A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers
Phase: PHASE1
Conditions: Colorectal Cancer, Colorectal Tumors, Colorectal Carcinoma, Colorectal Neoplasm
Sponsor: Bristol-Myers Squibb

Official Title of Study: 
A Study of Nivolumab in Combination With Trametinib With Or Without Ipilimumab In 
Participants With Previously Treated Metastatic Colorectal Cancers 
 
NCT Number: NCT03377361 
Document Date (Date in which document was last revised): 03 May 2023 
 
 
 

Page:
1
Protocol Number:
CA2099N9
IND Number:
119,381
EUDRACT Number:
2017-001830-24
Date:
10-Aug-2017
Revised Date
03-May-2023
Clinical Protocol CA2099N9
A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In 
Participants With Previously Treated Metastatic Colorectal Cancers
(CheckMate 9N9: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9N9)
Protocol Amendment: 04
Incorporates Administrative Letter 06
Clinical Trial Physician
Bristol-Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648
Telephone (office):
Clinical Scientist 
Bristol-Myers Squibb Company
86 Morris Avenue
Summit, NJ 07901 
Telephone (office): 
Email: 
Email: 
24-hr Emergency Telephone Number
USA: 
International: 
Bristol-Myers Squibb Research and Development
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 
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 
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BMS-936558
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Protocol Amendment No.: 04
Date: 03-May-2023
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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).
© 2023 Bristol-Myers Squibb Company
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BMS-936558
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Protocol Amendment No.: 04
Date: 03-May-2023
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 04
03-May-2023
Based on the emerging data, Bristol-Myers Squibb Company (BMS) has 
made a strategic decision to expedite the CA2099N9 study closure. This 
decision is not related to any safety concerns. The protocol has been 
revised to reduce the assessments and data collection to minimize the 
burden on study participants and site staff. In addition, some of the 
 are removed, the key objectives are achievable 
with reduced data collection and shorter follow-up.
Administrative 
Letter 06
24-Feb-2022
Correction made to Synopsis: Ipilimumab sourcing 50 mg was added to 
the study treatment table. In Appendix 10 for BRAF, revised text to 
clarify that BRAF mutation status is required for participants for 
eligibility and stratification purposes.
Protocol 
Amendment 03
17-Dec-2021
The main reasons for Protocol Amendment 03 are to expand the 
eligibility criteria of Part 2 to include participants who have received at 
least 2 (no more than 4) prior lines of therapy, 
 
 
 
. Additional 
updates include removal of the 40 mg (10 mg/mL) potency of nivolumab 
solution for use moving forward, 
 
, clarification of nivolumab intravenous administration 
procedure, and clarification of treatment discontinuation requirements. 
Administrative Letters 04 and 05 are also incorporated.
Administrative 
Letter 05
19-Jan-2021
Updated study personnel.
Administrative 
Letter 04
26-Oct-2020
Corrected a typo found in Table 2-3.
Revised Protocol 
02
06-Oct-2020
CA2099N9 has been revised to enroll participants to the selected triplet 
regimen in the second line (2L) and third line (3L) setting. The sample 
size of the study expansion has been increased to a total of 200 patients
to allow for further assessment of clinical safety, efficacy,
 
 in microsatellite stable metastatic colorectal cancer (MSS 
mCRC).
Part 1B 
 
(2L) for the triplet regimen 
(80 participants)
•
Cohort 6: nivolumab 6 mg/kg Q4W plus ipilimumab 1 mg/kg 
Q8W plus trametinib 1.5 mg continuous QD
Part 2
 
(3L) for the triplet regimen 
(120 participants randomized 2:1): 
•
Cohort 4: nivolumab 6 mg/kg Q4W plus ipilimumab 1 mg/kg 
Q8W plus trametinib 1.5 mg continuous QD
•
Cohort 5: A standard of care (SOC) arm with regorafenib
All relevant sections of the protocol have been revised to support the 
revision of the study design. Major revisions are included in the 
following sections: 
•
Sections 3.1 Study Rationale and 3.2 Background revised to 
include updated clinical data. 
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Protocol Amendment No.: 04
Date: 03-May-2023
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Document
Date of Issue
Summary of Change
•
Section 4 Objectives and Endpoints revised for Part 2 and Part
1B.
•
•
Section 10 Statistical Considerations updated to support new
study design.
Incorporates Administrative Letters 02 and 03.
Administrative 
Letter 03
23-Jul-2018
Correction to 
Administrative 
Letter 02
06-Apr-2018
Correction of two exclusion criteria bullets that were incorrectly 
renumbered.
Revised Protocol 
01
01-Mar-2018
The protocol has been amended to include a randomized comparator arm 
(Cohort 7) for Part 2 consisting of standard-of-care regimens (regorafenib 
or TAS-102) per investigator’s choice for ≥ 3rd line mCRC.
Administrative Letter 01 has been incorporated.
Of note, Revised Protocol 01 was not implemented.  
Administrative 
Letter 01
09-Oct-2017
Correction of footnote in Table 2-4: On-Treatment Assessments (Part 1A 
mCRC 2nd line).Day 15 and Day 43 assessments are only required for 
the first cycle rather than the first 2 cycles, then may be performed as 
clinically indicated at investigators discretion.
Original Protocol
10-Aug-2017
Not applicable
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OVERALL RATIONALE FOR THE PROTOCOL AMENDMENT 04
Based on the emerging data, Bristol-Myers Squibb Company (BMS) has made a strategic decision 
to expedite the CA2099N9 study closure. This decision is not related to any safety concerns. The 
protocol has been revised to reduce the assessments and data collection to minimize the burden on 
study participants and site staff. In addition,
, the 
key objectives are achievable with reduced data collection and shorter follow-up.
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Title page
Updated Clinical Trial Physician and 
Clinical Scientist contact information.
Administrative update.
Section 1: Synopsis
Updated to match with relevant protocol 
revisions.
Updated to align with changes in 
the protocol body.
Section 2: Schedule of 
Activities 
•
In Table 2-1:
o
Under “Informed Consent”,
added that all cohorts are closed
for enrollment.
o
Added to “Participant
Registration and Treatment
Assignment/Randomization” that
all cohorts are closed for
enrollment.
•
In Table 2-3:
o
Added “CLOSED FOR
ENROLLMENT” to the title.
o
o
Added another specification to
“Body Imaging” that imaging
assessments will occur every 8
weeks until end of trial.
•
In Table 2-4:
o
Added “CLOSED FOR
ENROLLMENT” to the title.
o
.
o
Added another specification to
“Body Imaging” that imaging
assessments will occur every 8
weeks until end of trial.
Updated for consistency with the 
revised protocol.
Protocol Amendment No.: 04
Date: 03-May-2023
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
•
In Table 2-5, added another 
specification to “Body Imaging” that 
imaging assessments will occur 
every 8 weeks until end of trial.
•
In Table 2-6:
o
Added “CLOSED FOR 
ENROLLMENT” to the title.
o
Added that 
 
 
 
collection of Healthcare 
Resource data are discontinued.
o
Added another specification to 
“Body Imaging” that imaging 
assessments will occur every 8 
weeks until end of trial.
•
In Table 2-7:
o
Added another specification to 
“Body Imaging” that imaging
assessments will occur every 8 
weeks until end of trial. 
o
The collection of 
 Healthcare 
Resource Use and Survival Status
is discontinued at Follow-up
and/or Survival Follow-up.
o
Deleted “for up to 3 years” from 
the notes in “Survival Status” and 
changed visits during Survival 
Follow-up from 3 to 6 months.
•
Added new Tables 2-8, 2-9, 2-10, 
and 2-11. 
Updated the duration of the 
imaging collection. 
Updated the duration and 
frequency of overall survival 
status collection.
Added tables to the schedule of 
activities that have reduced 
assessments as a contingency in 
the event alternate means for 
providing study treatment are not 
available within approximately 9 
months following last patient first 
treatment (LPFT) date.
Table 4-2: Objectives and 
Endpoints: Parts 1B and 2
Indicated in some of the 
 
 that they were not applicable 
per Protocol Amendment 04 or Part 1B
Cohort 6 and Part 2 Cohort 4.
Updated for consistency with the 
revised protocol for Part 2 and Part 
1B cohorts.
Section 5.1: Overall Design
Added text that defined what will be 
considered last patient last visit (LPLV)
date and the maximum duration that a 
patient may receive experimental 
treatment.
Updated to provide clarification.
Protocol Amendment No.: 04
Date: 03-May-2023
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
Section 5.1.4.1: Blinded 
Independent Central Review
Indicated that a blinded independent 
central review (BICR) “may” be utilized
instead of “will” be utilized.
Updated to reflect the change in 
objectives as BICR may not be 
performed.
Section 5.4.1: Rationale for 2
year treatment duration for 
Immunotherapy (Nivolumab + 
Ipilimumab)
Added text to reference Section 7.8.
Added for clarification.
Section 6: Study Population
Added the date enrollment was closed.
Updated for consistency with the 
revised protocol for Part 2 and Part 
1B cohorts.
Section 6.2 Exclusion Criteria
For exclusion criteria 3), changed the 
laboratory testing results to be obtained 
from within 14 days to 28 days prior to 
first dose.
Updated for consistency
Section 5.1.1: Part 1 and Part 
1A: Dose Optimization
Section 7.1.4: Part 2 (Triplet 
Regimen, Cohort 4 and 
Standard of Care (SOC) Arm, 
Cohort 5)
Section 7.1.6: Part 1B (Triplet 
Regimen, Cohort 6)
Section 7.2 Method of 
Treatment Assignment
Section 7.3: Blinding
Added text stating that enrollment is 
closed for Part 2 and Part 1B.
Updated for consistency with the 
revised protocol for Part 2 and Part 
1B cohorts.
Section 8.1.6: Post Study 
Treatment Study Follow-up
Deleted text stating that overall survival 
is the key endpoint. 
Replaced text for participants who
discontinue study treatment, stating that 
they must be followed until LPLV.
Updated to provide the details on 
the follow-up based on change in 
the study timelines.
Section 9.4.3: Ophthalmic
Examination
Added that standard ophthalmic 
examination will occur prior to 
Added for clarification.
Protocol Amendment No.: 04
Date: 03-May-2023
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BMS-936558
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SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04
Section Number & Title
Description of Change
Brief Rationale
randomization and on Month 6 from the 
first dose date. 
Section 10.3.7: Interim 
Analyses
Deleted text stating that interim analyses 
may be conducted for Part 2 and Part 1B.
Deleted to align with the reduced 
study timelines and early closure
per revised protocol 
Appendix 2: Study 
Governance Considerations
Added new sections: BMS Commitment 
to Diversity in Clinical Trials and Data 
Protection, Data Privacy, and Data 
Security, and Study and Site Closure as 
well as additional text to Clinical Study 
Report and Publications.
Added to align with BMS 
commitment to diversity in clinical 
trials and to comply with European 
Union Clinical Trials Regulation 
requirement.
Appendix 10: KRAS/NRAS 
and BRAF Mutational Testing
Updated BRAF mutation status 
requirement.
To incorporate Administrative 
Letter 06.
Protocol Amendment No.: 04
Date: 03-May-2023
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TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR THE PROTOCOL AMENDMENT 04 .................... 
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 04 .................. 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
 
3 INTRODUCTION ..................................................................................................... 
 
3.1 Study Rationale ................................................................................................. 
 
3.1.1 Research Hypothesis ................................................................................ 
 
3.1.2 Rationale for the Combination of Nivolumab and Ipilimumab with 
Trametinib in MSS CRC Population ........................................................... 
 
3.2 Background ....................................................................................................... 
 
3.2.1 Colon Cancer Background and Treatment Options ................................ 
 
3.2.2 RAS/BRAF Wild-type and RAS/BRAF Mutant CRC ................................ 
 
3.2.3 MSS/pMMR and MSI-H/dMMR CRC ...................................................... 
 
3.2.4 Consensus Molecular Subtypes ................................................................ 
 
3.2.5 Nivolumab Mechanism of Action ............................................................. 
 
3.2.6 Ipilimumab Mechanism of Action ............................................................ 
 
3.2.7 Nivolumab Combined with Ipilimumab Clinical Activity ........................ 
 
3.2.7.1 CA209012 in NSCLC ...................................................................... 
 
3.2.7.2 CA209016 in mRCC ........................................................................ 
 
3.2.7.3 CA209004 in Melanoma ................................................................. 
 
3.2.8 Trametinib Mechanism of Action and Clinical Activity ........................... 
 
3.2.9 Nivolumab Monotherapy and Nivolumab and Ipilimumab Combination 
Therapy ....................................................................................................... 
 
3.3 Overall Benefit/Risk Assessment ..................................................................... 
 
3.3.1 Summary of Safety and Efficacy in Relevant Clinical Trials ................... 
 
3.3.2 Safety Monitoring on Study Treatment .................................................... 
 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
 
5 STUDY DESIGN....................................................................................................... 
 
5.1 Overall Design .................................................................................................. 
 
5.1.1 Part 1 and Part 1A: Dose Optimization .................................................. 
 
5.1.1.1 Dose Limiting Toxicity .................................................................... 
 
5.1.1.2 Toxicity Management during DLT Observation ............................. 
 
5.1.2 Part 1B: 
 
 The Triplet Regimen .................... 
 
5.1.3 Part 2: 
 
 the Triplet Regimen and Standard of 
Care Arm ..................................................................................................... 
 
5.1.4 Data Monitoring Committee and Other External Committees ................ 
 
5.1.4.1 Blinded Independent Central Review .............................................. 
 
5.2 Number of Participants ..................................................................................... 
 
5.3 End of Study Definition .................................................................................... 
 
5.4 Scientific Rationale for Study Design............................................................... 
 
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Clinical Protocol
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CA2099N9
nivolumab
Protocol Amendment No.: 04
Date: 03-May-2023
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5.4.1 Rationale for 2 year treatment duration for Immunotherapy (Nivolumab 
+ Ipilimumab) ............................................................................................. 
 
5.4.2 Rationale for Choice of Standard of Care Treatment in Part 2 .............. 
 
5.4.3 Rationale for Stratification in Part 2 ....................................................... 
 
5.5 Justification for Dose ........................................................................................ 
 
5.5.1 Rationale for Dose Selection of Nivolumab and Ipilimumab .................. 
 
5.5.1.1 Rationale for Nivolumab Dosing .................................................... 
 
5.5.1.2 Rationale for Ipilimumab Dosing ................................................... 
 
5.5.2 Rationale for the Dose of Trametinib ...................................................... 
 
5.5.3 Rationale for Shorter Infusion Time ........................................................ 
 
5.5.4 Rationale for Dose Selection of Regorafenib in 3rd line MSS/mCRC ..... 
 
6 STUDY POPULATION ............................................................................................ 
 
6.1 Inclusion Criteria .............................................................................................. 
 
6.2 Exclusion Criteria ............................................................................................. 
 
6.3 Lifestyle Restrictions ........................................................................................ 
 
6.4 Screen Failures .................................................................................................. 
 
6.4.1 Retesting During Screening ..................................................................... 
 
7 TREATMENT ........................................................................................................... 
 
7.1 Treatments Administered .................................................................................. 
 
7.1.1 Nivolumab and Ipilimumab Infusion ....................................................... 
 
7.1.2 Trametinib Dosing ................................................................................... 
 
7.1.3 Part 1 (Completed) (Doublet Regimen, Cohort 1 Group: Enrollment 
Closed) ........................................................................................................ 
 
