC patients, including first line.
5.4.4
Rationale for Nivolumab and Ipilimumab Combination
The combination of nivolumab and ipilimumab was chosen based on preclinical and preliminary 
clinical evidence suggesting synergy between nivolumab and ipilimumab across different tumor 
types. Nivolumab in combination with ipilimumab, has demonstrated remarkable benefit for 
several solid tumor types, including previously treated dMMR/MSI-H mCRC. 61 Preliminary 
evidence from nivolumab plus ipilimumab cohort (n = 119) of CA209142 study demonstrated 
additional clinical improvement of this combination in mCRC patients over the cohort of patients 
treated with nivolumab monotherapy (n = 74) beyond second-line of treatment. At data cutoff of 
Jul 2017 the median follow up in the nivolumab plus ipilimumab combination therapy cohort was 
13.4 months (range 9 - 25 months). The BICR-assessed ORR achieved in 49% (95% CI: 39.5, 
58.1), including 4% of patients who demonstrated CR. This was numerically higher than in the 
cohort of 74 patients who received nivolumab monotherapy (31.1%, 95% CI: 20.8, 42.9) in the 
same study with similar median follow up of 13.4 months.29 Thus, nivolumab plus ipilimumab 
combination therapy provided a numerically higher ORR, including CRs, and DCR relative to 
monotherapy during a similar follow-up period. Superior OR rates with nivolumab plus 
ipilimumab combination were translated to the numerically improved PFS and OS rates over 
nivolumab monotherapy. The investigator assessed 12-month PFS and OS rates in nivolumab 
monotherapy and nivolumab plus ipilimumab cohorts were 50% (95% CI: 38-61) vs 71% (95% 
CI: 61.4, 78.7) and 73% (95% CI: 62-82) vs 85% (95% CI: 77.0-90.2), respectively. In the 
combination cohort Grade 3 to 4 treatment-related AEs occurred in 32% of patients and were 
manageable.62
Internal data from recent DBL of the CA209142 study as well as external evidence from the 
Keynote-177 study indicate flattened tails of PFS curves for nivolumab monotherapy and 
nivolumab plus ipilimumab combination therapies, constant HR for PFS between nivolumab plus 
ipilimumab combination and nivolumab monotherapy by line of therapy, and stronger than initially 
anticipated treatment effect of combination vs monotherapy. 
5.4.5
Rationale for Optional Crossover from Chemotherapy Arm
Immunotherapy has proven benefit in dMMR/MSI-H mCRC patients and lead to dramatic 
improvement in PFS and OS in chemo-refractory setting. Nivolumab and nivolumab plus ipilimumab 
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combination approved in few countries for the treatment of dMMR/MSI-H mCRC that has progressed 
following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Thus, to ensure access to 
immunotherapy, across all participating countries to patients that were randomized to arm C and 
progressed on or after receiving chemotherapy, an optional crossover to nivolumab plus ipilimumab 
combination therapy is introduced. Eligible patients may receive nivolumab plus ipilimumab 
combination for a maximum treatment period of 2 years. It is recognized that this crossover 
immunotherapy treatment may confound any OS endpoints, but it will not affect other key endpoints. 
5.4.6
Rationale for Choice of Primary Endpoints
The primary endpoints of the study are PFS per BICR. Although OS is considered the most reliable 
cancer endpoint, PFS has been an acceptable endpoint to support regulatory approvals in mCRC. 
PFS has been selected as a primary endpoint for comparison of clinical benefit between nivolumab 
monotherapy (arm A) and nivolumab plus ipilimumab combination therapy (arm B). Decision to 
use PFS as a primary endpoint is driven by long OS reported for nivolumab and nivolumab plus 
ipilimumab in dMMR/MSI-H mCRC in CA209142 study. Demonstration of benefit in terms of 
OS would require a larger study and/or longer follow up that could be challenging to achieve 
within clinical study for dMMR/MSI-H mCRC patients. In addition, nonuniform access to 
subsequent cancer therapy may potentially confound survival analysis. PFS is viewed as benefit 
on its own right considering the duration of PFS observed with nivolumab alone or in combination 
with ipilimumab.
Prioritization of PFS over OS for the second primary endpoint is imposed by the optional crossover 
for patients treated with chemotherapy. Provision of nivolumab plus ipilimumab for patients 
progressing on chemotherapy will confound OS. The benefit in OS for arm C patients is expected 
to be substantial after switching to nivolumab plus ipilimumab. Thus, selection of OS as a second 
primary endpoint, will face the same challenges as comparison of survival between arms A and B. 
Therefore, PFS being an important indicator of clinical benefit in mCRC, is more suitable as the 
primary endpoint for CA2098HW trial. 
5.4.7
Clinical Validation of Companion Diagnostics
The design of CA209-8HW study accounts for the development of companion diagnostics for 
dMMR/MSI-H testing (IHC and a PCR-based assays), a post marketing commitment to US FDA.  
Choice of primary population in CA209-8HW trial consisting of patients with centrally confirmed 
dMMR/MSI-H mCRC is driven by this companion diagnostic development. Patients’ enrollment 
is based on local testing result allowing rapid accrual and minimizing delay in treatment initiation, 
while pre-defining primary population (confirmed dMMR/MSI-H by central laboratory) allows 
adequate clinical validation of the assays. All enrolled patients will have tumor tissue samples 
analyzed retrospectively in a central laboratory setting, using both the IHC assay and the PCR 
assay. 
5.4.8
Rationale for Tissue Requirements
One of the objectives of the CA2098HW clinical trial is to fulfil the commitment to support the 
availability of companion in vitro diagnostic device. Therefore, an appropriate analytical and 
clinical validation study using CA2098HW clinical trial data will be conducted  to support labeling 
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of an immunohistochemistry-and nucleic acid-based in vitro diagnostic devices that are essential 
to the safe and effective use of nivolumab for patients with tumors that are mismatch repair 
deficient. To meet this commitment the CA2098HW clinical trial has tissue requirements that are 
outlined in the inclusion criteria 2 e) (see Section 6.1). 
5.4.9
Rationale for Duration of Study Treatment
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumors types in the nivolumab and ipilimumab development 
program indicate that most of the responses occur early, with a median time to response of 2 to 4 
months,47,63,64,65, 66 and emerging data suggests that benefit can be maintained in the absence of  
continued treatment. A recent analysis in a melanoma study suggests the majority of patients who 
discontinue nivolumab and/or ipilimumab for toxicity maintain disease control in the absence of 
further treatment.67 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.68
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 participants with NSCLC), specified a maximum treatment duration of 2 years. 
Among 16 participants with NSCLC who discontinued nivolumab after completing 2 years of 
treatment, 12 participants were alive > 5 years and remained progression-free without any 
subsequent therapy. In the CA209003 NSCLC cohort, the OS curve begins to plateau after 2 years, 
with an OS rate of 25% at 2 years and 18% at 3 years.69 These survival outcomes are similar to 
Phase 3 studies in previously treated NSCLC, in which nivolumab treatment was continued until 
progression or unacceptable toxicity (2-year OS rates of 23% and 29%, and 3 year OS rates of 
16% to18% for squamous and non-squamous NSCLC, respectively).70
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in participants with previously treated, PD-L1-positive, advanced 
NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab and stopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.71
Keynote-006 was a randomized Phase 3 study of pembrolizumab versus ipilimumab in patients 
with advanced melanoma, which also specified a maximum 2 year duration of pembrolizumab 
treatment. 104 (19%) of 556 patients randomized to pembrolizumab completed 2 years of 
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treatment. With a median follow-up of 9 months after completion of pembrolizumab, the estimated 
risk of progression or death was 9% in these patients.72
Recent analysis of the data from CA209142 study in patients with dMMR/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).73 It 
is 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.
The optimal treatment duration of initial chemotherapy for unresectable disease is controversial. 
Per NCCN and ESMO guidelines chemotherapy should be administered until disease progression 
or unacceptable toxicity with potential to switching from initial intensive therapy to less intensive 
therapy (maintenance therapy) in patients with good response to initial treatment.33,74  
5.5
Justification for Dose
Nivolumab is currently approved for the treatment of various tumors, including melanoma, 
NSCLC, SCLC, RCC, cHL, SCCHN, UC, and dMMR/MSI-H mCRC using a regimen of either 
nivolumab 240 mg Q2W or nivolumab 480 mg Q4W.
The nivolumab dose of 240 mg Q2W and 480 mg Q4W were selected based on clinical data and 
modeling and simulation approaches using PPK and exposure-response analyses of data from 
studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight normalized 
dosing (mg/kg) has been used.
PPK analyses have shown that the PK of nivolumab is linear with proportional exposure over a 
dose range of 0.1 to 10 mg/kg, and no differences in PK across ethnicities and tumor types were 
observed. Nivolumab clearance and volume of distribution were found to increase as the body 
weight increases, but less than proportionally with increasing weight, indicating that mg/kg dosing 
represents an over-adjustment for the effect of body weight on nivolumab PK. The PPK model 
previously developed using data from NSCLC participants has recently been updated, using data 
from 1544 participants from 7 studies investigating nivolumab in the treatment of melanoma, 
NSCLC, and RCC. In this dataset, the median (minimum - maximum) weight was 77 kg 
(35 - 160 kg) and thus, an approximately equivalent dose of 3 mg/kg for an 80 kg participant, 
nivolumab 240 mg Q2W was selected for future studies. To predict relevant summary exposures 
of nivolumab 240 mg Q2W and 480 mg Q4W in CRC patients from CA209142, a PPK model was 
used to simulate nivolumab 3 mg/kg Q2W, 240 mg Q2W and 480 mg Q4W. Table 5.5-1 presents 
the comparison of nivolumab exposures at the different dosing regimens in mCRC patients. The 
geometric mean of all 8 of the key summary measures of nivolumab exposures achieved with 240 
mg Q2W dosing were slightly greater (< 10%) relative to the corresponding exposures achieved 
with 3 mg/kg Q2W. Additionally, the geometric means of nivolumab exposure in the dMMR/MSI-
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H mCRC population were greater with 480 mg Q4W dosing relative to 3 mg/kg Q2W dosing for 
6 of the 8 summary measures of exposure, namely: Cavg1, Cmax1, Cmin1, Cavgd28, Cavgss and 
Cmaxss; whereas the exposures were lower by ~19% for Cmind28 and ~11% Cminss. This 
magnitude of difference is not expected to be clinically significant. Notably, nivolumab 
concentrations averaged over the first 4-weeks were higher with 480 mg/kg Q4W relative to 3 
mg/kg, and approximately twice as high during the first 2 weeks. Therefore, since exposures 
following 480 mg Q4W are predicted to be similar to those at 3 mg/kg, no impact on efficacy is 
expected. The PPK model predicted Cmax1 with 480 mg Q4W to be about 117% higher than seen 
with 3 mg/kg Q2W for dMMR/MSI-H mCRC and this difference is reduced to 46.7% when steady 
state is achieved. The Cmax achieved with 480 mg Q4W is well below the Cmax achieved by a 
dose of 10 mg/kg Q2W (Figure 5.5-1), which is a regimen that has been shown to be safe and 
tolerable. Therefore, no impact on safety is expected with the dosing regimen to be used in this 
study.
Table 5.5-1:
Geometric Mean Exposure for Nivolumab 3 mg/kg Q2W, 240 mg 
Q2W or 480 mg Q4W, dMMR/MSI-H mCRC
Tumor Type
Summary 
Exposure
G1 - Nivo 3 
mg/kg Q2W 
GM [μg/mL] 
(%CV)
G2 - Nivo 240 
mg Q2W GM 
[μg/mL] 
(%CV)
G3 - Nivo 480 
mg Q4W GM 
[μg/mL] 
(%CV)
%Diff GM 
(240 mg) G2-
G1a
%Diff GM
(480 mg) G3-
G1b
dMMR/MSI-
H mCRC
(N=62)
CAVG1
26.9(21.8)
29.2(23.5)
43.9(26.5)
8.55
63.2
CAVGD28
33.8(23.2)
36.6(25.2)
43.9(26.5)
8.28
29.9
CAVGSS
93.6(41.5)
101(48)
101(48)
7.91
7.91
CMAX1
60.3(15.3)
65.4(27.9)
131(28)
8.46
117
CMAXSS
137(32.6)
148(40.9)
201(36.8)
8.03
46.7
CMIN1
17(27.8)
18.5(29.8)
22.5(36.9)
8.82
32.4
CMIND28
27.8(29.2)
30.2(32.2)
22.5(36.9)
8.63
-19.1
CMINSS
73.9(48.3)
80.1(55.5)
65.5(62.3)
8.39
-11.4
a Geometric mean (GM) difference in percentage of 240 mg Q2W (G2) relative to 3 mg/kg Q2W (G1)
b Geometric mean (GM) difference in percentage of 480 mg Q4W (G3) relative to 3 mg/kg Q2W (G1)
Source: Table 5.1-1 in the DCN 930127488
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Figure 5.5-1:
Predicted Nivolumab Concentration (with 90% PI) versus Time by 
Dosing Regimen in Participants with dMMR/MSI-H mCRC
Source: Figure 5.1-5 in DCN 930127488 
Note:  Median and 95th percentile Cmaxss lines are calculated from 157 participants receiving 10 mg/kg Q2W 
nivolumab from Studies MDX1106-01, MDX1106-03, and CA209005
In a previous analysis in participants with solid tumors such as NSCLC, RCC, and advanced 
melanoma treated over a wide dose range, it was determined that the exposure-response 
relationships were flat for efficacy and safety. In NSCLC participants, Cmin1 was not a significant 
predictor of efficacy (OR), and the risk of Grade 3+ DR-AE and AE leading to DC/D did not 
increase with Cavgss. In advanced melanoma participants, nivolumab Cavgss was not a significant 
predictor of OS; and risk of Grade 3+ DR-AEs and AEs leading to DC/D in advanced melanoma 
participants did not increase with higher exposures.  In advanced RCC participants, Cavgss was 
not a significant predictor of hazard of death and the risk of AE-DC/D actually decreased with 
increasing Cavgss. Given that the E-R relationships in dMMR/MSI-H mCRC are expected to be 
similar to what has been previously observed, and that the exposures with 240 mg Q2W and 
480 mg Q4W are expected to be on the flat portion of the E-R curve, the PPK data presented 
support the use of 240 mg Q2W and 480 mg Q4W in these participants.
Based on the collective understanding of nivolumab PK, flat exposure-response relationships for 
safety and efficacy previously observed, and the well-established safety up to the 10 mg/kg Q2W 
dose level, the benefit-risk profiles following nivolumab 240 mg Q2W and 480 mg Q4W are 
expected to be similar to that following nivolumab 3 mg/kg Q2W for participants with 
dMMR/MSI-H mCRC.
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Thus nivolumab 240 mg over 30 minutes will be used across both arms (nivolumab monotherapy 
and nivolumab plus ipilimumab combination) for the first 12 weeks, and nivolumab 480 mg will 
be used thereafter. 
Rationale for nivolumab/ipilimumab combination schedule
In CA209004, the 3 mg/kg nivolumab and 3 mg/kg ipilimumab cohort exceeded the maximum 
tolerated dose per protocol. In CA209004, while both Cohort 2 (1 mg/kg nivolumab + 3 mg/kg 
ipilimumab) and Cohort 2a (3 mg/kg nivolumab + 1 mg/kg ipilimumab) had similar clinical 
activity, a dose of 3 mg/kg of ipilimumab every 3 weeks for a total of four doses and 1 mg/kg 
nivolumab every 3 weeks for four doses followed by nivolumab 3 mg/kg every 2 weeks until 
progression was chosen. Exposure-response analysis of nivolumab monotherapy across dose 
ranges of 1 mg/kg to 10 mg/kg revealed similar clinical activity while exposure-response analysis 
of 0.3 mg/kg, 3 mg/kg, and 10 mg/kg of ipilimumab monotherapy have demonstrated increasing 
activity with increase in dose in the Phase 2 study CA184022. Therefore, theoretically, the 
selection of 3 mg/kg of ipilimumab (Cohort 2) may be more clinically impactful than selection of 
3 mg/kg of nivolumab (Cohort 2a). The combination arm in this study has a similar dose and 
schedule as that in CA209004 for the first 12 weeks, increasing the likelihood of replicating the 
clinical activity seen in the CA209004 study. Based on the clinical activity in CA209004, the 
majority of responses to the combination of nivolumab and ipilimumab occur in the first 12 weeks. 
Given the uncertainty of whether the ipilimumab administered past week 12 contributes to the 
clinical benefit and in line with the approved schedule for ipilimumab which is every 3 weeks for 
a total of four doses in the FDA and EMA approved label dosing section, ipilimumab will be 
administered every 3 weeks for a total of 4 doses. Additionally, data on the clinical efficacy of the 
combination therapy of 3 mg/kg nivolumab + 1 mg/kg ipilimumab in the dMMR/MSI-H CRC 
population (CA209142 combo CSR) is described in Section 3.2.3. 
Clinical activity of nivolumab and ipilimumab combination was further evaluated in patients with 
stage IIB-IV NSCLC as first-line treatment in CA209012, a large Phase 1, multi-arm safety study 
of nivolumab monotherapy and nivolumab in combination with various systemic anticancer 
therapies. Early combination cohorts of nivolumab 1 mg/kg + ipilimumab 3 mg/kg and nivolumab 
3 mg/kg + ipilimumab 1 mg/kg, both followed by maintenance nivolumab 3 mg/kg Q2W, resulted 
in significant toxicity in the NSCLC population, with 39% of patients discontinuing treatment due 
to a treatment-related adverse events.75 Thus, additional combination cohorts were initiated using 
lower doses of both nivolumab (1 mg/kg) and ipilimumab (1 mg/kg), or the approved dose of 
nivolumab (3 mg/kg Q2W) with less frequent dosing of ipilimumab (Q6W or Q12W). These new 
regimens were better tolerated, and the safety profile was comparable to what has been observed 
in the nivolumab monotherapy cohort study. Clinical activity was observed in all combination 
cohorts, but numerically higher response rates were observed in the cohorts evaluating the 
approved dose of nivolumab 3 mg/kg, with confirmed response rates ≥ 30% for the ipilimumab 1 
mg/kg Q12W and Q6W regimens, cohorts P and Q, respectively.76 Given the similarity in patient 
profiles of advanced NSCLC and CRC, nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 
mg/kg every 6 weeks will be studied in the Crossover Cohort with the expectation that there will 
not be changes in the safety profile, as has been demonstrated in NSCLC and in CA209142 study 
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for the cohort of dMMR/MSI-H mCRC patients who have not received prior systemic therapy for 
metastatic disease. Nivolumab (3 mg/kg Q2W) plus ipilimumab (1 mg/kg Q6W) combination was 
studied in dMMR/MSI-H mCRC patients in front-line setting (C3 cohort in CA209142 study).77
This combination demonstrated robust and durable clinical benefit as a 1L treatment for 
dMMR/MSI-H mCRC. The ORR and disease control rate (DCR) were 60% and 84%, respectively, 
with a 7% complete response rate. Median DOR was not reached. At 12 months, PFS and OS rates 
were 77% and 83%, respectively. Importantly, the safety profile was comparable to Nivolumab 
monotherapy. The Grade 3 to 4 treatment related AEs (TRAEs) observed in 16% of patients, and 
the rate of discontinuation due to TRAEs was low (7%).
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants or their legally authorized representative (see Appendix 2) must have signed 
and dated an IRB/IEC approved written informed consent form in accordance with 
regulatory and institutional guidelines. This must be obtained before the performance of 
any protocol-related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study. 
2) Type of Participant and Target Disease Characteristics
a) Histologically confirmed recurrent or metastatic CRC irrespective of prior treatment 
history with chemotherapy and/or targeted agents not amenable to surgery. Inclusion 
Criterion 2a is applicable only during Part 1 enrollment of the study.
b) Known tumor MSI-H or dMMR status per local standard of practice. See Appendix 8.
c) All participants must have measurable disease by CT or MRI per RECIST 1.1 criteria. See 
Appendix 7.
d) 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.
e) Adequate tumor tissue available. Tumor tissue specimens, either a FFPE tissue block 
(preferred) or unstained tumor tissue sections (minimum of 30 positively charged slides) 
from primary or metastatic site, must be submitted to the central laboratory. Central 
laboratory must provide IRT with confirmation of receipt of evaluable tumor tissue prior 
to randomization. Tumor tissue specimen must meet either of the criteria below:
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i)
Obtained within 3 months of enrollment with no intervening systemic anti-cancer 
treatment between time of acquisition and randomization AND this must be the same 
tissue sample as was used for local MMR/MSI testing. 
OR
ii) If above is not available, archival tissue can be accepted if the same tissue was used for 
MMR/MSI testing.
Biopsy should be excisional, incisional or core needle. Fine needle aspiration is unacceptable 
for submission. Biopsies of bone lesions that do not have a soft tissue component or decalcified 
bone samples are also unacceptable for submission.
f)
ECOG Performance Status ≤ 1 (see Appendix 6)
g) Histologically confirmed recurrent or metastatic CRC with no prior treatment history with 
chemotherapy and/or targeted agents for metastatic disease and not amenable to surgery. 
Participants treated with adjuvant chemotherapy are eligible if disease progression 
occurred later than 6 months (≥ 6 months) after completion of chemotherapy. Inclusion 
Criterion 2g is applicable during Part 2 enrollment of the study
3) Age and Reproductive Status
a) Males and Females, ages 18 years and above 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) receiving nivolumab without or with 
ipilimumab must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study treatment(s) plus at least 5 months after the last dose of 
study treatment (ie, the time required for nivolumab to undergo approximately five half-
lives). Women of childbearing potential (WOCBP) receiving investigator’s choice 
chemotherapy must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study treatment(s) plus at least 6 months after the last dose of 
study treatment.
e) Males who are sexually active with WOCBP and who are assigned to receive nivolumab 
without or with ipilimumab are exempt from contraceptive requirements. Males who are 
sexually active with WOCBP and who are assigned to receive chemotherapy must agree to 
follow instructions for method(s) of contraception (Appendix 4) for the duration of 
treatment with study treatment(s) plus at least 6 months after the last dose of study 
treatment. In addition, male participants assigned to chemotherapy arm must be willing to 
refrain from sperm donation during this time. 
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in Section 2.
Investigators shall counsel WOCBP (as defined in Appendix 4) participants, and male participants 
who are sexually active with WOCBP, on the importance of pregnancy prevention, and the 
implications of an unexpected pregnancy. Additionally, male participants assigned to 
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chemotherapy arm should be counseled about the potential of fetal toxicity occurring due to 
transmission of study intervention present in seminal fluid to a developing fetus, even if the 
participant has undergone a successful vasectomy or if the partner is already pregnant. WOCBP
participants and WOCBP who are sexual partners of male participants are required to use a highly 
effective method of contraception (Appendix 4) which have a failure rate of < 1% when used 
consistently and correctly.
6.2
Exclusion Criteria 
1) Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if these have been treated and there is no MRI evidence of progression for at 
least 8 weeks after treatment is complete and within 28 days prior to first dose of study 
drug administration. (CT scan is acceptable if there is a contraindication for MRI). There 
must also be no requirement for immunosuppressive doses of systemic corticosteroids 
(> 10 mg/day prednisone equivalents) for at least 14 days prior to study drug 
administration.
b) Ascites that cannot be controlled with medical therapy alone. Exclusion Criterion 1b is 
no longer applicable per Protocol revision 04.
2) Medical Conditions
a) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
b) History of interstitial lung disease or pneumonitis.
c) Known history of positive test for HIV or known AIDS. NOTE: Testing for HIV must be 
performed at sites where mandated locally (see Appendix 9).
d) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
e) Prior malignancy active within the previous 2 years except for locally curable cancers that 
have been apparently cured (for example squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast).
f)
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 results. 
g) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
o) Participants with known dihydropyrimidine dehydrogenase (DPD) deficiency. Systematic 
screening for DPD deficiency has to be performed at sites where mandated locally 
(see Appendix 9)
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Additional exclusion criteria (h-n) for participants who have not received prior systemic 
therapy or who have received one prior line of systemic therapy.
h) Prior major surgery, open biopsy or significant traumatic injury within 28 days prior to 
randomization. Any wound-related AE(s) must have resolved prior to randomization.
i)
Clinically significant cardiovascular disease, including but not limited to congenital long 
QT syndrome. Pre-existing hypertension should be adequately controlled.
j)
Clinically significant bleeding diathesis or coagulopathy.
k) Myocardial infarction, arterial thrombosis or cerebrovascular accident within 6 months 
prior to enrollment.
l)
Non-healing wound, ulcer, or bone fracture.
m) History of gastrointestinal perforation or abscess within 6 month prior to enrollment.
n) Persistence of toxicities related to first-line chemotherapy grade > 1 (CTCAE v5.0) (except 
alopecia, fatigue or peripheral sensory neuropathy which can be Grade 2)
3) 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) Participants who received cancer-related Investigational Products (IPs) within 28 days or 
5 half-lives, whichever is longer, prior to randomization.
c) Prior systemic anti-cancer treatment must have been completed at least 14 days prior to
randomization.
d) Prior focal palliative radiotherapy must have been completed at least 14 days prior to 
randomization.
e) Participants who have received a live/attenuated vaccine within 30 days of randomization 
(e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella 
[MMR]). If a study participant has received an investigational COVID-19 vaccine or other 
investigational product designed to treat or prevent COVID-19 prior to screening, 
enrollment must be delayed until the biologic impact of the vaccine or investigational 
product is stabilized. 
f)
Treatment with botanical preparations (e.g. herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study within 2 weeks prior to randomization. 
Refer to Section 7.7.1 for prohibited therapies.
g) Participants who received treatment in this clinical study (CA2098HW).
Additional exclusion criteria for participants who have not received prior systemic therapy or 
who have received one prior line of systemic therapy.
h) Current treatment with a non-topical medications known to be a strong inducers or 
inhibitors of CYP3A4, or strong inhibitors of UGT1A1. However, patients who either 
discontinue this treatment or switch to another medication at least 7 days prior to starting 
study treatment are eligible.
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4) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100 × 103/μL
d) Hemoglobin < 9.0 g/dL (transfusion to achieve the level of hemoglobin ≥9 g/dL is not 
permitted within 7 days of this laboratory assessment)
e) PT/INR and PTT > 1.5 × ULN unless participants are receiving anticoagulant therapy and 
their INR is stable and within the recommended range for the desired level of 
anticoagulation.
f)
Serum creatinine > 1.5 × ULN, unless creatinine clearance (CLcr) ≥40 mL/minute 
(measured or calculated using the Cockcroft-Gault formula)
g) AST or ALT > 3.0 × ULN, unless participant has documented liver metastases in which 
case AST/ALT > 5.0 × ULN are exclusionary 
h) Total bilirubin > 1.5 × ULN (except participants with Gilbert syndrome who must have a 
total bilirubin level of < 3.0 × ULN)
i)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, HBsAg, Australia antigen positive, or hepatitis C antibody (anti-HCV) positive 
(except if HCV RNA negative)
j)
Positive pregnancy test at enrollment or prior to administration of study medication
Additional exclusion criteria for participants who have not received prior systemic therapy or 
who have received one line prior systemic therapy.
k) For participants with proteinuria ≥2+ by urine dipstick or urinalysis at baseline, 24-hr urine 
must be collected. Proteinuria > 1g/24hrs is exclusionary. It is acceptable to estimate urine 
protein to creatinine ratio (UPCR) instead of 24hr urine collection. UPCR > 1000 mg/g is 
exclusionary.
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody
6) 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 Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
6.3
Optional Crossover for Participants treated in the Arm C
Participants in arm C who have BICR-confirmed PD on or following Investigator’s Choice 
chemotherapy have the option to receive nivolumab plus ipilimumab combination therapy (see 
Figure 5.1-2). Crossover is optional and is at the discretion of investigator. To be eligible to 
crossover to nivolumab plus ipilimumab combination therapy the following criteria should be 
met:
1) BICR-confirmed PD per RECIST 1.1
2) ECOG Performance Status 0 or 1
3) Available tumor tissue sample obtained upon progression on arm C, if medically feasible
4) No exposure to any systemic anticancer therapies after discontinuation of chemotherapy in arm 
C
5) Completed Follow-up Visit 1 after discontinuation of treatment on arm C (occurs 
approximately 30 days after the last dose of study treatment)
In addition the investigator must ensure that the participant meets all other eligibility criteria based 
on inclusion and exclusion criteria of the protocol as described below: 
Inclusion criteria (Crossover Cohort ONLY): 
1) Signed Written Informed Consent
a) Participants or their legally authorized representative must have signed and dated an 
IRB/IEC approved written informed consent form in accordance with regulatory and 
institutional guidelines. This must be obtained before the performance of any protocol-
related procedures that are not part of normal patient care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory testing, and other requirements of the study. 
2) Age and Reproductive Status
a) Males and Females, ages 18 years and above 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) receiving nivolumab without or with 
ipilimumab must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study treatment(s) plus at least 5 months after the last dose of 
study treatment (i.e., the time required for nivolumab to undergo approximately five half-
lives).
e) Males who are sexually active with WOCBP and who are assigned to receive nivolumab 
without or with ipilimumab are exempt from contraceptive requirements.
f)
Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in Section 2.
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Investigators shall counsel WOCBP (as defined in Appendix 4) participants, and male participants 
who are sexually active with WOCBP, on the importance of pregnancy prevention, and the 
implications of an unexpected pregnancy. WOCBP participants and WOCBP who are sexual 
partners of male participants are required to use a highly effective method of contraception 
(Appendix 4) which have a failure rate of < 1% when used consistently and correctly.
Exclusion criteria (Crossover Cohort ONLY): 
1) Target Disease Exceptions
a) Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if these have been treated and there is no MRI evidence of progression for at 
least 8 weeks after treatment is complete and within 28 days prior to first dose of study 
drug administration. (CT scan is acceptable if there is a contraindication for MRI). There 
must also be no requirement for immunosuppressive doses of systemic corticosteroids 
(> 10 mg/day prednisone equivalents) for at least 14 days prior to study drug 
administration.
b) Ascites that cannot be controlled with medical therapy alone. Exclusion Criterion 1b is 
no longer applicable per Protocol revision 04.