7.1.4 Part 2 (Triplet Regimen, Cohort 4 and Standard of Care (SOC) Arm, 
Cohort 5) Enrollment Closed ...................................................................... 
 
7.1.4.1 Cohort 4 Triplet Regimen ............................................................... 
 
7.1.4.2 Cohort 5 Regorafenib ..................................................................... 
 
7.1.4.3 Regorafenib Dosing ........................................................................ 
 
7.1.5 Part 1A Completed (Triplet Regimen, Cohort 2 Group and Cohort 3 
Group: Closed for Enrollment) ................................................................... 
 
7.1.6 Part 1B (Triplet Regimen, Cohort 6) Enrollment Closed ........................ 
 
7.2 Method of Treatment Assignment .................................................................... 
 
7.3 Blinding............................................................................................................. 
 
7.4 Dosage Modification ......................................................................................... 
 
7.4.1 Nivolumab/Ipilimumab Dose Delay ......................................................... 
 
7.4.2 Criteria to Resume Treatment with Nivolumab or Ipilimumab ............... 
 
7.4.3 Treatment of Nivolumab- or Ipilimumab-related Infusion Reactions ...... 
 
7.4.4 Trametinib Dose Delay/Modifications ..................................................... 
 
7.4.4.1 General Guidelines for Trametinib Related Toxicities ................... 
 
7.4.4.2 Guidelines for Specific Trametinib-related Toxicities .................... 
 
7.4.4.3 Dose Modification for Trametinib .................................................. 
 
7.4.5 Criteria to Resume Treatment with Trametinib ....................................... 
 
7.4.6 Dose Modification for Regorafenib ......................................................... 
 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
 
7.6 Treatment Compliance ...................................................................................... 
 
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Clinical Protocol
BMS-936558
CA2099N9
nivolumab
Protocol Amendment No.: 04
Date: 03-May-2023
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7.7 Concomitant Therapy........................................................................................ 
 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
 
7.7.2 Other Restrictions and Precautions ......................................................... 
 
7.7.2.1 Imaging Restriction and Precautions ............................................. 
 
7.7.3 Permitted Therapies ................................................................................. 
 
7.8 Treatment After the End of the Study ............................................................... 
 
8 DISCONTINUATION CRITERIA ........................................................................... 
 
8.1 Discontinuation from Study Treatment ............................................................ 
 
8.1.1 Nivolumab Dose Discontinuation (Part 1 Only) ..................................... 
 
8.1.2 Nivolumab and Ipilimumab Dose Discontinuation .................................. 
 
8.1.3 Trametinib Dose Discontinuation ............................................................ 
 
8.1.4 Regorafenib Dose Discontinuation .......................................................... 
 
8.1.5 Treatment Beyond Progression ................................................................ 
 
8.1.6 Post Study Treatment Study Follow-up.................................................... 
 
8.2 Discontinuation from the Study ........................................................................ 
 
8.3 Lost to Follow-Up ............................................................................................. 
 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
 
9.1 Efficacy Assessments ........................................................................................ 
 
9.1.1 Imaging Assessment for the Study............................................................ 
 
9.1.1.1 Methods of Measurements .............................................................. 
 
9.1.1.2 Imaging Schedule and Assessment.................................................. 
 
9.1.1.3 Tumor Assessment by Investigator Sites ......................................... 
 
 ..................................................................... 
 
9.2 Adverse Events ................................................................................................. 
 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
 
9.2.5 Pregnancy ................................................................................................ 
 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
 
9.2.8 Other Safety Considerations .................................................................... 
 
9.3 Overdose ........................................................................................................... 
 
9.3.1 Nivolumab or Ipilimumab Overdose ........................................................ 
 
9.3.2 Trametinib Overdose ............................................................................... 
 
9.3.3 Regorafenib Overdose ............................................................................. 
 
9.4 Safety ................................................................................................................ 
 
9.4.1 Physical Examinations ............................................................................. 
 
9.4.2 Vital signs................................................................................................. 
 
9.4.3 Ophthalmic Examination ......................................................................... 
 
9.4.4 Electrocardiograms ................................................................................. 
 
9.4.5 Echocardiogram/MUGA .......................................................................... 
 
9.4.6 Clinical Safety Laboratory Assessments .................................................. 
 
9.4.7 Imaging Safety Assessment ...................................................................... 
 
 
 
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Clinical Protocol
BMS-936558
CA2099N9
nivolumab
Protocol Amendment No.: 04
Date: 03-May-2023
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9.9 Health Economics OR Medical Resource Utilization and Health Economics . 
 
10 STATISTICAL CONSIDERATIONS .................................................................... 
 
10.1 Sample Size Determination ............................................................................. 
 
10.1.1 mCRC 3rd line Participants: Part 1 Dose Optimization Cohorts ......... 
 
10.1.2 mCRC 3rd line Plus Participants: Part 2 
 
 
Cohort ......................................................................................................... 
 
10.1.3 mCRC 2nd line Participants: Part 1A Dose Optimization Cohorts ...... 
 
10.1.4 mCRC 2nd line Participants: Part 1B 
 
 Cohorts
..................................................................................................................... 
 
10.2 Populations for Analyses ................................................................................ 
 
10.3 Statistical Analyses ......................................................................................... 
 
10.3.1 Efficacy Analyses ................................................................................... 
 
10.3.2 Safety Analyses....................................................................................... 
 
............................................. 
 
............................................. 
 
............................................. 
 
10.3.6 Outcomes Research Analyses ................................................................ 
 
 ......................................................................... 
 
 ..................................................................................... 
 
10.3.6.3 Other Analyses .............................................................................. 
 
10.3.7 Interim Analyses ..................................................................................... 
 
11 REFERENCES ........................................................................................................ 
 
12 APPENDICES ......................................................................................................... 
 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
 
APPENDIX 5 NIVOLUMAB MANAGEMENT ALGORITHMS FOR STUDIES 
UNDER CTCAE VERSION 4.0 ............................................................................ 
 
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Clinical Protocol
BMS-936558
CA2099N9
nivolumab
Protocol Amendment No.: 04
Date: 03-May-2023
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APPENDIX 6 TRAMETINIB DOSE MODIFICATION GUIDELINES .................... 
 
APPENDIX 7 ECOG PERFORMANCE STATUS ..................................................... 
 
APPENDIX 8 RECIST 1.1 GUIDELINES (WITH BMS MODIFICATIONS) .......... 
 
APPENDIX 9 MSI/MSS STATUS TESTING ............................................................. 
 
APPENDIX 10 KRAS/NRAS AND BRAF MUTATIONAL TESTING .................... 
 
APPENDIX 11 NYHA FUNCTIONAL CLASSIFICATION ..................................... 
 
APPENDIX 12 COUNTRY SPECIFIC APPENDIX................................................... 
 
APPENDIX 13 GUIDANCE TO SITES ON TUMOR LOCATION AND 
SIDEDNESS ........................................................................................................... 
 
APPENDIX 14 PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
................................................................................................................................. 
 
 
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Clinical Protocol
BMS-936558
CA2099N9
nivolumab
Protocol Amendment No.: 04
Date: 03-May-2023
13
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v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
1
SYNOPSIS 
Protocol Title: A Study Of Nivolumab In Combination With Trametinib With Or Without 
Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers
(CheckMate 9N9: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 9N9)
Study Phase: 1/2
Rationale:
CA2099N9 (CHECKpoint pathway and nivoluMAb clinical Trial Evaluation [CHECKMATE] 
9N9) is a Phase 1/2, open-label, multi-center trial of nivolumab in combination with trametinib, 
with or without ipilimumab for the treatment of proficient mismatch repair (pMMR)/microsatellite 
stable (MSS) metastatic colorectal cancer (mCRC). Parts 1A and 1B of this trial investigate
nivolumab and ipilimumab plus trametinib as 2nd-line (2L) treatment for pMMR/MSS mCRC 
participants. Part 2 provides an opportunity to evaluate nivolumab and ipilimumab in combination 
with trametinib for the treatment of later-line (3rd line plus [3L+]) pMMR/MSS mCRC 
participants who failed at least 2 prior lines (no more than 4 prior lines) of therapy for metastatic 
disease. Part 2 will include 2 treatment arms, including the triplet regimen and standard of care 
treatment (SOC) option (regorafenib). The objective of Part 2 is to further develop and optimize a 
 patient selection strategy for combination therapy of immune checkpoint 
inhibitors with a mitogen-activated protein kinase enzymes (MEK) inhibitor.
Additionally, the study presents an opportunity to validate the tolerability and preliminary efficacy, 
and further optimize a 
 patient selection strategy for nivolumab and ipilimumab 
in combination with trametinib in earlier line (2nd line [2L]) pMMR/MSS mCRC participants who 
failed only 1 prior line of therapy for metastatic disease (Part 1B). 
Study Population:
Participants with previously treated metastatic, pMMR/MSS colorectal cancer (CRC) in the 2L
and 3L+ setting.
Participants must have progressed or been intolerant to 2 prior lines of chemotherapy in the 
metastatic disease setting (doublet regimen; Part 1), participants must have progressed or been 
intolerant to at least 2 prior lines (no more than 4 prior lines) in the metastatic disease setting 
(triplet regimen, Part 2), and participants must have progressed or been intolerant to 1 prior line of 
chemotherapy in the metastatic disease setting (triplet regimen, Parts 1A and 1B).
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Objectives and Endpoints: 
Objectives and Endpoints: Parts 1 and 1A
Objectives
Endpoints
Primary
•
To characterize the safety and tolerability of 
combination therapies 
•
DLTs in Part 1 and Part 1A, only, observed for 1 
treatment cycle (4 weeks for the doublet regimen and 8 
weeks for the triplet regimen)
•
To establish recommended dosing regimen for 
the combination (nivolumab plus ipilimumab 
plus trametinib OR nivolumab plus 
trametinib) 
•
Safety (including but not limited to): AEs, SAEs, 
deaths, and clinical laboratory abnormalities per 
CTCAE (version 4.0)
Secondary
•
To evaluate preliminary efficacy  
•
ORR, DCR, DOR, TTR, and PFS by investigator per 
RECIST v1.1
•
OS
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; RECIST, Response Evaluation 
Criteria in Solid Tumors; SAE, serious adverse event; DLTs, dose limiting toxicities; ORR, objective response rate; 
DCR, disease control rate; DOR, duration of response; TTR, time to response; PFS, progression free survival; OS, 
overall survival.  
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Objectives and Endpoints: Parts 1B and 2
Objectives
Endpoints
Primary
•
To evaluate the ORR in all participants 
treated with nivolumab plus ipilimumab and 
trametinib in the 2L and 3L+a setting (Parts
1B and 2, respectively); and regorafenib in 
3L+a (Part 2 Only).
•
ORR by investigatorb
Secondary
•
To evaluate efficacy in all participants 
treated with nivolumab plus ipilimumab and 
trametinib in the 2L and 3L+a setting (Parts
1B and 2, respectively) and regorafenib in 
3L+a (Part 2 only).
 
 
•
BOR, DCR, DOR, TTR, and PFS by investigator b
•
OS
•
To characterize the safety and tolerability of 
combination therapies.
•
Safety (including but not limited to): AEs, SAEs, deaths, 
and clinical laboratory abnormalities per CTCAE 
(version 4.0)
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Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Objectives and Endpoints: Parts 1B and 2
AE, adverse event; 
, BOR, best overall response; 
 
; CTCAE, Common Terminology Criteria for Adverse Events; DCR, 
disease control rate; DOR, duration of response; 
 
; 
; 
; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PFS2, 
time to second objective disease progression; 
; 
 
; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; TTR, time to response; 
; 2l, second line; 3L+, third-line plus.
a No more than 4 prior lines of therapy.
b per RECIST v 1.1.
Overall Design:
This is a Phase 1/2 open-label, multi-center trial of nivolumab in combination with trametinib, 
with or without ipilimumab, to evaluate the safety profile and clinical activity of these regimens 
in participants with metastatic colorectal cancer (mCRC).
Participants were dosed in the dose optimization phases of the study (Parts 1 and 1A) with either 
the doublet (nivolumab + trametinib) in third line participants or triplet (nivolumab + ipilimumab 
+ trametinib) regimen in second line participants. The dose optimization phase of the study is now 
completed. Decisions regarding dosages of trametinib to be used in Parts 1B and 2 are based on 
observed safety and efficacy signals in Parts 1A and 1. The recommended Phase 2 dose for Part 2 
and 1B was determined to be the triplet regimen (nivolumab 6 mg/kg Q4W + ipilimumab 1 mg/kg 
Q8W + trametinib 1.5 mg continuous QD). Assessment of the preliminary benefit/risk based on 
the safety and efficacy profile for the doublet and triplet regimens used in the non-randomized 
parts of the study was reviewed along with additional emerging safety and efficacy data from other 
relevant trials to determine the optimal dose of trametinib to be used in Part 2 and Part 1B in 
combination with nivolumab and ipilimumab as presented in Figure 1-1. Participants in each part 
of the study will be treated until progression, unacceptable toxicity, withdrawal of consent, or a 
maximum of 2 years. Maximum treatment duration is not applicable to participants receiving 
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Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
standard of care (SOC) therapy in Part 2, Cohort 5, which may be continued until progression of 
disease, unacceptable toxicity, or withdrawal of consent.
Per Protocol Amendment 04, due to early study closure the last participant last treatment (LPLT) 
date on CA209-9N9 study will occur approximately 9 months after last participant first treatment 
(LPFT); and last participant last visit (LPLV) date will occur approximately 12 months after 
LPFT. When this LPLV date is reached, participants follow-up will be ceased and all participants 
will complete the study. Any participant still on treatment after LPLT date who continue to 
demonstrate clinical benefit will be eligible to receive treatment outside of this study in accordance 
with protocol Section 7.8. For Cohort 4 and Cohort 6 participants the total maximum duration of 
treatment will be 2 years, including the treatment duration on CA209-9N9. For participants in 
Cohort 5, the treatment will be administered as per the local standard of care. In the event 
alternative means of supplying study treatment as described in Section 7.8 is not accessible by
approximately 9 months after LPFT, the study may remain open until such means become 
available or last participant ends treatment and completes follow-up visits 1 and 2, under these 
circumstances the study procedures will be in accordance with Table 2-8, Table 2-9, Table 2-10, 
and Table 2-11.
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Figure 1-1:
Study Schematic
mCRC, metastatic colorectal cancer; Ipi, ipilimumab; MSS, microsatellite stable; Nivo, nivolumab; pMMR, proficient mismatch repair; QD, quaque die, once 
daily; Q4W, every 4 weeks; Q8W, every 8 weeks; wk, week; 2L, second line; 3L, third line; 3L+, third line plus.
a See Table 7.2-1 for unique cohort numbers for dose escalation and de-escalation.
b Participants in Part 1A were assigned to each treatment cohort on an alternating basis in IRT (interactive response technology). NOTE: Enrollment is closed.
NOTE: Participants in each part of the study will be treated until progression, unacceptable toxicity, withdrawal of consent, or a maximum of 2 years. Maximum 
treatment duration is not applicable to standard of care therapy (regorafenib).
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Number of Participants: 
Part 1 and Part 1A follow a 3 + 3 design with potential dose escalation and de-escalation based on 
DLT observations, will treat up to approximately 18 and 24 participants, respectively. NOTE: 
Part 1 and Part 1A have completed.
Part 1B will treat approximately 80 participants. Part 2 will randomize approximately 120
participants into 2 arms, nivolumab + ipilimumab +trametinib and regorafenib, in a 2:1 ratio. See 
Section 10.1 for sample size determination.
Treatment Arms and Duration: Dose optimization phase of the study (Part 1 and Part 1A)
has been completed. Enrollment is closed in Part 1 and Part 1A cohorts.
For dose optimization (Parts 1 and 1A) phase, participants will be allocated to treatment as 
follows:
•
Part 1: Participants with 3rd line mCRC will be assigned to receive doublet therapy as 
nivolumab 480 mg Q4W plus trametinib 1.5 mg QD (continuous dosing, Cohort 1) 
•
Part 1A: Participants with 2nd line mCRC will be assigned to receive triplet therapy of
either:
−
6 mg/kg nivolumab (Q4W) plus ipilimumab 1 mg/kg (Q8W) plus trametinib 1.5 mg QD 
(continuous dosing, Cohort 2), OR
−
6 mg/kg nivolumab (Q4W) plus ipilimumab 1 mg/kg (Q8W) plus trametinib 1.5 mg QD 
(2 week ON/2 week OFF, Cohort 3)
Only pMMR/MSS participants can be enrolled in Part 1 and Part 1A.
For 
 