2) Medical Conditions
a) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll.
b) History of interstitial lung disease or pneumonitis.
c) Known history of positive test for HIV or known AIDS. NOTE: Testing for HIV must be 
performed at sites where mandated locally (see Appendix 9).
d) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
e) Prior malignancy active within the previous 2 years except for locally curable cancers that 
have been apparently cured (squamous cell skin cancer, superficial bladder cancer, or 
carcinoma in situ of the prostate, cervix, or breast).
f)
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 results. 
g) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
3) Prior/Concomitant Therapy
a) Prior focal palliative radiotherapy must have been completed at least 14 days prior to vial 
assignment.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
b) Participants who have received a live/attenuated vaccine within 30 days of vial assignment 
(e.g., varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella 
[MMR]).
c) Treatment with botanical preparations (e.g. herbal supplements or traditional Chinese 
medicines) intended to treat the disease under study within 2 weeks prior to vial 
assignment. Refer to Section 7.7.1 for prohibited therapies.
4) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100 × 103/μL
d) Hemoglobin < 9.0 g/dL (transfusion to achieve the level of hemoglobin ≥9 g/dL is not 
permitted within 7 days of this laboratory assessment)
e) PT/INR and PTT > 1.5 × ULN unless participants are receiving anticoagulant therapy and 
their INR is stable and within the recommended range for the desired level of 
anticoagulation.
f)
Serum creatinine > 1.5 × ULN, unless creatinine clearance (CLcr) ≥40 mL/minute 
(measured or calculated using the Cockcroft-Gault formula)
g) AST or ALT > 3.0 × ULN, unless participant has documented liver metastases in which 
case AST/ALT > 5.0 × ULN are exclusionary 
h) Total bilirubin > 1.5 × ULN (except participants with Gilbert syndrome who must have a 
total bilirubin level of < 3.0 × ULN)
i)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, HBsAg, Australia antigen positive, or Hepatitis C antibody (anti-HCV) positive 
(except if HCV RNA negative)
j)
Positive pregnancy test at enrollment or prior to administration of study medication
5) Allergies and Adverse Drug Reaction
a) History of allergy or hypersensitivity to study drug components
b) History of severe hypersensitivity reaction to any monoclonal antibody
6) 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 Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness.
Upon confirmation of eligibility to enter the Crossover Cohort participants will receive nivolumab 
plus ipilimumab combination therapy for a maximum of 2 years (including treatment beyond 
progression) or less if treatment to be discontinued due to disease progression, toxicity or other 
reasons. Participants that complete treatment in the Crossover Cohort will enter the Follow Up 
phase (second treatment Follow Up) and will follow the assessment schedules outlined in the Table 
2-5 of the protocol.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Arm C participants who enter the Follow Up phase (first treatment Follow Up) without PD should 
follow the assessment schedules per protocol. If they experience PD during Follow Up phase that 
is confirmed by BICR they should be assessed against eligibility criteria for Crossover Cohort. 
Participants who are not eligible to enter the Crossover Cohort will continue to follow the 
assessment schedules for Follow Up phase of the study per Table 2-5.
6.4
Lifestyle Restrictions
Not applicable. No restrictions are required. Please also refer to local SOC products labels for 
possible restrictions.
6.5
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently entered in the study/included in the analysis population. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, 
to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements, as 
applicable, and to respond to queries from regulatory authorities. Minimal information includes 
date of consent, demography, screen failure details, eligibility criteria, and any serious AEs.
6.5.1
Retesting During Screening or Lead-In Period
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 and assigned a new participant number via IRT.
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Section 2, 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.
7
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization.
Study treatment includes the following IP/IMPs:
•
Nivolumab 
•
Ipilimumab
•
Oxaliplatin
•
Leucovorin
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
•
Fluorouracil
•
Irinotecan
•
Bevacizumab
•
Cetuximab
An investigational product, also known as investigational medicinal product in some regions, is 
defined 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.
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. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7-1:
Study treatments for CA2098HW 
Product Description / Class and 
Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab
(BMS-936558-01)
Solution for Injection
100 mg (10 mg/mL) and 
40 mg (10 mg/mL)
IP
Open label
Vial or Various 
packaging 
configurations
Refer to the label on container 
and/or pharmacy manual
Ipilimumab Solution for Injection
200 mg (5 mg/mL) 
and 50 mg (5 mg/mL)
IP
Open-label
Vial or Various 
packaging 
configurations
Refer to the label on container 
and/or pharmacy manual
Oxaliplatina,b
various strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the label on container 
and/or Pharmacy manual.
Leucovorin (folinic acid)a,b
various strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the label on container 
and/or Pharmacy manual.
Fluorouracila,b
various strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the label on container 
and/or Pharmacy manual.
Irinotecana,b
various strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the label on container 
and/or Pharmacy manual.
Bevacizumaba,b
various strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the label on container 
and/or Pharmacy manual.
Cetuximaba,b
various strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the label on container 
and/or Pharmacy manual.
a These products may be obtained by the investigational sites as local commercial products in certain countries if allowed by local regulations. In these cases, 
products may be in a different pack size/potency/pharmaceutical form than listed in the table. These products should be prepared/stored/administered in 
accordance with the package inserts or summaries of product characteristics. 
b Potency, packaging, and storage conditions may vary for China. Storage conditions will be indicated on the label. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
7.1
Treatments Administered
7.1.1
Study Treatment Duration
The study treatment will be given until one of the following conditions are met, whichever occurs 
first:
•
Disease progression, unless participant will receive treatment beyond progression. Treatment 
beyond progression is applicable for participants randomized to arm A, B, or enrolled to 
Crossover Cohort. 
•
Unacceptable toxicity 
•
Withdrawal of consent
•
Maximum treatment duration as described below (not applicable for arm C participants)
•
The end of study
In this study maximum treatment duration for arm A or arm B will be 2 years from the first dose 
of study treatment 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 includes treatment beyond progression. 
Participants enrolled to Crossover Cohort may have maximum treatment duration, including 
treatment beyond progression, of 2 years from the first dose in Crossover Cohort. 
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
7.1.2
Treatment Schedules
The selection and timing of dose for each participant is summarized in Table 7.1.2-1 through Table 
7.1.2-4. The first dose is to be administered within 3 days following randomization/vial assignment. 
Table 7.1.2-1:
Selection and Timing of Dose for Nivolumab 
Monotherapy (Arm A). Cycles 1-2, Cycle 3 and Beyond
Cycle 1
(cycle = 6 weeks)
Cycle 2
(cycle = 6 weeks)
Cycle 3 and Beyond 
(cycle = 4 weeks)
Day 
1
Day 
15
Day 
29
Day 1
Day 
15
Day 
29
Day 1 of every 4 
weeks
Nivolumab, 240 mg 
flat dose
X
X
X
X
X
X
Nivolumab, 480 mg 
flat dose
X
Table 7.1.2-2:
Selection and Timing of Dose for Nivolumab plus 
Ipilimumab Combination Therapy (Arm B). Cycles 1-
2, Cycle 3 and Beyond
Cycle 1
(cycle = 6 weeks)
Cycle 2
(cycle = 6 weeks)
Cycle 3 and Beyond 
(cycle = 4 weeks)
Day 1
Day 22
Day 1
Day 22
Day 1 of every 4 
weeks
Nivolumab, 240 mg 
flat dose
X
X
X
X
Ipilimumab, 
1 mg/kg
X
X
X
X
Nivolumab, 480 mg 
flat dose
X
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.1.2-3:
Selection and Timing of Dose for Chemotherapy (Arm 
C). Cycles 1-2, Cycle 3 and Beyond
Cycle 1
(cycle = 6 weeks)
Cycle 2
(cycle = 6 weeks)
Cycle 3 and Beyond 
(cycle = 4 weeks)
Day 
1
Day 
15
Day 
29
Day   
1
Day 
15
Day 
29
Day 1
Day 15
Bevacizumab, 
5 mg/kg
X
X
X
X
X
X
X
X
Cetuximab, 
500 mg/m2
X
X
X
X
X
X
X
X
Oxaliplatin, 
85 mg/m2
X
X
X
X
X
X
X
X
Irinotecan, 
180 mg/m2
X
X
X
X
X
X
X
X
Leucovorin, 
400 mg/m2
X
X
X
X
X
X
X
X
Fluorouracil bolus, 
400 mg/m2
X
X
X
X
X
X
X
X
Fluorouracil 
infusion, 
2400 mg/m2 over 
46 hours
X
X
X
X
X
X
X
X
Table 7.1.2-4:
Selection and Timing of Dose for Crossover Cohort. 
Cycles 1-2, Cycle 3 and Beyond
Cycle 1
(cycle = 6 weeks)
Cycle 2
(cycle = 6 weeks)
Cycle 3 and Beyond 
(cycle = 4 weeks)
Day  
1
Day 
15
Day 
29
Day   
1
Day 
15
Day 
29
Day 1
Day 15
Nivolumab, 
240 mg flat dose
X
X
X
X
X
X
Ipilimumab, 
1 mg/kg
X
X
X
C3D1 
and D1 
of every 
3 cycles
X
C4D15 
and D15 
of every 
3 cycles
Nivolumab, 
480 mg flat dose
X
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
7.1.2.1
Arm A - Nivolumab Monotherapy
Participants should receive nivolumab at a dose of 240 mg as a 30 minute infusion on Day 1, and 
every 2 weeks (± 3 days) thereafter during Cycles 1 and 2 for a total of 6 doses (Q2W × 6 doses). 
Starting from Cycle 3 Day 1 participants should receive nivolumab as a 30 minutes infusion at a 
dose of 480 mg every 4 weeks (Q4W). The infusion start and stop time will be recorded in the 
CRF. Treatment with nivolumab will continue as defined in Section 7.1.1. 
7.1.2.2
Arm B - Nivolumab Plus Ipilimumab (Q3W x 4)
Participants randomized to the nivolumab plus ipilimumab arm should receive nivolumab at a dose 
of 240 mg as a 30 minute IV infusion followed by ipilimumab at a dose of 1 mg/kg administered 
IV over 30 minutes on Day 1 of Cycle 1 and every 3 weeks (± 3 days) thereafter during Cycles 1 
and 2 for a total of 4 doses (Q3W × 4 doses). Starting from Cycle 3 Day 1 participants should 
receive nivolumab as a 30 minutes infusion at a dose of 480 mg every 4 weeks (Q4W). The 
infusion start and stop time for nivolumab and ipilimumab will be recorded in the CRF, 
respectively. Treatment with nivolumab will continue as described in Section 7.1.1. Ipilimumab 
can be discontinued earlier due to unacceptable toxicity as described in Section 8.1.1. Ipilimumab 
is not permitted to continue on study after nivolumab is discontinued.
When both nivolumab and ipilimumab are to be administered on the same day, nivolumab is to be 
administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear 
the line of nivolumab before starting the ipilimumab infusion. The second infusion will always be 
the ipilimumab and will start after the infusion line has been flushed, filters changed and patient 
has been observed for approximately 30 minutes to ensure no infusion reaction has occurred. 
Participants should be carefully monitored for infusion reactions during nivolumab or ipilimumab 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.6.
7.1.2.3
Arm C - Investigator’s Choice Chemotherapy
Participants randomized to the chemotherapy arm may receive one of 6 SOC regimens described 
below. 
mFOLFOX6
Participants who will receive mFOLFOX6 will receive oxaliplatin 85 mg/m2, leucovorin 400 
mg/m2, fluorouracil 400 mg/m2 bolus followed by fluorouracil 2400 mg/m2 in continuous infusion 
administered over 46 hours IV on Day 1, Day 15 and Day 29 during Cycles 1 and 2. Starting from 
Cycle 3 the drugs will be administered on Day 1 and Day 15 of each cycle.
mFOLFOX6 + bevacizumab
Participants who will receive mFOLFOX6 + bevacizumab regimen, will have bevacizumab 
administered first, followed by mFOLFOX6.
It is recommended that the first administration (C1D1) of bevacizumab 5 mg/kg to be delivered 
over a 90-minute infusion. If well tolerated the second administration (C1D15) will delivered over 
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
60 min; if the 60-minute infusion is well tolerated, all subsequent infusions will be delivered over 
30 min. Sites may follow local institutional standards for bevacizumab administration.
Bevacizumab 5 mg/kg administration will then be followed by oxaliplatin 85 mg/m2, leucovorin 
400 mg/m2, fluorouracil bolus 400 mg/m2 and fluorouracil 2400 mg/m2 in continuous infusion 
administered over 46 hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter 
on Day 1 and Day 15 for all subsequent cycles (see Table 7.1.2-3). The infusion start and stop time 
will be recorded in the CRF. 
mFOLFOX6 + cetuximab
Participants who will receive FOLFOX + cetuximab regimen, will have cetuximab administered 
first, followed by FOLFOX.
It is recommended that the first administration (C1D1) of cetuximab 500 mg/m2 to be delivered 
over 2 hours. If well tolerated all subsequent administrations can be delivered over 1 hour. Sites 
may follow local institutional standards for cetuximab administration.
Cetuximab 500 mg/m2 administration will then be followed by oxaliplatin 85 mg/m2, leucovorin 
400 mg/m2, fluorouracil bolus 400 mg/m2 and fluorouracil 2400 mg/m2 in continuous infusion 
administered over 46 hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter 
on Day 1 and Day 15 for all subsequent cycles (see Table 7.1.2-3). The infusion start and stop time 
will be recorded in the CRF. 
FOLFIRI
Participants who will be assigned to receive FOLFIRI will receive irinotecan 180 mg/m2, 
leucovorin 400 mg/m2, fluorouracil bolus 400 mg/m2 and fluorouracil 2400 mg/m2 in continuous 
infusion administered over 46 hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles. The 
infusion start and stop time will be recorded in the CRF. Starting from Cycle 3 the drugs will be 
administered on Day 1 and Day 15 of each cycle.
FOLFIRI + bevacizumab
Participants who will receive FOLFIRI + bevacizumab regimen, will have bevacizumab 
administered first, followed by FOLFIRI.
It is recommended that the first administration (C1D1) of bevacizumab 5 mg/kg to be delivered 
over a 90-minute infusion. If well tolerated the second administration (C1D15) will delivered over 
60 min; if the 60-minute infusion is well tolerated, all subsequent infusions will be delivered over 
30 min. Sites may follow local institutional standards for bevacizumab administration.
Bevacizumab 5 mg/kg administration will then be followed by irinotecan 180 mg/m2, leucovorin 
400 mg/m2, fluorouracil bolus 400 mg/m2 and fluorouracil 2400 mg/m2 in continuous infusion 
administered over 46 hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter 
on Day 1 and Day 15 for all subsequent cycles (see Table 7.1.2-3). The infusion start and stop time 
will be recorded in the CRF. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
FOLFIRI + cetuximab
Participants who will receive FOLFIRI + cetuximab regimen, will have cetuximab administered 
first, followed by FOLFIRI.
It’s recommended that the first administration (C1D1) of cetuximab 500 mg/m2 to be delivered 
over 2 hours. If well tolerated all subsequent administrations can be delivered over 1 hour. Sites
may follow local institutional standards for cetuximab administration.
Cetuximab 500 mg/m2 administration will then be followed by irinotecan 180 mg/m2, leucovorin 
400 mg/m2, fluorouracil bolus 400 mg/m2 and fluorouracil 2400 mg/m2 in continuous infusion 
administered over 46 hours IV on Day 1, Day 15 and Day 29 for the first 2 cycles and thereafter 
on Day 1 and Day 15 for all subsequent cycles (see Table 7.1.2-3). The infusion start and stop time 
will be recorded in the CRF.
7.1.2.4
Crossover Cohort - Nivolumab Plus Ipilimumab (Q6W continuously)
Participants who will meet all the criteria to enroll to the optional crossover cohort will receive 
nivolumab plus ipilimumab therapy. Nivolumab at a dose of 240 mg will be administered as a 30 
minute IV infusion on Day 1 of Cycle 1 and every 2 weeks (± 3 days) thereafter during Cycles 1 
and 2 for a total of 6 doses (Q2W x 6 doses). Starting from Cycle 3 Day 1 participants should 
receive nivolumab as a 30 minutes infusion at a dose of 480 mg every 4 weeks (Q4W). The 
infusion start and stop time for nivolumab and ipilimumab will be recorded in the CRF, 
respectively. Ipilimumab at a dose of 1 mg/kg will administered IV over 30 minutes on Day 1 of 
Cycle 1 and every 6 weeks (± 3 days) thereafter (see Table 7.1.2-4 ).
Treatment with nivolumab and ipilimumab in crossover cohort will continue as described in 
Section 7.1.1. Ipilimumab can be discontinued earlier due to unacceptable toxicity as described in 
Section 8.1.1. Ipilimumab is not permitted to continue on study after nivolumab is discontinued.
When both nivolumab and ipilimumab are to be administered on the same day, nivolumab is to be 
administered first. Nivolumab infusion must be promptly followed by a flush of diluent to clear 
the line of nivolumab before starting the ipilimumab infusion. The second infusion will always be 
the ipilimumab and will start after the infusion line has been flushed, filters changed and patient 
has been observed for approximately 30 minutes to ensure no infusion reaction has occurred. 
Participants should be carefully monitored for infusion reactions during nivolumab or ipilimumab 
administration. If an acute infusion reaction is noted, participants should be managed according to 
Section 7.4.6.
7.1.3
Antiemetic Premedications
Antiemetic premedications should not be routinely administered prior to dosing of study drugs in 
arm A, arm B, or Crossover Cohort. See Section 7.4.6 for premedication recommendations 
following a nivolumab or ipilimumab-related infusion reaction. For participants randomized to 
arm C premedication may be administrated per local standard.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
7.2
Method of Treatment Assignment 
CA2098HW is a randomized, open-label study. After the participant’s initial eligibility is 
established and informed consent has been obtained, the participant must be enrolled into the study 
by using an IRT to obtain the participant number. Every participant that signs the informed consent 
form must be assigned a participant number using IRT. Specific instructions for using IRT will be 
provided to the investigational site in a separate document.
7.2.1
Initial Treatment Assignment
All participants will be centrally randomized using an IRT. Before the study is initiated, each site 
user will receive log in information and directions on how to access the IRT. The investigator or 
designee will register the participant for enrollment by following the enrollment procedures 
established by BMS. The following information is required for enrollment:
•
Date that informed consent was obtained 
•
Year of birth
•
Gender at birth
•
MSI/MMR Status 
Once enrolled in IRT, enrolled participants that have met all eligibility criteria will be ready for 
randomization and drug vial assignment through the IRT. All tissue submitted for participants will 
be assessed for quality with an H&E stain, and only those participants who have met tissue quality 
thresholds can be randomized and assigned study drug. The choice of chemotherapy regimen 
should be declared prior to randomization and this information be documented in the patients’ 
medical records.
The following information is required for randomization
•
Participant number
•
Year of birth
•
Confirmation that evaluable tumor tissue has been received at the central lab
•
Tumor sidedness (right, left)*
•
Number of prior treatments for metastatic disease (none, one, two or more)*
*Study specific definitions of the number of prior treatments for metastatic disease (line of therapy) and 
tumor sidedness are provided in the Appendices 10 and 12, respectively.
Randomization during Part 1 enrollment
Participants meeting all eligibility criteria will be randomized to the study. The randomization ratio 
across study arms will be defined according to the number of prior lines of systemic treatments for 
metastatic disease the participant has received. Participants who have not received (1L), or who 
have received one (2L) prior line of systemic therapy for metastatic disease will be randomized in 
a 2:2:1 ratio to nivolumab monotherapy, nivolumab plus ipilimumab combination therapy or 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
chemotherapy arms stratified by tumor sidedness and number of prior treatments for metastatic 
disease. Participants who have received two or more prior lines of therapy for metastatic disease 
will be randomized in a 1:1 ratio to receive nivolumab monotherapy or nivolumab plus ipilimumab 
combination therapy stratified by tumor sidedness and number of prior treatments. Study treatment 
will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
Randomization during Part 2 enrollment
1L participants meeting all eligibility criteria will be randomized in a 2:2:1 ratio to nivolumab 
monotherapy, nivolumab plus ipilimumab combination therapy or chemotherapy arms stratified 
by tumor sidedness. Study treatment will be dispensed at the study visits as listed in Schedule of 
Activities (Section 2). 
Every effort should be made to avoid randomizing participants who will not be treated. For 
participants who are randomized but never treated a minimal amount of data must be collected: all 
baseline data, SAEs. If available information on the off treatment reason and participant status 
should be collected.
7.2.2
Crossover Cohort Treatment Assignment 
Participants in arm C who have BICR-documented PD on or following treatment with 
investigator’s choice chemotherapy have the option to receive nivolumab plus ipilimumab 
combination therapy (see Figure 5.1-2). Once it has been confirmed that a participant meets all 
criteria for entry into the Crossover Cohort (Section 6.3), cohort registration and drug assignment 
will be made using the IRT system. For participants enrolled in the Crossover Cohort, the IVRS 
will assign the nivolumab plus ipilimumab treatment. Study treatment will be dispensed at the 
study visits as listed in Schedule of Activities (Section 2). The exact procedures for using the IRT 
and information required for assignment to the Crossover Cohort will be detailed in the IRT 
manual. 
7.3
Blinding
This is an open-label study; however, the specific treatment to be taken by a participant will be 
assigned using an Interactive Response Technology (IRT). Assessment of primary end point (PFS 
per BICR) will be done by BICR who will remained blinded to patient treatment assignment. 
Designated staff of Bristol-Myers Squibb Research & Development may obtain the randomization 
codes prior to database lock to facilitate the bioanalytical analysis of pharmacokinetic samples and 
immunogenicity. A bioanalytical scientist in the Bioanalytical Sciences department of Bristol-
Myers Squibb Research & Development (or a designee in the external central bioanalytical 
laboratory) may obtain the randomized treatment assignments in order to minimize unnecessary 
bioanalytical analysis of samples. BMS will not generate any aggregated reports until pre-specified 
interim or final analyses. An independent external statistical group will be utilized to conduct 
unblinded monitoring of pooled events of the two corresponding arms of each comparison in order 
to track the number of events by each comparison.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
7.4
Dosage Modification
Participants will be monitored continuously for AEs while on study therapy. Participants will be 
instructed to notify their physician for any and all AEs. If AEs are considered to be related to study 
treatment, every attempt must be made to attribute individual study treatment to adverse event, if 
possible, or to the combination regimen. 
Guidance for Dose Modification for Nivolumab and/or Ipilimumab
Dose modifications for arm A, arm B, and the Crossover Cohort should comply with the protocol 
Sections 7.4.1.1 (Delay), 7.4.2.1 (Reduction), and 7.4.3.1 (Criteria to Resume Treatment). For the 
reporting of all AEs, including severity, on case report forms, please follow the definitions in 
CTCAE version 5 (see Section 9.2 for more details). AE criteria for delaying, resuming, and 
discontinuing of study treatment is provided in Table 7.4-1.
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
Gastrointestinal
Colitis or Diarrhea
Grade 2 
Delay dose
Dosing may resume when AE 
resolves to baseline 
Grade 3 
Nivolumab 
monotherapy: Delay 
dose
Dosing may resume when AE 
resolves to baseline
When administered 
with ipilimumab: 
Permanently 
discontinue Ipilimumab
Nivolumab monotherapy may 
be resumed when AE resolves 
to baseline. If Grade 3 diarrhea 
or colitis recurs while on 
nivolumab monotherapy, 
permanently discontinue
Grade 4 
Permanently 
discontinue
Renal
Serum Creatinine Increased
Grade 2 or 3 
Delay dose
Dosing may resume when AE 
resolves to Grade ≤ 1 or 
baseline value
Grade 4 
Permanently 
discontinue
Pulmonary
Pneumonitis
Grade 2 
Delay dose
Dosing may resume after 
pneumonitis has resolved to 
≤ Grade 1.
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930125433
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
Grade 3 or 4 
Permanently 
discontinue
Hepatic
AST, ALT, or T.bili 
increased
AST or ALT > 3x 
and ≤5x ULN or 
T.bili  >1.5x and 
≤3x ULN, 
regardless of 
baseline value
Delay dose
Dosing may resume when 
laboratory values return to 
baseline.
AST or ALT > 5 x 
ULN or T.bili > 3 x 
ULN, regardless of 
baseline value
Delay dose or 
permanently 
discontinue 
In most cases of AST or ALT 
> 5 x ULN, study treatment 
will be permanently 
discontinued. If the 
investigator determines a 
possible favorable benefit/risk 
ratio that warrants 
continuation of study 
treatment, a discussion 
between the investigator and 
the Medical Monitor/designee 
must occur prior to resuming 
therapy.
Concurrent AST or 
ALT > 3 x ULN and 
T.bili > 2 x ULN, 
regardless of 
baseline value
Permanently 
discontinue 
In most cases of concurrent 
AST or ALT > 3 x ULN and 
T.bili > 2 x ULN, study 
treatment will be permanently 
discontinued. However, in 
patients with baseline 
elevation of liver enzymes 
and/or T.bili levels if the 
investigator determines a 
possible favorable benefit/risk 
ratio that warrants 
continuation of study 
treatment, a discussion 
between the investigator and 
the Medical Monitor/designee 
must occur prior to resuming 
therapy.
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13.0
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930125433
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
Endocrinopathy
Adrenal Insufficiency
Grade 2 adrenal 
insufficiency
Delay dose
Dosing may resume after 
adequately controlled with 
hormone replacement.
Grade 3 or 4 adrenal 
insufficiency or 
adrenal crisis
Delay dose or 
permanently 
discontinue
Mandatory discussion with 
and approval from the Medical 
Monitor/ designee needed 
prior to resuming therapy. If 
adrenal insufficiency resolves 
or is adequately controlled 
with physiologic hormone 
replacement, participant may 
not require discontinuation of 
study drug.
Hyperglycemia
Hyperglycemia 
requiring initiation 
or change in daily 
management (Grade 
2 or 3)
Delay dose
Dosing may resume if 
hyperglycemia resolves to 
Grade ≤1 or baseline value, or 
is adequately controlled with 
glucose-controlling agents.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with 
and approval from the Medical 
Monitor/ designee needed 
prior to resuming therapy. If 
hyperglycemia resolves, or is 
adequately controlled with 
glucose-controlling agents, 
participant may not require 
discontinuation of study drug.
Hypophysitis/
Hypopituitarism 
Symptomatic Grade 
1-3 that is also 
associated with 
corresponding 
abnormal lab and/or 
pituitary scan
Delay dose 
Dosing may resume if 
endocrinopathy resolves to be 
asymptomatic, or is adequately 
controlled with only 
physiologic hormone 
replacement.
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with 
and approval from the Medical 
Monitor/ designee needed 
prior to resuming therapy. If 
endocrinopathy resolves or is 
adequately controlled with 
physiologic hormone 
replacement, participant may 
not require discontinuation of 
study drug.
Hyperthyroidism or  
Hypothyroidism
Grade 2 or 3
Delay dose
Dosing may resume if 
endocrinopathy resolves to be 
asymptomatic, or is adequately 
controlled with only 
physiologic hormone 
replacement or other medical 
management.
Grade 4
Delay dose or 
permanently 
discontinue
Mandatory discussion with 
and approval from the Medical 
Monitor/ designee needed 
prior to resuming therapy. If 
endocrinopathy resolves or is 
adequately controlled with 
physiologic hormone 
replacement or other medical 
management, participant may 
not require discontinuation of 
study drug.
Skin
Rash
Grade 2 rash 
covering >30% 
body surface area or 
Grade 3 rash 
Delay dose 
Dosing may resume when rash 
reduces to ≤10% body surface 
area.
Suspected Stevens-
Johnson syndrome 
(SJS), toxic 
epidermal necrolysis 
(TEN), or drug 
reaction with 
eosinophilia and 
systemic symptoms 
(DRESS)
Delay dose
Dosing may resume if SJS, 
TEN, or DRESS is ruled out 
and rash reduces to is ≤10% 
body surface area.
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
Grade 4 rash or 
confirmed SJS,TEN, 
or DRESS
Permanently 
discontinue
Neurological
Guillain-Barre Syndrome 
(GBS)
Any Grade
Permanently 
discontinue
Myasthenia Gravis (MG)
Any Grade
Permanently 
discontinue
Encephalitis
Any Grade 
encephalitis
Delay dose 
After workup for differential 
diagnosis, (ie, infection, 
tumor-related), if encephalitis 
is not drug related, then dosing 
may resume when AE 
resolves. 
Any Grade drug-
related encephalitis 
Permanently 
discontinue
Myelitis
Any Grade myelitis
Delay dose
After workup for differential 
diagnosis, (ie, infection, 
tumor-related), if myelitis is 
not drug related, then dosing 
may resume when AE 
resolves. 
Any Grade drug-
related myelitis
Permanently 
discontinue
Neurological (other than 
GBS, MG, encephalitis, or 
myelitis)
Grade 2
Delay dose
Dosing may resume when AE 
resolves to baseline. 
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Myocarditis
Symptoms induced 
from mild to 
moderate activity or 
exertion
Delay dose
Dosing may resume after
myocarditis has resolved.
Severe or life-
threatening, with 
symptoms at rest or 
with minimal 
activity or exertion, 
and/or where 
Permanently 
discontinue
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13.0
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
intervention 
indicated.
Other Clinical AE
Pancreatitis: 
Amylase or Lipase increased
Grade 3 with
symptoms
Delay dose
Note: Grade 3 increased 
amylase or lipase without 
signs or symptoms of 
pancreatitis does not require 
dose delay. 
Dosing may resume when 
patient becomes 
asymptomatic.
Grade 4
Permanently 
discontinue
Uveitis 
Grade 2 uveitis
Delay dose
Dosing may resume if uveitis 
responds to topical therapy 
(eye drops) and after uveitis 
resolves to Grade ≤ 1 or 
baseline. If patient requires 
oral steroids for uveitis, then 
permanently discontinue study 
drug. 
Grade 3 or 4 uveitis
Permanently 
discontinue
Other Drug-Related AE (not 
listed above)
Grade 2 non-skin 
AE, except fatigue
Delay dose
Dosing may resume when AE 
resolves to Grade ≤ 1 or 
baseline value.
Grade 3 AE - First 
occurrence lasting ≤ 
7 days
Delay dose
Dosing may resume when AE 
resolves to Grade ≤ 1 or 
baseline value.
Grade 3 AE- First 
occurrence lasting > 
7 days
Permanently 
discontinue
Recurrence of Grade 
3 AE of any 
duration
Permanently 
discontinue
Grade 4 or Life-
threatening adverse 
reaction
Permanently 
discontinue
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13.0
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4-1:
Adverse Event Criteria for Delay, Resume, and Discontinue of 
Nivolumab Monotherapy (Arm A), Nivolumab Plus Ipilimumab 
Combination Therapy (Arm B) or Crossover Cohort
Drug-Related AE per 
CTCAE v5
Severity
Action Takena
Clarifications, Exceptions, 
and Resume Criteria
Other Lab abnormalities
Other Drug-Related lab 
abnormality (not listed 
above)
Grade 3
Delay dose
Exceptions:
No delay required for:  Grade 
3 lymphopenia 
Permanent Discontinuation 
for: Grade 3 thrombocytopenia 
> 7 days or associated with 
bleeding 
Grade 4
Permanently 
discontinue
Exceptions: The following 
events do not require 
discontinuation of study drug: 
Grade 4 neutropenia ≤ 7 days.
Grade 4 lymphopenia or 
leukopenia.
Grade 4 isolated electrolyte 
imbalances/abnormalities that 
are not associated with clinical 
sequelae and are responding to 
supplementation/appropriate 
management within 72 hours 
of their onset
Infusion Reactions (manifested by fever, chills, rigors, headache, rash, pruritus, arthralgia, hypotension, 
hypertension, bronchospasm, or other allergic-like reactions.)
Hypersensitivity reaction or 
infusion reaction
Grade 3 or 4
Permanently 
discontinue
Refer to Section 7.4.6 on 
Treatment of Related Infusion 
Reactions 
a All actions taken, clarifications, exceptions, and resume criteria apply to nivolumab monotherapy (arm A), 
nivolumab plus ipilimumab combination therapy (arm B) or crossover cohort.
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = 
Common Terminology Criteria for Adverse Events; DRESS = drug reaction with eosinophilia and systemic 
symptoms; GBS = Guillain-Barre syndrome; MG = Myasthenia gravis; SJS = Stevens-Johnson syndrome; T.bili = 
total bilirubin; TEN = toxic epidermal necrolysis; ULN = upper limit of normal.
Guidance for Dose Modification for Chemotherapy 
Dose modifications for arm C (chemotherapy) provided in the protocol Sections 7.4.1.2, 7.4.2.2, 
and 7.4.5 serve as a recommendation. Chemotherapy dose modifications should be applied by the 
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
investigator’s judgment and according to local standards. The general guidance for dose 
modification for chemotherapy are summarized below.
•
Treatment for the first cycle should only commence if all eligibility criteria are met and the 
participant has been randomized. For the first dosing of study treatment all components of the 
regimen should be administered. For all subsequent dosing, dose delay/modification is 
permitted per local standards.
•
Doses of any study drug omitted for toxicity are not replaced or restored. Supportive care (for 
example, colony-stimulating factors [CSFs], blood and blood products, etc. can be 
administered in accordance with the latest American Society of Clinical Oncology (ASCO) or 
other equivalent guidelines).
•
Dose modification, for non-serious and non-life-threatening toxicities like alopecia, altered 
taste or nail changes may not be required and the final decision is left to the discretion of the 
treating investigator.
•
In situations where concomitant toxicities of varying severity exist, dose modification will be 
tailored for the toxicity with highest CTCAE grading.
•
If there is a delay or modification in administration of study drug(s) due to toxicity, treatment 
with the other study agent(s) should continue as scheduled.
If uracil testing is locally required, and blood uracil level is between ≥16 ng/mL and < 150 ng/mL 
(evoking partial deficit in DPD), the dose of 5-FU, has to be adapted taking into account the blood 
uracil level and the other risk factors (dose scheme, participant’s age, participant’s general 
condition). A therapeutic adjustment should be performed before next 5-FU dosing depending on 
treatment tolerability and pharmacologic follow-up if available. It is essential to be particularly 
vigilant with regard to participants whose blood uracil level is above the upper limit of the normal, 
especially when this level is high, although less than 150 ng/mL.
7.4.1
Dose Delay Criteria
7.4.1.1
Dose Delay Criteria for Nivolumab and/or Ipilimumab
•
Table 7.4-1 provides criteria for nivolumab or nivolumab plus ipilimumab dose delay due to 
immune mediated AE.
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 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 re-
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
treatment criteria are met. 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. During Q4W dosing participants may be dosed no less than 25 days from the 
previous treatment. 
If dose delay is necessary for participants during combination treatment, both nivolumab and 
ipilimumab must be delayed until treatment can resume. However, if a nivolumab-related infusion 
reaction prevents subsequent infusion of ipilimumab on the same day, the dose of ipilimumab 
should be replaced as soon as possible. In such instances, at least 19 days must elapse between the 
replacement dose of ipilimumab and the administration of the next dose of nivolumab combined 
with ipilimumab.
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.
7.4.1.2
Dose Delay Criteria for Investigator’s Choice of Chemotherapy
In arm C, dosing of chemotherapy drugs in the regimen selected as the investigator’s choice 
chemotherapy 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. 
For details on dose delay and other dose modifications, and discontinuations due to AEs refer to 
the protocol Section 7.4.1.2 and 8.1.2.
On C1D1 all components of study treatment should be administered. For all subsequent dosing 
any individual component of the study treatment can be delayed as per local standards. 
7.4.2
Dose Reductions
7.4.2.1
Dose Reduction for Nivolumab and/or Ipilimumab
There will be no dose escalations or reductions of nivolumab allowed. Ipilimumab dosing 
calculations for the 1 mg/kg dosing should be based on the body weight, assessed at either the day 
of dosing, the start of each cycle, or the last recorded weight and if the participant’s weight on the 
day of dosing differs by > 10% from the weight used to calculate the dose, then the dose must be 
recalculated. All doses should be rounded to the nearest milligram. There will be no other dose 
modifications allowed. 
7.4.2.2
Dose Reductions for Investigator’s Choice Chemotherapy
Chemotherapy dose reductions are permanent; once the dose of any chemotherapy agent is 
reduced, it may not be re-escalated in subsequent cycles. Any participant with two prior dose 
reductions for one agent who experiences a toxicity that would cause a third dose reduction must 
be discontinued from that agent.
Chemotherapy - Dose Reductions for Hematologic Toxicity
Dose adjustments are based on nadir blood counts (assessed as per local standards) since the 
preceding drug administration. After the first treatment administration, growth factors may be used 
to assist hematologic recovery. 
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13.0
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Chemotherapy - Dose Reductions for Non- Hematologic Toxicities
All dose reductions should be made based on the worst grade toxicity. Participants experiencing 
toxicity meeting dose-delay criteria should have their chemotherapy delayed until retreatment 
criteria are met (per Section 7.4.5).
For FOLFOX
Recommended dose modifications of FOLFOX are provided in Table 7.4.2.2-1 and Table 7.4.2.2-
2. Modifications may be made as per local standards.
Table 7.4.2.2-1:
Recommended Dose Modifications of FOLFOX
Drug
Starting Dose
Dose Modification
Dose Level - 1
Dose Level - 2
Oxaliplatin
85 mg/m2
70 mg/m2
50 mg/m2
5-FU
Bolus 5-FU: 400 mg/m2 
Leucovorin: 400 mg/m2  
Infusion 5-FU: 2400 
mg/m2 continuous infusion 
over 46-48 hours
Bolus 5-FU: 300 mg/m2 
Leucovorin: 300 mg/m2  Infusion 
5-FU: 2000 mg/m2 continuous 
infusion over 46-48 hours
Bolus 5-FU: 200 mg/m2 
Leucovorin: 200 mg/m2 Infusion 
5-FU: 1600 mg/m2 continuous 
infusion over 46-48 hours
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4.2.2-2:
Dose Modifications of FOLFOX for selected AEs
Toxicity 
Definition
During a course of 
therapy
Dose adjustment for next 
treatments
Neutropenia
Grade 3 or greater
Interrupt until resolved to 
Grade 2
Dose level -1
*If treatment delayed for 
4 consecutive weeks, discontinue all 
treatment
Thrombocytopenia
Grade 2
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 2 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1 
Grade 3
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 3 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Grade 4
Interrupt until resolved to 
Grade 1
Dose level -2
*If Grade 4 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
*If Grade 4 with bleeding, 
discontinue oxaliplatin
Neurologic toxicity
Grade 2 peripheral 
sensory neuropathy
Interrupt until resolved to 
Grade 1 or management as 
per institutional standard
Oxaliplatin dose -1
Continue 5-FU and leucovorin
*If oxaliplatin delayed for 
neurologic toxicity for 4 
consecutive weeks, discontinue 
oxaliplatin, continue 5-FU and 
leucovorin
Grade 3 or greater 
peripheral sensory 
neuropathy
Discontinue oxaliplatin
Continue 5-FU and leucovorin
Gastrointestinal 
toxicities
Grade 2 or greater 
diarrhea
Interrupt until resolved to 
Grade 1
Dose level -1
If dose delayed for diarrhea for 
4 consecutive weeks, discontinue all 
treatment
For toxicities not listed above, dose modifications are permitted per local standards. Participants 
may also discontinue oxaliplatin following multiple cycles if, in the investigator’s judgment, 
cumulative toxicity is likely to increase over time.
For FOLFIRI
Recommended dose modifications of FOLFIRI are provided in Table 7.4.2.2-3 and Table 7.4.2.2-
4.  Modifications may be made as per local standards.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4.2.2-3:
Recommended Dose Modifications of FOLFIRI
Drug
Starting Dose
Dose Modification
Dose Level - 1
Dose Level - 2
Irinotecan
180 mg/m2
150 mg/m2
120 mg/m2
5-FU
Bolus 5-FU: 400 mg/m2 
Leucovorin: 400 mg/m2  
Infusion 5-FU: 2400 
mg/m2/ continuous 
infusion over 46 hours
Bolus 5-FU: 300 mg/m2 
Leucovorin: 300 mg/m2  Infusion 
5-FU: 2000 mg/m2/ continuous 
infusion over 46 hours
Bolus 5-FU: 200 mg/m2 
Leucovorin: 200 mg/m2 Infusion 
5-FU: 1600 mg/m2/ continuous 
infusion over 46 hours
Table 7.4.2.2-4:
Dose modifications of FOLFIRI for selected AEs 
Toxicity CTCAE Gradea
Neutropenia/Thrombocytopenia
Grade 1 
Grade 2
Grade 3 
Grade 4 
Maintain dose level
Reduce 1 dose level
Omit dose until resolved to ≤ Grade 2, then reduce 1 dose level
Omit dose until resolved to ≤ Grade 2, then reduce 2 dose levels
Neutropenic fever
Omit dose until resolved, then reduce 2 dose levels
Diarrhea
Grade 1 
Grade 2 
Grade 3 
Grade 4
Delay dose until resolved to baseline, then give same dose
Omit dose until resolved to baseline, then reduce 1 dose level
Omit dose until resolved to baseline, then reduce 1 dose level
Omit dose until resolved to baseline, then reduce 2 dose levels
Other non-hematologic toxicitiesb
Grade 1 
Grade 2 
Grade 3 
Grade 4
Maintain dose level
Reduce 1 dose level
Omit dose until resolved to ≤ Grade 2, then reduce 1 dose level
Omit dose until resolved to ≤ Grade 2, then reduce 2 dose levels
For mucositis/stomatitis decrease only FU, not irinotecan
a National Cancer Institute Common Toxicity Criteria
b Excludes alopecia, anorexia, asthenia
A reduced irinotecan starting dose should be considered for patients who have experienced prior 
haematologic or gastrointestinal toxicity with previous treatment. The exact reduction in starting 
dose in this patient population has not been established and any subsequent dose modifications 
should be based on a patient's tolerance of the treatment.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
For Bevacizumab: 
Dose modifications or delay are allowed per institutional standards. Recommended dose 
modifications for proteinuria are summarized in Table 7.4.2.2-5. 
Table 7.4.2.2-5:
Recommended Guidelines for Management of Proteinuria
Grade
Description
Management
Grade 1
1+ protein on urinalysis, or 
0.15 to 1g of protein in 
24hrs urine collection, or
150 to 1000 mg/g if UPCR 
is used to assess the 
proteinuria
Continue Bevacizumab
Grade 2
2+ or 3+, or
1 to 3.4g/24hrs, or
1000 to 3400 mg/g
Give Bevacizumab and collect 
24 hour urine or test UPCR 
before the next cycle
Resume Bevacizumab only if 
< 2g/24hours, or < 2000 mg/g
If not < 2g/24h, or < 2000 mg/g 
for 3 months, discontinue 
Bevacizumab
Grade 3
Urinary protein 
≥3.5 g/24hrs, or
≥ 3500 mg/g
Discontinue Bevacizumab
UPCR, urine protein to creatinine ratio
For Cetuximab: 
Dose modifications or delay are allowed per institutional standards. For Infusion-related Reactions 
recommended dose modifications are summarized in Table 7.4.2.2-6:
Table 7.4.2.2-6:
Cetuximab dose modifications for infusion-related reactions
Infusion-related 
reaction 
toxicity 
CTCAE Gradea
Management
Grade 1 or 2 and non-serious Grade 3
Reduce the infusion rate by 50%
Serious infusion reactions, requiring 
medical intervention and/or 
hospitalization 
Permanently discontinue cetuximab
a
National Cancer Institute Common Toxicity Criteria
Skin reactions are very common and treatment interruption or discontinuation may be required. 
Cetuximab dose modifications for the management of dermatologic toxicity are summarized in 
Table 7.4.2.2-7 and Table 7.4.2.2-8.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 7.4.2.2-7:
Cetuximab dose modifications for all grades of skin toxicity
Cetuximab Dose Modification 
Guidelines for Rash toxicity 
CTCAE Gradea
Management
Grade 1 
Continue Cetuximab
Grade 2
Continue Cetuximab
Grade 3
Delay Cetuximab (continue other chemotherapy)
Grade 4
Discontinue Cetuximab permanently
a
National Cancer Institute Common Toxicity Criteria
Table 7.4.2.2-8:
Cetuximab dose modifications for Grade 3 skin toxicity
Occurrence of ≥ Grade 3 toxicity
Cetuximab dose once resolved to ≤ Grade 2a
1st Occurrence
Resume at full dose
2nd Occurrence
400 mg/m2
3rd Occurrence
300 mg/m2
4th Occurrence
Discontinue Cetuximab
a
If skin toxicity has not resolved to Grade 2 or better within 3 weeks, discontinue cetuximab. 
7.4.3
Criteria to Resume Treatment
7.4.3.1
Criteria to Resume Treatment in Arm A, Arm B or Crossover Cohort
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value and meet the requirements per Table 7.4-1.
Participants with SARS-CoV-2 infection (either confirmed or suspected) may resume treatment 
after all of the following conditions are met:
−
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 [RT-
PCR] 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. 
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Clinical Protocol
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nivolumab
Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 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 6 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 one of the agents must be discontinued due to toxicity 
attributed to that agent alone. Ipilimumab is not permitted to continue on study after nivolumab is 
discontinued.
7.4.4
Management Algorithms for Nivolumab and Ipilimumab
Immuno-oncology (IO) agents are associated with AEs that can differ in severity and duration 
from AEs caused by other therapeutic classes. Nivolumab and ipilimumab are considered IO 
agents, and the management algorithms in Appendix 5 provide guidance on assessing and 
managing the following groups of AEs:
•
Gastrointestinal
•
Renal
•
Pulmonary
•
Hepatic
•
Endocrinopathy
•
Skin
•
Neurological
•
Myocarditis
7.4.5
Criteria to Resume Treatment in Arm C
Treatment resumption in arm C to be guided by institutional standards. When resuming 
investigator’s choice chemotherapy treatment, please follow the dose reduction recommendations 
in Section 7.4.2.2. 
If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed and the 
participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to investigator’s choice chemotherapy to 
baseline or Grade ≤ 1 (except Grade 2 alopecia and fatigue) within 6 weeks from the last dose 
given should discontinue the drug(s) that caused the delay, unless it is determined by the treating 
investigator that the patient might benefit from continuation of the component. If treatment was 
delayed for more than 42 days (6 weeks) the approval of medical monitor is required.
7.4.6
Treatment of Treatment-related Infusion Reactions
Since nivolumab and ipilimumab contain only human immunoglobulin protein sequences, they are 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions.
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BMS-936558
nivolumab
If an infusion-related reaction occur, it might manifest with fever, chills, rigors, headache, rash, 
pruritus, arthralgias, hypotension, hypertension, bronchospasm, or other allergic-like reactions. All 
Grade 3 or 4 infusion reactions should be reported within 24 hours to the study medical monitor 
and reported as an SAE if it meets the criteria. Infusion reactions should be graded according to 
NCI CTCAE (Version 5) 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 and/or ipilimumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (e.g., antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids); prophylactic medications indicated for 
≤24 hours):
•
Stop the study drug 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 study medication will be administered at that visit.
•
For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab and/or ipilimumab infusions. If 
necessary, corticosteroids (up to 25 mg of hydrocortisone or equivalent) may be used.
For Grade 3 or 4 symptoms: (severe reaction, Grade 3: prolonged [ie, not rapidly responsive to 
symptomatic medication and/or brief interruption of infusion]; recurrence of symptoms following 
initial improvement; hospitalization indicated for other clinical sequelae (eg, renal impairment, 
pulmonary infiltrates). Grade 4: Life threatening; pressor or ventilatory support indicated):
•
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline and 
treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the Investigator is comfortable that the symptoms will not recur. Study drug will be 
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Clinical Protocol
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BMS-936558
nivolumab
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 (e.g., appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.5
Preparation/Handling/Storage/Accountability
The 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.
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact BMS immediately.
Study treatment not supplied by BMS will be stored in accordance with the package insert.
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 (e.g., required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2.
7.5.1
Retained Samples for Bioavailability / Bioequivalence 
Not applicable. 
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability as well as the 
participant’s medical records and eCRF.
7.7
Concomitant Therapy 
7.7.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study (unless utilized to treat a drug-related 
adverse event):
•
Immunosuppressive agents
•
Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.4)
•
Any 
concurrent 
anti-neoplastic 
therapy 
(i.e., 
chemotherapy, 
hormonal 
therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational 
agents for treatment of cancer)
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Clinical Protocol
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BMS-936558
nivolumab
•
Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study. Use of marijuana and its derivatives for treatment of symptoms 
related to cancer or cancer treatment are permitted if obtained by medical prescription or if its 
use (even without a medical prescription) has been legalized locally.  
•
Any live/attenuated vaccine (e.g., varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) within 100 days post last dose of nivolumab without or with 
ipilimumab.
−
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 study therapy is unknown.
•
Concomitant use of non-topical medications known to be a strong inducers or inhibitors of 
CYP3A4, or strong inhibitors of UGT1A1 is prohibited in participants receiving irinotecan.
•
Ongoing treatment with aspirin (>325 mg per day) or other medications known to predispose 
participants to gastrointestinal ulceration is prohibited for participants receiving bevacizumab.
•
Also refer to local institutional guidelines and/or product labels of SOC components for other 
possible prohibited and/or restricted treatments.
•
Caution should be exercised in participants treated with oxaliplatin who concurrently receive
medicinal products known to prolong the QT interval (refer to local standards and/or
www.crediblemeds.org).
7.7.2
Other Restrictions and Precautions
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.3
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 randomized 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 PR who go 
on to have surgical resection of remaining disease will be considered a PR. Participants with 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 9.8). 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.
Some patients treated with chemotherapy may have complete pathological response (pCR) on 
pathological assessment following surgery with curative intent (defined in Appendix 13). 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Similarly, evidence accumulates suggesting that some patients with long-standing radiologic 
stable disease or partial response while on or following completion of immunotherapy may have 
pCR after undergoing surgery with curative intent. Exploratory analyses to assess the rate of 
pathological complete response in patients undergoing surgery and recurrence-free survival will 
be conducted. 
7.7.4
Permitted Therapies 
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. Prior palliative 
radiotherapy must have been completed at least 2 weeks prior to first dose.
7.7.5
Palliative Local Therapy
Participants requiring palliative local therapy (radiotherapy or palliative surgical resection) should 
be evaluated for objective evidence of disease progression prior to the initiation of such therapy, 
particularly if the most recent tumor assessment was more than 4 weeks prior to the start of local 
therapy. If progression per study defined response criteria is identified on any tumor assessments 
prior to the initiation of palliative local therapy, then participants must either discontinue study 
drug treatment or they must meet criteria to continue treatment beyond progression in order to 
resume immunotherapy after palliative local therapy. The potential for overlapping toxicities with 
radiotherapy and nivolumab/nivolumab plus ipilimumab currently is not known; however, 
anecdotal data suggests that it is tolerable. If palliative radiotherapy is required, then study drugs 
should be withheld for at least 1 week before, during, and 1 week after radiation. Participants 
should be closely monitored for any potential toxicity during and after receiving radiotherapy, and 
AEs considered related to radiotherapy should resolve to Grade ≤1 prior to resuming study drugs. 
Only non-target lesions included in the planned radiation field or CNS lesions may receive 
palliative radiotherapy. Details of palliative radiotherapy should be documented in the source 
records and electronic case report form (eCRF). Details in the source records should include: dates 
of treatment, anatomical site, dose administered and fractionation schedule, and adverse events. 
Participants receiving limited field palliative radiation therapy will be considered to have 
unequivocal progression of disease in the non-target lesion.
7.7.6
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 
this assessment. Participants with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, eGFR < 30 mL/min/1.73 m2) are at increased risk 
of nephrogenic systemic fibrosis. MRI contrast should not be given to this participant population. 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
In addition, participants may be excluded from MRI if they have tattoos, metallic implants, 
pacemakers, etc.
Gentle hydration before and after IV contrast should follow local standard of care. The ultimate 
decision to perform MRI in an individual participant in this study rests with the site radiologist, 
the investigator and the standard set by the local Ethics Committee.
7.8
Post Study Drug Access
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 
specified in protocol Section 7.1.1. 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.
8
DISCONTINUATION CRITERIA
8.1
Discontinuation from Study Treatment
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. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness. (Note: Under 
specific circumstances, a participant who has been imprisoned may be permitted to continue 
as a participant. Strict conditions apply and BMS approval is required.)
•
Documented disease progression (or documentation of further progression for participants 
receiving treatment beyond progression)
•
Additional protocol-specified reasons for discontinuation (see Sections 8.1.1 and 8.1.2). 
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 Pregnancy. See Appendix 9 for country-
specific requirements.
All participants who discontinue study treatment, including participants in Crossover Cohort,
should comply with protocol specified follow-up procedures as outlined in Section 2. The only 
exception to this requirement is when a participant withdraws consent for all study procedures 
including post-treatment study follow-up or loses the ability to consent freely (ie, is imprisoned or 
involuntarily incarcerated for the treatment of either a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page. 
8.1.1
Nivolumab and/or Ipilimumab Dose Discontinuation (Arm A, B or 
Crossover Cohort)
Table 7.4-1 provides criteria for nivolumab or nivolumab plus ipilimumab discontinuation due to 
immune-mediated AE.
In addition, treatment should be discontinued for:
•
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 study 
treatment dosing.
•
Any event that leads to delay in dosing as per table below:
•
Dosing schedule 
•
Delay 
in 
dosing 
that 
requires 
treatment 
discontinuation
•
Q2W 
•
> 6 weeks
•
Q3W 
•
> 8 weeks
•
Q4W 
•
> 10 weeks
•
Q6W
•
> 14 weeks
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. 
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 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
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 7.1.2-2)
Participants receiving nivolumab plus ipilimumab treatment, 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.
8.1.2
Investigator’s Choice Chemotherapy Dose Discontinuation (Arm C)
Except where specified below, the medications in the SOC chemotherapy regimen should be 
discontinued for any of the following:
•
Any Grade ≥4 drug-related peripheral neuropathy requires discontinuation of oxaliplatin. In 
case of persistent Grade 3 drug-related paraesthesia, oxaliplatin should be discontinued.
•
Any Grade ≥3 drug-related mucocutaneous reaction possibly attributable to leucovorin 
requires permanent discontinuation.
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria 
requires discontinuation:
−
AST or ALT > 5-10 × upper limit of normal (ULN) for > 2 weeks*
−
AST or ALT > 10 × ULN*
−
Concurrent AST or ALT > 3 × ULN and total bilirubin > 2× ULN*
*In most indicated cases of AST or ALT elevations permanent discontinuation of study treatment 
is required. This may not be applicable for participants with elevated liver enzymes at baseline. 
For such cases as well as for situations when the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
investigator and the BMS Medical Monitor must occur.
•
Any oxaliplatin-related decrease in creatinine clearance to < 30 mL/minute (using the Cockroft 
Gault formula) requires discontinuation of oxaliplatin.
•
Any drug-related AE which recurs after 2 prior dose reductions for the same drug-related AE 
requires discontinuation of the drug(s) which was/were previously dose reduced.
•
Any Grade ≥3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
•
Any Grade 4 drug-related AE which the investigator deems is inappropriate to be managed by 
dose reduction(s) requires discontinuation of the drug(s) felt to be causing the event. The drug 
not felt to be related to the event may be continued.
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13.0
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13.0
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v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
•
If any drug-related toxicity does not resolve within 42 days, that component will be 
discontinued unless it is determined by the treating investigator that the participant might 
benefit from continuation of the component.
•
In case of unexplained drug-related respiratory symptoms such as non-productive cough, 
dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued 
until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
Treatment with bevacizumab must be permanently discontinued according to the bevacizumab 
package insert including the following: 
•
Grade 4 drug-related hypertension including hypertensive encephalopathy
•
Grade 3-4 drug-related hemorrhage 
•
Grade 4 drug-related non-pulmonary or non-CNS hemorrhage
•
Grade ≥1 drug-related pulmonary or CNS hemorrhage
•
Drug-related arterial thromboembolic event (any grade)
•
Any grade of drug-related congestive heart failure
•
Participants who develop drug-related gastrointestinal perforation, tracheoesophageal fistula 
or any Grade 4 fistula.  Discontinue in patients with fistula formation involving any internal 
organ 
•
Grade 4 drug-related venous thromboembolic event (VTE), including pulmonary embolism
•
Drug-related wound dehiscence (any grade –requiring medical or surgical therapy)
•
Drug-related reversible posterior leukoencephalopathy (any grade - confirmed by MRI)
•
Other unspecified bevacizumab related AE’s (Grade 4)
Treatment with cetuximab must be permanently discontinued according to the cetuximab package 
insert including the following: 
•
Confirmed drug-related interstitial lung disease (ILD)
•
Serious drug-related infusion reactions, requiring medical intervention and/or hospitalization 
•
Grade 4 drug-related skin toxicity
For toxicities not listed above, the treating investigators can decide to discontinue any individual 
chemotherapy agent or all chemotherapy agents if it is not the best interest in the participant per 
the local standards.
Dosing delays lasting > 6 weeks from the previous dose that occur for drug-related and non-drug-
related reasons may be allowed if approved by the BMS Medical Monitor. 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.
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
8.1.3
Treatment Beyond Progression for Participants in the Arms A, B or 
Crossover Cohort
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.40
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 as long 
as they meet the following criteria:
1) Investigator-assessed clinical benefit
2) Tolerance of study treatment
3) Stable performance status
4) Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
5) Participant provides written informed consent prior to receiving additional study treatment. All 
other elements of the main consent including description of reasonably foreseeable risks or 
discomforts, or other alternative treatment options will still apply.
6) Participant has not reached maximum treatment duration as defined in protocol Section 7.1.1
7) Approval from BMS medical monitor or designee
Treatment 
beyond 
progression 
may 
be 
administered 
after 
localized 
interventions 
(surgery/radiation therapy).
Radiographic assessment/scan(s) should continue in accordance with the Section 2 Schedule of 
Activities for the duration of the treatment beyond progression and should be submitted to the 
central imaging vendor.
The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab or nivolumab plus ipilimumab.
If the investigator feels that the participant continues to achieve clinical benefit by continuing study 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities, Section 2. 
For the participants who continue study treatment 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. Study treatment 
should be discontinued permanently upon documentation of further progression.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes 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 
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
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 inclusion of 
new lesions which become measurable, these new lesions must demonstrate an absolute increase 
of at least 5 mm.
8.1.4
Post Study Treatment Study Follow-up
In this study, PFS and OS are critical endpoints. Post study follow-up is of critical importance and 
is essential to preserving participant safety and the integrity of the study. Participants who 
discontinue study treatment must continue to be followed for collection of outcome and/or survival 
follow-up data as required and in line with Section 5 until death or the conclusion of the study.
BMS may request that survival data be collected on all treated participants outside of the protocol 
defined window (Section 2). At the time of this request, each participant will be contacted to 
determine their survival status unless the participant has withdrawn consent for all contacts or is 
lost to follow-up.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
•
If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
•
If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study. 
•
The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.
•
If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records.
9
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and timing are summarized in the Schedule of Activities (Section 2). 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct.
•
All screening/baseline evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization, or treatment in the Crossover 
Cohort. The investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities.
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
labs until all study drug-related toxicities resolve, return to baseline, or are deemed irreversible.