(Part 1B) phase: Participants with 2nd line pMMR/MSS mCRC 
will be assigned to receive 6 mg/kg nivolumab (Q4W) plus ipilimumab 1 mg/kg (Q8W) plus 
trametinib 1.5 mg continuous QD (Cohort 6).
For 
 
 (Part 2) phase: Participants with 3L+ (no more than 4 prior lines of 
therapy) pMMR/MSS mCRC will be randomized at 2:1 ratio to receive nivolumab 6 mg/kg Q4W 
plus ipilimumab 1 mg/kg Q8W plus trametinib 1.5 mg continuous QD (Cohort 4), OR regorafenib 
in the SOC arm (Cohort 5).
For Part 1B (Cohort 6) and Part 2 (Cohorts 4 and 5), the proportion of participants with RAS 
mutations will be monitored on an ongoing basis. The IRT system will be set up to notify the 
Sponsor once the pre-defined number of RAS mutant participants have been enrolled. The target 
will be approximately 65% mutant, 35% wild type. If accrual diverges significantly from this goal, 
accrual in a cohort may be paused after discussion between the Sponsor and the investigators. 
Patients with BRAF V600 mutations are not eligible for the study.
An interim analysis (IA) of Part 2 and Part 1B cohorts will be conducted after an overall total of 
approximately 100 treated participants (including approximately 60 treated participants from Part 
2) have a minimum of 4 months of follow-up after the first treatment (corresponding to at least 2 
tumor assessments).
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Study treatment: 
Study Drug for CA2099N9
Medication 
Potency 
IP/Non-IP 
Nivolumab
Solution for Injection
100 mg (10 mg/mL) 
IP
Ipilimumab
Solution for Injection
200 mg
50 mg
(5 mg/mL)
IP
Trametinib tablet
0.5 mg and various strengths
IP
Regorafenib tablet
40 mg and various strengths
IP
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES 
Table 2-1:
Screening Procedural Outline (CA2099N9)
Procedure
Screening 
Proceduresa
Notes
Eligibility Assessments
Informed Consent
X
Must be obtained prior to performing any protocol related screening procedures.
Study allows for re-enrollment of a participant that has discontinued the study as a pre-
treatment failure. If re-enrolled, the participant must be re-consented and assigned a new 
participant number from Interactive Response system IRT.
All cohorts on the study are now closed for enrollment.
Contact Sponsor to ensure that the appropriate Part is open to enrollment prior to consenting a 
participant.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening (re-enrollment if applicable) and
must be confirmed prior to first dose. 
Medical History
X
Includes prior conditions and any toxicities or allergy related to previous treatments. 
For Part 2, participant’s primary tumor location (sidedness), detailed in Appendix 13, is 
required for randomization/stratification.
Prior anti-cancer therapy
X
Prior Radiotherapy
X
ECOG Status Assessment
X
Within 28 days prior to first dose
Safety Assessments
Assessment of Signs and Symptoms
X
Within 28 days prior to first dose
Physical Examination (PE)
X
If the screening PE is performed within 24 hours prior to first dose, then a single exam may 
count as both the screening and pre-dose evaluation.
Physical Measurements
X
Includes height and weight
Vital Signs
X
BP, HR, temperature 
Serious Adverse Event Assessment
X
All SAEs must be collected from the date of participant’s written consent. 
See Section 9.2, and Appendix 3.
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099N9)
Procedure
Screening 
Proceduresa
Notes
Concomitant Medication Use
X
Includes medications taken within 14 days prior to first dose. Vaccine use must be collected 
within 30 days prior to first dose. For Part 2 and Part 1B participants, includes antibiotics taken 
within 2 months prior to first dose.
Echocardiogram or MUGA
X
Within 28 days prior to first dose. Refer to eligibility criteria. 
ECG
X
Within 28 days prior to first dose. Refer to eligibility criteria.
Ophthalmic Evaluation
X
Participants will be evaluated for baseline visual disturbances; Refer to eligibility criteria. 
Laboratory Tests
X
Local testing must be performed within 28 days prior to first dose.
•
CBC w/differential and platelet count
•
Chemistry panel including: AST, ALT, ALP, total bilirubin, blood urea nitrogen (BUN) or
serum urea level, creatinine (if abnormal creatinine clearance should be reported), phosphate,
Ca, Na, K, Mg, Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, leukocyte esterase, specific gravity, pHb
•
Coagulation including PT/INR and PTT
•
Thyroid panel including TSH, Free T4, Free T3
•
Hepatitis B/C (HBsAg, HCV antibody or HCV RNA) Testing for HIV must be performed
at sites where mandated locally. (see Appendix 12)
•
Carcinoembryonic antigen (CEA) for participants with unknown results or history of
abnormal results per local testing. For Part 2 and Part 1B, CEA for all participants and for
participants with history of normal CEA, collect CA19-9.
Pregnancy Test (WOCBP only)
X
For WOCBP only: Serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent 
units of HCG) to be done at screening visit and within 24 hours prior to first dose. See
Appendix 4
For females under the age of 55, FSH > 40mIU/mL is required to confirm menopause.
pMMR/MSS Assessment
X
Verify pMMR/Microsatellite stable (MSS) based on available local testing results as part of 
medical history prior to study entry.
Confirm availability of pathology report for MMR or MSS testing results. Report must contain 
MMR or MSS results and should also contain specific results per markers tested for MMR or 
MSS.
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Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099N9)
Procedure
Screening 
Proceduresa
Notes
Please see inclusion criteria (Section 6.1) and Appendix 9 for details.
RAS mutation status
X
Verify RAS mutation status, including KRAS and NRAS, based on available local testing 
results as part of medical history prior to study entry. Refer to Appendix 10 for local testing 
methodology permitted by the study.
BRAF Mutation status
X
Verify BRAF mutation status based on available local testing results as part of medical history 
prior to study entry (Appendix 10). BRAF V600 mutant participants are NOT eligible. 
(Exclusion Criteria Section 6.2).
Body Imaging
X
See Section 9.1.1. Existing scans performed within 28 days prior to first dose could be used as 
baseline scan for the study provided all requirements are met.
Brain Imaging
X
See Section 9.1.1. Performed at screening for participants with a history or clinical symptoms 
of brain metastasis. 
Existing scans performed within 28 days prior to first dose could be used as baseline scan for 
the study provided all requirements are met.
Other Imaging Bone Scan 
X
As clinically indicated. See Section 9.1.1.2.
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Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099N9)
Procedure
Screening 
Proceduresa
Notes
Clinical Drug Supply
IRT
Participant Registration and Treatment 
Assignment/Randomization 
X
Register in IRT to obtain participant number.
All cohorts on the study are now closed for enrollment. 
Treatment assignment/randomization will occur after eligibility is confirmed. Refer to Section 
7.2 for stratification factors. Refer to IRT instruction manual for details.
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. 
Protocol Amendment No.: 04
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-2:
On-Treatment Assessments (Part 1 mCRC 3rd line, DOUBLET, DOSE OPTIMIZATION CA2099N9 
[Cohort 1 Group]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
C1D1 and subsequent 
cycles D1 (C2D1, C3D1 
etc.)
C1D15 and C2D15 b
C1D8 and C1D22 c
Safety Assessments
Targeted Physical Examination
X
X
Targeted examination must include at a minimum the following 
body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain metastases
Ophthalmic Evaluation
Participants are required to have a standard ophthalmic examination conducted by an ophthalmologist at C2D1, Month 6, 
and then annually thereafter unless clinically indicated sooner. (See Section 9.4.3)
For C2D1: Results must be evaluated within 7 days prior to study treatment.
Vital Signs 
X
X
Including BP, HR, and temperature. Obtain vital signs within 72 
hours prior to dosing.
Physical Measurements 
(including performance status)
X
X
Weight and ECOG performance status within 72 hours prior to 
dosing. 
ECOG must be assessed prior to first dose on Cycle 1 Day 1 to re-
confirm eligibility.
See Appendix 7 for ECOG Performance Status scale.
Echocardiogram or MUGA
Evaluate LVEF within 7 days prior to C2D1, C4D1, and then every 12 weeks thereafter until discontinuation of treatment. 
Results must be evaluated within 7 days prior to study treatment.
ECG
Participants will be evaluated within 7 days prior to C2D1 of treatment, and then as clinically indicated until 
discontinuation of treatment.
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE 
(version 4.0)
Serious Adverse Event 
Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE 
(version 4.0).
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Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-2:
On-Treatment Assessments (Part 1 mCRC 3rd line, DOUBLET, DOSE OPTIMIZATION CA2099N9 
[Cohort 1 Group]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
C1D1 and subsequent 
cycles D1 (C2D1, C3D1 
etc.)
C1D15 and C2D15 b
C1D8 and C1D22 c
Review of Concomitant 
Medications
X
X
Laboratory Tests
X
X
Local CBC, chemistry assessments, and thyroid panel should be 
performed within 72 hours prior to Day 1 of each cycle through 
Cycle 13 and may be collected every alternate cycle thereafter if 
deemed medically appropriate. Laboratory tests do not need to be 
repeated on C1D1 if screening lab results are deemed still clinically 
valid by the treating investigator.
Lab assessments will include:
•
CBC w/differential and platelet count
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN, or 
serum urea level, creatinine (if abnormal creatinine clearance 
should be reported), phosphate, Ca, Na, Mg, K, Cl, LDH, 
glucose, and albumin
•
Urinalysis including protein, glucose, blood, leukocyte esterase, 
specific gravity, pHd,e
•
Coagulation including PT/INR and PTT (as clinically indicated)
•
TSH with reflexive Free T4, and Free T3 if TSH is abnormal 
(not required at D15 of each cycle if not clinically indicated)
•
CEA every 8 weeks for participants with history of abnormal 
results per local testing
Pregnancy Test (WOCBP Only) 
X
Serum or urine pregnancy test to be done within 24 hours prior to 
first dose, and then every 4 weeks (± 1 week) regardless of dosing 
schedule. See Appendix 4.
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-2:
On-Treatment Assessments (Part 1 mCRC 3rd line, DOUBLET, DOSE OPTIMIZATION CA2099N9 
[Cohort 1 Group]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
C1D1 and subsequent 
cycles D1 (C2D1, C3D1 
etc.)
C1D15 and C2D15 b
C1D8 and C1D22 c
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 8 weeks 
(± 7 days) from the date of first dose until disease progression, or
withdrawal of consent, whichever occurs first.
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical symptoms 
of brain metastasis should have surveillance MRI per local standard 
of care (SOC) (approximately every 12 weeks) or sooner if 
clinically indicated. 
Other Imaging Bone Scan
See notes
As clinically indicated. See Section 9.1.1.
Clinical Drug Supply
IRT contact
X
First dose should be administered within 3 calendar days of 
treatment assignment.
Administer Nivolumab (480 mg)
X
Nivolumab flat dosing every 4 weeks.
Administer Trametinib
See note
Trametinib dosing described in Section 7.1.3.
Note: All scheduled clinic visits are to occur within ± 3 days of scheduled day. Part 1 enrolls participants assigned to Cohort 1 Group (Refer to Table 7.2-1).
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
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 regulation. If a dose is delayed,
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Day 15 assessments are mandatory for the first 2 cycles, and then as clinically indicated by treating physicians.
c Telephone contact with participants on C1D8 and C1D22 are mandatory to assess adverse events and provide toxicity management. If clinically indicated,
participants should be evaluated in the clinic.
d Urinalysis should be assessed every 4 weeks for the first year of study treatment, and then every 8 weeks unless more frequent testing is clinically indicated.
e Urinalysis or urine dipstick. If blood, protein or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
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Date: 03-May-2023
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5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 
Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 
(required);
C1D43
(optional) b
Day 29
Safety Assessments
Targeted Physical 
Examination
X
X
X
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain metastases
Ophthalmic 
Evaluation
Participants are required to have a standard ophthalmic examination conducted by an ophthalmologist at Month 1, Month 6, and then 
annually thereafter unless clinically indicated sooner. (See Section 9.4.3)
For Month 1: Results must be evaluated within 7 days prior to study treatment.
Vital Signs 
X
X
X
Including BP, HR, and temperature. Obtain vital signs within 
72 hours prior to first dose.
Physical 
Measurements 
(including 
performance status)
X
X
X
Weight and ECOG performance status within 72 hours prior 
to dosing. 
ECOG must be assessed prior to first dose on Cycle 1 Day 1 
to re-confirm eligibility
See Appendix 7 for ECOG Performance Status scale.
ECG 
Participants will be evaluated within 7 days prior to C1D29 of treatment, and then as clinically indicated until discontinuation of 
treatment.
Echocardiogram or 
MUGA
Evaluate LVEF within 7 days prior to C1D29 and C2D29, and then every 12 weeks thereafter until discontinuation of treatment. 
Adverse Events 
Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE 
(version 4.0).
Serious Adverse 
Event Assessment
Continuously
Serious adverse events will be graded according to the NCI-
CTCAE (version 4.0).
Protocol Amendment No.: 04
Date: 03-May-2023
30
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 
Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 
(required);
C1D43
(optional) b
Day 29
Review of 
Concomitant 
Medications
X
X
X
Laboratory Tests
X
X
X
Local CBC, chemistry assessments, and thyroid panel should 
be done within 72 hours prior to D1 and D29 of each cycle 
through Cycle 6 (in addition to C1D15 and C1D43), and 
may be collected only prior to D1 of each cycle thereafter if 
deemed medically appropriate. 
Laboratory tests do not need to be repeated on C1D1 if 
screening labs results are deemed still clinically valid by the 
treating investigator.
Lab assessments will include:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine (if abnormal 
creatinine clearance should be reported), phosphate, Ca, 
Na, K, Mg, Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, leukocyte 
esterase, specific gravity, pHc,c
•
Coagulation including PT/INR and PTT (as clinically 
indicated)
•
If TSH is abnormal, refer to Appendix 5 for instructions 
on Free T4 and Free T3. (TSH is not required at C1D15 
and C1D43 if not clinically indicated)
Protocol Amendment No.: 04
Date: 03-May-2023
31
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 
Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 
(required);
C1D43
(optional) b
Day 29
•
CEA every 4 weeks CEA for all participants. For
participants with elevated CA19-9 at screening, monitor
CA19-9 AND CEA.
Pregnancy Test 
(WOCBP Only) 
X
X
Serum or urine pregnancy test to be done within 24 hours 
prior to first dose, and then every 4 weeks (± 1 week) 
regardless of dosing schedule. See Appendix 4.
Protocol Amendment No.: 04
Date: 03-May-2023
32
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 
Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 
(required);
C1D43
(optional) b
Day 29
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 8 
weeks (± 7 days) from the date of first dose until disease 
progression, end of trial, or withdrawal of consent, 
whichever occurs first.
For participants who continue treatment beyond initial 
progression see Section 8.1.5.
Tumor assessment scans should be submitted to the imaging 
vendor within 14 days of acquisition.
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance MRI 
per local SOC (approximately every 12 weeks) or sooner if 
clinically indicated. 
Other Imaging Bone 
Scan
See notes
As clinically indicated. See Section 9.1.1.2
Protocol Amendment No.: 04
Date: 03-May-2023
33
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 
Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 
(required);
C1D43
(optional) b
Day 29
Healthcare Resource 
Use
X
X
See Section 9.9.
Clinical Drug Supply
Contact IRT
X
X
First dose should be administered within 3 calendar days of 
randomization.
Administer 
Nivolumab (6 
mg/kg) 
X
X
Nivolumab dosing will occur every 4 weeks.
Administer 
Ipilimumab (1 
mg/kg)
X
Ipilimumab dosing will occur every 8 weeks. 
Protocol Amendment No.: 04
Date: 03-May-2023
34
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-3:
On-Treatment Assessments (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 
Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 
(required);
C1D43
(optional) b
Day 29
Administer 
Trametinib (1.5mg 
QD)
See notes
Trametinib dosing will occur once daily. Trametinib bottles 
will be dispensed at D1 and D29 of each cycle
Note: All scheduled clinic visits are to occur within ± 3 days of scheduled day
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 regulation. If a dose is delayed,
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Cycle 1 Day 15 assessments are required for the first cycle. C1 D43 and subsequent D15 and D43 assessments are optional and may be performed as clinically 
indicated at the investigator’s discretion.
c Urinalysis should be assessed every 4 weeks for the first year of study treatment, and then every 8 weeks unless more frequent testing is clinically indicated.
Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
Protocol Amendment No.: 04
Date: 03-May-2023
35
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 
[Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 
(required); 
subsequent cycle 
D15 (if clinically 
indicated)b
Safety Assessments
Targeted Physical Examination
X
X
Targeted examination must include at a minimum the following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain metastases
Vital Signs 
X
See Note
Including BPc, HR, and temperature. Obtain vital signs within 72 hours prior to
dosing
Physical Measurements 
(including performance status)
X
See Note
Weight and ECOG performance status within 72 hours prior to dosing. 
ECOG must be assessed prior to first dose on Cycle 1 Day 1 to re-confirm 
eligibility.
See Appendix 7 for ECOG Performance Status scale.
ECG
Participants will be evaluated within 7 days prior to C2D1 of treatment, and then as clinically indicated until 
discontinuation of treatment.
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE (version 4.0).
Serious Adverse Event 
Assessment
Continuously
Serious adverse events will be graded according to the NCI-CTCAE (version 
4.0).
Review of Concomitant 
Medications
X
X
Laboratory Tests
X
See Notes
Local CBC and chemistry assessments should be done within 72 hours prior to 
D1 of each cycle, and D15 of each cycle if clinically indicated (C1D15 is 
Protocol Amendment No.: 04
Date: 03-May-2023
36
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 
[Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 
(required); 
subsequent cycle 
D15 (if clinically 
indicated)b
required). Laboratory tests do not need to be repeated on C1D1 if screening 
laboratory results are deemed still clinically valid by the treating investigator.
Lab assessments will include:
•
CBC w/differential and platelet count,d
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN or serum urea 
level, creatinine (if abnormal creatinine clearance should be reported), 
phosphate, Ca, Na, K, Cl, Mg,  LDH, glucose, albumin
•
Coagulation including PT/INR and PTT (as clinically indicated)
•
TSH every 4 weeks.e If TSH is abnormal, see Appendix 5 for instructions on 
Free T4 and Free T3. (TSH is not required at C1D15 if not clinically 
indicated).
•
CEA for all participants. For participants with elevated CA19-9 at screening, 
monitor CA19-9 AND CEA.f
•
Urine dipstick or urinalysisg
Pregnancy Test (WOCBP Only) 
X
Serum or urine pregnancy test to be done within 24 hours prior to first dose, and 
then every 4 weeks (± 1 week) regardless of dosing schedule. See Appendix 4.
Protocol Amendment No.: 04
Date: 03-May-2023
37
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 
[Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 
(required); 
subsequent cycle 
D15 (if clinically 
indicated)b
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 8 weeks (±7 days) 
from the date of first dose until disease progression, end of trial, or withdrawal 
of consent, whichever occurs first.
Tumor assessment scans should be submitted to the imaging vendor within 
14 days of acquisition. 
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical symptoms of brain 
metastasis should have surveillance MRI per local SOC (approximately every 
12 weeks) or sooner if clinically indicated. 
Other Imaging Bone Scan
See notes
As clinically indicated. See Section 9.1.1.2
Protocol Amendment No.: 04
Date: 03-May-2023
38
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-4:
On-Treatment Assessments (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 
[Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 
(required); 
subsequent cycle 
D15 (if clinically 
indicated)b
Healthcare Resource Use
See notes
See notes
To be collected at C1D1, and at D1 of each subsequent cycle. See Section 9.9.
Clinical Drug Supply
IRT contact
X
First dose should be administered within 3 calendar days of randomization
Administer Regorafenib (160 
mg)
See notes 
Orally, once daily for the first 21 days (D1 to D21) of each cycle. See Section 
7.1.4
Note: All scheduled clinic visits are to occur within ±3 days of scheduled day.
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 regulation. If a dose is delayed,
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Cycle 1, D15 clinic visit is required. Day 15 visits in the subsequent cycles are optional and should be performed as clinically indicated or per local institutional
guidelines.
c Monitor BP more frequently as clinically indicated or per local institutional guidelines.
d Monitor coagulation more frequently for increased risk of bleeding per local institutional guidelines.
e Monitor TSH per local product label and/or institutional guideline.
Protocol Amendment No.: 04
Date: 03-May-2023
39
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
f CEA at C1D1, C1D15, C2D1, C3D1, C4D1, C5D1, and then every 8 weeks thereafter or more frequent if clinically indicated. If CA19-9 is also monitored,
follow same collection frequency as CEA.
g Urine dipstick or urinalysis to monitor urine protein per local product label and/or institutional guideline. Protocol recommended frequency is every 4 weeks.
Protocol Amendment No.: 04
Date: 03-May-2023
40
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-5:
On-Treatment Assessments (Part 1A mCRC 2nd line, TRIPLET, DOSE OPTIMIZATION CA2099N9 
[Cohorts 2 and 3 Groups]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
C1D1 (and D1 
each 
subsequent 
cycle, C2D1, 
C3D1, etc.)
C1D15 and 
C1D43;b
C1D8, C1D22, 
C1D36, 
C1D50c
C1D29 (and 
D29 each 
subsequent 
cycle, C2D29, 
C3D29, etc.)
Safety Assessments
Targeted Physical Examination
X
X
X
Targeted examination must include at a minimum the following 
body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain metastases
Ophthalmic Evaluation
Participants are required to have a standard ophthalmic examination conducted by an ophthalmologist at C1D29, 
Month 6, and then annually thereafter unless clinically indicated sooner. (See Section 9.4.3)
For C1D29: Results must be evaluated within 7 days prior to study treatment.
Vital Signs 
X
X
X
Including BP, HR, and temperature. Obtain vital signs within 72 
hours prior to first dose.
Physical Measurements (including 
performance status)
X
X
X
Weight and ECOG performance status within 72 hours prior to 
dosing. 
ECOG must be assessed prior to first dose on Cycle 1 Day 1 to 
re-confirm eligibility. 
See Appendix 7 for ECOG Performance Status scale.
ECG on treatment
Participants will be evaluated within 7 days prior to C1D29 of treatment, and then as clinically indicated until 
discontinuation of treatment.
Echocardiogram or MUGA
Evaluate LVEF within 7 days prior to C1D29 and C2D29, and then every 12 weeks thereafter until discontinuation of 
treatment. Results must be evaluated within 7 days prior to study treatment.
Protocol Amendment No.: 04
Date: 03-May-2023
41
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-5:
On-Treatment Assessments (Part 1A mCRC 2nd line, TRIPLET, DOSE OPTIMIZATION CA2099N9 
[Cohorts 2 and 3 Groups]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
C1D1 (and D1 
each 
subsequent 
cycle, C2D1, 
C3D1, etc.)
C1D15 and 
C1D43;b
C1D8, C1D22, 
C1D36, 
C1D50c
C1D29 (and 
D29 each 
subsequent 
cycle, C2D29, 
C3D29, etc.)
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE 
(version 4.0).
Serious Adverse Event Assessment
Continuously
Serious adverse events will be graded according to the NCI-
CTCAE (version 4.0).
Review of Concomitant 
Medications
X
X
X
Laboratory Tests
X
X
X
Local CBC, chemistry assessments, and thyroid panel should be 
done within 72 hours prior to D1 and D29 of each cycle through 
Cycle 6 (in addition to C1D15 and C1D43), and may be 
collected only prior to D1 of each cycle thereafter if deemed 
medically appropriate. Laboratory tests do not need to be 
repeated on C1D1 if screening labs were performed within 72 
hours prior to first dose.
Lab assessments will include:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN or 
serum urea level, creatinine (if abnormal creatinine clearance 
should be reported), phosphate, Ca, Na, K, Mg, Cl, LDH, 
glucose, albumin
•
Urinalysis including protein, glucose, blood, leukocyte 
esterase, specific gravity, pHd,e
•
Coagulation including PT/INR and PTT (as clinically 
indicated)
Protocol Amendment No.: 04
Date: 03-May-2023
42
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-5:
On-Treatment Assessments (Part 1A mCRC 2nd line, TRIPLET, DOSE OPTIMIZATION CA2099N9 
[Cohorts 2 and 3 Groups]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
C1D1 (and D1 
each 
subsequent 
cycle, C2D1, 
C3D1, etc.)
C1D15 and 
C1D43;b
C1D8, C1D22, 
C1D36, 
C1D50c
C1D29 (and 
D29 each 
subsequent 
cycle, C2D29, 
C3D29, etc.)
•
TSH with reflexive Free T4, and Free T3 if TSH is abnormal 
(not required at C1D15 and C1D43 if not clinically 
indicated) 
•
CEA every 8 weeks for participants with history of 
abnormal results per local testing
Pregnancy Test (WOCBP Only) 
X
X
Serum or urine pregnancy test to be done within 24 hours prior 
to first dose, and then every 4 weeks (± 1 week) regardless of 
dosing schedule. See Appendix 4.
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 8 
weeks (±7 days) from the date of first dose until disease 
progression, end of trial, or withdrawal of consent, whichever 
occurs first.
Protocol Amendment No.: 04
Date: 03-May-2023
43
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-5:
On-Treatment Assessments (Part 1A mCRC 2nd line, TRIPLET, DOSE OPTIMIZATION CA2099N9 
[Cohorts 2 and 3 Groups]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
C1D1 (and D1 
each 
subsequent 
cycle, C2D1, 
C3D1, etc.)
C1D15 and 
C1D43;b
C1D8, C1D22, 
C1D36, 
C1D50c
C1D29 (and 
D29 each 
subsequent 
cycle, C2D29, 
C3D29, etc.)
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance MRI per 
local SOC (approximately every 12 weeks) or sooner if 
clinically indicated. 
Other Imaging Bone Scan
See notes
As clinically indicated. See Section 9.1.1. 
Clinical Drug Supply
IRT contact
X
X
First dose should be administered within 3 calendar days of 
treatment assignment.
Administer Nivolumab (6 mg/kg)
X
X
Nivolumab weight-based dosing every 4 weeks.
Administer Ipilimumab (1 mg/kg)
X
Ipilimumab weight-based dosing every 8 weeks. 
Administer Trametinib (see note)
See notes
Participants will receive Trametinib as described in 
Section 7.1.5. Obtain confirmation on dosing from sponsor 
study team prior to first dose.
Note: All scheduled clinic visits are to occur within ±3 days of scheduled day. Part 1A enrolls participants assigned to Cohort 2 and Cohort 3 Group (Refer to 
Table 7.2-1).
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 regulation. If a dose is delayed,
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Day 15 and Day 43 assessments are required for the first cycle; then may be performed as clinically indicated at investigators discretion. 
c Telephone contact with participants on C1D8, C1D22, C1D36 and C1D50 are mandatory to assess adverse events and provide toxicity management.  If clinically 
indicated, participants should be evaluated in the clinic.
Protocol Amendment No.: 04
Date: 03-May-2023
44
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
d Urinalysis should be assessed every 4 weeks for the first year of study treatment, and then every 8 weeks unless more frequent testing is clinically indicated.
e Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
Protocol Amendment No.: 04
Date: 03-May-2023
45
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 
[Cohort 6]) CLOSED FOR ENROLLMENT 
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Safety Assessments
Targeted Physical Examination
X
X
X
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain 
metastases
Ophthalmic Evaluation
Participants are required to have a standard ophthalmic examination conducted by an ophthalmologist at Month 1, 
Month 6, and then annually thereafter unless clinically indicated sooner. (See Section 9.4.3)
For Month 1: Results must be evaluated within 7 days prior to study treatment.
Vital Signs 
X
X
X
Including BP, HR, and temperature. Obtain vital signs 
within 72 hours prior to first dose.
Physical Measurements (including 
performance status)
X
X
X
Weight and ECOG performance status within 72 hours 
prior to dosing. 
ECOG must be assessed prior to first dose on Cycle 1 
Day 1 to re-confirm eligibility
See Appendix 7 for ECOG Performance Status scale.
ECG 
Participants will be evaluated within 7 days prior to C1D29 of treatment, and then as clinically indicated until 
discontinuation of treatment.
Echocardiogram or MUGA
Evaluate LVEF within 7 days prior to C1D29 and C2D29, and then every 12 weeks thereafter until discontinuation of 
treatment.
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-
CTCAE (version 4.0).
Serious Adverse Event Assessment
Continuously
Serious adverse events will be graded according to the 
NCI-CTCAE (version 4.0).
Protocol Amendment No.: 04
Date: 03-May-2023
46
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 
[Cohort 6]) CLOSED FOR ENROLLMENT 
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Review of Concomitant 
Medications
X
X
X
Laboratory Tests
X
X
X
Local CBC, chemistry assessments, and thyroid panel 
should be done within 72 hours prior to D1 and D29 of 
each cycle through Cycle 6 (in addition to C1D15 and 
C1D43) and may be collected only prior to D1 of each 
cycle thereafter if deemed medically appropriate.
Laboratory tests do not need to be repeated on C1D1 if 
screening labs results are deemed still clinically valid by 
the treating investigator. 
Lab assessments will include:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine (if abnormal 
creatinine clearance should be reported), phosphate, 
Ca, Na, K, Mg, Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, 
leukocyte esterase, specific gravity, pHc,d
•
Coagulation including PT/INR and PTT (as 
clinically indicated)
•
TSH. If TSH is abnormal, see Appendix 5 for 
instructions on Free T4 and Free T3. (TSH is not 
required at C1D15 and C1D43 if not clinically 
indicated).
•
CEA every 4 weeks for all participants. For 
participants with elevated CA19-9 at screening, 
monitor CA19-9 AND CEA.
Protocol Amendment No.: 04
Date: 03-May-2023
47
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 
[Cohort 6]) CLOSED FOR ENROLLMENT 
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Pregnancy Test (WOCBP Only) 
X
X
Serum or urine pregnancy test to be done within 24 
hours prior to first dose, and then every 4 weeks (± 1 
week) regardless of dosing schedule. See Appendix 4.
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 
8 weeks (± 7 days) from the date of first dose until 
disease progression, end of trial, or withdrawal of 
consent, whichever occurs first.
For participants who continue treatment beyond initial 
progression see Section 8.1.5.
Tumor assessment scans should be submitted to the 
imaging vendor within 14 days of acquisition.
Protocol Amendment No.: 04
Date: 03-May-2023
48
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 
[Cohort 6]) CLOSED FOR ENROLLMENT 
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance 
MRI per local SOC (approximately every 12 weeks) or 
sooner if clinically indicated. 
Other Imaging Bone Scan
See notes
As clinically indicated. See Section 9.1.1.2
Protocol Amendment No.: 04
Date: 03-May-2023
49
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-6:
On-Treatment Assessments (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 
[Cohort 6]) CLOSED FOR ENROLLMENT 
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Healthcare Resource Use
See notes
See Section 9.9.
Per Protocol Amendment 04, the collection of 
Healthcare Resource Use data for Cohort 6 must be 
discontinued.
Clinical Drug Supply
Contact IRT
X
X
First dose should be administered within 3 calendar days 
of treatment assignment.
Administer Nivolumab (6 mg/kg)
X
X
Nivolumab dosing will occur every 4 weeks.
Administer Ipilimumab (1 mg/kg)
X
Ipilimumab dosing will occur every 8 weeks.
Administer Trametinib (1.5mg QD)
See notes
Trametinib dosing will occur once daily. Trametinib 
bottles will be dispensed at D1 and D29 of each cycle.
Note: All scheduled clinic visits are to occur within ± 3 days of scheduled day
Protocol Amendment No.: 04
Date: 03-May-2023
50
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
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 regulation. If a dose is delayed, 
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Cycle 1, Day 15 assessments are required. C1, D43 and subsequent D15 and D43 assessments are optional and may be performed as clinically indicated at the 
investigator’s discretion. 
c Urinalysis should be assessed every 4 weeks for the first year of study treatment, and then every 8 weeks unless more frequent testing is clinically indicated.   
d Urinalysis or urine dipstick.  If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
Protocol Amendment No.: 04
Date: 03-May-2023
51
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-7:
Follow-Up Period (All treatment cohorts, CA2099N9)
Procedurea
Follow-Up, 
Visits 1 and 2b
Survival Follow-Up 
Visitsc
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related 
issues, Targeted examination must include at a minimum the
following body systems:
•
Cardiovascular
•
Gastrointestinal
•
Pulmonary
•
Neurological exam for participants with brain metastases
Ophthalmic Evaluation 
X
To be performed at Follow Up Visit 1 only, and at any time a 
participant reports new or worsening visual disturbances (See 
Section 9.4.3). Not required for Cohort 5 unless clinically 
indicated.
Echocardiogram or MUGA
X*
*At Follow-up Visit 1 only, not required for Cohort 5 unless 
clinically indicated.
Adverse Events Assessment
X
Participants will be followed for treatment related toxicities 
until these toxicities resolve, return to baseline, or are deemed 
irreversible. All adverse events will be documented for a 
minimum of 100 days after last dose. 
(See Appendix 3)
ECG
X
At Follow-up Visit 1 only
Review of Concomitant Medication
X
Review of Subsequent Cancer 
Therapies
X
X
Additional subsequent cancer therapy details such as 
regimen, line of therapy, start date and end date of each 
regimen, best response to the regimen, and date of 
progression after additional line of therapy will be collected.
Protocol Amendment No.: 04
Date: 03-May-2023
52
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-7:
Follow-Up Period (All treatment cohorts, CA2099N9)
Procedurea
Follow-Up, 
Visits 1 and 2b
Survival Follow-Up 
Visitsc
Notes
Laboratory Tests
X
•
Local testing:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN 
or serum urea level, creatinine (if abnormal creatinine 
clearance should be reported), phosphate, Ca, Na, K, Mg, 
Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, leukocyte 
esterase, specific gravity, pHd
•
Coagulation including PT/INR and PTT (as clinically 
indicated)
•
TSH. If TSH is abnormal, see Appendix 5 for instructions 
on Free T4 and Free T3. 
To be done at FU1. To be repeated at FU2 if study related 
toxicity persists.
Pregnancy Test (WOCBP only)
X
Serum or urine
Efficacy Assessments
Body Imaging 
See note
Only for participants without progression on study therapy.
See Section 9.1.1. Imaging assessments will occur every 8 
weeks (± 7 days) from the date of first dose until disease 
progression, end of study, or withdrawal of consent, 
whichever occurs first. 
For Part 1B and Part 2: Tumor assessment scans should be 
submitted to the imaging vendor within 14 days of 
acquisition.
Brain Imaging
See note
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance MRI 
per local SOC (approximately every 12 weeks) or sooner if 
clinically indicated. 
Other Imaging: Bone Scan
See note
As clinically indicated. See Section 9.1.1.2.
Protocol Amendment No.: 04
Date: 03-May-2023
53
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-7:
Follow-Up Period (All treatment cohorts, CA2099N9)
Procedurea
Follow-Up, 
Visits 1 and 2b
Survival Follow-Up 
Visitsc
Notes
Healthcare Resource Use
Per Protocol Amendment 04, the collection of data for 
Healthcare Resource use must be discontinued.
Participant Status
Survival Status
X
X
Per Protocol Amendment 04, survival status collection will 
end at the LPLV date, which is defined in Section 5.1.
Every 6 months after FU 2; may be accomplished by visit, 
phone contact or email, to assess subsequent anti-cancer 
therapy.
a Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulation.
b Participants must be followed for at least 100 days after last dose of study treatment.  Follow-up visit 1 (FU1) = 30 days from 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) = 100 days (± 7 days) from 
last dose. Both Follow Up visits should be conducted in person.
Protocol Amendment No.: 04
Date: 03-May-2023
54
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
c Survival Follow Up Visits may be conducted in clinic or via telephone contact: Every 6 Months (± 14 days) from FU2. BMS may request that survival data be 
collected on all treated participants outside of the 6-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.
d Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
Protocol Amendment No.: 04
Date: 03-May-2023
55
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-8:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required);
C1D43 (optional)b
Day 29
Safety Assessments
Targeted Physical 
Examination
X
X
X
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain metastases
Ophthalmic 
Evaluation
Participants are required to have a standard ophthalmic examination conducted by an ophthalmologist at Month 1, Month 6, and then 
annually thereafter unless clinically indicated sooner. (See Section 9.4.3)
For Month 1: Results must be evaluated within 7 days prior to study treatment.
Vital Signs 
X
X
X
Including BP, HR, and temperature. Obtain vital signs within 
72 hours prior to first dose.
Physical 
Measurements 
(including 
performance status)
X
X
X
Weight and ECOG performance status within 72 hours prior 
to dosing. 
ECOG must be assessed prior to first dose on Cycle 1 Day 1 
to re-confirm eligibility
See Appendix 7 for ECOG Performance Status scale.
ECG 
Participants will be evaluated within 7 days prior to C1D29 of treatment, and then as clinically indicated until discontinuation of 
treatment.
Echocardiogram or 
MUGA
Evaluate LVEF within 7 days prior to C1D29 and C2D29, and then every 12 weeks thereafter until discontinuation of treatment. 
Adverse Events 
Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE 
(version 4.0).
Serious Adverse 
Event Assessment
Continuously
Serious adverse events will be graded according to the NCI-
CTCAE (version 4.0).
Protocol Amendment No.: 04
Date: 03-May-2023
56
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-8:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required);
C1D43 (optional)b
Day 29
Review of 
Concomitant 
Medications
X
X
X
Laboratory Tests
X
X
X
Local CBC, chemistry assessments, and thyroid panel should 
be done within 72 hours prior to D1 and D29 of each cycle 
through Cycle 6 (in addition to C1D15 and C1D43), and 
may be collected only prior to D1 of each cycle thereafter if 
deemed medically appropriate. 
Laboratory tests do not need to be repeated on C1D1 if 
screening labs results are deemed still clinically valid by the 
treating investigator.
Lab assessments will include:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine (if abnormal 
creatinine clearance should be reported), phosphate, Ca, 
Na, K, Mg, Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, leukocyte 
esterase, specific gravity, pHc,c
•
Coagulation including PT/INR and PTT (as clinically 
indicated)
•
If TSH is abnormal, refer to Appendix 5 for instructions 
on Free T4 and Free T3. (TSH is not required at C1D15 
and C1D43 if not clinically indicated)
Protocol Amendment No.: 04
Date: 03-May-2023
57
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-8:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required);
C1D43 (optional)b
Day 29
•
CEA every 4 weeks CEA for all participants. For 
participants with elevated CA19-9 at screening, monitor 
CA19-9 AND CEA.
Pregnancy Test 
(WOCBP Only) 
X
X
Serum or urine pregnancy test to be done within 24 hours 
prior to first dose, and then every 4 weeks (± 1 week) 
regardless of dosing schedule. See Appendix 4.
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 8 
weeks (± 7 days) from the date of first dose until disease 
progression, end of trial, or withdrawal of consent, 
whichever occurs first.
For participants who continue treatment beyond initial 
progression see Section 8.1.5.
Tumor assessment scans should be submitted to the imaging 
vendor within 14 days of acquisition. 
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance MRI 
per local SOC (approximately every 12 weeks) or sooner if 
clinically indicated. 
Other Imaging Bone 
Scan
See notes
As clinically indicated. See Section 9.1.1.2
Clinical Drug Supply
Contact IRT
X
X
First dose should be administered within 3 calendar days of 
randomization.
Protocol Amendment No.: 04
Date: 03-May-2023
58
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-8:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, TRIPLET, 
 