Testing for asymptomatic SARS-CoV-2 infection, for example by RT-PCR or viral antigen, is not 
required. However, some participants may develop suspected or confirmed symptomatic SARS-
CoV-2 infection or be discovered to have asymptomatic SARS-CoV-2 infection during the 
screening period. In such cases, participants may be eligible for the study after recovery from 
infection or completion of quarantine period in case of asymptomatic infection/potential exposure.  
If exceptional circumstances preclude the continued administration of measures using planned 
modalities, then alternate administration methods may be required.
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13.0
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Approved
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg, dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 
evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) Investigator Brochure.
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.
9.1
Efficacy Assessments 
9.1.1
Imaging Assessment for the Study 
Images will be submitted to an imaging core lab for 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 CA2098HW Imaging Manual to 
be provided by the core lab. 
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.
Screening and on study images should be acquired as outlined in the Schedule of Activities 
(Section 2). To facilitate the transition of the imaging acquisition to be unified across study 
participants schedule from every 8 weeks (12 weeks in the Crossover cohort) to every 16 weeks 
(during year 3) or 24 weeks (during year 4 and beyond) from randomization, the collection of 
imaging at additional timepoints maybe required. This will depend on the timing of approval of 
the reduced imaging acquisition schedule at study sites and upcoming timepoint of tumor 
assessment. Additional details are provided in a memo to the sites. 
Every attempt should be made to image each participant using an identical acquisition protocol on 
the same scanner for all imaging time points. Tumor assessments at other timepoints may be 
performed if clinically indicated and should be submitted to the central imaging vendor as soon as 
possible. 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. 
9.1.1.1
Methods of Measurement
Contrast-enhanced CT of the chest, CT/MRI of the abdomen, pelvis, and all other 
known/suspected sites of disease should be performed for tumor assessments. Images should be 
acquired with slice thickness of 5 mm or less with no intervening gap (contiguous). Every attempt 
should be made to image each participant using an identical acquisition protocol on the same 
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
scanner for all imaging time points. Tumor measurements should be made by the same investigator 
or radiologist for each assessment whenever possible. Change in tumor measurements and tumor 
response to guide ongoing study treatment decisions will be assessed by the Investigator using the 
RECIST 1.1 criteria.
Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.  
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET-
CT is increasingly used in clinical care, and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-based 
RECIST 1.1 measurements. However, if a site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the 
CT portion of the PET-CT can be used for RECIST 1.1 measurements. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.
Bone scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. 
In selected circumstances where such modalities are the sole modality used to assess certain 
nontarget organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected.
MRI of brain should be acquired as outlined in Schedule of Activities (see Section 2). CT of the 
Brain (with and without contrast) can be performed if MRI is contraindicated.
Bone scans may be collected per local standards, as clinically indicated. 
9.1.1.2
BICR Assessment of Progression
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. When progression per RECIST 1.1 criteria is assessed 
by the investigator, the site will inform the central imaging vendor, so that the BICR assessment 
of progression can be expedited. The BICR review will be completed and limited results provided 
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
to the site as specified within the imaging vendor document, provided there are no pending queries 
to the site.
Participants whose progression is not confirmed by the BICR should continue tumor assessments 
(if clinically feasible) according to the protocol-specified schedule, or sooner if clinically 
indicated. Also, if participants discontinue treatment without radiographic progression, tumor 
assessments will continue according to the protocol-specified schedule, as noted in Section 2, until 
progression has been confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment. The BICR assessment of progression is only relevant for determining 
when tumor assessments for a given participant are no longer required to be submitted to the 
imaging vendor.
BICR confirmation of disease progression per RECIST 1.1 is mandatory before enrollment to 
crossover cohort. The participant will be re-baselined based on the investigator’s assessment of 
the scans with which BICR progression was confirmed. If additional scans were obtained after 
BICR-assessed progression but before the beginning of study therapy in the Crossover Cohort, 
these scans should be used as crossover baseline scans. Tumor assessments in participants in 
crossover cohort will be done by BICR and should comply with the requirements outlined in this 
Section of the protocol.
9.1.1.3
Imaging and Clinical Assessment 
Tumor assessments for all participants (arm A, B, C, and crossover cohort) 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 
timepoint of tumor assessments will be reported on the eCRF based on the investigator’s 
assessment using RECIST 1.1 criteria (See Appendix 7 for specifics of RECIST 1.1 criteria to be 
utilized in this study). 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 randomization to the date of the first imaging assessment.
9.1.2
Patient-Reported Outcomes
The evaluation of health-related quality of life is an increasingly important aspect of clinical 
efficacy in oncology trials. Such data provide an understanding of the impact of treatment from
the participant’s perspective and offer insights into participant experience that may not be captured 
through physician reporting. Additionally, generic health-related quality of life measures provide 
data needed for calculating utility values to inform health economic models.
The European Organisation for the Research and Treatment of Cancer (EORTC) Quality of Life 
Questionnaire–Core 30 (QLQ-C30) and 29-item Colorectal-specific (QLQ-CR29) modules will 
be used to assess the effects of cancer and treatment on symptoms, functioning and well-being. 
The EORTC QLQ-C30 is one of the most commonly used quality of life instrument in oncology 
trials. The instrument’s 30 items are divided among 5 functional scales (physical, role, cognitive, 
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
emotional, and social), 9 symptom scales (fatigue, pain, nausea/vomiting, dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties), and a global health/quality of life 
scale. With the exception of 2 items included in the global health/quality of life scale, for which 
responses range from 1 (Very poor) to 7 (Excellent), item responses range from 1 (Not at all) to 4 
(Very much). Raw scores for the QLQ-C30 are transformed to a 0-100 metric such that higher 
values indicate better functioning or quality of life or a higher level of symptoms. The EORTC 
QLQ-CR29 comprises colorectal cancer-specific domains and symptoms, including sexual 
function-, stoma-, and bowel function-related items. 78,79
The 3-level version of the EQ-5D (EQ-5D-3L) will be used to assess treatment effects on perceived 
health status and to generate utility data for health economic evaluations. The EQ-5D-3L is a 
generic multi-attribute health-state classification system by which health is described in 5 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension is evaluated using 3 levels: no problems, some problems, and severe problems. 
Responses to these 5 dimensions are converted into 1 of 243 unique EQ-5D health state 
descriptions, which range between no problems on all 5 dimensions (11111) to severe/extreme 
problems on all 5 dimensions (33333). Using appropriate country-specific value weighting 
algorithms, a respondent’s self-described health state can be converted into a utility representing 
the societal desirability of his/her own health. In addition, the EQ-5D includes a visual analogue 
scale (VAS) allowing a respondent to rate his/her health on a scale ranging from 0–100 with 0 
being the worst health state imaginable and 100 being the best health state imaginable. 
The questionnaires will be provided in the participant’s preferred language when available and the 
EQ-5D-3L may be administered by telephone during survival follow up using a script for 
telephone administration.  
The EQ-5D-3L and the EORTC QLQ-C30 and QLQ-CR29 will be collected for all participants 
per the schedule provided in Section 2. 
9.2
Adverse Events
Use CTCAE v5 definitions and grading for safety reporting of all AE and SAEs on the case report 
form. 
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
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 
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Contacts for SAE reporting specified in Appendix 3.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious 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, at 
the time points specified in the Schedule of Activities (Section 2). Nonserious 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 be collected from the date of 
the participant’s written consent until 100 days following discontinuation of dosing.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events 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 from the time of signing the 
consent, including those thought to be associated with protocol-specified procedures and 
within 100 days of discontinuation of dosing. 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 randomized/assigned to treatment and never treated with study drug, SAEs 
should be collected for 30 days from the date of randomization.
•
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, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
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13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement in 
the context of known adverse events, when appropriate for the program or protocol.
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following discontinuation 
of study treatment.
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.
9.2.3
Follow-up of AEs and SAEs
•
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3).
•
Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate.
•
All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study.
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2) 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 8.3), or for suspected cases, until SARS-CoV-2 infection is ruled out.
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met.
•
An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Regulation 536/2014 and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements.
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half-
lives after product administration, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to BMS 
Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy has ended), following approvals of participant /sponsor
/IRB/EC, as applicable. Study treatment must be permanently discontinued where locally 
mandated, see Appendix 9 for country-specific requirements.
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 
Sponsor or designee. In order for Sponsor or designee to collect any pregnancy surveillance 
information from the female partner, the female partner must sign an informed consent form for 
disclosure of this information. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form.
9.2.6
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the 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.
1) Any laboratory test result that is clinically significant or meets the definition of an SAE 
2) Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted
3) 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).
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
9.2.7
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details).
Potential drug induced liver injury is defined as:
1) 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.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3).
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (Section 2). 
A systematic screening for DPD deficiency has to be performed during screening period for 
participants who have not received prior therapy or receive one line of prior therapy if locally 
required. QT prolongation and ventricular arrhythmias, including fatal torsades de pointes, have 
been reported with oxaliplatin. Correct electrolyte abnormalities (particularly potassium and 
magnesium) prior to initiating oxaliplatin and periodically during treatment. In the event of an 
extension of the QT/QTc interval, including the prolongation of the QT/QTc interval > 500 msec, 
implement close and adapted ECG monitoring (continuously) in a hospital until the advice of a 
cardiologist is available, and permanently discontinue oxaliplatin. Follow local standards for the 
management of QT interval prolongation.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
9.4.1
Physical Examinations
Physical examinations are to be performed as clinically indicated. If there are any new or 
worsening clinically significant changes since the last exam, report changes on the appropriate 
non-serious or serious adverse event page.
Refer to Schedule of Activities in Section 2.
9.4.2
Vital signs
Vital signs are to be collected within 14 days prior to randomization, and collected just prior to 
each dose of study medication. Refer to Schedule of Activities in Section 2.
9.4.3
Electrocardiograms
Refer to Schedule of Activities in Section 2. Additional monitoring of electrocardiograms is to be 
performed in accordance with local standards in participants with congestive heart failure, 
bradyarrhythmias, and electrolyte abnormalities, and in participants taking drugs known to prolong 
the QT interval.
9.4.4
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Hematology - CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Amylase
Lipase
Creatinine
Blood Urea Nitrogen (BUN) or serum urea
Glucose (fasting is not reqired)
PTT/INR - screening and as clinically 
indicated during bevacizumab treatment
PTT - screening
Albumin - screening only
Sodium
Potassium
Chloride
Calcium
Magnesium screening and during treatment if 
study treatment contains cetuximab
Phosphorus
Blood uracil (if locally required) - screening 
only
Endocrine function testing
Screening - TSH, free T3 and free T4. Additional tests (e.g. ACTH, cortisol, etc) per local 
requirements to be performed.
On treatment - TSH, with reflexive fT3 and fT4 if TSH is abnormal. Additional tests (e.g. 
ACTH, cortisol, etc.) per local requirements should be performed if clinically indicated.
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930125433
13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Follow up - TSH, free T3, free T4. Additional tests (e.g. ACTH, cortisol, etc.) per local 
requirements should be performed if clinically indicated.
Urinalysis 
Protein
Glucose
Blood
Leukocyte esterase
Specific gravity 
pH
Serology
Hepatitis B and Hepatitis C, (HBV sAg, HCV antibody or HCV RNA), - screening only. If 
anti-HCV test is positive, then HCV RNA is mandatory.
SARS-CoV-2 (screening, Cycle 6 Day 1 and every 6 cycles)
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) 
CEA and CA19-9 Assessment – during screening, and at re-staging timepoints
DPD-deficiency testing per local standards
9.4.5
Imaging Safety Assessment
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment. 
9.5
Pharmacokinetics and Immunogenicity Assessments
Table 9.5-1 provides a detailed sampling schedule for pharmacokinetic and immunogenicity 
measurements for nivolumab for participants in arm A. Table 9.5-2 and Table 9.5-3 provide a 
detailed sampling schedule for pharmacokinetic and immunogenicity measurements for 
nivolumab and ipilimumab for participants in arm B and the Crossover Cohort, respectively. All 
on treatment PK timepoints are intended to align with days on which study drug is administered. 
Further details of sample collection, processing, and shipment will be provided in the laboratory 
manual. 
Draw blood samples from a site other than the infusion site (ie, contralateral arm) on days of 
infusion for all pre-dose and end of infusion-PK (EOI-PK) samples. Please ensure accurate 
documentation of the time and date of sample collection. Samples will be evaluated for 
development of anti-drug antibody (ADA). Samples may also be analyzed for neutralizing 
antibodies and PK samples may be used for ADA analysis in the event of insufficient volume, to 
complete immunogenicity assessment, or to follow-up on suspected immunogenicity-related AEs.
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 9.5-1:
PK Sampling- Pharmacokinetic & Immunogenicity Sampling 
Schedule - Nivolumab Monotherapy (Arm A)
Study Day of Sample 
Collection
Cycles 1-2 = 6 weeks each
Cycle 3 and beyond = 4 
weeks each
Event
Time
(Relative To Start of 
Nivolumab Infusion )
Hour: Min
Pharmacokinetic 
Serum Sample for 
Nivolumab
Immunogenicity 
Serum Sample 
for 
Nivolumab
Cycle 1 Day 1
Predosea
0:00
X
X
Cycle 1 Day 29
Predosea
0:00
X
X
Cycle 3 Day 1
Predosea
0:00
X
X
Cycle 3 Day 1
End of 
Infusionb
0:30
X
Cycle 6  Day 1
Predosea
0:00
X
X
Day 1 every 6 cycles 
starting at Cycle 12 (Cycle 
12, Cycle 18, Cycle 24, etc) 
up to 2 years of treatment
Predosea
0:00
X
X
a Predose samples should be collected just prior to the start of infusion on the day the study drug is administered. 
However, if a predose sample is collected but the dose is subsequently delayed, an additional predose sample should 
not be collected
b End of infusion (EOI) sample should be taken immediately prior to the stopping of nivolumab infusion, preferably 
within 2 minutes prior to the end of infusion. If the end of infusion is delayed beyond the nominal infusion duration, 
the collection of this sample should also be delayed accordingly. EOI samples may not be collected from the same 
IV access as the drug was administered.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 9.5-2:
PK Sampling- Pharmacokinetic & Immunogenicity Sampling Schedule - Nivolumab plus Ipilimumab 
Combination Therapy (Arm B)
Study Day of Sample 
Collection
Cycles 1-2 = 6 weeks each
Cycle 3 and beyond = 4 
weeks each
Event
Time
(Relative to Start 
of Nivolumab 
Infusion)
Hour: Min
Pharmacokinetic 
Serum Sample for 
Nivolumab
Immunogenicity 
Serum Sample for 
Nivolumab
Pharmacokinetic 
Serum Sample 
for Ipilimumab
Immunogenicity 
Serum Sample for 
Ipilimumab
Cycle 1 Day 1
Predosea
0:00
X
X
X
X
Cycle 1 Day 22
Predosea
0:00
X
X
X
X
Cycle 2 Day 22
Predosea
0:00
X
X
X
X
Cycle 3 Day 1
Predosea
0:00
X
X
X
X
Cycle 3 Day 1
End of 
Infusionb
00:30
X
Cycle 6 Day 1
Predosea
0:00
X
X
X
X
Day 1 every 6 cycles 
starting at Cycle 12 (Cycle 
12, Cycle 18, Cycle 24, etc) 
up to 2 years of treatment
Predosea
0:00
X
X
a On study days where nivolumab and ipilimumab are coadministered, the predose samples for both nivolumab and ipilimumab should be collected just prior to 
the start of nivolumab infusion (preferably within 30 minutes). 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.  
b End of infusion (EOI) sample should be taken immediately prior to the stopping of nivolumab infusion, preferably within 2 minutes prior to the end of infusion. 
If the end of infusion is delayed beyond the nominal infusion duration, the collection of this sample should also be delayed accordingly. EOI samples may not 
be collected from the same IV access as the drug was administered.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 9.5-3:
PK Sampling- Pharmacokinetic & Immunogenicity Sampling Schedule - Crossover Cohort
Study Day of Sample 
Collection
Cycles 1-2 = 6 weeks each
Cycle 3 and beyond = 4 
weeks each
Event
Time
(Relative to Start 
of Nivolumab 
Infusion)
Hour: Min
Pharmacokinetic 
Serum Sample for 
Nivolumab
Immunogenicity 
Serum Sample for 
Nivolumab
Pharmacokinetic 
Serum Sample
for `Ipilimumab
Immunogenicity 
Serum Sample for 
Ipilimumab
Cycle 1 Day 1
Predosea
0:00
X
X
X
X
Cycle 1 Day 15
Predosea
0:00
X
X
X
X
Cycle 2 Day 1
Predosea
0:00
X
X
X
X
Cycle 3 Day 1
Predosea
0:00
X
X
X
X
Cycle 3 Day 1
End of 
Infusionb
--c
X
X
Cycle 6 Day 1
Predosea
0:00
X
X
X
X
Cycle 7 Day 1
Predosea
0:00
X
X
X
X
Day 1 every 6 cycles 
starting at Cycle 12 (Cycle 
12, Cycle 18, Cycle 24, etc) 
up to 2 years of treatment
Predosea
0:00
X
X
X
X
a
Predose samples should be collected just before the administration of the first drug (preferably within 30 minutes). 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.
b EOI samples for nivolumab and ipilimumab should be collected together at the end of (preferably, within 2 minutes prior to the end of) ipilimumab infusion. If 
the end of infusion is delayed beyond the nominal infusion duration, the collection of these samples should also be delayed accordingly. EOI samples may not 
be collected from the same IV access as the drug was administered.
c Since both nivolumab and ipilimumab EOI samples will be collected at the end of Ipilimumab infusion, the relative time will be 1:30 for nivolumab and 0:30 
for ipilimumab EOI sample.
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13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
9.6
Pharmacodynamics
See Section 9.8.
9.7
Pharmacogenomics
See Section 9.8. 
9.8
Biomarkers
Biomarker sample collection schedules are presented in Table 9.8-1 for nivolumab monotherapy 
(arm A) and investigator’s choice chemotherapy (arm C), Table 9.8-2 for nivolumab plus 
ipilimumab combination (arm B), and Table 9.8-3 for the Crossover Cohort. 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 9.8-1:
Biomarker Sampling Schedule - Nivolumab Monotherapy (Arm A) and Investigator’s Choice 
Chemotherapy (Arm C)
Study Day of 
Sample Collection
Cycles 1 -2 (cycle = 
6 weeks)
Cycles 3 to EOT 
(cycle = 4 weeks)
Tumor
Whole 
Blood
Plasma
Serum
MDSC
PBMC
Microbiome
SARS-CoV-2 
Serology
Screening
X
Xa
X
Cycle 1 Day 1
X
X
X
X
X
Cycle 1 Day 15
X
X
X
X
Cycle 1 Day 22-28
Xb
Cycle 2 Day 1
X
X
X
X
Xc
Cycle 3 Day 1 
X
X
X
Cycle 4 Day 1
X
Cycle 6  Day 1 and 
every 2 cycles
X
Cycle 6 Day 1 and 
every 6 cyclesd
X
Upon Progression
Xb
X
X
X
X
X
Follow-Up Visit 1
X
a Stool should be collected within 7 days prior to first dose.
b On-treatment (1 week  after  2nd dosing and prior to the 3rd dosing, i.e. between Day 22-28 of Cycle 1) and at progression (PD + 14 days) tumor biopsy are 
optional but strongly encouraged to understand the resistance/response to nivolumab or SOC treatment. The biopsy upon progression on arm C is mandatory, if 
medically feasible, for enrollment to Crossover Cohort. If biopsy is performed, biopsy samples must be submitted. If biopsies/surgical resection are done at any 
other time on treatment, tissue samples should be submitted as well.
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
c Stool should be collected within 3 days prior to dosing.
d Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection.  If a documented or suspected SARS-CoV-2 
infection occurs within 4 weeks of the 6 month sampling time point, a single serum sample will be collected to satisfy the requirements for both the every 6 
month and approximately 4 week after infection time points.
Abbreviations: MSDC, myeloid-derived suppressor cells; PBMC, peripheral blood mononuclear cells; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2; SOC, standard of care.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 9.8-2:
Biomarker Sampling Schedule - Nivolumab plus Ipilimumab Combination Therapy (Arm B)
Study Day of Sample Collection
Cycles 1 -2 (cycle = 6 weeks)
Cycles 3 to EOT (cycle = 4 
weeks)
Tumor
Whole 
Blood
Plasma
Serum
MDSC
PBMC
Microbiome
SARS-CoV-
2 Serology
Screening
X
Xa
X
Cycle 1 Day 1
X
X
X
X
X
Cycle 1 Day 22
X
X
X
X
Cycle 1 Day 29-35
Xb
Cycle 2 Day 1
X
X
X
X
Xc
Cycle 3 Day 1
X
X
X
Cycle 4 Day 1
X
Cycle 6 Day 1 and every 2 cycles
X
Cycle 6 Day 1 and every 6 
cyclesd
X
Upon Progression
Xb
X
X
X
X
X
Follow-Up Visit 1
X
a Stool should be collected within 7 days prior to first dose.
b On-treatment (1 week after 2nd dosing and prior to the 3rd dosing, i.e. between Day 29-35 of Cycle 1) and at progression (PD + 14 days) tumor biopsy are 
optional but strongly encouraged to understand the resistance/response to nivolumab plus ipilimumab treatment. If biopsy is performed, biopsy samples must be 
submitted. If biopsies/ surgical resection are done at any other time on treatment, tissue samples should be submitted as well.
c Stool should be collected within 3 days prior to dosing.
d Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection. If a documented or suspected SARS-CoV-2 
infection occurs within 4 weeks of the 6 month sampling time point, a single serum sample will be collected to satisfy the requirements for both the every 6 
month and approximately 4 week after infection time points.
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Abbreviations: MSDC, myeloid-derived suppressor cells; PBMC, peripheral blood mononuclear cells; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2.
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 9.8-3:
Biomarker Sampling Schedule - Crossover Cohort
Study Day of Sample 
Collection
Cycles 1 -2 (cycle = 6 weeks)
Cycles 3 to EOT (cycle = 4 
weeks)
Tumor
Whole Blood
Plasma
Serum
MDSC
PBMC
Microbiom
e
SARS-
CoV-2 
Serology
Baseline
X
Xa
X
Cycle 1 Day 1
X
X
X
X
X
Cycle 1 Day 15
X
X
X
X
Cycle 1 Day 22-28
Xb
Cycle 2 Day 1
X
X
X
X
Xc
Cycle 3 Day 1
X
X
X
Cycle 4 Day 1
X
Cycle 6 Day 1 and every 3 
cycles
X
Cycle 6 Day 1 and every 6 
cyclesd
X
Upon Progression
Xb
X
X
X
X
X
Follow-Up Visit 1
X
a Stool should be collected within 7 days prior to first dose.
b On-treatment (1 week after 2nd dosing and prior to the 3rd dosing, i.e. between Day 22-28 of Cycle 1) and at progression (PD + 14 days) tumor biopsy are 
optional but strongly encouraged to understand the resistance/response to nivolumab plus ipilimumab treatment. If biopsy is performed, biopsy samples must be 
submitted. If biopsies/ surgical resection are done at any other time on treatment, tissue samples should be submitted as well.
c Stool should be collected within 3 days prior to dosing.
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
d Serum should also be collected approximately 4 weeks after a documented or suspected SARS-CoV-2 infection. If a documented or suspected SARS-CoV-2 
infection occurs within 4 weeks of the 6 month sampling time point, a single serum sample will be collected to satisfy the requirements for both the every 6 
month and approximately 4 week after infection time points.
Abbreviations: MSDC, myeloid-derived suppressor cells; PBMC, peripheral blood mononuclear cells; SARS-CoV-2, severe acute respiratory syndrome 
coronavirus 2.
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
9.8.1
Tissue biomarkers
Tissue samples will be collected for MSI/MMR and additional biomarker assessment. Either a 
FFPE tissue block (preferred) or unstained tumor tissue sections (minimum of 30 positively 
charged slides), from primary or metastatic site, must be submitted to the central laboratory. Tumor 
tissue specimen must meet either of the criteria below:
i)
Obtained within 3 months of enrollment with no intervening systemic anti-cancer 
treatment between time of acquisition and randomization AND this must be the same 
tissue sample as was used for local MMR/MSI testing; 
OR
ii) If above is not available, archival tissue can be accepted if the same tissue was used for 
local MMR/MSI testing.
Central lab must provide IRT with confirmation of receipt of evaluable tumor tissue prior to 
randomization. Tumor tissue should be excisional, incisional or core needle biopsies or surgical 
specimens. Fine needle biopsies are not acceptable. Biopsies of bone lesions that do not have a 
soft tissue component or decalcified bone samples are also not acceptable. These requirements are 
crucial to fulfill the commitment to develop in vitro diagnostic devices for dMMR/MSI-H 
detection in mCRC and ensure the quality of the tissue for biomarker analyses. In addition, 
peripheral blood and stool samples will be collected. Biomarker analyses will aim at identifying 
potential predictive biomarkers of nivolumab monotherapy, and combination therapy of 
nivolumab with ipilimumab treatment and furthering our understanding of CRC disease biology 
in relation to checkpoint blockade therapy. 
Biomarker analyses of tumor samples may include but are not be limited to: 
•
MSI/MMR: In association with the Accelerated Approval of nivolumab monotherapy and 
nivolumab plus ipilimumab combination therapy in this indication, BMS is required to fulfill 
a post-marketing commitment with the US FDA to support labeling of an 
immunohistochemistry based in vitro diagnostic, as well as a nucleic acid-based in vitro 
diagnostic device that is essential to the safe and effective use of nivolumab and nivolumab in 
combination with ipilimumab for patients with tumors that are dMMR/MSI-H. 
•
Gene expression profiling (GEP) will be performed to examine potential signatures that may 
predict or associate with response/resistance to therapy. Potential signatures may include but 
not be limited to:  
−
CRC subtyping signatures. Different CRC subtypes may respond differently to checkpoint 
blockade because of the different molecular biology underlying each subtype. Consensus 
molecular subtype (CMS) has categorized CRC into 4 different CMSs, with dMMR/MSI-
H CRC falling under CMS1. 80 However, even within the dMMR/MSI-H CRCs, 
differential outcomes were observed in CheckMate-142 (CA209142). Potential subtyping 
signatures that can predict response in the dMMR/MSI-H population may be explored. 
−
Signatures of the tumor microenvironment. The tumor immune microenvironment plays a 
pivotal role in tumorigenesis and is important in determining response to checkpoint 
blockade therapy. Signatures of the tumor immune microenvironment, such as various 
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inflammatory signatures, may be explored to examine their association with response to 
nivolumab or nivolumab plus ipilimumab therapy.
•
Tumor Mutational Analysis: 
−
TMB (tumor mutational burden) has been associated with response to checkpoint blockade 
therapy in lung cancer. The CA209026 study evaluated 1L NSCLC patients treated with 
nivolumab versus chemotherapy. For patients with higher TMB, higher response rates and 
longer progression-free survival were observed in the nivolumab treated group compared 
to the chemotherapy group.81 The recent evaluation of TMB and clinical response in 
different tumor types has also suggested a correlation between TMB and objective response 
rate across different disease indications. 82 TMB correlation with response will be 
examined further in the dMMR/MSI-H CRC indication in this study. In addition, neo-
antigen profiling may be performed based on the predicted affinity of the detected 
mutations to MHC proteins and correlated with response.
−
Other genomic/genetic alterations of interest, such as BRAF, RAS, and other genes 
involved in CRC biology may be analyzed as well.
•
For gene expression profiling and tumor mutational or genetic alteration analyses, DNA and/or
RNA isolated from the tumor tissue collected at baseline and on treatment may be analyzed 
using sequencing techniques including, but not limited to, whole exome and whole 
transcriptome sequencing.
•
Characterization of the tumor microenvironment. A growing body of evidence suggests the 
importance of tumor associated immune cells in the tumor microenvironment. Immunoscore 
has been shown to be prognostic in both dMMR/MSI-H and MSS CRC. 83
Immunohistochemistry (IHC) or other technologies will be used to assess the number and 
composition of immune infiltrates in order to define the immune cell subsets present within 
tumor tissue before and after exposure to therapy. These analyses may include, but not 
necessarily be limited to PD-L1, PD-1, CD3, CD8, MHC-I, MHC-II, and LAG3.
9.8.2
Peripheral Blood
A variety of factors that may impact the immunomodulatory properties and efficacy of study 
treatment will be investigated in peripheral blood specimens taken from all participants prior to or 
during treatment. Data from these investigations will be evaluated for associations with response, 
survival, and/or safety (adverse event) data. Several analyses will be completed and are described 
briefly below.
9.8.3
Soluble Biomarkers
Soluble factors, such as cytokines, chemokines, soluble receptors, and antibodies to tumor antigens 
will be characterized and quantified. Analyses may include, but not necessarily be limited to, 
Carcinoembryonic antigen (CEA), CA19-9, IL2Ralpha and IL-8. Collected serum samples may 
also be used for the assessment of tumor antigen-specific responses elicited following study 
treatment to explore which antitumor antibodies are most associated with clinical response. 
Antibody levels to cancer test antigens may be assessed.
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Serum will be collected for potential future measurements of anti-SARS-CoV-2 antibodies by 
serology (anti-SARS-CoV-2 total or IgG) to explore potential association with safety, efficacy, 
and/or immune biomarkers.
9.8.3.1
Immunophenotyping
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory 
markers in peripheral blood mononuclear cell (PBMC) preparations will be quantified. Analyses 
may include, but not necessarily be limited to, the proportion of T, B, and NK cells, granulocytes, 
the proportion of memory and effector T cell subsets, and expression levels of PD-1, PD-L1, other 
B7 family members, and Ki67.
9.8.3.2
Whole Blood for Germline DNA
Whole blood will be collected from all participants prior to treatment to generate genomic DNA 
for genetic analyses and to serve as a reference for tumor genomic testing. Whole blood DNA may 
be analyzed using sequencing techniques including, but not limited to, whole exome sequencing.
9.8.3.3
Myeloid Derived Suppressor Cells
Myeloid derived suppressor cells (MDSCs) are an immune cell population capable of suppressing 
T cell activation and proliferation and may potentially affect outcomes to checkpoint blockade 
therapy.84 Higher MDSC in peripheral blood was observed in CRC patients compared with healthy 
individual.85 MDSCs will be measured at baseline and on-treatment to assess pharmacodynamic 
changes or associations with outcome.
9.8.3.4
Circulating Tumor DNA Analysis (Plasma) Biomarkers
Peripheral blood samples will be collected to generate plasma for cell free circulating tumor-DNA 
(ctDNA) analysis. Liquid biopsy, such as ctDNA analysis, offers a non-invasive alternative for 
monitoring tumor evolution and therapeutic response compared to traditional tissue biopsy.86
Plasma samples will be collected at baseline and on treatment and upon progression will be 
analyzed to determine the presence, frequency and genomic profile of ctDNA.  Plasma samples 
may be analyzed using sequencing techniques including, but not limited to, panel-based next-
generation sequencing.
9.8.4
Stool Sample Collection
The gut microbiome influences cancer development and response to therapy. The efficacy of 
cancer immunotherapy with checkpoint blockade could be diminished with the administration of 
antibiotics. Clinical efficacy has been associated with microbiome composition and the presence 
of specific microbe species.87,88,89 The association of microbiome with efficacy and safety will be 
evaluated using stool samples collected before and during treatment. 
9.8.5
Additional Research Collection
This protocol will include residual sample storage for additional research.
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For All US sites:
Additional research is required for all study participants, except where prohibited by IRBs/ethics 
committees, or academic/institutional requirements. Where one or more of these exceptions occurs, 
participation in the additional research should be encouraged but will not be a condition of overall 
study participation. 
•
If the IRB/ethics committees and site agree to the mandatory additional research retention 
and/or collection, then the study participant must agree to the mandatory additional research 
as a requirement for inclusion in the study. 
•
If optional participation is permitted and approved, then the study participants may opt out of 
the additional research retention and/or collection.
For non-US Sites
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. 
This collection for additional research is intended to expand the translational R&D capability at 
Bristol-Myers Squibb, and will support as yet undefined research aims that will advance our 
understanding of disease and options for treatment. It may also be used to support health authority 
requests for analysis, and advancement of pharmacodiagnostic development to better target drugs 
to the right patients. This may also include genetic/genomic exploration aimed at exploring disease 
pathways, progression and response to treatment etc. 
Sample Collection and Storage
All requests for access to samples or data for additional research will be vetted through a diverse 
committee of the study sponsor’s senior leaders in Research and Development (or designee) to 
ensure the research supports appropriate and well-defined scientific research activities.
Residual tumor tissue and Serum samples from biomarker and PK collections (see Table 9.8.5-1) 
will also be retained for additional research purposes.
•
Samples kept for future research will be stored at 
 an independent, BMS-approved storage vendor.
The manager of these samples will ensure they are properly used throughout their usable life and 
will destroy the samples at the end of the scheduled storage period, no longer than fifteen (15) 
years after the end of the study or the maximum allowed by applicable law.
Transfers of samples by research sponsor to third parties will be participant to the recipient’s 
agreement to establish similar storage procedures.
Samples will be stored in a coded fashion, and no researcher will have access to the key. The key 
is securely held by the Investigator at the clinical site, so there is no direct ability for a researcher 
to connect a sample to a specific individual.
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Further details of sample collection and processing will be provided to the site in the procedure 
manual.
Table 9.8.5-1:
Residual Sample Retention for Additional Research Schedule
Sample Type
Time points for which residual samples will be retained
PK
All
Tumor Biopsy
All
Serum samples
All
9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
Health Economics/Medical Resource Utilization and Health Economics parameters will not be 
evaluated in this study.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
The study will enroll participants irrespective of the line of therapy, however their randomization 
across study arms will depend on the number of prior lines of systemic treatments they have been 
exposed. In protocol revision 04, 1L expansion was added and the study has two parts of 
enrollment. During part 1 enrollment, participants who have received no more than 1 prior line of 
systemic therapy (0 or 1) will be randomized to nivolumab monotherapy arm (arm A), nivolumab 
plus ipilimumab combination therapy arm (arm B) or an investigator’s choice of chemotherapy 
arm (arm C) at a 2:2:1 ratio. Participants who have received 2 or more prior lines of systemic 
therapy will be randomized to arm A or to arm B at a 1:1 ratio. During Part 1 enrollment, of all 
randomized participants it is expected that proportion of those who have had 0 prior line of 
systemic therapy (1L) will be approximately 35%, those who had 1 prior line of systemic therapy 
(2L) will be approximately 35%, and those who have had a least 2 lines of systemic therapy (3L+) 
will be approximately 30%. Completion of Part 1 enrollment will be triggered based on internal 
assessments to ensure the randomization of approximately 442 participants with dMMR/MSI-H 
per central testing, a number pre-specified in protocol revision 03. Part 2 enrollment was added in 
protocol revision 04 in order to provide appropriate power for PFS comparison among 1L 
participants between arms B vs C and arms B vs A. Part 2 enrollment will start immediately after 
the closure of Part 1 enrollment and only 1L eligible participants will be randomized to arms A, B 
and C at 2:2:1 ratio. 
Comparisons of an efficacy endpoint (eg, PFS, ORR, or OS) between a given two arms will be 
based on concurrently randomized participants to the corresponding two arms, except otherwise 
specified.
Participants will be enrolled based on local evaluation of their dMMR/MSI-H status but the 
primary efficacy populations will consist of participants with centrally confirmed dMMR/MSI-H 
mCRC by either central test (IHC or PCR-based) (Section 5.4.7). It is expected that approximately 
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15% of the participants may not have their local dMMR/MSI-H mCRC confirmed centrally. The 
sample size calculation is based on randomized participants with dMMR/MSI-H status confirmed 
by central tests. Unless otherwise specified, “participants” of Study CA2098HW mentioned in 
Section 10.1 refer to “randomized participants with dMMR/MSI-H status confirmed by central 
tests”; clinical outcomes (e.g., “event,” “response,” etc) of Study CA2098HW mentioned in 
Section 10.1 refer to those observed among randomized participants with dMMR/MSI-H status 
confirmed by central tests.
The sample size of this study will be driven by the comparison of the two primary endpoints and 
the secondary endpoint of PFS comparison between 1L participants randomized to arm B and arm 
A: 
1. PFS comparison between participants randomized to arm B and arm A during Part 1 and 
Part 2 enrollment, hereafter denoted as ‘PFS B vs A in all lines’
2. PFS comparison between participants who have not received prior line of systemic therapy 
and randomized to arm B and arm C during Part 1 and Part 2 enrollment, hereafter denoted 
as ‘PFS B vs C in 1L’. 
3.
PFS comparison between participants who have not received prior line of systemic therapy 
and randomized to arm B and arm A during Part 1 and Part 2 enrollment, hereafter denoted 
as ‘PFS B vs A in 1L’. 
The power calculation for the key secondary endpoints will also be discussed in this section.
Generally, in studies with time-to-event type endpoint, the sample size calculation assumes an 
exponential distribution of the endpoint when treated with chemotherapies. However, in the 
CA209142 study long-term PFS and survival benefit were observed as it has been observed in 
multiple studies evaluating immunotherapeutic agents. When treated with nivolumab monotherapy 
or treated with nivolumab plus ipilimumab, a long lasting plateau towards the end of the Kaplan-
Meier (KM) curves of PFS and OS were observed.29,30,31,32 Recent published results from the 
Keynote-177 study also demonstrated a long lasting plateau towards the end of KM curve of PFS 
in the pembrolizumab arm when directly compared to the chemotherapy arm.1 Based on these data, 
sample size determination for PFS is calculated by assuming a piecewise exponential distribution 
in arm A and B and exponential distribution in arm C.
In order to control the overall type I error at 5%, for the purpose of sample size calculation, the 
alpha is initially split between the two primary endpoints, with 0.6% for PFS B vs A in all lines 
and 4.4% for PFS B vs C in 1L. The secondary endpoint of PFS B vs A in 1L will be tested 
hierarchically. The testing procedure for the other secondary endpoints is provided in the protocol 
Section 10.3.10.
10.1.1
Sample Size Determination of Primary Endpoints
PFS in all lines for comparison between arms B vs A
Initial assumptions
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Prior to Revised Protocol 04, based on the observed PFS curve and rates at different time points 
in the nivolumab monotherapy cohorts of CA209142 (data on file, August 2018 database lock), 
the PFS distribution for nivolumab monotherapy (arm A) was assumed to be piecewise exponential 
with the following landmark PFS rates, as presented in Table 10.1.1-1 below.
Since both arm A and arm B are immunotherapies, no delayed separation of PFS KM curves will 
be expected. A constant hazard ratio (HR) of 0.65 for arm B compared with arm A is assumed 
which therefore translates to piecewise exponential distribution of PFS in arm B (Table 10.1.1-1). 
Under these assumptions, the median estimates for PFS is 6 months and 27 months for 
monotherapy and combination therapy arms, respectively.
Table 10.1.1-1:
PFS Rates of Arm A and Arm B in All Lines and Hazard Ratios
Period
Cumulative PFS Rate 
for Nivolumab (%)
Cumulative PFS Rate 
for Nivolumab and 
Ipilimumab 
Combination (%)
Hazard Ratio
0 - 1 month
93.0
95.4
0.65
3 months
65.0
75.6
0.65
6 months
50.0
63.7
0.65
9 months
45.0
59.5
0.65
12 months
43.0
57.8
0.65
18 months
40.0
55.1
0.65
24 months
36.0
51.5
0.65
36 months
30.0
45.7
0.65
48 months
20.0
35.1
0.65
60 months and after
10.0
22.4
0.65
Abbreviations: PFS, progression free survival
Approximately 354 PFS events will provide about 90% power to detect a HR of 0.65 with an 
overall type 1 error of 0.006 (two-sided). Under the assumption of a staggered enrollment, it is 
required to randomize approximately 564 participants to both arm A and B during Part 1 and Part 
2 enrollment. 
This initial design accounts for one PFS interim look when approximately 80% of the total number 
of events are observed (approximately 283 events). It is projected that Part 1 enrollment will take 
approximately 16 months and Part 2 enrollment will take approximately 14 months. The timing of 
final analysis is projected to be 49 months from the date of first participant being randomized 
during Part 1 enrollment.
Updated assumptions
In protocol revision 03, the assumed PFS rates in arm A in all lines (Table 10.1.1-1) were from the
nivolumab monotherapy cohort of CA209142 based on data with a minimum follow-up of 27.6 
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months (follow-up duration is defined as clinical cut-off date minus first dose date). At the time of 
protocol revision 04 development, updated data from the nivolumab monotherapy cohort of 
CA209142 were available with minimum follow-up of 43 months for nivolumab monotherapy. 
The updated KM curve of PFS in the monotherapy arm suggested even more flattened tail or higher 
PFS rates than currently assumed PFS rates in arm A from 18 months onward (Table 10.1.1-1). 
Meanwhile, the PFS KM curve observed in the pembrolizumab arm of the Keynote-177 study also 
suggested a similar pattern in 1L setting.  Therefore, these newly available data outside of the study 
suggested a more reliable assumption of PFS rates in arm A as presented in Table 10.1.1-2 and 
Figure 10.1.1-1. The updated PFS rates of arm A in all lines suggested that the final analysis timing 
(when at least 354 PFS events are observed) will be delayed to 62 months after first participant 
randomized during Part 1 enrollment. To ensure a timely readout of PFS in all lines in order to 
fulfill the PMR, the final analysis of the primary endpoint of PFS B vs A in all lines will be 
conducted when at least 319 PFS events are observed, which is projected to be approximately 50 
months after the first participant is randomized during Part 1 enrollment. A total of 319 PFS events 
will provide approximately 86% power under the assumption that HR=0.65 for PFS B vs A in all 
lines with two-sided alpha of 0.006. 
Table 10.1.1-2:
PFS Rates in Arm A in All Lines Updated Based on Most Recent 
Data Outside of the Study
Period
Cumulative PFS Rate for Nivolumab (Arm A) (%)  
Across Lines
0 - 1 month
93.0
3 months
65.0
6 months
50.0
9 months
45.0
12 months
44.0
18 months
43.0
24 months
40.0
30 months
38.0
36 months
35.0
42 months and after
32.0
Abbreviations: PFS, progression free survival
In addition, indirect comparisons between the combination cohort vs monotherapy cohort of the 
CA209142 study have consistently suggested a lower HR than assumed 0.65 between arms B vs 
A in the 2L+ setting. In 1L setting, the indirect comparison of PFS from 1L combination cohort of 
CA209142 and the pembrolizumab monotherapy of the Keynote-177 study also suggested a lower 
HR than 0.65. Under the assumption that HR=0.635 for PFS B vs A in all lines, the 319 PFS events 
will provide 90% power for PFS B vs A in all lines. Figure 10.1.1-1 shows the assumed PFS 
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distribution of arm A and arm B in all lines, under a constant HR of 0.65 and 0.635 for PFS in B 
vs A.
Overall, with the 564 participants concurrently randomized to arm B and arm A across lines and 
followed until at least 319 PFS events are observed, it will provide a power of 90% with two-side 
alpha of 0.006 for HR of 0.635. If PFS B vs C in 1L meets the pre-specified statistical criteria at 
the interim or final analysis and 0.024 alpha is passed to PFS B vs A in all lines, 319 PFS events 
will provide approximately 96.8% power with two-sided alpha of 0.03 for HR of 0.635. Details on 
alpha for this test is described in Section 10.3.10. An interim analysis will be conducted when 
approximately 85% of the total number of events are observed (approximately 271 events) and 
after the last participant is randomized during Part 2 enrollment. 
PFS B vs C in 1L has been tested at its interim analysis (Data cut-off date: 12-Oct-2023; 
DBL: 15-Nov-2023) and met the pre-specified statistical criteria. Therefore, 0.024 alpha was 
passed to PFS B vs A in all lines. PFS B vs A in all lines has not been tested yet and is projected 
to be significantly delayed from protocol assumption. As a result of the PFS events delay, the 
study-wise final analysis (OS final analyses), defined at the 5 years from the first participant’s 
randomization (Aug-2019), which is around Aug-2024, is no longer feasible because it is prior to 
the conclusion of its precedents endpoints thus will deviate from the testing strategy (Figure 
10.3.10-1). In order to maintain the testing strategy in the pre-planned analysis around Aug-2024, 
the study-wise final analysis for OS at the 5-year mark is removed and an interim analysis of PFS 
B vs A in all lines is added at this time. It is projected that the PFS events for Arm B vs A in all 
lines will reach approximately 240 events (~75% of the total number of events) around Aug-2024. 
If PFS B vs A in all lines met its pre-specified statistical significance in this IA, the secondary 
endpoints including OS (IA) are allowed to be tested following the testing strategy. The originally 
planned PFS IA B vs A in all lines at approximately 271 events will be the second IA after the one 
around Aug 2024. The target number of events for the PFS FA B vs A in all lines (approximately 
319 events) remain unchanged. The final analysis of PFS B vs A in all lines will be conducted 
when approximately 319 events are observed or 2 years after the last participant from Part 2
enrollment was randomized (“2-year minimum follow-up”), whichever occurs first.
At a 2-year minimum follow-up, the estimated median follow-up will be approximately 4 years, 
given the long enrollment period. Data from study CA209142 and from an external study of single 
agent checkpoint inhibitors in 1L MSI-H/dMMR mCRC for which long-term results are available, 
clearly illustrates flattening of PFS KM curves (for nivo+ipi and nivo [from study CA209142] and 
single agent checkpoint inhibitors) starting at Month 24.90,91 Assuming a similar trend in study 
CA2098HW, a limited accumulation of PFS events is expected beyond the 2-year minimum 
follow-up for all participants. 
Therefore, PFS B vs A in all lines will have 2 IAs (1 at approximately 240 events with a data 
cut-off around Aug-2024 [newly added] and 1 at approximately 271 events [previously planned]) 
and a FA (previously planned, but with updated timing: when approximately 319 events are 
observed or 2 years after the last participant from Part 2 enrollment was randomized, whichever 
occurs first). The second IA will be skipped if the projected time of the second PFS IA B vs A in
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all lines is too close to the proposed PFS FA time (eg, less than 6 months apart), or it is projected 
to be after the proposed PFS FA time.
The significance level for the PFS IA(s) will be determined based on the observed information 
fraction (“IF”) of the planned total number of 319 events. If the second IA is skipped, no alpha 
will be spent for the second IA and the remaining alpha level after the first IA will be used at the 
FA. The significance level for the PFS FA will be calculated according to the actual alpha(s) spent 
at IA(s). If less than 319 events are observed, the significance level will be based on the planned 
319 events without further adjustment for the actual total number of PFS events. 
Figure 10.1.1-1:
PFS Assumptions of the CA209-8HW Study
Abbreviations: ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
PFS in 1L for comparison between arms B vs C
The sample size for the PFS B vs C in 1L is determined with following additional assumptions:
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•
The distribution of PFS in arm A in 1L is assumed based on observed data in the Keynote-177 
study. Table 10.1.1-3 presents the assumed PFS rates for arm A in 1L and the PFS rates in arm 
B in 1L by assuming a constant HR of 0.6 vs arm A in lL.
•
The distribution of PFS in arm C in 1L follows exponential distribution with median PFS of 9 
months.
The assumed PFS curves of arms A, B and C in 1L is presented in Figure 10.1.1-1. Based on 
simulations, approximately 125 PFS events will provide about 99% power to detect an average 
HR of 0.55 with an overall type 1 error of 0.044 (two-sided). Under the assumption of a staggered 
enrollment, it is required to randomize approximately 230 1L participants to arms B and C during 
Part 1 and Part 2 enrollment at 2:1 ratio. 
This design accounts for one PFS interim look when 85% of the total number of events are 
observed (approximately 106 events) and after the last participant is randomized during Part 2 
enrollment. The final analysis is projected to be approximately 47 months, from the date of first 
participant being randomized to Part 1.
To ensure the sample size is sufficient for both of the primary endpoints as discussed above, Part 
1 randomization will be closed when approximately 442 participants randomized with central lab 
confirmed dMMR/MSI-H. This translates to an approximate number of participants in arm A 
(N=190), B (N=190) and C (N=62) as arm C will only randomize participants who received 0 or 
1 prior lines of therapy. Part 2 will randomize approximately 230 1L participants with central lab 
confirmed dMMR/MSI-H.  This translates to an approximate number of participants in arm A 
(N=92), B (N=92) and C (N=46). 
PFS B vs C in 1L has been tested at its interim analysis (Data cut-off date: 12-Oct-2023; 
DBL: 15-Nov-2023) and met the pre-specified statistical criteria. Therefore, PFS B vs C in 1L is 
concluded and will not be tested again in a final analysis.
Table 10.1.1-3:
PFS Rates and Hazard Ratio for 1L Participants
Period
Cumulative PFS rates 
for Nivolumab (Arm A) 
(%) in 1L
Cumulative PFS rates 
for Nivolumab + 
Ipilimumab (Arm B) 
(%) in 1L
Hazard Ratio of B vs A 
in 1L 
0 - 1 month
93.0
95.7
0.6
3 months
67.0
78.6
0.6
6 months
55.0
69.9
0.6
9 months
52.0
67.5
0.6
12 months
50.0
66
0.6
18 months
47.0
63.6
0.6
24 months
45.0
61.9
0.6
30  months
42.0
59.4
0.6
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930125433
13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Table 10.1.1-3:
PFS Rates and Hazard Ratio for 1L Participants
Period
Cumulative PFS rates 
for Nivolumab (Arm A) 
(%) in 1L
Cumulative PFS rates 
for Nivolumab + 
Ipilimumab (Arm B) 
(%) in 1L
Hazard Ratio of B vs A 
in 1L 
36 months
37.0
55.1
0.6
42 months and after
35.0
53.3
0.6
Abbreviations: PFS, progression free survival
10.1.2
Power Calculation of Secondary Endpoints
This section describes the power for the secondary endpoints of PFS of arms B vs A in 1L, ORR 
and OS comparisons between arms B vs A in all lines and ORR of arms B vs C in 1L and B vs A 
in 1L to be tested under the planned testing procedure (Section 10.3.10). Based on the planned 
testing procedure, there is no initial alpha allocation to these endpoints. These endpoints only will 
be tested once alpha from endpoint(s) at higher order meet the statistical significance at the pre-
specified significance level at IA or FA. 
PFS in 1L for comparison between arms B vs A 
The PFS comparison between arm B vs arm A for 1L participants is the first secondary endpoint. 
Using the sample size as determined for the primary endpoints, the power calculation for PFS B 
vs A in 1L is calculated under the following assumptions:
•
The PFS KM curve in arm A 1L follows the piece-wise exponential distribution as presented 
in Table 10.1.1-3 (Figure 10.1.1-1). 
•
A constant HR of 0.6 is assumed for PFS in 1L arm B vs arm A
•
The concurrent randomization ratio of arm B vs arm A is 1:1 Based on the sample size 
determined by the primary endpoints, it is estimated that a total of 308 1L participants will be 
concurrently randomized to arms A and B
•
One interim analysis of PFS of arm B vs arm A in 1L is planned. PFS B vs C in 1L has been 
tested at its interim analysis (Data cut-off date: 12-Oct-2023; DBL: 15-Nov-2023) and met the 
pre-specified statistical criteria. If PFS B vs A in all lines meets its pre-specified statistical 
criteria at its first interim analysis with the data cut-off around Aug-2024, interim analysis of 
PFS B vs A in 1L will be conducted at the same time. It is projected that approximately 75%
of the total number of PFS events of arm B vs arm A in 1L will be observed (approximately 
117 events) in around Aug-2024. If PFS B vs A in all lines does not meet the pre-specified 
statistical criteria at its first interim analysis, PFS B vs A in 1L interim analysis will be skipped
and the endpoint will be tested at its final analysis. Details on the testing procedure is described 
in Section 10.3.10. 
•
Under the above assumptions, a total of 156 PFS events will provide approximately 87% power 
with two-sided alpha of 0.044 to demonstrate statistical significance of arm B vs arm A in  1L. 
If PFS B vs A in all lines does not meet the pre-specified statistical criteria in the final analysis 
and PFS B vs A in 1L is tested with alpha of 0.02 passed only from PFS B vs C in 1L, 156 PFS 
events will provide approximately 79.5% power. Final analysis of PFS B vs A in 1L will be 
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13.0
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930125433
13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
conducted when approximately 156 events are observed or 2 years after the last participant
from Part 2 enrollment was randomized, whichever occurs first.
The secondary endpoints of ORR of arms B vs A in all lines, OS of arms B vs A in all lines, ORR 
of arms B vs C in 1L, ORR of B vs A in 1L, OS of arm B vs C in 1L and OS of arm B vs A in 1L 
will be tested under the planned testing procedure described in protocol Section 10.3.10. Based on 
the planned testing procedure, there is no initial alpha allocation to these endpoints. These 
endpoints will only be tested once alpha from endpoint(s) at higher order meets the statistical 
significance at the pre-specified significance level at IA or FA. The power of ORR and OS tests 
based on the assumption that all PFS tests meet the pre-specified statistical criteria at the interim 
or final analysis is listed below. 
ORR in all lines for comparison between arms B vs A
ORR comparison between arm B vs arm A in all lines is a key secondary endpoint. The observed 
ORR per BICR assessment for all treated participants in study CA209142 are 54.6% and 36.5% 
for the combination and monotherapy arms, respectively (data on file, Aug 2018), resulting in the 
ORR difference of approximately 18%. Considering the approximately 564 randomized 
participants to arm A and arm B as determined by the primary endpoints of PFS, there will be 
about 93.1% power to show a statistically significant result in ORR between arm B and arm A 
with an overall type 1 error of 0.006 (two-sided).  The ORR comparison between arm B vs arm A 
will be tested under the pre-specified testing procedure in order to control the overall type I error 
of the study (Section 10.3.10).
ORR in 1L for comparison between arms B vs C
ORR comparison between arm B vs arm C in 1L is a key secondary endpoint. The observed ORR 
per BICR assessment in the chemotherapy arm in the Keynote-177 study is 33% and the observed 
ORR per BICR assessment for 1L combination cohort is 62% (data on file, Nov 2019 DBL),92
resulting in the ORR difference of approximately 29%. Considering the approximately 230 
randomized participants to arm B and arm C as determined by the primary endpoints of PFS, there 
will be about 98% power to show a statistical significant result in ORR between arm B and arm C 
with an overall type 1 error of 0.044 (two-sided). The ORR comparison between arm B vs arm C 
in 1L will be tested under the pre-specified testing procedure in order to control the overall type I 
error of the study (Section 10.3.10).
ORR in 1L for comparison between arms B vs A
ORR comparison between arm B vs arm A in 1L is a key secondary endpoint. The observed ORR 
per BICR assessment in the pembrolizumab arm in the Keynote-177 study is 44% and the observed 
ORR per BICR assessment for 1L combination cohort is 62% (data on file, Nov 2019 DBL),92
resulting in the ORR difference of approximately 18%. Considering the approximately 308 
randomized participants to arm A and arm B as determine by the primary endpoints of PFS, there 
will be about 86% power to show a statistical significant result in ORR between arm B and arm A 
with an overall type 1 error of 0.044 (two-sided). The ORR comparison between arm B vs arm A 
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13.0
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
in 1L will be tested under the pre-specified testing procedure in order to control the overall type I 
error of the study (Section 10.3.10).
OS in all lines for comparison between arms B vs A
OS comparison between arm B vs arm A in all lines is a key secondary endpoint. The OS 
distribution is under similar assumptions as for PFS, ie, of a piecewise exponential distribution for 
OS KM curve in arm A and a constant HR of arm B compared to arm A.
Based on the observed OS curve and rates in the nivolumab monotherapy cohort of CA209142 
from the November 2019 DBL (data on file), the OS distribution for nivolumab monotherapy arm 
was assumed to be piecewise exponential with the following landmark OS rates, as presented in 
Table 10.1.2-1 below:
Table 10.1.2-1:
OS Rates and Hazard Ratios
Period
Cumulative OS Rate for 
Nivolumab (%)
Cumulative OS Rate for 
Nivolumab and 
Ipilimumab 
Combination (%)
Hazard Ratio
0 - 1 month
97.0
98.0
0.65
3 months
89.0
92.7
0.65
6 months
82.0
87.9
0.65
9 months
75.0
82.9
0.65
12 months
70.0
79.3
0.65
18 months
65.0
75.6
0.65
24 months
58.0
70.2
0.65
30 months
55.0
67.8
0.65
36 months
54.0
67.0
0.65
42 months and after
52.0
65.4
0.65
Abbreviations: OS, overall survival
Under this assumption of a constant HR and considering the approximately 564 randomized 
participants to arm A and arm B as determined by the primary endpoints of PFS, approximately 
243 OS events provide about 91% power to detect a HR of 0.65 with an overall type 1 error of 
0.05 (two-sided). 
This calculation accounts for two OS interim looks planned: the first look is at the time of the PFS 
interim analyses and the second look is at the time of the PFS final analyses. The final OS analysis 
was initially planned at approximately 5 years after the randomization of the first participant, 
which is no longer feasible as explained in Section 10.1.1. To allow extended follow-up for 
survival data collection, final OS analyses will be conducted 3 years after the last participant from 
Part 2 enrollment was randomized (“3-year minimum follow-up”): the final analysis of OS B vs 
A in all lines will be conducted when approximately 243 events are observed or 3-year minimum 
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13.0
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
follow-up is achieved, whichever occurs first. OS event accumulation is expected to be very 
limited (eg, very few events per year) after 3-year minimum follow-up based on blinded OS event 
projections. Data from study CA209142 and from an external study of single agent checkpoint 
inhibitors in 1L MSI-H/dMMR mCRC for which long-term results are available illustrates
flattening of OS Kaplan-Meier curves starting from Month 36.91,93
The OS will be tested under the pre-specified testing procedure (Section 10.3.10) in order to 
control the type I error. 
10.2
Populations for Analyses
Corresponding with the two primary endpoints, the study will have two sets of participants for 
conducting statistical analyses. The populations defined below (except for enrolled participants) 
will apply to each of the sets of participants unless otherwise specified: 
•
All lines participants: all participants across lines randomized to arms A, B and C through Part 
1 and Part 2 enrollment.
•
1L participants: all  participants in 1L randomized to arms A, B and C through Part 1 and Part 
2 enrollment.
For purposes of analyses, the following populations are defined:
Population
Description
Enrolled 
All participants who signed an informed consent form and were 
registered into the IRT system.
Randomized
All participants who were randomized to any treatment arm in the 
study. 
Confirmed dMMR/MSI-H
All randomized participants who have centrally confirmed 
dMMR/MSI-H status by either central test (IHC or PCR). This is 
the primary population for efficacy analyses.
Confirmed dMMR/MSI-H 
by IHC
All randomized participants who have centrally confirmed 
dMMR/MSI-H status by central test per IHC. This is the primary 
population for efficacy analyses supporting IVD of IHC.
Confirmed dMMR/MSI-H 
by PCR
All randomized participants who have centrally confirmed 
dMMR/MSI-H status by central test per PCR. This is the primary 
population for efficacy analyses supporting IVD of PCR.
Treated
All participants who received at least one dose of study treatment 
(nivolumab or ipilimumab or investigator’s choice 
chemotherapy). This is the primary population for safety 
analyses.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Population
Description
Response Evaluable
All randomized participants who have baseline and at least one 
on-study evaluable tumor measurement. This population will be 
defined based on Investigator and BICR data.
PK
All treated participants with available serum time-concentration 
data.
Immunogenicity
All treated participants with available immunogenicity data.
Biomarker
All randomized participants with available biomarker data.
Outcomes Research
All randomized participants who have an assessment at baseline 
and at least one subsequent post-baseline assessment (for 
EORTC QLQ-C30, QLQ-CR29 and EQ-5D-3L separately).