 CA2099N9 Cohort 4) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required);
C1D43 (optional)b
Day 29
Administer 
Nivolumab (6 
mg/kg) 
X
X
Nivolumab dosing will occur every 4 weeks.
Administer 
Ipilimumab (1 
mg/kg)
X
Ipilimumab dosing will occur every 8 weeks. 
Administer 
Trametinib (1.5mg 
QD)
See notes
Trametinib dosing will occur once daily. Trametinib bottles 
will be dispensed at D1 and D29 of each cycle
Note: All scheduled clinic visits are to occur within ± 3 days of scheduled day 
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 regulation. If a dose is delayed, 
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule. 
b Cycle 1 Day 15 assessments are required for the first cycle. C1 D43 and subsequent D15 and D43 assessments are optional and may be performed as clinically 
indicated at the investigator’s discretion.
c Urinalysis should be assessed every 4 weeks for the first year of study treatment, and then every 8 weeks unless more frequent testing is clinically indicated.
Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
Protocol Amendment No.: 04
Date: 03-May-2023
59
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-9:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 [Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 (required); 
subsequent cycle 
D15 (if clinically 
indicated)b
Safety Assessments
Targeted Physical Examination
X
X
Targeted examination must include at a minimum the following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain metastases
Vital Signs 
X
See Note
Including BPc, HR, and temperature. Obtain vital signs within 72 hours prior to 
dosing
Physical Measurements 
(including performance status)
X
See Note
Weight and ECOG performance status within 72 hours prior to dosing. 
ECOG must be assessed prior to first dose on Cycle 1 Day 1 to re-confirm 
eligibility.
See Appendix 7 for ECOG Performance Status scale.
ECG
Participants will be evaluated within 7 days prior to C2D1 of treatment, and then as clinically indicated until 
discontinuation of treatment.
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-CTCAE (version 4.0).
Serious Adverse Event 
Assessment
Continuously
Serious adverse events will be graded according to the NCI-CTCAE (version 
4.0).
Review of Concomitant 
Medications
X
X
Laboratory Tests
X
See Notes
Local CBC and chemistry assessments should be done within 72 hours prior to 
D1 of each cycle, and D15 of each cycle if clinically indicated (C1D15 is 
required). Laboratory tests do not need to be repeated on C1D1 if screening 
laboratory results are deemed still clinically valid by the treating investigator.
Protocol Amendment No.: 04
Date: 03-May-2023
60
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-9:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 [Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 (required); 
subsequent cycle 
D15 (if clinically 
indicated)b
Lab assessments will include:
•
CBC w/differential and platelet count,d
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN or serum urea 
level, creatinine (if abnormal creatinine clearance should be reported), 
phosphate, Ca, Na, K, Cl, Mg,  LDH, glucose, albumin
•
Coagulation including PT/INR and PTT (as clinically indicated)
•
TSH every 4 weeks.e If TSH is abnormal, see Appendix 5 for instructions on 
Free T4 and Free T3. (TSH is not required at C1D15 if not clinically 
indicated).
•
CEA for all participants. For participants with elevated CA19-9 at screening, 
monitor CA19-9 AND CEA.f
•
Urine dipstick or urinalysisg
Pregnancy Test (WOCBP Only) 
X
Serum or urine pregnancy test to be done within 24 hours prior to first dose, and 
then every 4 weeks (± 1 week) regardless of dosing schedule. See Appendix 4.
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 8 weeks (±7 days) 
from the date of first dose until disease progression, end of trial, or withdrawal 
of consent, whichever occurs first.
Tumor assessment scans should be submitted to the imaging vendor within 
14 days of acquisition. 
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical symptoms of brain 
metastasis should have surveillance MRI per local SOC (approximately every 
12 weeks) or sooner if clinically indicated. 
Protocol Amendment No.: 04
Date: 03-May-2023
61
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-9:
On-Treatment REDUCED ASSESSMENTS (Part 2 mCRC 3rd line, Regorafenib, 
 
 CA2099N9 [Cohort 5]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 4 weeks)
Notes
Day 1
C1 D15 (required); 
subsequent cycle 
D15 (if clinically 
indicated)b
Other Imaging Bone Scan
See notes
As clinically indicated. See Section 9.1.1.2
Clinical Drug Supply
IRT contact
X
First dose should be administered within 3 calendar days of randomization
Administer Regorafenib (160 
mg)
See notes 
Orally, once daily for the first 21 days (D1 to D21) of each cycle. See Section 
7.1.4
Note: All scheduled clinic visits are to occur within ±3 days of scheduled day.
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 regulation. If a dose is delayed,
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Cycle 1, D15 clinic visit is required. Day 15 visits in the subsequent cycles are optional and should be performed as clinically indicated or per local institutional 
guidelines.
c Monitor BP more frequently as clinically indicated or per local institutional guidelines.
d Monitor coagulation more frequently for increased risk of bleeding per local institutional guidelines.
e Monitor TSH per local product label and/or institutional guideline.
f CEA at C1D1, C1D15, C2D1, C3D1, C4D1, C5D1, and then every 8 weeks thereafter or more frequent if clinically indicated. If CA19-9 is also monitored, 
follow same collection frequency as CEA. 
g Urine dipstick or urinalysis to monitor urine protein per local product label and/or institutional guideline. Protocol recommended frequency is every 4 weeks.
Protocol Amendment No.: 04
Date: 03-May-2023
62
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-10:
On-Treatment REDUCED ASSESSMENTS (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 [Cohort 6]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Safety Assessments
Targeted Physical Examination
X
X
X
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for participants with brain 
metastases
Ophthalmic Evaluation
Participants are required to have a standard ophthalmic examination conducted by an ophthalmologist at Month 1, 
Month 6, and then annually thereafter unless clinically indicated sooner. (See Section 9.4.3)
For Month 1: Results must be evaluated within 7 days prior to study treatment.
Vital Signs 
X
X
X
Including BP, HR, and temperature. Obtain vital signs 
within 72 hours prior to first dose.
Physical Measurements (including 
performance status)
X
X
X
Weight and ECOG performance status within 72 hours 
prior to dosing. 
ECOG must be assessed prior to first dose on Cycle 1 
Day 1 to re-confirm eligibility
See Appendix 7 for ECOG Performance Status scale.
ECG 
Participants will be evaluated within 7 days prior to C1D29 of treatment, and then as clinically indicated until 
discontinuation of treatment.
Echocardiogram or MUGA
Evaluate LVEF within 7 days prior to C1D29 and C2D29, and then every 12 weeks thereafter until discontinuation of 
treatment. 
Adverse Events Assessment
Continuously
Adverse events will be graded according to the NCI-
CTCAE (version 4.0).
Protocol Amendment No.: 04
Date: 03-May-2023
63
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-10:
On-Treatment REDUCED ASSESSMENTS (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 [Cohort 6]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Serious Adverse Event Assessment
Continuously
Serious adverse events will be graded according to the 
NCI-CTCAE (version 4.0).
Review of Concomitant 
Medications
X
X
X
Laboratory Tests
X
X
X
Local CBC, chemistry assessments, and thyroid panel 
should be done within 72 hours prior to D1 and D29 of 
each cycle through Cycle 6 (in addition to C1D15 and 
C1D43) and may be collected only prior to D1 of each 
cycle thereafter if deemed medically appropriate.
Laboratory tests do not need to be repeated on C1D1 if 
screening labs results are deemed still clinically valid by 
the treating investigator. 
Lab assessments will include:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, 
BUN or serum urea level, creatinine (if abnormal 
creatinine clearance should be reported), phosphate, 
Ca, Na, K, Mg, Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, 
leukocyte esterase, specific gravity, pHc,d
•
Coagulation including PT/INR and PTT (as 
clinically indicated)
•
TSH. If TSH is abnormal, see Appendix 5 for 
instructions on Free T4 and Free T3. (TSH is not 
required at C1D15 and C1D43 if not clinically 
indicated).
Protocol Amendment No.: 04
Date: 03-May-2023
64
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Table 2-10:
On-Treatment REDUCED ASSESSMENTS (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 [Cohort 6]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
•
CEA every 4 weeks for all participants. For 
participants with elevated CA19-9 at screening, 
monitor CA19-9 AND CEA.
Pregnancy Test (WOCBP Only) 
X
X
Serum or urine pregnancy test to be done within 24 
hours prior to first dose, and then every 4 weeks (± 1 
week) regardless of dosing schedule. See Appendix 4.
Efficacy Assessments
Body Imaging
See notes
See Section 9.1.1. Imaging assessments will occur every 
8 weeks (± 7 days) from the date of first dose until 
disease progression, end of trial, or withdrawal of 
consent, whichever occurs first.
For participants who continue treatment beyond initial 
progression see Section 8.1.5.
Tumor assessment scans should be submitted to the 
imaging vendor within 14 days of acquisition.
Brain Imaging
See notes
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance 
MRI per local SOC (approximately every 12 weeks) or 
sooner if clinically indicated. 
Other Imaging Bone Scan
See notes
As clinically indicated. See Section 9.1.1.2
Clinical Drug Supply
Contact IRT
X
X
First dose should be administered within 3 calendar days 
of treatment assignment.
Administer Nivolumab (6 mg/kg)
X
X
Nivolumab dosing will occur every 4 weeks.
Administer Ipilimumab (1 mg/kg)
X
Ipilimumab dosing will occur every 8 weeks.
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Table 2-10:
On-Treatment REDUCED ASSESSMENTS (Part 1B mCRC 2nd line, TRIPLET, 
 