Crossover Cohort treated 
All participants who received at least one dose of study 
medication following crossover to the nivolumab plus 
ipilimumab treatment.
As appropriate, other populations will be defined in the Statistical Analysis Plan (SAP).
Participants enrolled in the China extension will not be included in the above listed populations 
for analyses. 
10.3
Statistical Analyses
10.3.1
General Considerations
The primary and key secondary estimands are described in Table 4-1.
The statistical analysis plan (SAP) will be developed and finalized before database lock and will 
describe the selection of participants to be included in the analyses, and procedures for accounting 
for missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary, secondary and other key endpoints. 
A description of the participant population will be included in a statistical output report, including 
subgroups of age, gender, and race. 
Analyses related to the China Sub-study which includes enrolled participants in China extension 
will be specified in the China-specific protocol and China-specific SAP. 
10.3.2
Efficacy Analyses
The primary efficacy population will be the “Confirmed dMMR/MSI-H” participants. Appropriate 
analyses will be performed for “Confirmed dMMR/MSI-H by IHC” and “Confirmed dMMR/MSI-
H by PCR” to demonstrate comparable efficacy based on dMMR/MSI-H by one of the central test. 
These analyses will support the clinical utility of the IVD for each of the central test. SAP will 
document further details. The endpoints defined below will apply to both All participants and 1L 
participants, unless otherwise specified.
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930125433
13.0
v
Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Endpoint 
Statistical Analysis Methods
Primary
BICR-assessed Progression-free survival (PFS) is 
defined as the time from the randomization 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.
•
Participants who die without a reported prior 
progression and without initiation of subsequent 
anti-cancer therapy will be considered to have 
progressed on the date of their death.
•
Participants who did not progress or die will be 
censored on the date of their last tumor assessment. 
•
Participants who did not have any on study tumor 
assessments and did not die will be censored on the 
randomization date. 
•
Participants who started any subsequent anti-cancer 
therapy without a prior reported progression or 
prior to death will be censored at the last tumor 
assessment prior to initiation of the subsequent anti-
cancer therapy.
•
Further explanation for various censoring scenarios 
for PFS will be specified in SAP.
The distribution of PFS will be 
compared via a two-sided, log-rank 
test 
stratified 
by 
randomization 
stratification factors of line of therapy 
(not applicable to PFS in 1L) and 
tumor sidedness recorded in IRT at the 
allocated significance level at IA and 
FA.
The hazard ratio (HR) and the 
corresponding 
100x 
(1-adjusted 
alpha)% confidence interval (CI) will 
be estimated in a stratified Cox 
proportional hazards model using the 
randomized arm as a single covariate, 
stratified by line of therapy and tumor 
sidedness as recorded in IRT. 
PFS curves will be estimated using 
Kaplan-Meier (KM) product-limit 
methodology. Median PFS with two-
sided 95% confidence interval (CI) 
using the Brookmeyer and Crowley 
method (with log-log transformation) 
will be computed. 
In addition, PFS rates at a specific 
time point (eg, 6, 12, 24 months) with 
two-sided 95% CI using the log-log 
transformation will be computed.
Secondary
Investigator-assessed PFS is defined similarly as 
BICR-assessed PFS.
Analyses methods for PFS by 
investigator will be similar as PFS by 
BICR.
Overall Survival (OS) is defined as the time from the 
randomization 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 methods for OS will be 
similar as PFS.
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13.0
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930125433
13.0
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Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Endpoint 
Statistical Analysis Methods
Best Overall Response (BOR) for a participant will be 
assessed per RECIST 1.1 by BICR and by investigator. 
BOR is defined as the best response designation, 
recorded between the randomization date and the date 
of the initial objectively documented tumor progression 
per RECIST v1.1 or the date of initiation of subsequent 
therapy, whichever occurs first. For participants 
without documented progression or initiation of 
subsequent therapy, all available response designations 
will contribute to the BOR determination.
Objective Response Rate (ORR) is defined as the 
proportion of all randomized participants whose BOR 
is either confirmed complete response (CR) or 
confirmed partial response (PR). 
Disease Control Rate (DCR) is defined as the 
proportion of participants whose BOR is confirmed CR 
or confirmed PR or stable disease (SD) for at least 12 
weeks. 
Time to Response (TTR) is defined as the time from the 
randomization date to the date of first confirmed CR or 
PR. TTR will be evaluated for responders only.
Duration of Response (DOR) for a participant with a 
BOR of confirmed CR or PR, is defined as the time 
between the date of first confirmed response and the 
date of the first objectively documented tumor 
progression per RECIST 1.1 or death due to any cause, 
whichever occurs first. The rules of censoring are the 
same as PFS.
ORR will be compared using a two-
sided 
stratified 
Cochran 
Mantel 
Haenszel 
(CMH) 
test 
using 
stratification as recorded in IRT.
Associated odds ratio and estimate of 
the difference in ORRs with 95% CI 
will be calculated. The ORR/DCR 
will be summarized by binomial 
response rates and corresponding two-
sided 95% exact CI using the Clopper-
Pearson method.
TTR will be summarized using the 
mean, 
median, 
minimum 
and 
maximum 
values, 
and 
standard 
deviation.
Analyses methods for DOR will be 
similar as PFS/OS.
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13.0
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930125433
13.0
v
Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Endpoint 
Statistical Analysis Methods
Exploratory
Investigator-assessed second disease progression or 
death (PFS2) is defined as the time from randomization 
to the date of investigator-defined documented disease 
progression per RECIST 1.1 during next line of 
treatment or death due to any cause, whichever comes 
first. Clinical deterioration will not be considered as 
progression. Participants who were alive and without 
progression after the next line of therapy will be 
censored at last known alive date. Explanation for 
censoring of PFS2 will be specified in SAP.
Analyses methods for PFS2 by 
investigator 
will 
be 
similar 
as 
PFS/OS.
Investigator-assessed time to treatment failure (TTF) is 
defined as the time from randomization to the date of 
treatment discontinuation regardless of the cause. 
Participants who were on treatment will be censored at 
the last know alive date.
Analyses 
methods 
for
TTF 
by 
Investigator 
assessment
will 
be 
similar as PFS/OS.
Recurrence free survival (RFS) is defined as the time 
from the date of the on study curative surgery to the 
disease recurrence as assessed by investigator per 
RECIST 1.1 or death due to any cause, whichever 
occurs first. This will be evaluated for participants who 
receive on study curative surgery.
Analyses 
methods 
for
RFS 
by 
Investigator 
assessment
will 
be 
similar as PFS/OS.
10.3.3
Safety Analyses
All safety analyses will be performed on the Treated population. Below is a summary of planned 
statistical analyses of key safety endpoints. Additional analyses will be described in the SAP.
Endpoint 
Statistical Analysis Methods
Exploratory
Incidence of AEs, SAEs, AEs leading to 
discontinuation (with or without relationship 
to study drug), and deaths
AEs will be graded according to CTCAE 
(Version 5).
AEs will be summarized using the worst CTC 
grade. Participants will only be counted (1) 
once at the preferred term (PT) level, (2) once 
at the system organ class (SOC) level, and (3) 
once in the ‘Total participant’ row at their 
worst CTC grade, regardless of SOC or PT.
Deaths will be summarized using frequency 
distribution.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Endpoint 
Statistical Analysis Methods
Laboratory abnormalities
Laboratory values will be graded according to 
NCI CTCAE (Version 5)
Laboratory abnormalities will be summarized 
using the worst CTC grade on treatment per 
participant
10.3.4
Analyses of Crossover Cohort Treated Participants
As discussed in Section 5.1 participants in arm C who have BICR-confirmed PD on or following 
Investigator’s Choice chemotherapy have the option to receive nivolumab plus ipilimumab 
combination therapy. 
Impact of crossover in arm C to the key efficacy and safety endpoints: 
As crossover occurs after the BICR confirmed disease progression and completion of follow-up 
visit 1, it will not impact the tumor based efficacy endpoint such as PFS, ORR, DOR and DCR. 
For the OS analyses, intention to treat principle will be followed, i.e., regardless of crossover status 
of participants in the arm C. It should not impact safety analyses as crossover occurs after 
completion of follow-up visit 1. However, for rare situations such as an adverse event lasts beyond 
the first follow-up visit, or the IMAE analyses which uses 100 days window from last dose date 
(although it is unlikely to see IMAE in arm C), safety analysis will include all events occur upon 
initiation of crossover. 
Analyses of Crossover Cohort:
The same methodologies as used for the primary, secondary and exploratory efficacy endpoints 
will be used to analyze any specific endpoints defined to evaluate the clinical activity of the 
nivolumab plus ipilimumab combination treatment after crossover, if feasible. 
Selected safety analyses will be repeated to evaluate the safety of the combination treatment after 
crossover. 
Other analyses including pharmacokinetic, immunogenicity, biomarker and outcome research will 
be conducted as described in respective sections of the protocol, if feasible. Details on the analysis 
of the crossover-treated participants will be defined in the SAP. 
10.3.5
Pharmacokinetic Analyses
The nivolumab and ipilimumab serum concentration vs time data obtained in this study may be 
combined with data from other studies in the clinical development program to develop population 
PK models. These models may be used to evaluate the effects of intrinsic and extrinsic covariates 
on the PK of nivolumab and ipilimumab and to determine measures of individual exposure (such 
as steady state peak, trough and time averaged concentration). Model determined exposures may 
be used for exposure response analyses of selected efficacy and safety endpoints. If the analyses 
are conducted, the results of population PK and exposure response analyses will be reported in a 
standalone report.
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
10.3.6
Immunogenicity
Summary of the incidence of ADA-positive status (such as persistent positive, only last sample 
positive, other positive, baseline positive) and ADA-negative status relative to baseline will be 
reported. In addition, presence of neutralizing antibodies may be reported, if applicable. Effect of 
immunogenicity on safety, efficacy, biomarkers and PK may be explored. Additional details will 
be described in the SAP.
10.3.7
Biomarker Analyses
Summary measures of change (or % change) from baseline in various biomarkers and summary 
measures of anti-tumor activity by pretreatment level of biomarkers of interest will be provided. 
Methodology for exploratory biomarker analyses will be further described in the SAP.
10.3.8
Outcomes Research Analyses
10.3.8.1
EORTC QLQ-C30 and QLQ-CR29
The analysis of EORTC QLQ-C30 and QLQ-CR29 will be performed in all randomized 
participants who have an assessment at baseline and at least one subsequent assessment. 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/QoL composite scale data and the remaining EORTC QLQ-C30 and QLQ-CR29 
scale data will be summarized by time point using descriptive statistics for each cohort (N, mean 
with SC 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 participants assessed at assessment time point.
10.3.8.2
EQ-5D-3L
Participant’s overall health state on a visual analog scale (EQ-VAS) and utility index scores (based 
on UK weighting algorithm94), 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. 
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.
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13.0
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930125433
13.0
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Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
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.
10.3.9
Other Analyses
Data on PFS, OS, ORR, and BOR will be summarized for randomized participants with 
dMMR/MSI-H confirmation per each in vitro diagnostic (IVD)/companion diagnostics (CDx) 
testing methodology.
10.3.10
Strong Control of Type I Error
The following testing strategy provides a strong control of family wise error rate (FWER) at alpha 
(α) level of 5% for the primary and key secondary endpoints of this study. 
For the 2 primary endpoints of PFS B vs A in all lines and PFS B vs C in 1L, 0.6% and 4.4% are 
initially allocated respectively. The interim analysis (IA) of each primary PFS will be event driven. 
If the projection suggests that IA of PFS B vs A in all lines and IA of PFS B vs C 1L will occur 
within 3 months from each other, they can be combined and conducted at the latest projected time. 
Details are defined in Section 10.3.11. Figure 10.3.10-1 presents the graphical approach to be used 
to control the type I error in a strong sense for testing of primary and key secondary endpoints.95
For example, if PFS B vs C in 1L meets the pre-specified statistical criteria at the interim or final 
analysis, then 2.4% α will be passed to PFS B vs A in all lines and 2% α will be passed to PFS B 
vs A in 1L. PFS B vs A in all lines will then be tested with 3% α (0.6% initial α plus 2.4% α passed 
from PFS B vs C in 1L). If PFS B vs A in all lines meets the pre-specified statistical criteria at the 
interim or final analysis, then 2.4% α will be passed to PFS B vs A in 1L, and PFS B vs A in 1L 
will be tested with a total of 4.4% α. If PFS B vs A in all lines does not meet the pre-specified 
statistical criteria at the final analysis, then PFS B vs A in 1L will be tested with 2% α which is 
collected from PFS B vs C in 1L only.    
The testing procedure will only allow to test a secondary endpoint if all the precedent endpoints 
complete their tests. Testing will only be performed in the forwarding path (no retrospectively 
testing) and if an endpoint receives alpha from two precedent endpoints, the endpoint will only be 
tested once the testing of these two endpoints are completed (regardless of significance or not). 
Full scope of statistical testing procedure will be documented in the SAP, including additional 
secondary endpoints of OS to be tested and details of alpha spending at IA and FA for each 
endpoint.
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Clinical Protocol
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BMS-936558
nivolumab
Figure 10.3.10-1:
Testing Procedure for Primary and Secondary Endpoints
Abbreviations: ORR, objective response rate; OS, overall survival; PFS, progression-free survival.
10.3.11
Interim Analyses
The DMC will be utilized to provide an independent evaluation of the study interim data. An 
independent statistical group will be utilized to conduct unblinded monitoring of pooled events of 
the two corresponding arms of each comparison in order to track the number of events by each 
comparison. 
Study-wise, there are two interim analyses (IA) planned for primary and secondary endpoints prior 
to the final analysis of OS endpoints. 
•
The first interim analysis of the study is planned for the interim analysis for both the primary 
endpoints of PFS. Considering the variability of the enrollment assumptions from the actual 
enrollment rate and differences of the shape of PFS curves in arms A, B, and C, this study 
plans to have the interim analysis of PFS for the 2 primary endpoints at the same time when 
the latest of the targeted number of events of each endpoint is observed and after the last 
participant is randomized during Part 2 enrollment. In other words, the first interim analysis of 
the study was planned to be triggered when at least 85% of the total number of events were 
observed for both PFS primary endpoints and after the last participant was randomized during 
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nivolumab
Part 2 enrollment. Separate database locks for IA PFS B vs C in 1L and IA PFS B vs A in all 
lines may be conducted if the locks are expected to occur at least 3 months apart from each 
other. As of Protocol Amendment 10, PFS B vs C in 1L has been tested at its interim analysis 
(Data cut-off date: 12-Oct-2023; DBL: 15-Nov-2023) and met the pre-specified statistical 
criteria. Interim analysis of PFS B vs A in all lines will be conducted in a separate DBL with 
a data cut-off in around Aug-2024 (“PFS B vs A all lines IA1 DBL”). If PFS B vs A in all lines 
does not meet the pre-specified statistical criteria in the first interim look, a second interim 
look (“PFS B vs A all lines IA2 DBL”) may be conducted if the projected time between the 
second interim look and final look is more than 6 months. The interim analysis of the secondary 
endpoint PFS B vs A in 1L will be conducted when PFS B vs A in all lines meets the 
pre-specified statistical criteria at its interim analysis. The stopping boundaries at the interim 
analysis for each of the PFS endpoints will be derived based on the exact number of events 
observed in the locked database using Lan-DeMets alpha spending function with 
O’Brien-Fleming boundaries. For any PFS endpoint, if the timing of interim analysis based on 
this trigger is too close to the projected time of its final analysis (eg, within 6 months), the 
interim analysis of this specific PFS endpoint may be skipped and the endpoint will be tested 
at the final analysis.
•
Since PFS B vs C in 1L has been concluded, the second interim analysis of the study will be 
the final analysis of PFS B vs A in all lines and PFS B vs A in 1L, which will be conducted 
when the required number of total events are observed or 2 years after the last participant from 
Part 2 enrollment was randomized, whichever occurs first.
•
The final analysis of this study will include the final OS analysis for arm B vs arm A in all 
lines, Arm B vs Arm C in 1L, and Arm B vs Arm A in 1L, which will be conducted 3 years 
after the last participant in Part 2 enrollment was randomized. 
•
As described above, these interim and final analyses may be triggered by more than one 
endpoints and therefore all the events observed in the two arms for the corresponding 
comparisons will be used for the analyses. For a given endpoint, the stopping boundaries (alpha 
allocation) at interim analysis will be derived based on the exact number of events observed in 
the locked database (vs target number of events at final analysis) using Lan-DeMets alpha 
spending function with O’Brien-Fleming boundaries. In the scenario that the final analysis of 
an endpoint is events-driven and the locked database has more events than planned, the final 
allocation of alpha will be adjusted based on actual number of events observed at the final 
analysis.   
Additional secondary endpoints will be tested per the testing procedure (Section 10.3.10) at these 
interim and final analyses. Once one of the primary endpoints of PFS meets the pre-specified 
statistical criteria at the interim or final analyses, the secondary and exploratory endpoints in the 
same set of participants will be analyzed. Secondary endpoints (to be tested under the testing 
procedure, Section 10.3.10) which have not met the pre-specified statistical significance level may 
not be reported in an aggregated fashion and may be analyzed at the final analysis. 
In addition, an ad hoc interim analysis of ORR estimation in arm A, B and arm C for 1L participants 
may be conducted to support potential 1L regulatory submission’s need. No statistical comparison 
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will be made among arms. Should such an interim analysis occur, the SAP will specify the details, 
including the timing, and number of participants to be used, prior to the database lock.
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11
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nivolumab
14 Sargent DJ, Marsoni S, Monges G, et al. Defective mismatch repair as a predictive marker for 
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2008;134:988–97.
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27 Saeterdal I, Bjørheim J, Lislerud K, et al. Frameshift mutation-derived peptides as tumor 
specific antigens in inherited and spontaneous colorectal cancer. Proc Nat Acad Sci USA 
2001;98:13255–60.
28 Brahmer JR, Drake CG, Wollner, I, et al. Phase I study of single-agent anti–programmed death-
1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and 
immunologic correlates. J Clin Oncol 2010;28:3167-75.
29 Overman, MJ, McDermott, R, Leach, JL et al. Nivolumab in patients with metastatic DNA 
mismatch repair deficient/microsatellite instability-high colorectal cancer (CheckMate 142): 
results of an open-label, multicentre, phase 2 study. (published online July 19.) Lancet Oncol. 
2017.
30 Overman M, Bergamo F, McDermott R et al. Journal of Clinical Oncology 36, no. 4_suppl 
(February 1 2018) 554-554.
31 Andre T, Lonardi S, Wong M, et al. Nivolumab + ipilimumab combination in patients with 
DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic 
colorectal cancer (mCRC): First report of the full cohort from CheckMate-142.Journal of 
Clinical Oncology 36, no. 4_suppl (February 1 2018) 553-553
32 Lenz H-J., et al. Nivolumab (NIVO) + low-dose ipilimumab (IPI) as first-line (1L) therapy in 
microsatellite instability-high/DNA mismatch repair deficient (MSI-H/dMMR) metastatic 
colorectal cancer (mCRC): Clinical update. J Clin Oncol 37, 2019 (suppl; abstr 3521).
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37 Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
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39 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
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40 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(23):7412-20.
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41 Postow MA, Harding J, Wolchok JD. Targeting immune checkpoints: Releasing the restraints 
on anti-tumor immunity for patients with melanoma. Cancer J. 2012;18:153-159.
42 BMS-936558. A Phase 1b, open-label, mulicenter, multidose, dose-escalation study of MDX-
1106 (BMS-936558) in combination with ipilimumab (BMS-734016) in subjects with 
unresectable stage III or stage IV malignant melanoma. BMS Clinical Study Report 
CA209004, December 2014.
43 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med. 2013;369:122-33.
44  Hammers HJ, Plimack ER, Infante JR, et al., Safety and Efficacy of Nivolumab in Combination 
With Ipilimumab in Metastatic Renal Cell Carcinoma: The CheckMate 016 Study. J Clin 
Oncol. 2017 Dec 1;35(34):3851-3858.
45 BMS-936558. A Phase 1 Study of Nivolumab (BMS-936558) plus suntinib, pazopanib or 
ipilimumab in subjects with metastatic renal cell carcinoma (Study CA209016). Bristol-Myers 
Squibb Company; 2016. Document Control No. 930108520. 
46 Hellmann, MD, Gettinger, SN, Goldman, JW, et al. CheckMate 012: Safety and efficacy of 
first-line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. J Clin 
Oncol. 2016;34 (suppl; abstr 3001). 
47 Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med. 2015 Jul 2;373(1):23-34.
48 Venook AP, Niedzwiecki D, Lenz HJ et al., Effect of First-Line Chemotherapy Combined 
With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type 
Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017 Jun 
20;317(23):2392-2401.
49 Hurwitz HI, Tebbutt NC, Kabbinavar F, et al. Efficacy and safety of bevacizumab in 
metastatic colorectal cancer: pooled analysis from seven randomized controlled trials. 
Oncologist. 2013;18(9):1004-12.
50 Cicek MS, Lindor NM, Gallinger S, et al. Quality assessment and correlation of microsatellite 
instability and immunohistochemical markers among population- and clinic-based colorectal 
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: JMD. 2011 May;13(3):271-281. DOI: 10.1016/j.jmoldx.2010.12.004.
51 https://clinicaltrials.gov/ct2/show/NCT02563002
52 https://clinicaltrials.gov/ct2/show/NCT02997228
53 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.
54 Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse 
sequence in advanced colorectal cancer: a randomized GERCOR study.J Clin Oncol. 2004 Jan 
15;22(2):229-37.
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55 Hellmann MD, Gettinger SN, Goldman JW, et al: CheckMate 012: Safety and efficacy of first-
line (1L) nivolumab (nivo; N) and ipilimumab (ipi; I) in advanced (adv) NSCLC. ASCO 
Meeting Abstracts 34:3001, 2016.
56 Lenz HJ,van Cutsem E, Limon ML, et al. Durable clinical benefit with nivolumab (NIVO) plus 
low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch 
repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC)‘ will be presented by 
Heinz-Josef Lenz during Proffered Paper  Session on Monday 22 October, 09:15 to 10.50 
(CEST) in Hall A2 - Room 18. Annals of Oncology, Volume 29 Supplement 8 October 2018
57 Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in 
metastatic colorectal cancer (ML18147): a randomized phase 3 trial. 2013 Jan;14(1):29-37.
58 Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated 
metastatic colorectal cancer (CORRECT): an international, multicenter, randomized, placebo-
controlled, Phase 2 trial. Lancet. 2013. Jan 26;381(9863):303-12.
59 Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic 
colorectal cancer: a double-blind, randomized, placebo-controlled phase 2 trial. Lancet Oncol. 
2012 Oct;13(10):993-1001. 
60 Overman MJ, Bergamo F, McDermott R, 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. 
Presented at the 2018 Gastrointenstinal Cancer Symposium; January 20, 2018. Abstract 554. 
61 Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. 
N Engl J Med. 2015;372:2509–2520.
62 Overman MJ, Lonardi S, Wong KYM. Durable Clinical Benefit With Nivolumab Plus 
Ipilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic 
Colorectal Cancer. J Clin Oncol. 2018 Mar 10;36(8):773-779
63 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;373:123-35.
64 Borghaei H, Luis Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced 
nonsquamous non–small-cell lung cancer. N Engl J Med.2015; 373:1627-39
65 Hellmann, MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipilimumab as first-line 
treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, 
phase 1, multicohort study. The Lancet Oncol. 2017;8(1):31-41.
66 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
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67 Schadendorf D, Larkin J, Chiarion-Sileni V, et al. Efficacy and quality of life outcomes in 
patients with advanced melanoma (MEL) who discontinued treatment with nivolumab (NIVO) 
plus ipilimumab (IPI) due to toxicity in a phase III trial (CheckMate 067). Presented at the 
2016 Annual Meeting of the European Association of Dermato-Oncology, August 31-
September 3, 2016, Vienna, Austria.
68 Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from 
Phase II and Phase III trials of ipilimumab in unresectable or metastatic melanoma. J Clin 
Oncol 2015;33:1889-94.
69 Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of 
nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics 
of long-term survivors. Oral presentation presented at: American Association for Cancer 
Research (AACR) Annual Meeting, April 1-5, 2017, Washington, DC.
70 Felip Font E, Gettinger SN, Burgio MA, et al. Three-year follow-up from Checkmate 017/057: 
Nivolumab versus docetaxel in patients with previously treated advanced non-small lung 
cancer (NSCLC). Poster discussion presentation at the European Society of Medical Oncology 
Annual Meeting, September 8-12, 2017, Madrid, Spain.  
71 Herbst RS. Garon E, Kim DW et al. KEYNOTE-010: Durable clinical benefit in patients with 
previously treated, PD-L1-expressing NSCLC who completed pembrolizumab. Poster 
presentation at the World Conference on Lung Cancer 2016 Dec 4-7; Vienna, Austria.
72 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.
73 Nivolumab (BMS-936558): Study CA209-142 Ad Hoc efficacy report. Bristol-Myers Squibb 
Company. 2017. Document Control No. 930111779.
74 Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management 
of patients with metastatic colorectal cancer. Ann Oncol. 2016;27(8):1386–1422. 
doi:10.1093/annonc/mdw235
75 Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin, 
Pemetrexed/Cisplatin, 
Carboplatin/Paclitaxel, 
Bevacizumab 
Maintenance, 
Erlotinib, 
Ipilimumab or as Monotherapy in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer 
(NSCLC) (CheckMate 012) ClinicalTrials.gov Identifier: NCT01454102.
76 Nivolumab Investigator Brochure, V17. 25 Jun2019. DCN 930140925
77 Lenz H.J., van Cutsem E., Limon M.L., Durable Clinical Benefit With Nivolumab (NIVO) 
Plus Low-Dose Ipilimumab (IPI) as First-Line Therapy in Microsatellite Instability-
High/Mismatch Repair Deficient Metastatic Colorectal Cancer. Annals of Oncology, Volume 
29 Supplement 8 October 2018 ESMO 2018. LBA18_PR.
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78 Whistance RN, Conroy T, Chie W, Costantini A, Sezer O, Koller M, Johnson CD, Pilkington 
SA, Arraras J, Ben-Jsef E, Pullyblank AM, Fayers P, Blazeby JM, European Organisation for 
the Research and Treatment of Cancer (EORTC) Quality of Life Group. Clinical and
psychometric validation of the EORTC QLQ-CR29 questionnaire module to assess health-
related quality of life in patients with colorectal cancer. Eur J Cancer. 2009 Nov; 45(14): 3017-
2.
79
Gurjal S, Conroy T, Fleissner C, Sezer O, King PM, Avery KN, Sylvester P, Koller M, 
Sprangers MA, Blazeby JM; European Organisation for Research and Treatment of Cancer 
Quality of Life Group.  Assessing quality of life in patients with colorectal cancer: an update 
of the EORTC quality of life questionnaire. Eur J Cancer. 2007 Jul; 43(10): 1564-73
80 Guinney J. The consensus molecular subtypes of colorectal cancer. Nature Medicine. 
2015;21:1350-1356.
81
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.
82 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.
83 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. 
84 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.
85 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.
86 Jia S, Zhang R, Li Z et al. Clinical and biological significance of circulating tumor cells, 
circulating tumor DNA, and exosomes as biomarkers in colorectal cancer. Oncotarget. 2017 
Apr 18;8(33):55632-55645.
87 Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based 
immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97.
88 Zitvogel L, Ma Y, Raoult D, et al. The microbiome in cancer immunotherapy: Diagnostic tools 
and therapeutic strategies. Science. 2018 Mar 23;359(6382):1366-1370.
89 Gopalakrishnan V, Spencer CN, Nezi L, et al. Gut microbiome modulates response to anti–
PD-1 immunotherapy in melanoma patients. 2018. Science; 05 Jan, 359 (6371):97-103.
90 Andre T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced 
colorectal cancer. N Engl J Med 2020;383:2207-18.
91 Overman MJ, Lenz HJ, Andre T, et al. Nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) 
with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic 
colorectal cancer (mCRC): Five-year follow-up from CheckMate 142. Presented at the 2022 
ASCO Annual Meeting 1; June 02, 2022. Abstract 3510. J Clin Oncol. 2022;40(Suppl 
16):3510.
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92 Lenz HJ., Lonardi S., Zagonel V., J Clin Oncol 38: 2020 (suppl; abstr 4040).
93 Diaz Jr LA, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite 
instability-high or mismatch repair-deficient metastatic colorectal cancer (KEYNOTE-177): 
final analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 2022;23(5):659-70.