, CA2099N9 [Cohort 6]) CLOSED FOR ENROLLMENT
Procedurea
Each Cycle (1 Cycle = 8 weeks)
Notes
Day 1
C1D15 (required),
C1D43 (optional)b
Day 29
Administer Trametinib (1.5mg QD)
See notes
Trametinib dosing will occur once daily. Trametinib 
bottles will be dispensed at D1 and D29 of each cycle.
Note: All scheduled clinic visits are to occur within ± 3 days of scheduled day
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 regulation. If a dose is delayed, 
the procedures are to be delayed if deemed appropriate by treating physicians, except for tumor assessments that continue per schedule.
b Cycle 1, Day 15 assessments are required. C1, D43 and subsequent D15 and D43 assessments are optional and may be performed as clinically indicated at the 
investigator’s discretion. 
c Urinalysis should be assessed every 4 weeks for the first year of study treatment, and then every 8 weeks unless more frequent testing is clinically indicated.
d Urinalysis or urine dipstick.  If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
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Table 2-11:
Follow-Up Period REDUCED ASSESSMENTS (All treatment cohorts, CA2099N9)
Procedurea
Follow-Up, 
Visits 1 and 2b
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related 
issues, Targeted examination must include at a minimum the 
following body systems:
•
Cardiovascular
•
Gastrointestinal
•
Pulmonary
•
Neurological exam for participants with brain metastases
Ophthalmic Evaluation 
X
To be performed at Follow Up Visit 1 only, and at any time a 
participant reports new or worsening visual disturbances (See 
Section 9.4.3). Not required for Cohort 5 unless clinically 
indicated.
Echocardiogram or MUGA
X*
*At Follow-up Visit 1 only, not required for Cohort 5 unless 
clinically indicated.
Adverse Events Assessment
X
Participants will be followed for treatment related toxicities 
until these toxicities resolve, return to baseline, or are deemed 
irreversible. All adverse events will be documented for a 
minimum of 100 days after last dose. 
(See Appendix 3)
ECG
X
At Follow-up Visit 1 only
Review of Concomitant Medication
X
Review of Subsequent Cancer 
Therapies
X
Additional subsequent cancer therapy details such as 
regimen, line of therapy, start date and end date of each 
regimen, best response to the regimen, and date of 
progression after additional line of therapy will be collected.
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Table 2-11:
Follow-Up Period REDUCED ASSESSMENTS (All treatment cohorts, CA2099N9)
Procedurea
Follow-Up, 
Visits 1 and 2b
Notes
Laboratory Tests
X
•
Local testing:
•
CBC w/differential and platelet count,
•
Chemistry panel including: AST, ALT, ALP, T.Bili, BUN 
or serum urea level, creatinine (if abnormal creatinine 
clearance should be reported), phosphate, Ca, Na, K, Mg, 
Cl, LDH, glucose, albumin
•
Urinalysis including protein, glucose, blood, leukocyte 
esterase, specific gravity, pHc
•
Coagulation including PT/INR and PTT (as clinically 
indicated)
•
TSH. If TSH is abnormal, see Appendix 5 for instructions 
on Free T4 and Free T3.  
To be done at FU1. To be repeated at FU2 if study related 
toxicity persists.
Pregnancy Test (WOCBP only)
X
Serum or urine
Efficacy Assessments
Body Imaging 
See note
Only for participants without progression on study therapy.
See Section 9.1.1. Imaging assessments will occur every 8 
weeks (± 7 days) from the date of first dose until disease 
progression, end of study, or withdrawal of consent, 
whichever occurs first. 
For Part 1B and Part 2: Tumor assessment scans should be 
submitted to the imaging vendor within 14 days of 
acquisition.
Brain Imaging
See note
See Section 9.1.1. Participants with a history or clinical 
symptoms of brain metastasis should have surveillance MRI 
per local SOC (approximately every 12 weeks) or sooner if 
clinically indicated. 
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Table 2-11:
Follow-Up Period REDUCED ASSESSMENTS (All treatment cohorts, CA2099N9)
Procedurea
Follow-Up, 
Visits 1 and 2b
Notes
Other Imaging: Bone Scan
See note
As clinically indicated. See Section 9.1.1.2.
a Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulation.
b Participants must be followed for at least 100 days after last dose of study treatment.  Follow-up visit 1 (FU1) = 30 days from 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) = 100 days (± 7 days) from 
last dose. Both Follow Up visits should be conducted in person.
c Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required.
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3
INTRODUCTION
3.1
Study Rationale
CA2099N9 (CHECKpoint pathway and nivoluMAb clinical Trial Evaluation [CHECKMATE] 
9N9) is a Phase 1/2, open-label, multi-center trial of nivolumab in combination with trametinib, 
with or without ipilimumab for the treatment of proficient mismatch repair (pMMR)/microsatellite 
stable (MSS) metastatic colorectal cancer (mCRC). This trial provides an opportunity to evaluate 
nivolumab and ipilimumab in combination with trametinib for the treatment of later-line (3rd line
plus [3L+]) (pMMR)/MSS mCRC participants who failed at least 2 prior lines of therapy (no more 
than 4 prior lines) for metastatic disease. Part 2 will include 2 treatment arms, including the triplet 
regimen and standard of care treatment (SOC) option (regorafenib). The objective of Part 2 is to 
further develop and optimize a 
 patient selection strategy for combination therapy 
of immune checkpoint inhibitors with a MEK inhibitor.
Additionally, the study presents an opportunity to validate the tolerability and preliminary efficacy 
and to further optimize a 
 patient selection strategy for nivolumab and ipilimumab 
in combination with trametinib in earlier line (2nd line [2L]) pMMR/MSS mCRC participants who 
failed only 1 prior line of therapy for metastatic disease (Part 1B). 
3.1.1
Research Hypothesis 
Combining MEK inhibition using trametinib with nivolumab and ipilimumab will improve the 
clinical activity in MSS metastatic CRC.
3.1.2
Rationale for the Combination of Nivolumab and Ipilimumab with 
Trametinib in MSS CRC Population
Nivolumab administered as monotherapy has demonstrated remarkable clinical benefit in several 
solid tumor types, including the microsatellite instable (MSI-H)-CRC. However, the MSS-CRC is 
highly immunosuppressive, and inhibits the activation of anti-tumor immune responses that allow 
T-cells to engage with the tumor.1 Single-agent immunotherapies are largely ineffective in 
pMMR/MSS CRC, which represents approximately 85%-96% of the CRC patient population.2,3,4
Preclinical and clinical evidence suggests synergy between nivolumab and ipilimumab, which 
target distinct mechanisms to limit T-cell activation, PD-1, and CTLA-4, respectively.  In vitro 
combinations of nivolumab plus ipilimumab increase IFN-γ production 2- to 7-fold over either 
agent alone in a mixed lymphocyte reaction. In a murine melanoma vaccine model, blockade with 
either CTLA-4 or PD-1 antibodies increased the proportion of CTLA-4 and PD-1-expressing 
CD4/CD8 tumor infiltrating T effector cells, and dual blockade increased tumor infiltration of T 
effector cells and decreased intratumoral T regulatory cells, as compared to either agent alone.5
The combination of nivolumab and ipilimumab has been shown to be more effective than either 
agent in monotherapy in the treatment of a variety of tumors including melanoma, lung, and renal 
cell carcinoma.6,7,8,9 Most relevant, this combination has also demonstrated meaningful clinical 
efficacy (Checkmate 142) in MSI-H CRC of improved efficacy compared to IO monotherapy. 
However, there was only modest activity observed for combination therapy in MSS CRC. The 
combination of durvalumab + tremelimumab only resulted in a median overall survival of 
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6.6 months (CI 90%, 6.0-7.4) and a HR of 0.66 (CI 90%, 0.48-0.89, p = 0.02) compared with best 
supportive care. 10,This relative lack of response to immune therapies may be related to the MAP 
Kinase pathway. Recent published data have suggested combination therapy with a MEK inhibitor 
and antibody targeting PD-1 and CTLA-4 pathways were more efficacious in colon cancer model, 
CT26.11 Therefore, targeting the CTLA-4 pathway in addition to PD-1 and MEK1/2 inhibition 
may enhance clinically effective anti-tumor immune response.
Immuno-oncologic approaches with checkpoint inhibition alone might not be sufficient in patients 
who have limited tumor immune cell infiltration like in MSS CRC tumors. In a fraction of patients 
who are resistant to anti-PD-L1 monoclonal Ab (mAb) therapy, CD8+ T cells localize at the edge 
of the tumors, whereas they are found to accumulate in the tumor mass of patients who respond to 
PD-L1 blockade. This suggests that in addition to PD-L1 inhibition, strategies aimed at promoting 
T cell accumulation in the tumor mass are essential for the induction of therapeutic immunity.12
The mitogen-activated protein kinase (MAPK) pathway is one of the most frequently dysregulated 
pathways in cancer. The signaling molecule MEK (Mitogen/Extracellular signal regulated Kinase) 
is a key intermediate in the MAPK pathway. Two MEK isoforms (MEK1 and MEK2) are known, 
both of which phosphorylate ERK1 and/or ERK2 downstream of RAS and RAF. MEK has been 
well characterized as a critical mediator of the constitutively active mutant form of KRAS, 
KRASG12D, in many cancers.13 The MEK pathway is presumed to be upregulated in a large 
fraction of colorectal tumors, due to mutation of several components of the pathway, most notably 
KRAS, NRAS, and BRAF. In addition to RAS and RAF mutations, many tumors are activated by 
amplification or overexpression of upstream pathway components.14
MEK is not only a critical signaling component for tumors with RAS mutation, it is also mediates 
TCR-mediated apoptosis. Mellman and colleagues demonstrated that MEK inhibition protected 
tumor-infiltrating CD8+ T cells from death driven by chronic TCR stimulation while sparing 
cytotoxic activities.13
Importantly, there is likely a role of the activated MAPK/MEK pathway in immune evasion by 
tumors. It has been shown that tumor cells with an activated MAPK/MEK pathway produce factors 
including, but not limited to, interleukin (IL)-10, and IL-6, that inhibit dendritic cells. Signal 
transducer and activator of transcription 3 (STAT3) is also essential for immune evasion by human 
melanomas.15 Pharmacologic intervention with a MEK inhibitor decreased production of 
immunosuppressive soluble factors from melanoma cells to levels comparable to STAT3 
inactivation. Therefore, the MAPK/MEK pathway is a potential molecular target for overcoming 
tumor cell evasion of the immune system.15
The antigen presenting dendritic cells (DC) which are CD103+ (the cross-presenting DC) are also 
critical for response to PD-1 pathway blockade and may also be modulated by MEK inhibition. In 
a mouse model, activated CD103+ DC progenitors in the tumor enhanced responses to PD-L1 
blockade and protected mice from tumor rechallenge. The DCs are also affected by the 
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MAPK/MEK pathway, which produces factors including, but not limited to, IL-10 and IL-6, that 
inhibit DC.15
Early experience in mCRC with MEK-inhibition has demonstrated no single-agent activity for this 
class of agents.16,17 However, MEK inhibitors have been combined preclinically with anti-PD-1 
to provide additional efficacy in mouse models.18 Numerous preclinical studies have demonstrated 
that MEK inhibitors modulate the mechanisms of T cell mediated cell killing and MHC class I 
expression. In melanoma cell lines, the MEK inhibitor trametinib increased expression of HLA-I 
and/or II in 5 of 6 lines tested, and a similar effect was found in an in vivo mouse model which 
demonstrated that the combination of trametinib with anti–PD-1 increased tumor-infiltrating CD8+
T cells in CT26 tumors and potentiated antitumor activity with PD-1 blockade.18 MEK inhibition 
alone in immunocompetent mice harboring a colon carcinoma cell line with mutant KRASG12D 
who were treated with the potent and highly specific MEK inhibitor G-38963 resulted in 
intratumoral CD8+T cell accumulation and class I MHC upregulation.13 Observed increases ranged 
from 0- to almost 4-fold among several mouse and human tumor cell lines as determined by flow 
cytometry. In further experiments in preclinical models, MEK inhibition synergized with anti-PD-
1 to promote durable tumor regression while promoting the effector phenotype and longevity of 
tumor-infiltrating CD8+ T cells.13
However, the promising preclinical observations of combining MEK inhibition with PD-1 
blockade have not been replicated in the clinic. To this point, the doublet treatment regimen of 
PD-(L)1 inhibition in combination with MEK inhibition has not exhibited significant clinical 
efficacy in MSS CRC. In the recent IMblaze370 Phase 3 trial, atezolizumab + cobimetinib failed 
to demonstrate improved overall survival versus regorafenib in later lines (3L or later) with a mOS 
8.87 months, HR = 1.00 (0.73-1.38; p=0.99). 19 Similarly in a Phase 2 clinical study assessing the 
use of durvalumab plus trametinib in ≥ 2L MSS CRC, the combination only resulted in a partial 
response (PR) in 1 of 29 treated patients, and did not meet efficacy criteria to proceed with the 
second phase of the study.10
These clinical findings suggest that PD-(L)1 inhibition + MEKi doublet regimens do not provide 
meaningful improvement over existing treatment options, and triplet regimens may be needed to 
provide additional clinical efficacy. Additional combination strategies will be required to elicit the 
desired 
immunomodulatory 
effects 
to 
alter 
the 
tumor 
microenvironment, 
reduce 
immunosuppression, and allow for enhanced T-cell infiltration. Therefore, novel therapies using 
MEK inhibition with PD-1/PD-L1 and CTLA-4 antibodies as a triplet regimen may present a 
unique and much-needed opportunity to improve the effectiveness of this strategy in patients with 
MSS mCRC.
3.2
Background
3.2.1
Colon Cancer Background and Treatment Options
Worldwide, colon cancer (including rectal cancer) is the third most common form of cancer in 
men with 1,026,200 cases (11.6% of the total), and second most common in women with 823,300 
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cases (10% of the total) per year.20 This disease predominately occurs in developed regions with 
the highest rates being found in Australia/New Zealand and Western Europe and to a lower extent 
in Africa and South-Central Asia. Each year, there are about 880,800 deaths from colon cancer, 
which is approximately 9% of all cancer deaths, making colon cancer the second most common 
cause of cancer death.20 In 2020 in the United States (US), an estimated 147,950 new cases of 
CRC will be diagnosed, and an estimated 53,200 deaths.21 At initial diagnosis, approximately 25% 
of patients present with metastatic disease and almost 50% of patients will develop metastasis 
which contributes to the high mortality rate reported in CRC patients.22
Treatment options for patients with metastatic colon or rectal cancer (mCRC) are predominantly 
5-fluorouracil (5-FU) containing regimens in combination with either oxaliplatin or irinotecan 
(FOLFOX or FOLFIRI) with a biologic agent such as bevacizumab. The EGFR inhibitors, 
cetuximab and panitumumab, are also options if KRAS status is non-mutated.23 Both 
chemotherapy regimens have demonstrated similar progression-free survival (PFS) benefit, a 
median first-line (1L) PFS of 8.5 months for FOLFIRI and 8 months for FOLFOX.24
In second-line therapy for those patients who had 1L therapy with FOLFOX or another 5-FU 
containing therapy, the median PFS for patients receiving FOLFIRI is approximately 
4.5 months.25, 26 Bevacizumab, ramucirumab, and ziv-afilbercept have indications for second-line 
treatment in combination with chemotherapy and have demonstrated improvement in median OS 
(mOS); for biologic agents, the improvement in mOS is less than 2 months: 13.5 months vs 
12.06 months for bevacizumab,27 13.3 months vs 11.7 months for ramucirumab,28 and 
11.2 months vs 9.8 month for ziv-aflibercept.29 In the chemorefractory setting, cetuximab also has 
demonstrated an improvement in mOS of less than 2 months in patients who have previously 
received chemotherapy, 6.1 months vs 4.6 months, when compared to best supportive care 
(BSC).30 In later-line therapy, regorafenib, in patients who have been previously treated with 
fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if 
KRAS wild-type, an anti-EGFR therapy, has demonstrated an improvement in mOS- of less than 
2 months, 6.4 months vs 5 months, when compared to BSC.31 Similar results in mOS were 
demonstrated for trifluridine/tipiracil (as hydrochloride) (TAS-102), 7.1 months in TAS-102 group 
vs 5.3 months in BSC group.32
Despite the numerous initial treatment options for mCRC, the benefit of these therapies after 1L
therapy is modest, and complete radiographic responses are rare, highlighting the need for more 
effective therapies. 
3.2.2
RAS/BRAF Wild-type and RAS/BRAF Mutant CRC
Kirsten rat sarcoma (KRAS) and neuroblastoma rat sarcoma (NRAS) genes are two of the three 
human RAS genes that have been identified. The KRAS protein is one of the most pivotal effectors 
downstream of EGFR receptor tyrosine kinase activity. KRAS activates intracellular signaling 
cascades mediated by the RAF/MEK (mitogen-activated and extracellular signal regulated kinase)/ 
ERK(extracellular signal-regulated kinase) pathway, and PI3K (phosphatidylinositol 3-kinase)/ 
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PDK1 (3-phosphoinositide-dependent protein kinase 1)/Akt pathways.33 Constitutive activation of 
these pathways is achieved by point mutations in codons 12 or 13 of exon 2 of the KRAS gene; 
such mutations arise in approximately 33% to 48% of patients with mCRC.34,35,36,37 Other relevant 
point mutations in the KRAS gene include those in codon 61 (exon 3) and codon 146 (exon 4).51
Moreover, a high level of concordance exists between KRAS mutational status in patient-matched 
primary tumors and metastases, implying that KRAS mutations frequently occur early during the 
course of tumor evolution.38
The prognostic value of KRAS mutations in CRC (independent of anti-EGFR therapy) is unclear 
due to conflicting data from various meta-analyses across all disease stages. However, KRAS 
mutations are predictive for a lack of response and clinical benefit from anti-EGFR mAbs in 
patients with mCRC based on several large clinical trials, including CO.17, CRYSTAL, OPUS, 
and PRIME. In addition, retrospective analyses from several Phase 2 and 3 clinical trials of 
cetuximab and panitumumab have indicated that WT status in KRAS and NRAS exons 2 to 4 
results in more pronounced treatment effects than the WT status of solely KRAS exon 2 
(CALGB/SWOG 80405, CRYSTAL, FIRE-3, PEAK, and PRIME). Thereby increasing the 
proportion of patients ineligible for anti-EGFR therapy from approximately 45% to 55%.  
Consequently, DNA sequencing methods used for RAS testing have been introduced to capture 
hot spot-activating RAS (KRAS and NRAS) mutations in codons 12 and 13 (exon 2), 59 and 61 
(exon 3), and 117 and 146 (exon 4).51
BRAF proto-oncogene kinase is an important player in the EGFR-mediated MAPK pathway.  
BRAF mutations have been recently reported in 5 to 15% of CRC cases.39 Similar association 
between the BRAF mutations and resistance to EGFR-targeting agents in CRC patients has also 
been shown recently.39 BRAF was reported to be mutated at several sites, however, the vast 
majority of mutated BRAF are V600E (1799T>A), representing up to 80% of all BRAF 
mutations.40 Such mutations (V600) are associated with short progression-free and overall 
survival.40 See Appendix 10 for KRAS, NRAS, and BRAF mutational testing suitable for this 
study.
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The below table (Table 3.2.2-1) summarizes Response Rate, PFS, and OS of selected Standard of 
Care (SOC) treatment for ≥2L mCRC with KRAS wild-type (WT) and KRAS mutation (MT):
Table 3.2.2-1:
Response Rate, PFS and OS for Patients with 2nd to 4th Line CRC 
treated with SOC
Line of 
therapy
KRAS status
Standard of Care 
(SOC)
RR
Median PFS 
(months)
Median OS
(months)
2nd line
KRAS MT
FOLFOX or FOLFIRI 
+ bevacizumab41, 42 or 
aflibercept43 or 
ramucirumab 39
11-22%
6-7
12.9-13.5
KRAS WT
FOLFOX or FOLFIRI 
+ bevacizumab 52, 53
or ramucirumab 39 or 
panitumumab44
11-22%
6-7
12.9-14.5
≥3rd Line
KRAS WT/MT
Regorafenib45
1%
1.9
6.4
TAS-102 32
1.6%
2.0
7.1
3.2.3
MSS/pMMR and MSI-H/dMMR CRC
Microsatellite stability (MSS) is the molecular fingerprint of a proficient mismatch repair system 