94 Dolan P. Modeling valuations for EuroQol health states. Med Care 1997; 35(11):1095-1108.
95 STATISTICS IN MEDICINE.Statist. Med. 2009; 28:586–604 Published online 2 December 
2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/sim.3495
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
1L
first-line
2L
Second-line
5-FU
5-fluorouracil
ACTH
adrenocorticotropic hormone
ADA
antidrug antibody
AE
adverse event
AIDS
acquired immunodeficiency syndrome
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APCs
antigen-presenting cells
AST
aspartate aminotransferase
AT
aminotransaminases
β-HCG
beta-human chorionic gonadotrophin
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
CA19-9
cancer antigen 19-9
CBC
complete blood count
CDx
companion diagnostics
CEA
carcino embryonic antigen
CFR
Code of Federal Regulations 
cHL
Classical Hodgkin’s Lymphoma
CI
confidence interval
Cl
Chloride
CL
Clearance
CLcr
creatinine clearance
CMH
Cochran Mantel Haenszel
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Term
Definition
CMS
consensus molecular subtype
CMV
cytomegalovirus
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CR
complete response
CRC
colorectal cancer
CRF
case report form, paper or electronic
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTC
circulating tumor cell
CTLA-4
cytotoxic T-lymphocyte-associated protein-4
D
Day
DBL
database lock
DCR
disease control rate 
DC/D
discontinuation/death
DILI
drug induced liver injury
dL
Deciliter
DLT
dose-limiting toxicity
DMC
data monitoring committee
dMMR
deficient mismatch repair
DNA
deoxyribonucleic acid 
DOR
duration of response
DPD
dihydropyrimidine dehydrogenase 
DRESS
drug reaction with eosinophilia and systemic symptoms
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
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Term
Definition
eg
exempli gratia (for example)
eGFR
estimated glomerular filtration rate
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
EORTC
European Organization for Research and Treatment of Cancer
EQ-5D-3L
EuroQol Group 5D-3L questionnaire
ESMO
European Society for Medical Oncology
FA
final analysis
FDA
Food and Drug Administration
FFPE
formalin-fixed, paraffin-embedded
FSH
follicle stimulating hormone
fT3 
free triiodothyronine
fT4 
free thyroxine 
FU
follow up
FWER
family wise error rate
g
Gram
GBS
Guillain-Barre syndrome
GCP
good clinical practice
GEP
gene-expression profiling
GFR
glomerular filtration rate
h
Hour
H&E
haemotoxylin and eosin
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
HR
hazard ratio
HRT
hormone replacement therapy
IA 
interim analysis
IB
investigator brochure
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Term
Definition
I-O 
immuno-oncology 
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ICOS
inducible T-cell costimulator
ID 
infectious disease 
ie
id est (that is)
IEC
Independent Ethics Committee
IFN-γ
interferon-γ
IHC
immunohistochemistry
IL
Interleukin
IMAE
immune-mediated adverse event
IMP
investigational medicinal products
INCa/HAS
Institut National du Cancer/Haute Authorite de Sante
IND
Investigational New Drug application
INR
international normalized ratio
IP
investigational product
Ipi
Ipilimumab
IRB
Institutional Review Board
Irino
Irinotecan
IRT
interactive response system
IU
International Unit
IV
Intravenous
IVD
in vitro diagnostic device
K+
Potassium
KM
Kaplan Meier
L
Liter
LDH
lactate dehydrogenase
LFT 
liver function tests 
mCRC
metastatic colorectal cancer
mOS
median overall survival
mPFS
median progression-free survival
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Term
Definition
mTTR
median time-to-response
MDSC
myeloid-derived suppressor cell
mg
Milligram
MG
myasthenia gravis
Mg++
Magnesium
min
Minute
mL
Milliliter
MLR
mixed lymphocyte reaction
mmHg
millimeters of mercury
MMR
mismatch repair (of DNA)
mRCC
metastatic renal cell carcinoma
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSI-H
microsatellite instability high
MSS
microsatellite stable
MTD
maximum tolerated dose
mWHO
modified World Health Organization
μg
Microgram
N
number of subjects or observations
Na+
Sodium
N/A
not applicable
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
non-evaluable
NGS
next generation sequencing
Non-IP
non-investigational product 
NSAID
nonsteroidal anti-inflammatory drug
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PCR
polymerase chain reaction
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Term
Definition
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death ligand-1
PD-L2
programmed cell death ligand-2
PET
positron Emission Tomography
PFS
progression-free survival
PFS2
progression-free survival from next line of treatment (time to second 
progression)
PK
pharmacokinetics
PBMC
peripheral blood mononuclear cells
pMMR
proficient mismatch repair (of DNA)
PMR
post-marketing requirement
PO
per os (by mouth route of administration)
PPK
population pharmacokinetics
PR
partial response
PRO
patient-reported outcomes
PT
prothrombin time/preferred term
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
QC
quality control
QD, qd
quaque die, once daily
QLQ-C30
Quality of Life Questionnaire-Core 30
QoL
quality of life 
RBC
red blood cell
RCC
renal cell carcinoma
RECIST
response evaluation criteria in solid tumors
RFS
recurrence free survival
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Term
Definition
RNA
ribonucleic acid
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SCLC
squamous cell lung cancer
SD
stable disease
SJS
Stevens-Johnson syndrome
SOC
system organ class
SOP
standard operating procedures
Subj
subject
SUSAR
suspected, unexpected serious adverse reaction
t
temperature
T
time
TAS-102
trifluridine/tipiracil
T. bili 
total bilirubin 
TCR
T-cell receptor
TEN
toxic epidermal necrolysis
TMB
tumor mutational burden
TRAE
treatment related adverse event
TTD
time to treatment discontinuation
TTF
time to treatment failure
TTR
time to response
TSH 
thyroid stimulating hormone 
TSST
time to subsequent therapy or death
ULN 
upper limit of normal 
UC
urothelial carcinoma
US
United States of America
UV
ultraviolet
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Term
Definition
VAS
visual analog scale
VEGF
vascular endothelial growth factor
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study. The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines Good Clinical Practice (GCP), 
•
as defined by the International Council on Harmonisation (ICH)
•
in accordance with the ethical principles underlying European Regulation 536/2014
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A breach of 
the conditions and principles of Good Clinical Practice (GCP) (occurring in any country) in 
connection with that trial or the protocol related to the trial which is likely to affect to a significant 
degree the safety or physical or mental integrity of 1 or more subjects of the trial or the scientific 
value of the trial.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials 
(eg, advertisements), and any other written information to be provided to subjects. The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
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COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
FINANCIAL DISCLOSURE
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the Sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
INFORMED CONSENT PROCESS
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
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Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
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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: 
1)
Responsibilities of IT Personnel
2) Securing the BMS Digital Infrastructure
3) Identity and Access Management
4) External Partner Connections
5) Cyber Threat Detection and Response
6) Internal Cyber Incident Investigation
SOURCE DOCUMENTS
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 
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electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage 
area
•
amount currently in storage area
•
label identification number or batch 
number
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
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If
Then
the sites stock or commercial supply, or a 
specialty pharmacy)
study treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy.
BMS or designee will provide forms to facilitate inventory control if the investigational site does 
not have an established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively. If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool. The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
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13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. Sponsor or designee 
representatives will review data centrally to identify potential issues to determine a schedule of 
on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to Sponsor or designee.
RECORDS RETENTION
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 
investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected and 
reconciled by the responsible Study Monitor 
unless study treatments containers must be 
immediately destroyed as required for safety, 
or to meet local regulations (eg, cytotoxics or 
biologics).
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
Study treatments sourced by site, not supplied 
by BMS (or its vendors) (examples include 
study treatments sourced from the sites stock 
or 
commercial 
supply, 
or 
a 
specialty 
pharmacy)
It 
is 
the 
investigator’s 
or 
designee’s 
responsibility to dispose of all containers 
according to the institutional guidelines and 
procedures.
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met:
•
On-site disposal practices must not expose humans to risks from the drug.
•
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
•
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS upon request.
•
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
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. 
In the European Union (EU), the summary of results and summary for laypersons will be submitted 
within 1 year of the end of trial in EU/European Economic Area and third countries.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
CLINICAL STUDY REPORT
A Signatory Investigator must be selected to sign the Clinical Study Report (CSR).
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
Involvement in trial design.
•
Participant recruitment (eg, among the top quartile of enrollers)
SCIENTIFIC PUBLICATIONS
The data collected during this study are confidential and proprietary to the Sponsor or designee. 
Any publications or abstracts arising from this study must adhere to the publication requirements 
set forth in the Clinical Trial Agreement (CTAg) governing [study site or Investigator] 
participation in the study. These requirements include, but are not limited to, submitting proposed 
publications to the Sponsor or designee at the earliest practicable time prior to submission or 
presentation and otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
Principal Investigator, sub-Investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1) Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable participants with quality data), analysis, or interpretation of data for the 
work (eg, problem solving, advice, evaluation, insights and conclusion); AND
2) Drafting the work or revising it critically for important intellectual content; AND
3) Final approval of the version to be published; AND
4) Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last author. Authors in first and last position have provided the most significant contributions 
to the work.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
•
1 week minimum for vaginal hormonal products (rings, creams, gels)
•
4 week minimum for transdermal products
•
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
•
End of relevant systemic exposure is the time point where the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
human teratogenicity or fetotoxicity. This should be evaluated in context of safety margins 
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
from the no-observed-adverse-effect level (NOAEL) 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 (This method of contraception can only be used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)b
−
oral (birth control pills)
−
intravaginal (vaginal birth control suppositories, rings, creams, gels)
−
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 can only be used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)b
•
Intrauterine device (IUD)
•
Intrauterine hormone-releasing system (IUS) (This method of contraception can only be 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol) b,c
•
Bilateral tubal occlusion
•
Vasectomized partner of WOCBP participant
−
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. 
•
Vasectomized participant assigned to receive chemotherapy
−
Male participants will be required to always use a latex or other synthetic condom 
during any sexual activity (eg, vaginal, anal, oral) with WOCBP; even if the participants 
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930125433
13.0
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1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
have undergone a successful vasectomy or if their partner is already pregnant or 
breastfeeding.
•
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, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical 
studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient 
evidence that the IMP and other study medications will not alter hormonal exposures such that contraception 
would be ineffective or result in increased exposures that could be potentially hazardous.  In this case, 
alternative methods of contraception should be utilized. 
c Intrauterine hormone releasing systems are acceptable methods of contraception in the absence of definitive 
drug interaction studies when hormone exposures from intrauterine devices do not alter contraception 
effectiveness
Less Than Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of >1% per year when used consistently and correctly.
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
•
Diaphragm with spermicide
•
Cervical cap with spermicide
•
Vaginal Sponge with spermicide
•
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action (This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
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13.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Unacceptable Methods of Contraception
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus)
•
Spermicide only
•
Lactation amenorrhea method (LAM)
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS UNDERGOING 
CHEMOTHERAPY WITH PARTNER(S) OF CHILD BEARING POTENTIAL
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 6 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 6 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 6 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 6 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 5
MANAGEMENT ALGORITHMS FOR STUDIES UNDER CTCAE 
VERSION 5.0
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 
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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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
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CA2098HW
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APPENDIX 6
ECOG PERFORMANCE STATUS 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and 
prognosis. They are included here for health care professionals to access. 
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 selfcare 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
* As published in Am. J. Clin. Oncol.:
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, 
please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair. 
How to contact ECOG:
All contents copyright © 1998-2000 Eastern Cooperative Oncology Group.
All rights reserved.
Revised: July 27, 2006
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nivolumab
APPENDIX 7
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 t 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 
t 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 t 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 t 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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nivolumab
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’).
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.
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Clinical Protocol
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BMS-936558
nivolumab
•
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 
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.
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BMS-936558
nivolumab
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 
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 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
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.
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.
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Clinical Protocol
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BMS-936558
nivolumab
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
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
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Clinical Protocol
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BMS-936558
nivolumab
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
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
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Clinical Protocol
CA2098HW
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nivolumab
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 = 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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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 8
MSI STATUS TESTING
TESTING PANEL DESCRIPTIONS (PCR, IHC and Next Generation Sequencing [NGS])
FDA or other health authority approved testing should be used. If not, documentation 
demonstrating validation of the test performance (preferable under CLIA or equivalent 
ex-US) should be submitted for sponsor or representative to review.
Bethesda method (PCR) Panel Description and Classification of MSI Status
•
Reference panel: 
−
BAT25 (mononucleotide)
−
BAT26 (mononucleotide)
−
NR-21 (mononucleotide)
−
NR-24 (mononucleotide)
−
MONO-27 (mononucleotide)
−
D5S346 (dinucleotide)
−
D2S123 (dinucleotide)
−
D17S250 (dinucleotide)
•
Alternative loci: 
−
BAT40
−
BAT34C4
−
NR-22
−
TGF-β-RII
−
ACTC (635/636
−
CAT25
−
D9S63
−
D1S158
−
ACVR2A
−
BTBD7
−
DIDO1
−
MRE11
−
RYR3
−
SEC31A
−
SULF2
−
•
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 markers with instability
−
In the case of 1 PCR amplification failure:
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♦If ≥3 markers of 4 Æ MSI-H
♦If 1 marker of 4 Æ re-amplify
Promega MSI Multiplex system version 1.1
•
5 mononucleotide markers:
−
BAT-25
−
BAT-26
−
NR-21
−
NR-24
−
MONO-27
•
Two polymorphic pentanucleotide markers
−
Penta C
−
Penta D
•
Data interpretation:
−
MSS: no instability at any of the loci
−
MSI-Low: instability at a single mononucleotide locus
−
MSI-H: instability at ≥2 monoucleotide loci
IHC method - Panel Description and Classification of MSI Status
Panel 
•
hMSH2 
•
hMLH1
•
hMSH6
•
hPMS2 
Classification: 
•
MSI-H: ≥1 markers with instability
•
MSS: 0 markers with instability
•
MSI-L: not evaluable with this technique
Next generation sequencing methods:
•
FoundationOne CDx
•
FoundationOne Liquid CDx
•
TSO500 Assay (Tissue)
•
TSO500 ctDNA Assay
•
PGDx Elio Plasma
•
PGDx Elio Tissue
•
Predicine ATLAS
•
Personalis ImmunoID NeXT
•
Tempus xT
•
Caris Molecular Intelligence
•
Oncomine Comprehensive Assay
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nivolumab
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OmnisSeq MSI NGS
•
QIAseq Tumor Mutational Burden Panels
•
Guardant 360
•
Guardant Omni
•
Whole exome sequencing (Please record vendor, library kit, sequencing platform, read length, 
and read depth in eCRF if available)
•
Whole genome sequencing (Please record vendor, library kit, sequencing platform, read length, 
and read depth in eCRF if available)
•
Other, please record assay, platform and other details specified in eCRF
Important Reminders:
•
Refer to Central Lab Flow Chart and protocol for specific sample requirements
•
A normal control ACD whole blood sample is required as well as tumor tissue
•
Please contact BMS or The Central Lab if there are any questions.
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BMS-936558
nivolumab
APPENDIX 9
COUNTRY SPECIFIC APPENDIX
Criteria for exclusion of HIV-positive participants in Argentina, Czech Republic, Germany,  
and any Other Countries Where Exclusion of HIV Positive Participants is Locally Mandated. 
Section Number & Title
Country-specific language
Section 6.2 Exclusion Criteria, Exclusion 
criterion
“Known history of testing positive for human 
immunodeficiency virus (HIV) or known acquired 
immunodeficiency syndrome (AIDS)”to be replaced with 
“Positive test for HIV”.
Section 2  Flow  Chart/Time and Events 
Schedule,  Table 2-1: Screening Assessments 
-
Laboratory Tests
Add  “HIV” to the list of laboratory tests
Additional information on systematic screening for DPD deficiency added per Institut 
National du Cancer/Haute Authorite de Sante (INCa/HAS) recommendations in France and 
any Other Countries Where Screening is Locally Mandated.
Section Number & Title
Country-specific language
Section 6.2 Exclusion Criteria, 2), o
Added verbiage in bold:
o)  Participants with known dihydropyrimidine dehydrogenase 
(DPD) deficiency. 
If locally required a systematic screening for DPD deficiency 
has to be performed during study screening period, in 
compliance with INCa/HAS/local recommendations. In the 
case of total deficiency of DPD, defined based on local 
standards or as blood uracil level ≥ 150 ng/mL, the 
participant should be excluded from the study. If testing for 
DPD-deficiency was done prior to study entry and the 
medical documentation is available there is no need to 
repeat testing.
Pregnancy added as a reason for permanent discontinuation from study treatment in Czech 
Republic and any Other Countries Where Locally Mandated
Section Number & Title
Country-specific language
Section 8.1 Discontinuation from Study 
Treatment
“In the case of pregnancy, the investigator must immediately, 
within 24 hours of awareness of the pregnancy, notify the BMS 
Medical Monitor/designee of this event. In all cases, the study
treatment will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for participant safety). 
Refer to Section 9.2.5 Pregnancy.”
Section 9.2.5 Pregnancy
The following language is not applicable for the Czech 
Republic:
“If the investigator determines a possible favorable benefit/risk 
ratio that warrants continuation of study treatment, or re-
initiation of study treatment, a discussion between the 
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BMS-936558
nivolumab
Section Number & Title
Country-specific language
investigator and the BMS Medical Monitor/designee must 
occur. If, for whatever reason, the pregnancy has ended,
confirmed by negative serum pregnancy test, treatment may be 
resumed (at least 3 weeks and not greater than 6 weeks after the 
pregnancy has ended), following approvals of participant 
/sponsor /IRB/EC, as applicable.”
Requirement added to perform additional endocrine tests (e.g. ACTH, cortisol) at screening 
and if clinically indicated while on treatment/FU in Japan and any Other Countries Where 
Locally Mandated
Section Number & Title
Country-specific language
Section 2 Schedule of Activities, 
Table 2-2: On Treatment Procedural Outline 
(CA2098HW) Arm A (Nivolumab 
Monotherapy) and 
Table 2-3: On Treatment Procedural Outline 
(CA2098HW) Arm B (Nivolumab + 
Ipilimumab Combination)
Endocrine function testing
Added language on additional endocrine testing if clinically 
indicated.
Additional tests (e.g. ACTH, cortisol, etc.) should be 
performed during treatment phase if clinically indicated. 
See Section 9.4.4
Section 2 Schedule of Activities, 
Table 2-5: Follow up assessments 
(CA2098HW)
Endocrine function
Added language on additional endocrine testing if clinically 
indicated for participants who received nivolumab without or 
with ipilimumab.
Thyroid function testing should be done. Additional tests 
(e.g. ACTH, cortisol, etc.) should be performed if clinically 
indicated.
Section 2 Schedule of Activities, 
Table 2-6: On Study (Baseline and on 
Treatment) Procedural Outline (CA2098HW) 
Optional Crossover Cohort
Endocrine function testing
Baseline visit: Testing must be performed within 14 days prior 
to vial assignment. See Section 9.4.4 
On-treatment visits: Thyroid function testing should be done 
every 6 weeks for the first 24 weeks, and then every 8 weeks 
until completion of study treatment. Additional tests (e.g. 
ACTH, cortisol, etc.) should be performed during the 
treatment phase if clinically indicated. See Section 9.4.4
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BMS-936558
nivolumab
APPENDIX 10
DEFINITION OF LINE OF THERAPY IN CA2098HW STUDY
In this study the number of prior systemic treatments for metastatic disease (line of therapy) will 
be used for stratification and treatment assignment purposes. Therefore proper identification of 
line of therapy is of critical importance. 
The line of therapy refers to various chemotherapy treatments without or with anti-VEGF or anti-
EGFR agent, that are given between diagnosis and each progression/recurrence.
The “line” changes when the patient progresses/recurs. Each line of therapy must be separated by 
a progression/recurrence date. Patients may have multiple regimens in each line if change of the 
regimen occured for reasons other than disease progression. 
Some examples of the first and second-line settings provided below for your reference. Please 
note, that patients who progressed on or after triplet chemotherapy (FOLFOXIRI) without or with 
anti-VEGF or anti-EGFR agent, will be considered as if they have received two prior lines of 
systemic therapy. 
No prior systemic treatment for metastatic disease = First-line therapy
•
no prior systemic treatment in metastatic setting
•
if patient received neoadjuvant/adjuvant therapy, then this therapy should be completed more 
than 6 months (> 6 months) before the diagnosis of metastatic or recurrent disease is made
One prior line of systemic treatment for metastatic disease = Second-line therapy
•
patient received one prior line of systemic therapy in metastatic setting and experienced 
progression
•
patient received neoadjuvant/adjuvant therapy and experienced recurrence within 6 months (≤ 
6 months) after completion of therapy
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 11
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 09, 01-Jun-2023
Given the heterogeneity of patient populations (first-line [1L] and all lines) and different mode of 
action of study drugs (chemotherapy and immuno-oncology [I-O] therapy) the progression-free 
survival (PFS) event accumulation may not align for the 2 primary endpoints (PFS Arm B vs Arm 
C 1L and PFS Arm B vs Arm A all lines). The protocol is being amended to allow the option to 
trigger the interim analysis (IA) for each primary endpoint independently if the projected number 
of PFS events do not occur in close proximity to each other. In this case, separate database locks 
(DBLs) may be conducted for IA of each primary endpoint.
The protocol synopsis was updated to reflect changes in the protocol. 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 09
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.3.10: Strong 
Control of Type I Error
Updated language about the timing of the 
interim analyses of the primary endpoints.
To align with Section 10.3.11 
language update. 
Section 10.3.11: Interim 
Analyses
Added a sentence to allow for flexibility to 
conduct separate database locks (DBLs), when 
the two primary endpoint interim analyses are 
projected to occur more than 3 months apart. 
  
To allow the option to trigger the 
interim analysis for each primary 
endpoint independently in case 
that projected number of 
progression-free survival (PFS) 
events do not occur in close 
proximity to each other. 
Appendix 8: MSI Status 
Testing
10 new markers/classifications were added.
Due to evolving testing methods 
per local standards, additional 
markers for local microsatellite 
instability (MSI) polymerase 
chain reaction (PCR) testing 
were added.
All
Minor edits and administrative changes.
To provide minor corrections 
and clarifications throughout the 
document.
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CA2098HW
BMS-936558
nivolumab
Overall Rationale for Protocol Amendment 08, 04-Aug-2022
The purpose of this amendment is to specify that the data monitoring committee (DMC) will be 
utilized for the assessment of the study interim data and it will be providing recommendation to 
Bristol-Myers Squibb (BMS) on the next steps with regards to the study conduct.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 08
Section Number & 
Title
Description of Change
Brief Rationale
Section 1: Synopsis
Changes below as applicable.
To align with protocol body.
Section 5.1: Overall Design
Updated language in study design. Updated 
participant numbers under Figure 5.1-1 Study 
Schematic notes.
To provide a justification for the 
revision of the discordance rate 
between central and local 
dMMR/MSI-H testing results.
Section 5.1.1.1: Data 
Monitoring Committee 
Added statement on DMC.
To implement an independent 
assessment of study interim data, 
without unblinding the sponsor. 
Section 7.3: Blinding
Revised language about purpose of unblinding 
to the independent external statistical group.
For clarification given that the 
DMC, instead of the independent 
external statistical group, will 
conduct the evaluation of the 
study interim data.
Section 10.3.1: General 
Considerations
Removed the version number of the China-
specific protocol.
To avoid referencing an outdated 
version of the China-specific 
protocol. 
Section 10.3.11: Interim 
Analyses
Revised language about purpose of unblinding 
to the independent external statistical group. 
Added language on DMC.
For clarification given that the 
DMC, instead of the independent 
external statistical group, will 
conduct the evaluation of the 
study interim data.
Appendix 12: Guidance to 
Sites on Tumor Location 
and Sidedness
Added sidedness assignment for tumors 
located in rectum and rectosigmoid junction.
To clarify the tumor sidedness 
assignment.
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CA2098HW
BMS-936558
nivolumab
Overall Rationale for Protocol Amendment 07, 10-May-2022
The main objective of Protocol Amendment 07 was to update the statistical analyses schedule to 
reflect new enrollment timelines for Part 2. In addition, the projection of the number of randomized 
participants based on local mismatch repair deficient/microsatellite instability high (dMMR/MSI-
H) status has been revised to reflect higher than initially assumed discordance rate between central 
and local dMMR/MSI-H testing results. Other changes made to comply with Health Authorities’ 
requests to include additional safety language around oxaliplatin use and clarification on 
contraception requirements for study participants. 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
Section 1: Synopsis
Incorporated changes below, as applicable.
To align the synopsis with 
updated protocol language.
Table 4-1: Main Estimands 
for the Primary and Key 
Secondary Endpoints
Added clarifying language in main estimands 
for primary and key secondary endpoints.
For clarity
Section 5.1: Overall Design
Updated language in study design. Updated 
participant numbers under Figure 5.1-1 Study 
Schematic notes.
To provide a justification for the 
revision of the discordance rate 
between central and local 
dMMR/MSI-H testing results.
Section 5.2: Number of 
Participants
Updated projected number of randomized 
participants based on local dMMR/MSI-H 
status.
To reflect higher than initially 
assumed discordance rate 
between central and local 
dMMR/MSI-H testing results.
Section 6.1: Inclusion 
Criteria
Added clarifying language surrounding 
pregnancy prevention and added a sentence 
requiring women of childbearing potential 
(WOCBP) to use highly effective methods of 
contraception (failure rate < 1%).
To include additional language 
on pregnancy prevention 
requirements from Appendix 4 
to the body of protocol to 
comply with health authority 
request and to updated to align 
with Bristol-Myers Squibb 
Company (BMS) internal 
guidance.
Section- 6.3: Optional 
Crossover for Participants 
treated in the Arm C
Added clarifying language surrounding 
pregnancy prevention and added a sentence 
requiring WOCBP to use highly effective 
methods of contraception (failure rate < 1%). 
To include additional language 
on pregnancy prevention 
requirements from Appendix 4 
to the body of protocol to 
comply with health authority 
request and to updated to align 
with BMS internal guidance.
Section 7.7.1: Prohibited 
and/or Restricted 
Treatments
Added statement about avoiding medicinal 
products that may prolong QT interval.
Incorporated language to global 
protocol to comply with health 
authority request.
Section 9.1.1: Imaging 
Assessment for the Study
Added language regarding the potential need 
for additional imaging acquisitions before 
Additional clarifying language to 
facilitate transitioning to a fixed 
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BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
transitioning to the every 16-week scan 
schedule.
schedule of tumor assessments 
from 8 to 16 weeks.
Section 9.1.1.2: BICR 
Assessment of Progression
Added language clarifying which scans should 
be used for crossover baseline scans.
Clarification for sites.
Section 9.4: Safety
Added language surrounding QT 
prolongation.
Incorporated language to global 
protocol to comply with health 
authority request.
Section 9.4.3: 
Electrocardiograms
Added additional language surrounding 
participant electrocardiogram monitoring. 
Incorporated language to global 
protocol to comply with health 
authority request.
Section 9.8.1: Tissue 
Biomarkers
Added additional language regarding 
deoxyribonucleic acid (DNA)/ribonucleic acid 
(RNA) analysis from collected tumor tissue 
using sequencing techniques
Provide more clarity that 
sequencing techniques could be 
used. 
Section 9.8.3.2: Whole 
Blood for Germline DNA
Added additional language that sequencing 
techniques such as whole exome sequencing 
can be used for whole blood DNA analysis
Provide more clarity that 
sequencing techniques could be 
used.
Section 9.8.3.4: Circulating 
Tumor DNA Analysis 
(Plasma) Biomarkers
Added additional detail on circulating tumor 
DNA (ctDNA) and that sequencing techniques 
can be used for ctDNA analysis. 
Provide more clarity on ctDNA 
analysis and that sequencing 
techniques could be used.
Section 10.1: Sample Size 
Determination
Added clarification language regarding 
participants and clinical outcomes referred in 
sample size determination.
Added for clarification.
Section 10.1.1: Sample Size 
Determination of Primary 
Endpoints
Updated language under the Updated 
assumptions section.
Described the updated and 
streamlined statistical analyses 
schedule due to the new 
enrollment timelines for part 2.
Section 10.1.2: Power 
Calculation of Secondary 
Endpoints
Updated language related to timing of the 
interim analysis.
Described the updated and 
streamlined statistical analyses 
schedule due to new enrollment 
timelines for part 2.
Section 10.3.1: General 
Considerations
Re-arranged text and language.
For clarity.
Section 10.3.2: Efficacy 
Analyses
Added clarification language related to 
objective response rate (ORR) to secondary 
endpoint statistical analysis methods.
For clarity.
Section 10.3.4: Analyses of 
Crossover Cohort Treated 
Participants
Added clarification language related to 
crossover phase. 
For clarity.
Section 10.3.11: Interim 
Analyses
Updated description of study-wise interim 
analyses.
Described the updated and
streamlined statistical analyses 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 07
Section Number & 
Title
Description of Change
Brief Rationale
schedule due to new enrollment 
timelines for part 2.
Appendix 2: Study 
Governance Considerations
Updated language surrounding clinical study 
report signatory. Added sections BMS 
Commitment to Diversity in Clinical Trials 
and Data Protection, Data Privacy and Data 
Security.
Correction of language. 
Added to align with BMS 
commitment to diversity in 
clinical trials and to comply with 
European Union Clinical Trials 
Regulation requirement.
Entire Document
Editorial and formatting updates as needed.
For clarity.
Overall Rationale for Protocol Amendment 06, 01-Oct-2021
The key rationales of this protocol amendment are to: 1) optimize the statistical testing strategy 
for primary endpoints; 2) decrease the burden to the study participants and sites by reducing the 
frequency of tumor assessments after the first 2 years from randomization. 
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Added title ‘clinical trial physician’ and 
‘clinical scientist’ to document.
To align with new BMS naming 
convention.
Section 1-Summary
Summary to include all changes below where 
applicable. Also incorporated updates to the 
statistical language that were not incorporated 
in the previous amendment.
To align summary with changes 
below and to incorporate 
changes from protocol 
amendment 05 that were 
inadvertently missed.
Section 2- Schedule of 
Activities
Added language surrounding DPD testing 
under laboratory tests in Table 2-1.  
To provide clarifying language 
Section 2- Schedule of 
Activities
Reduced frequency of tumor assessments after 
first 2 years from randomization in Tables 2-2, 
2-3, 2-4, 2-5, and 2-6 and added footnote.
Update made to reduce burden 
on study sites and study 
participants.
Section 2- Schedule of 
Activities
Updated every 6 months to every 6 cycles for 
SARs-CoV-2 testing in Tables 2-2, 2-3, 2-4, 
and 2-6.
Updated to align with study 
therapy administration schedule 
Section 2- Schedule of 
Activities
Added language to allow endocrine function 
testing to be completed at preceding dosing 
visit to Tables 2-2 and 2-3. Added language to 
allow CEA and CA19-9 sample collection to 
be obtained at corresponding dosing visit or 
preceding dosing visit to Tables 2-2, 2-3, 2-4, 
and 2-6 and updated corresponding footnote.
Added to provide flexibility to 
study sites and study 
participants.
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
Section 4 Objectives and 
Endpoints
Added new Table 4-1 for main estimands for 
primary and key secondary endpoints.
Added to address BMS internal 
decision on statistical analysis 
plan (SAP).
Section 5.1 - Overall Design
Added new paragraph about China sub-study.
Added to provide a reference in 
the Global protocol to China-
sub-study described in China 
specific protocol amendment
Section 6.1-Inclusion 
Criteria and Section 6.3-
Optional Crossover for 
Participants treated in the 
Arm C
Modified inclusion criteria to delete the 
following text “30 days [duration of ovulatory 
cycle] plus”
Correction to clarify the 5 month 
duration following last dose of 
study treatment is based on 5 
half-lives of nivolumab.
Section 7-Treatment
Added additional ipilimumab dose 50 mg (5 
mg/mL) in Table 7-1.
Added to align with upcoming 
drug product presentation.
Section 7.7.1- Prohibited 
and/or Restricted 
Treatments
Added language surrounding COVID-19 non-
live vaccine benefit risk.
To align with program related 
changes.
Section 9.4-Safety and 
Section 9.4.4-Clinical 
Safety Laboratory 
Assessments
Updated language surrounding DPD-
deficiency screening. Added DPD and SARS-
CoV-2 to clinical safety and laboratory 
assessments table, and added wording 
‘screening only’ after blood uracil.
To provide clarifying language.
Section 9.8-Biomarkers
Updated biomarker sampling schedule in 
Tables 9.8-1, 9.8-2, 9.8-3 from C4D15 to 
C4D1 and removed footnote.
To align collection dates with 
dosing visits.
Section 10.1-Sample Size 
Determination
Added word ‘initially’ before split.  
To align with new updated 
statistical testing strategy per 
BMS internal comments on 
SAP.
Section 10.1.1-Sample Size 
Determination of Primary 
Endpoints
Changed 85% to 80% of the total number of 
PFS events.
Added sub-headers and clarification languages 
for section “PFS in all lines for comparison 
between arms B vs A” and moved Table 
10.1.1-2 after the first paragraph under 
“updated assumption”.
Typo correction
To differentiate between initial 
assumptions and updated 
assumptions for clarification 
purpose. 
Section 10.1.2-Power 
Calculation of Secondary 
Endpoints
Updated statistical language surrounding PFS 
and ORR.
To provide further clarification 
on the testing procedure on the 
key secondary endpoints.
Section 10.2-Populations for 
Analyses
Added statement on China extension sub-
study analysis.
To clarify that participants 
enrolled in China sub-study after 
completion of global enrollment 
will not be included in the 
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 06
Section Number & 
Title
Description of Change
Brief Rationale
population for global CSR 
analyses.
Section 10.3- Statistical 
Analyses
Inserted new sub-heading 10.3.1-General 
Considerations’ and added statement that 
primary and key secondary estimands are 
described in Table 4-1. 
Added statement surrounding analysis related 
to the China sub-study. 
Added to address BMS internal 
comments on SAP.
To clarify that the newly added 
China extension for China sub-
study will not be included in the 
global CSR analyses.
Section 10.3.10-Strong 
control of Type I Error
Updated statistical language describing strong 
control of type I error. Updated figure 
10.3.10-1 Testing procedure for primary and 
secondary endpoints.
To align with new updated 
statistical testing strategy per 
BMS internal comments on 
SAP. 
Appendix 8-MSI Status 
Testing
Added list of next generation sequencing tests
To provide a list of NGS tests 
that can be used to determine 
MSI status locally.
Appendix 9-Country 
Specific Appendix
Updated language surrounding DPD-
deficiency screening.
To provide clarity.
Appendix 2-Study 
Governance Considerations
Updated language on monitoring, 
dissemination of clinical data, clinical study 
report, and scientific publications.
Added to align with BMS 
standard protocol text and to 
provide clarity.
Appendix 13-Definition of 
pathological response.
Added new appendix section 13-Definition of 
pathological response.
To provide guidance to the sites 
for consistent reporting of 
pathological assessment of 
tumor regression in study 
participants undergoing curative 
intent surgery.
Entire Document
Editorial or formatting changes where 
appropriate.
To provide clarity.
Overall Rationale For Protocol Amendment 05, 18-Nov-2020
The protocol was updated to include dose modification criteria for immuno-oncology (I-O) therapy 
and I-O-related AE management algorithms based on version 5 of Common Terminology Criteria 
(CTCAE v5). Program-level updates were incorporated, including new severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) study requirements, and male contraception requirements 
in connection with I-O therapy. Additional safety requirements for oxaliplatin were included.
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Title Page
Added new Study Director.
New member joined 8HW study
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Section 1- Synopsis
Updated instances referring to protocol v04 in 
the present tense. Updated to align with 
changes in the protocol body.
New protocol is v05.
Section 2- Schedule of 
Activities
Added SARS-CoV-2 AE assessments and 
serology testing within Section 2 tables.
Serum and AE/SAE collection in 
the context of SARS-CoV-2 was 
added to explore the impact of 
coronavirus disease 2019 
(COVID-19) on study 
events/results.
Section 3.2.5- Nivolumab 
Mechanism of Action, 
Section 3.2.6- Ipilimumab 
Mechanism of Action
Added additional sentences describing 
nivolumab production and origin. Added 
additional text to paragraph.
Added to align with program-
level updates.
Section 6.1- Inclusion 
Criteria
Edited language in inclusion criteria 1)a), 
2)g), 3)e) and subsequent paragraph below.
Added to align with program-
level updates and to provide 
clarity.
Section 6.2- Exclusion 
Criteria
Added clarifying language to exclusion 
criteria 2)i) and 3)e). Added exempt language 
under inclusion criteria (crossover cohort 
only) 2)e). 
Aligned with updates to other 
parts of the protocol related to 
SARS-CoV-2 and program-level 
updates.
Section 7.1.2.4 -Crossover 
Cohort Nivolumab Plus 
Ipilimumab
Added text on observation time.
Added to provide clarity.
Section 7.4-Dosage 
Modification
Added Table 7.4-1 for AE criteria for 
delaying, resuming, and discontinuation of 
study treatment. Removed paragraph on 
guidance for dose modification for nivolumab 
and/or ipilimumab.
Reorganized dose delay, resume, 
and discontinuation criteria for 
improved readability and to align 
with CTCAE v5.
Section 7.4.1.1-Dose Delay 
Criteria for Nivolumab 
and/or Ipilimumab
Added suspected or confirmed SARS-CoV-2 
infection as a criterion to delay treatment. 
Added paragraph on dose delay timing. 
Removed bullets relating to AE-related dose 
discontinuation criteria.
Updated dose delay criteria in 
cases of confirmed or suspected 
SARS-CoV-2 infection and to 
provide clarity.
Section 7.4.3.1- Criteria To 
Resume Treatment In Arm 
A, Arm B or Crossover 
Cohort
Modified text to align criteria for dose delay, 
resume, and discontinuation with Table 7.4-1, 
and added SARS-CoV-2 language. Removed 
bullets relating to AE-related dose. 
discontinuation criteria. Added language on 
ipilimumab treatment resumption.
Updated to align with CTCAE 
v5 and SARS-CoV-2 language 
and program-level updates.
Section 7.4.4- Management 
Algorithms for Nivolumab 
and Ipilimumab
Inserted new section with language to align 
with CTCAE v5 requirements.
Updated to align with CTCAE 
v5.
Section 7.4.6-Treatment of 
Treatment-related Infusion 
Reactions
Added statement on nivolumab and 
ipilimumab infusion reactions.
Added to provide clarity.
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13.0
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR PROTOCOL AMENDMENT 05
Section Number & Title
Description of Change
Brief Rationale
Section 8.1.1- Nivolumab 
and/or Ipilimumab Dose 
Discontinuation (Arm A, B 
or Crossover Cohort)
Added cross-reference to Table 7.4-1 and 
removed AE related dose discontinuation.
Updated to align with CTCAE 
v5.
Section 8.1.3-Treatment 
Beyond Progression for 
Participants in The Arms A, 
B or Crossover Cohort
Added statement on progression.
Added to align with program-
level updates.
Section 9- Study 
Assessments and 
Procedures
Added paragraph on SARS-CoV-2 infection 
as well as additional language on cardiac and 
pulmonary toxicity.
Updated to align with SARS-
CoV-2 recommendations and 
program-level updates.
Section 9.1.1-Imaging 
Assessments for the Study
Added statement on imaging for RECIST.
Added to align with program-
level updates.
Section 9.2-Adverse Events
Added statement on AE and SAE reporting.
Updated to align with CTCAE 
v5.
Section 9.2.1-Time Period 
and Frequency for 
Collecting AE and SAE 
Information.
Added language surrounding AEs related to 
SARS-CoV-2 infection.
Updated to align with SARS-
CoV-2 recommendations.
Section 9.2.3- Follow-up of 
AEs and SAEs
Added language surrounding AEs related to 
SARS-CoV-2 infection.
Updated to align with SARS-
CoV-2 recommendations.
Section 9.4-Safety
Added statement on patient monitoring prior 
to oxaliplatin. 
Added as an additional safety 
measure. 
Section 9.5-
Pharmacokinetics and 
Immunogenicity 
Assessments
Added additional paragraphs on blood sample 
collections.
Added to align with program-
level updates.
Section 9.8.- Biomarkers
Added SARS-CoV-2 and additional 
timepoints for ctDNA collection.to biomarker 
sampling Tables 9.8-1, 9.8-2 and 9.8-3.
Updated to align with SARS-
CoV-2 recommendations and to 
align with program-level 
updates.
Section 9.8.3- Soluble 
Markers
Added information related to SARS-CoV-2 
serology testing.
Updated to align with SARS-
CoV-2 recommendations.
Section 9.8.5- Additional 
Research Collection
Added additional paragraphs on additional 
research collection.
Added to align with program-
level updates.
Appendix 4
Updated language related to contraception.
Added to align with program-
level updates and corporate 
guidance.
Appendix 5
Updated I-O management algorithms.
Updated to align with CTCAE 
v5.
Entire document
Additional editorial or formatting changes, 
where appropriate.
Added to provide clarity.
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930125433
13.0
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1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Overall Rationale for Revised Protocol 04, 17-Jul-2020
This protocol revision is to expand enrollment of participants who have not received prior therapy. 
This extension will occur after completion of enrollment across lines of therapy. Thus study 
enrollment consists of 2 parts (enrollment across lines of therapy, part 1 enrollment, and extension 
of enrollment for participants who have not received prior therapy, part 2 enrollment). The protocol 
has been modified to incorporate the changes described below.
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 1 -Synopsis
The synopsis has been modified to incorporate 
the changes described below
Updated to align with revised 
study design
Section 2-Schedule of 
Activities
Modified the laboratory test parameter row in 
Table 2-1. Added ‘(± 7 days)’ under CEA and 
CA-19-9 assessment.
To clarify the timing of the 
respective tests
Section 2-Schedule of 
Activities
Added dose delayed statement to HEOR 
assessment rows in Tables 2-3 and 2-6
Added statement for consistency 
across study arms and periods
Section 2-Schedule of 
Activities
Added language on additional endocrine 
testing if clinically indicated, changed 
wording of Thyroid function test to Endocrine 
function test and added testing information 
throughout document and removed IRT drug 
vial assignments on C1D1 and C3D1 to 
Tables 2-2, 2-3, 2-4, and 2-6. 
Change required per Japan 
specific label recommendation
Section 2-Schedule of 
Activities
Removed in IRT drug vial assessment on 
C1D22 and C2D1, C2D22 under cycles 1 and 
2 in Table 2-3 and added review of 
concomitant medications, AE assessment, and 
laboratory tests in Table 2-4 upon PD. 
Added to provide clarity.
Sections 3.1-Study 
Rationale, 3.1.1-Research 
Hypothesis, 3.2.3-
Chemotherapy and targeted 
agents, 3.2.4-Nivolumab 
and Ipilimumab in 
dMMR/MSI-H Metastatic 
Colorectal Cancer: Check 
Mate 142 Study
Updated study rationale, hypothesis, 
background information with additional 
language and information.
Updated to align with revised 
study design 
Section 4-Objectives and 
Endpoints
Updated primary and secondary study 
objectives and endpoints. In addition the CDx, 
crossover cohort and exploratory analysis 
were updated with new endpoints to evaluate 
efficacy, safety and PK.
Updated to align with revised 
study design.
Section 5.1 Overall Design
Updated overall study design with additional 
language and information on the part 1 and 2 
enrollment.  Study design schematic was 
updated and added a study conduct scheme.
Updated to reflect changes of 
revised study design
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13.0
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930125433
13.0
v
Approved
1.0
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Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 5.2-Number of 
Participants
Updated number of participants 
Updated for alignment with 
revised study design
Sections 5.4-Scientific 
Rationale for Study Design, 
5.4.2-Rationale for 
Investigator’s Choice 
Treatment and PFS 
assumptions in 
Chemotherapy Arm, 5.4.4-
Rationale for Nivolumab 
and Ipilimumab 
Combination, 5.4.6-
Rationale for Choice of 
Primary Endpoints
Study design updated to expand enrollment 
for participant who have not received prior 
therapy. Added additional scientific rationale 
to the study design and additional data under 
rationale
Updated for alignment with 
revised study design
Section 5.4.7-Clinical 
Validation of Companion 
Diagnostics 
Added new section (5.4.7) on clinical 
validation of companion diagnostics 
Added to provide additional 
rationale and background for 
companion diagnostics 
component of the study
Section 5.4.9-Rationale for 
Duration of Study 
Treatment
Added statement to clarify study duration for 
arm C participants
Added to provide additional 
clarity and rationale for study 
treatment duration in arm C
Sections 6.1-Inclusion 
Criteria, 6.2-Exclusion 
Criteria, 6.3-Optional 
crossover for participants 
treated in arm C
Inserted statement regarding inclusion criteria 
2a, 2g and exclusion criteria 1b applicability 
to the study design. Added new exclusion 
criteria 2o on ‘participants with DPD 
deficiency’. Removed <140/90mm Hg stated 
in exclusion criteria 2i. Added clarification 
statement to exclusion criteria 1b. Updated 6.2 
and 6.3 -exclusion criteria 2e criteria to 2 yrs 
instead of 3 yrs
Added for alignment with 
revised study design (2a, 2g) and 
removed (1b) to reflect clinical 
practice. Added requirement for 
systematic DPD deficiency 
screening per French Authority 
for Health.
Section 7.1.1-Study 
Treatment Duration
Added statement (not applicable for arm C 
participants) to study treatment duration.
To clarify the treatment duration 
for arm C participants
Sections 7.1.2-Treatment 
Schedules, 7.1.2.2-Arm B 
Nivolumab Plus Ipilimumab 
(Q3Wx4), 7.1.2.3-Arm C 
Investigator’s Choice 
Chemotherapy, 7.1.2.4-
Crossover Cohort 
Nivolumab Plus Ipilimumab 
(Q6W continuously)
Added statement to include observation for 
approximately 30 minutes. Added statement 
that infusion start and stop times will be 
recorded in the CRF. Corrected cross 
reference from Table 7.1.2-1 to Table 7.1.2-4.
Updated to clarify the duration
of observation before 
ipilimumab infusion.
Section 7.2.1-Initial 
Treatment Assignment
Added statement to clarify the randomization 
during part 1 and part 2 enrollment 
Added for alignment with 
revised study design
Section 7.3-Blinding
Added statement surrounding generating 
aggregate reports
Added for clarity
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 04
Section Number & Title
Description of Change
Brief Rationale
Section 7.4-Dose 
Modification
Added new paragraph to clarify that dose 
modification criteria for nivolumab with or 
without ipilimumab should follow the CTCAE 
version 4, but reporting of the events intensity 
should follow CTCAE version 5. 
Added new paragraph on blood uracil and 
guidance for dose modifications
Added clarification regarding 
dose modifications/AE reporting 
and CTCAE versions.
Added requirement for 
systematic DPD deficiency 
screening if locally mandated
Section 7.7.3-Surgical 
Resection Following Initial 
Response
Added paragraph with additional language 
around surgical resection.
Added for clarity.
Section 8.1.2-Investigator’s 
Choice Chemotherapy Dose 
Discontinuation
Added new paragraph on dose delays lasting 
>6 weeks from previous dose
Added for clarity 
Section 8.1.3-Treatment 
Beyond Progression for 
Participants in the Arms A, 
B or Crossover Cohort
Added statement to include ‘Approval from  
BMS medical monitor or designee
Added as additional safety 
measure
Section 9.4-Safety, Section 
9.4.4-Clinical Safety and 
Laboratory Assessments
Added statement on systematic screening for 
DPD deficiency. Updated laboratory 
assessment table to include additional 
information on chemistry tests, endocrine 
function tests and added blood uracil to panel, 
and CEA/CA19-9 assessments.
Added additional safety 
measures per local requirements
Section 9.5
Added statement ‘up to 2 years of treatment’ 
to tables 9.5-1, 9.5-2, and 9.5-3
Added to provide clarity on 
duration of samples collection
Section 10-Statistical 
Considerations
Updated all relevant statistical section to 
include detailed changes on the primary and 
secondary endpoints, sample size 
determination and power calculations, 
population analyses, efficacy analyses, safety 
analyses, crossover cohort analyses, interim 
and other analyses for parts 1 and 2 of the 
study design. Updated testing procedure figure 
10.3.9-1 for primary and secondary endpoints
Changed for alignment with 
revised study design
Entire document
Additional editorial or formatting changes, 
where appropriate
Added to provide clarity
Appendix 5
Added myocarditis treatment algorithm
Update made to align with the 
most current nivolumab safety 
information. 
Appendix 9
Removed France and Spain from criteria for 
exclusion of HIV positive participants.  Added 
Tables to include France, Czech, and Japan 
specific language applicable to the protocol. 
Update made to meet country-
specific requirements in Spain 
and France. Additional country 
specific language tables were 
added as locally mandated.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Overall Rationale for Revised Protocol 03, 28-Mar-2019
The study design was amended to include the standard of care arm (SOC) that would allow to 
compare the efficacy and safety of immunotherapy vs chemotherapy in 1L and 2L settings in a 
prospective randomized study. 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 2, Schedule of 
Activities, Table 2-1 
Screening Procedural 
Outline
Update window of tissue collection 
acceptability to 3 months prior to enrolment 
instead of randomization. 
Clarify baseline tumor imaging to 28 days 
prior to randomization 
Note regarding urinalysis testing added. 
Due to poor predictability of the 
randomization date and 
associated risk of the tumor 
tissue not being valid the timing 
for tumor tissue has updated to 3 
months prior to enrolment
Since pts in SOC arm may 
receive bevacizumab, note added 
about exclusionary levels of 
proteinuria.
Section 2, Schedule of 
Activities, Table 2-2 (Arm 
A, Table 2-3 (Arm B), 
Added EORTC-QLQ-CR29 to the PRO 
collections. 
Added collection window for stool samples
Due to study design update the 
additional PRO assessment 
added. 
Stool sample collection window 
was added to clarify the 
allowable timing for sample 
collection. 
Section 2, Schedule of 
Activities, On-treatment 
Procedural Outline, Table 2-
4 (Arm C, Table 2-6 
(Crossover Cohort),
Tables for Investigator Choice Chemotherapy, 
and Crossover Cohort added. 
Updated due to updates in study 
design.
Table 2-5: Follow-Up 
Assessments 
Added CBC with differential chemistry, 
thyroid function, and urinalysis. 
Tumor assessment timing updated. 
Clarification added regarding follow up visits 
for Arm C and Crossover Cohort
Clarified the lab assessments at 
the follow up visits. 
Tumor assessment timing 
updated to correct the mistake in 
prior version of the protocol. 
Section 3.1 Study Rationale; 
Section 5.4 Scientific 
Rationale for Study Design; 
Section 5.4.2 Rationale for 
Investigators Choice 
Treatment in Chemotherapy 
Arm 
Updated to contain the details and rationale 
regarding the inclusion of a third treatment 
arm. 
Updated due to updates in study 
design.
Section 3.2.3 Chemotherapy 
in dMMR/MSI-H 
Metastatic Colorectal 
Cancer
Background on chemotherapy in participants 
with dMMR/MSI-H added. 
Updated due to updates in study 
design.
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 3.3 Benefit Risk 
Assessment
Additional details regarding benefit risk of 
chemotherapy treatment in this population has 
been added. 
Updated due to updates in study 
design. 
Section 4, Objectives and 
Endpoints 
Secondary and Exploratory objectives updated 
to evaluate comparisons with Arm C, and the 
Crossover Cohort
Updated due to updates in study 
design.
Section 5.1, Overall Design, 
Figure 5.1-1 Study Design 
Schema 
Updated to incorporate the details of Arm C in 
into the study design. 
Updated to include the details of the optional 
Crossover Cohort. 
Updated schematic included
Updated due to updates in study 
design. 
Section 5.2, Number of 
Study Participants; Section 
10.1 Sample Size 
Determination
Number of participants updated to reflect in 
the incorporation of Arm C. 
Updated due to updates in study 
design. 
Section 5.4.1. Rationale for 
Treatment Setting 
Rationale regarding first and second-line 
treatment settings added. 
Updated due to updates in study 
design. 
Section 5.4.5 Rationale for 
Optional Crossover from 
Chemotherapy Arm
Justification for Crossover Cohort for 
participants in Arm C was added. 
Crossover cohort will ensure 
participants in Arm C have 
access to immunotherapy 
treatment. 
Section 5.5 Justification for 
Dose
Justification for combination dosing of 
nivolumab and ipilimumab added. 
To provide a rationale for 
continuous dosing of ipilimumab 
every 6 weeks (Q6W) in 
participants in the Crossover 
cohort
Section 6.1 Inclusion 
Criteria, Appendix 4 
Women of Childbearing 
Potential Definitions and 
Methods of Contraception
Additional criteria added for participants that 
have received 0-1 prior therapy in the 
metastatic setting.
Contraceptive guidance added for participants 
randomized to Arm C. 
Updated due to updates in study 
design. 
Section 6.2, Exclusion 
Criteria 
Additional exclusion criteria added for 
participants who have received 0-1 prior line 
of therapy(2, h to n)
Updated due to updates in study 
design.
Section 6.2.1 Optional 
Crossover for Participants 
Treated in Arm C
Added specific criteria for participants in Arm 
C who will participate in Crossover Cohort
Updated due to updates in study 
design.
Section 6.3 Lifestyle 
Restrictions
Reference to SOC labels added. 
Updated due to updates in study 
design. 
Section 7 Treatment, Table 
7-1 Study Treatments, 
Section 7.1.1, Study 
Treatment Duration; Table 
7.1.2-3 Timing for 
Added in study treatments for investigators 
choice chemotherapy, treatment durations and 
details for Investigators Choice 
Chemotherapy, and the Crossover Cohort, and 
details for treatment assignment.
Updated due to updates in study 
design. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Investigators Choice 
Chemotherapy, Section 
7.1.2-4 Crossover Cohort; 
Section 7.1.2.3 Arm C-
Investigators Choice 
Chemotherapy; Section 
7.1.2.4 Crossover Cohort-
Nivolumab Plus Ipilimumab 
(Q6WContinuously); 
Section 7.2.1 Initial 
Treatment Assignment; 
Section 7.2.2 Crossover 
Cohort Treatment 
Assignment  
Section 7.4 Dosage 
Medications; Section 
7.4.1.2, Dose Delay for 
Investigators Choice of 
Chemotherapy; Section 
7.4.1.2 Dose Delay Criteria 
for Investigators Choice of 
Chemotherapy; Section 
7.4.2 Dose Reductions; 
Section 7.4.2.2. Dose 
Reductions for Investigators 
Choice Chemotherapy; 
Section 7.4.3.1 Criteria to 
Resume Treatment in Arm 
A, Arm B, or Crossover 
Cohort, Section 7.4.3.2 
Criteria to Resume 
Treatment in Arm C; 
Section 7.7.1 Prohibited 
and/or Restricted 
Treatments; Section 8.1.2 
Investigators Choice 
Chemotherapy Dose 
Discontinuation (Arm C). 
Additional details on dosage modifications, 
dose reductions, and criteria to resume 
treatment added for Arm C Investigators 
Choice Chemotherapy and the Crossover 
Cohort. 
Updated prohibited treatments list to include 
restrictions for treatments to be administered 
in Arm C. 
Updated due to updates in study 
design. 
Section 9.1.1.2 BICR-
Assessment of Progression
Language included regarding re-baseline
assessment of the scans by BICR prior to 
enrollment in the Crossover Cohort. 
Updated due to updates in study 
design.
Section 9.2.7 Potential Drug 
Induced Liver Injury
Removal of separate criteria for participants 
with elevated ALT/AST or total bilirubin at 
baseline
There is no uniformly accepted 
DILI criteria for participants 
with elevated ALT/AST or total 
bilirubin at baseline. In this 
situation to minimize the 
potential safety risk same criteria 
for potential DILI are applied to 
all patients. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 03
Section Number & Title
Description of Change
Brief Rationale
Section 9.5 
Pharmacokinetics and 
Immunogenicity 
Assessments 
Table 9.5-2 note regarding timing of 
collection, and clarification of dose delay. 
Table 9.5-3 Sampling schedule added for 
Crossover Cohort. 
Updated to clarify sampling in 
the event of dose delay. 
Added an additional table to 
reflect the updates to study 
design.
Section 9.8 Biomarkers
Table 9.8-1, Sampling for Investigators 
Choice Chemotherapy (Arm C)
Table 9.8-2- Biomarker Sampling Schedule 
for nivolumab plus ipilimumab Combination 
(Arm B), cycle length clarified. 
Table 9.8-3 Biomarker Sampling Schedule-
Crossover Cohort added. 
Table 9.8-1 and Table 9.8-2- Collection 
window added for stool sample collection. 
Updated due to updates in study 
design.
Stool sample collection window 
was added to clarify the 
allowable timing for sample 
collection.
Section 10.1.1 Sample Size 
Determination of PFS 
comparison in Arm B vs 
Arm A
Updated to reflect the incorporation of the 
additional participants for randomization 
(Arm C)
Updated due to updates in study 
design.
Section 10.1.2 Power 
Calculation of PFS 
Comparison in Arm B vs. 
Arm C 
Added in power calculation for comparison of 
Arm B vs Arm C
Updated due to updates in study 
design.
Section 10.2 Population for 
Analyses 
Added investigator Choice Chemotherapy as a 
treated population. 
Added description of the Crossover Cohort
Updated due to updates in study 
design.
Section 10.3.1
Added definition of the exploratory endpoint 
investigator-assessed time to treatment failure 
(TTF) and time to treatment discontinuation 
(TTD). 
Updated to enable the conduct of 
comparison of clinical study 
results and real world data
Section 10.3.3 Analyses or 
Crossover Cohort Treated 
Participants
Description of analyses for the Crossover 
Cohort added. 
Updated due to updates in study 
design.
Section 10.3.9 Interim 
Analyses 
Updated to reflect interim analysis of ORR 
and final analyses to incorporate Arm C into 
the details. 
Updated due to updates in study 
design.
Appendix 10 Definition of 
Line of Therapy in 
CA2098HW Study
Updated to clarify definitions of line of 
therapy in CA2098HW study
To ensure consistency across 
participating sites in definition of 
the line of therapy that is one of 
the randomization factors.
Appendix 12 Guidance to 
sites on Tumor Location 
and Sidedness
Guidance on tumor sideness added. 
Provided to assist sites in the 
assignment of tumor sideness to 
participants. 
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13.0
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930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
Overall Rationale for Revised Protocol 02
The Original Protocol and Revised Protocol 01 describe a single-arm, nivolumab monotherapy 
trial, and were never initiated. The current protocol (Revised Protocol 02) updates the design to a 
randomized trial of nivolumab vs nivolumab in combination with ipilimumab.
Overall Rationale for the Revised Protocol 01, 16-May-2018
This amendment extends eligibility to the subgroup of patients who received 5-FU, oxaliplatin and 
irinotecan all in the first line as a triplet chemotherapy combination (FOLFOXIRI). 
SUMMARY OF KEY CHANGES FOR REVISED PROTOCOL 01
Section Number & Title
Description of Change
Brief Rationale
Document History
Added Summary of changes
Document change to inclusion 
criteria.
Synopsis, Key Inclusion 
Criterion d); and Section 6.1: 
Inclusion Criterion 2) e
Revised inclusion criteria to include 
patients who received first line as a triplet 
chemotherapy combination (FOLFOXIRI).
Extends eligibility to the subgroup 
of patients who received first line 
as a triplet chemotherapy 
combination (FOLFOXIRI).
All
Minor formatting and typographical 
corrections
Minor, therefore have not been 
summarized
3URWRFRO$PHQGPHQW1R
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 12
GUIDANCE TO SITES ON TUMOR LOCATION AND SIDEDNESS
Please adhere to the following guidance when assigning tumor sidedness in eCRF and IRT 
transactions for participants enrolled to CA209-8HW:
Right Sided
•
Cecum
•
Ascending Colon 
•
Hepatic Flexure
•
Transverse Colon
•
Unknown OR Both-Sided locations
Left Sided
•
Splenic Flexure
•
Descending Colon
•
Sigmoid Colon
•
Rectum or Rectosigmoid Junction
Please note that the location of the primary tumor (not a metastatic site) should be used to define 
the sidedness. 
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13.0
Approved
930125433
13.0
v
Approved
1.0
v

Clinical Protocol
CA2098HW
BMS-936558
nivolumab
APPENDIX 13
DEFINITION OF PATHOLOGICAL RESPONSE 
Please adhere to the following definitions of pathological response in patients undergoing curative
surgery on study CA209-8HW:
•
Pathologic Complete response (pCR): no residual viable tumor cells
•
Pathologic Major response (pMR): < 10% of residual viable tumor cells (≥ 90% reduction 
of the tumor cells)
•
Pathologic Partial response (pPR): < 50% but ≥ 10% of residual viable tumor cells (≥ 50% 
reduction of tumor cells)
•
Pathologic Non-response: ≥ 50% residual viable tumor cells (< 50% reduction of tumor 
cells)
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13.0
Approved
930125433
13.0
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1.0
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