(pMMR). The term MSS is widely accepted as a surrogate for pMMR tumors. Approximately 85% 
of CRCs display MSS without novel microsatellite alleles.46 Studies have confirmed that MSS 
identification can be prognostic in that MSS tumors have a worse prognosis than microsatellite 
instable CRC.47
There are well established methods to differentiate pMMR/MSS from deficient MMR/MSI-H or 
L that are incorporated into clinical practice. The NCCN recommends MSI testing for all patients 
with CRC.48 There are several options for testing. The IHC MMR testing consists of staining of 
tumor tissue for loss of expression of the four mismatch repair proteins known to be mutated in 
Lynch syndrome: MLH1, MSH2, MSH6, and PMS2.60 If at least one of these is not normally 
expressed, then the testing indicates the dMMR (MSI) phenotype. PCR amplification of a set of 
mono-and/or di-nucleotide repeats on tumor and normal DNA, followed by comparison of the 
peak patterns by capillary electrophoresis, can also assess for MSI with three categories: MSI-H, 
MSI-Low, and MSS. MSI-Low will be grouped together with MSS for this study as the 
clinicopathologic and most molecular characteristics in such tumors do not seem to differ from 
MSS tumors.49
Characterization of the molecular basis of MSI in CRC is underway and initial results show that 
mutations in genes encoding kinases and candidate genes with microsatellite tracts are 
over̻represented in MSI tumors.50 Hypermethylation of MLH1 can cause BRAF mutations in CRC 
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and are more frequent in sporadic MSI-H cases compared to hereditary cases.51, 52 The strong local 
immune reaction observed in MSI-H CRC is characterized by peritumoral lymphoid nodules 
(Crohn’s-like reaction) and a dense overall infiltration of the tumor with lymphocytes,53 part of 
which are activated and cytotoxic.54, 55 Frameshift mutations encountered in MSI-H CRC might 
lead to the generation of tumor-specific antigens.56 In addition, it is known that antigens expressed 
in a noninflamed environment may induce tolerance rather than eliciting an antitumoral immune 
response57; however, the existence of T cell responses directed against a multiple tumor antigens 
in individuals with MSI-H CRC has been demonstrated in patients.58, 59 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. The cytokine milieu 
encountered at the MSI-H tumor site initially tends to be proinflammatory and favoring T-cell 
response rather than contributing to tolerance induction.60, 61 The mechanism by which immune 
tolerance is induced is not completely understood. This initial control of the MSI-H tumor by 
immune surveillance makes it hopeful that nivolumab, with its mechanism of action that abrogates 
immune tolerance, will have significant clinical activity in MSI-H CRC. In study CA209003, a 
Phase 1 trial of subjects with solid tumors, one trial subject with MSI-H metastatic CRC (mCRC) 
had a long-term complete response, suggesting the immune-modulatory approach warrants further 
evaluation.62
3.2.4
Consensus Molecular Subtypes 
The CRC Subtyping Consortium (CRCSC) was formed to evaluate the presence of core subtype 
transcriptional patterns in patients with primary CRC.63 This work led to the identification of four 
Consensus Molecular Subtypes (CMS1-4) with distinct molecular characteristics that consistently 
characterize primary and metastatic CRC tumors.63,64 CMS subtyping in turn allows further 
segmentation of CRC patients to evaluate differential response to treatment and potential rationale 
for future patient selection.63,65 The CMS1-4 subtypes are characterized below.
CMS1 (immune subtype) is observed in approximately 14% of CRC patients, and is primarily
associated with BRAF mutations and MSI-H CRC. Compared to other subtypes, CMS1 is 
considered to be highly immunogenic as it is better infiltrated with CD8 and CD4 T cells and 
natural killer (NK) cells. CMS1 is also characterized by overexpression of cytotoxic lymphocyte 
and T helper cell (TH1) specific genes.
CMS2 (canonical subtype) accounts for approximately 37% of CRC patients and is considered 
poorly immune-infiltrated epithelial tumors. This subtype is characterized by marked upregulation 
of canonical pathway genes and their downstream targets (WNT, MYC, MAPK, etc.). 
CMS3 (metabolic subtype), another set of poorly immune-infiltrated epithelial tumors, has 
elevated expression of genes that are associated with metabolic dysregulation. This subtype is 
found in ~13% of CRC patients.
CMS4 (mesenchymal subtype) is a set of tumors which are distinguished by an inflamed tumor 
microenvironment with CD8 TILs, upregulation of TH1 and cytotoxic T cell gene expression, but 
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are also infiltrated by immunosuppressive cells (eg, myeloid-derived suppressor cells [MDSC], 
T-regulatory cells [Tregs], T helper 17 cells [TH17]). This subtype is also identified as stroma-
enriched, with elevated gene expression of epithelial-mesenchymal transition (EMT), 
transforming growth factor- β (TGFβ), and fibroblast signaling. This subtype accounts for ~23% 
of early-stage CRC and found in approximately 30% of metastatic CRC tumors.6366
Retrospective analysis of clinical studies has explored the prognostic and/or predictive value of 
CMS in CRC patients receiving SOC therapies, chemotherapy +/- regorafenib;6768 or regorafinib,
in second- and third-line mCRC (Table 3.2.4-1).66 Late line SOC, regorafenib monotherapy, 
resulted in a survival benefit in CMS2 and CMS4, but not CMS1 and CMS3, compared to placebo 
in the CORRECT trial.66
These clinical findings have demonstrated that efficacy outcomes are varied across CMS subtypes 
with available treatment regimens in later lines of therapy (2L+). Furthermore, these observations 
suggest that the underlying biology of these distinct molecular subtypes that characterize the TME 
may play a key role in response to therapy. The literature is sparse in context of IO therapy and 
combinations thereof.69 Specifically, the association between CMS classification and efficacy 
following nivolumab + ipilimumab + trametinib needs further investigation to inform on potential 
patient selection strategies.
Table 3.2.4-1:
2L+ Clinical Data in CMS of mCRC
Treatment Regimen
CMS
Median OS
Median PFS
FOLFIRI +/-
Regorafenib70
1 (n=8)
7.3 months
2 months
2 (n=43)
12.3 months
5.5 months
3 (n=3)
23.3 months
9.2 months
4 (n=14)
10.9 months
5.8 months
Estimated Treatment Hazard Ratio: Regorafenib compared to Placebo
Treatment Regimen
CMS
OS
(CI 95%)
PFS
(CI 95%)
Regorafenib71
1 (n=24)
HR=1.116 
(0.290-4.690)
HR=0.850 
(0.321-2.252)
2 (n=140)
HR=0.779 
(0.486-1.249)
HR=0.571 
(0.387-0.842)
3 (n=32)
HR=1.047 
(0.399-2.749)
HR=0.287 
(0.112-0.737)
4 (n=85)
HR=0.672 
(0.358-1.261)
HR=0.483 
(0.286-0.814)
CI confidence interval; HR, hazard ratio; CMS, consensus molecular subtype; mCRC, metastatic colorectal 
cancer; PFS, progression free survival; OS, overall survival. 
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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.71,72,73
Current immunotherapy efforts attempt to break the apparent tolerance of the immune system to 
tumor cells and antigens by either introducing cancer antigens by therapeutic vaccination or by 
modulating regulatory checkpoints of the immune system. T-cell stimulation is a complex process 
involving the integration of numerous positive as well as negative co-stimulatory signals in 
addition to antigen recognition by the T-cell receptor (TCR).74 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.75 PD-1 signaling has been shown to inhibit CD-28-mediated 
upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 expression also been 
noted to inhibit T cell activation, and expansion of previously activated cells. Evidence for a 
negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, which develop a 
variety of autoimmune phenotypes.76 These results suggest that PD-1 blockade has the potential 
to activate anti-self T-cell responses, but these responses are variable and dependent upon various 
host genetic factors. Thus, PD-1 deficiency or inhibition is not accompanied by a universal loss of 
tolerance to self-antigens.
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 ± 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-
4 and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
re stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall response 
indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells in a dose-
dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine analog 
of nivolumab enhances the anti-tumor immune response and result in tumor rejection in several 
immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).77
Nivolumab (also referred to as BMS-936558, MDX1106, or ONO-4538) is a human monoclonal 
antibody (immunoglobulin G4-S228P) that targets the PD-1 cluster of differentiation 279 cell 
surface membrane receptor. PD-1 is a negative regulatory molecule expressed by activated T and 
B lymphocytes. Binding of PD-1 to its ligands, PD-L1 and PD-L2, results in the down-regulation 
of lymphocyte activation. Inhibition of the interaction between PD-1 and its ligands promotes 
immune responses and antigen-specific T-cell responses to both foreign antigens as well as self-
antigens. Nivolumab is expressed in Chinese hamster ovary cells and is produced using standard 
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mammalian cell cultivation and chromatographic purification technologies. The clinical study 
product is a sterile solution for parenteral administration.
Nivolumab (OPDIVOTM) is approved for the treatment of several types of cancer in multiple 
regions including the United States (US, Dec-2014), the European Union (EU, Jun-2015), and 
Japan (Jul-2014).
3.2.6
Ipilimumab Mechanism of Action 
Ipilimumab (BMS-734016, MDX010, MDX-CTLA4) is a fully human monoclonal 
immunoglobulin G1 kappa specific for human CTLA-4 (CD152), which is expressed on a subset 
of activated T cells. CTLA-4 is a negative regulator of T-cell activity. Ipilimumab is a monoclonal 
antibody (mAb) that binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, 
CD80/CD86. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation, 
including the activation and proliferation of tumor-infiltrating T-effector cells. Inhibition of 
CTLA-4 signaling can also reduce T-regulatory cell (Treg) function, which may contribute to a 
general increase in T-cell responsiveness, including the anti-tumor response.
3.2.7
Nivolumab Combined with Ipilimumab Clinical Activity
Multiple clinical studies have evaluated nivolumab combined with ipilimumab at different doses 
and schedules. Based on Phase 3 data showing improved survival over standard of care therapies, 
nivolumab combined with ipilimumab has been approved in multiple countries for the treatment 
of patients with chemotherapy-naïve advanced nonsmall cell lung cancer (NSCLC), unresectable
or metastatic melanoma, intermediate or poor risk, previously untreated advanced renal cell 
carcinoma (RCC), and microsatellite instability-high or mismatch repair deficient colorectal 
cancer. Details of the clinical activity in these various malignancies are provided in the United 
States Package Insert (USPI) and Summary of Product Characteristics (SmPC).
3.2.7.1
CA209012 in NSCLC
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 objective response rate (ORR) per RECIST 1.1 
and 24-week progression-free survival (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 + I1q6w) and 23% (N3 Q2W). The median duration of response (DOR) was 
not reached in any of these groups. 
The rate of treatment-related adverse events (AEs) in the Q12W (82%) and Q6W (72%) arms were 
comparable to monotherapy (72%). In the study, Grade 3/4 adverse events were 37%, 33%, and 
19% for the 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-related select AEs in patients administered the optimized dosing schedule (3 mg/kg 
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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.89
3.2.7.2
CA209016 in mRCC
The combination of nivolumab with ipilimumab is being studied in the Phase 1 study CA209016.
Subjects with metastatic RCC (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. 
Subjects were randomized to N3 + I1 (n = 47) and N1 + I3 (n = 47). Approximately half (n = 46; 
51%) had prior systemic therapy (N3 + I1: 22; N1 + I3: 26). 
After a median follow-up of 22.3 months, the confirmed ORR per 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.
The safety of nivolumab combined with ipilimumab was assessed in study CA209016. 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
serious adverse events (SAEs) (34% versus 23.4%) occurred more commonly in subjects in
the N1 + I3 arm than in the N3 + I1 arm, respectively.78
3.2.7.3
CA209004 in Melanoma
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 plus ipilimumab
3 mg/kg; n = 14), Cohort 2 (nivolumab 1.0 g/kg plus ipilimumab 3 mg/kg; n = 17) and Cohort 3 
(nivolumab 3.0 mg/kg plus ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include 
Cohort 2a which evaluated nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 16). The primary 
objective was to assess safety/tolerability; the secondary objective was to assess preliminary 
efficacy.
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Of the 52 subjects evaluable for response as of the 15-Feb-2013 clinical cut-off in CA209004,
of the 52 participants evaluable for response, 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%); 1
CR and 2 PRs with an additional PR by immune-related mWHO criteria (irPR).80 In Cohort 2
(1 mg/kg nivolumab + 3 mg/kg ipilimumab), 9 out of 17 evaluable participants had an objective
response by mWHO (53%; 3 CRs (18%), 6 PRs (35%) with two additional participants
experiencing immune-related SD (irSD). In Cohort 2a (3 mg/kg nivolumab + 1 mg/kg
ipilimumab), 6 out of 15 response evaluable participants had an objective response rate by
mWHO (40%; 1 CR (7%), 5 PRs (33%) with 2 additional uPRs (13%) and 2 irSDs and 1
irPR). In Cohort 3 (3 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 6 evaluable participants
had an objective response by mWHO (50%;3 PRs (50%) with 1 additional irPR and 1 irSD.
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 dose-limiting toxicities (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 one AE regardless of causality has been
reported in 98% of participants treated. The most common (reported at > 10% incidence)
treatment related AEs (any Grade %; Grade 3-4 %: 93; 53) are rash (55; 4), pruritus (47; 0), 
vitiligo (11; 0), fatigue (38; 0), pyrexia (21, 0), diarrhea (34; 6), nausea (21, 0), vomiting (11, 2), 
ALT increased (21; 11), AST increased (21; 13), lipase increased (19; 13), amylase increased 
(15, 6), headache (11, 0), and cough (13, 0).
The majority of AEs
leading to discontinuation (regardless of causality) were Grade 3 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.79, 80
3.2.8
Trametinib Mechanism of Action and Clinical Activity
Trametinib (Mekinist®) is a reversible and highly selective allosteric inhibitor of MEK1 and 
MEK2. MEK proteins are critical components of the MAPK pathway which is commonly 
hyperactivated in tumor cells. Oncogenic mutations in both BRAF and RAS signal through MEK1 
or MEK2. Trametinib was first approved by the FDA on 2013 as a single-agent oral treatment for 
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unresectable or metastatic melanoma in adult patients with BRAF V600 mutations. Trametinib is 
currently also approved in the EU, Canada, and Australia and multiple other countries for the 
treatment of adult patients with unresectable or metastatic melanoma. The recommended dose of 
trametinib is 2 mg once daily (QD). Trametinib in combination with the BRAF inhibitor, 
dabrafenib, was first approved by the FDA in 2014 to treat unresectable or metastatic melanoma 
in adult patients with BRAF V600 mutations. The combination therapy is currently also approved 
in the EU, Australia, Chile, Canada, and multiple other countries.
Trametinib monotherapy has demonstrated a manageable safety profile in > 700 patients across all 
clinical trials. Across all completed studies for trametinib at the recommended dose of 2 mg daily, 
the most common AEs were rash, diarrhea, fatigue, edema peripheral, nausea, dermatitis 
acneiform, vomiting, constipation, anemia, pruritus, alopecia, hypertension, decreased appetite, 
dyspnea and dry skin. For more details, please refer to the most current trametinib Investigator’s 
Brochure and the approved product information.
3.2.9
Nivolumab Monotherapy and Nivolumab and Ipilimumab Combination 
Therapy
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure,81
and will not be repeated herein.
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.
A pattern of immune-related adverse events 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 or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms. 
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the nivolumab IB.
The combination of nivolumab and ipilimumab has demonstrated increased benefit compared to 
both ipilimumab monotherapy and nivolumab monotherapy. The deep anti-tumor response 
observed in study CA209004 is described in Section 3.2.7 and is the basis for an ongoing 
randomized phase 3 study in advanced melanoma (CA209067). In Study CA209142, 55% of the 
participants with recurrent or metastatic MSI-H CRC treated with nivolumab 3 mg/kg combined 
with ipilimumab 1 mg/kg Q3W had objective response. Seventy-nine percent (79%) of participants 
achieved disease control for ≥12 weeks. This durable and sustained response compares favorably 
to results with 3 mg/kg Q2W nivolumab monotherapy (Study CA209142).82 Studies investigating 
the efficacy and safety of nivolumab in combination with ipilimumab are ongoing in NSCLC, 
RCC, and CRC.
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The combination of nivolumab and ipilimumab has the potential for increased frequencies of 
adverse events compared to ipilimumab monotherapy or nivolumab monotherapy. The most 
common (reported at > 10% incidence) treatment related AEs are fatigue, rash, pruritus, diarrhea, 
lipase increased, pyrexia, ALT increase, AST increased, amylase increased and vitiligo. This class 
of AEs are expected for the combination of nivolumab and ipilimumab based on the known AE 
profile of each drug alone. In addition, many of the Grade 3-4 adverse events were laboratory in 
nature (ie, LFTs, lipase, amylase), were without clinical sequelae and have been manageable and 
reversible following intervention dose delays or with systemic steroid treatment. However, these 
AEs have the potential to be fatal if not detected early and managed per the established algorithm 
and fatal AEs have been reported for both ipilimumab and nivolumab monotherapy. Adverse drug 
reactions with fatal outcome in clinical trial participants treated with nivolumab monotherapy and 
nivolumab and ipilimumab combination therapy are listed in the current version of the nivolumab 
IB.81
3.3
Overall Benefit/Risk Assessment
Despite several therapies available for the treatment of mCRC, the incremental benefit of these 
treatments after treatment with a 1L regimen is small, as discussed in Section 3.2.1, and represents 
an area of unmet medical need.
The safety profiles of all agents proposed for the doublet and triplet combination are well defined 
as either monotherapy or in combination and the products are already commercially available for 
the treatment of several advanced and metastatic tumor types. The safety profile of the combination 
of nivolumab with ipilimumab (3 mg/kg) is well characterized and it is approved for treatment of 
unresectable or metastatic melanoma.83 The toxicity profile of the nivolumab + ipilimumab 
combination has been shown to correlate with the ipilimumab dose: with increasing doses of 
ipilimumab, there has been an increase in frequency of adverse events and, potentially, the severity 
of these events; however, no novel toxicities have been demonstrated versus either agent alone.84, 
85, 86, 87, 88 In the current regimen for this protocol, the dose of ipilimumab will be cumulatively 
lower than the approved dose level for the combination for the treatment of advanced and 
metastatic melanoma. The toxicity profile with lower doses of ipilimumab has been established to 
be very similar to that of nivolumab monotherapy.89
Some potential overlapping toxicities are expected in the doublet (nivolumab + trametinib) and 
triplet (nivolumab + ipilimumab + trametinib) combination regimens, including, but not limited 
to, dermatologic toxicities, mucositis, pneumonitis, diarrhea, hepatitis/LFT elevation. For adverse 
events that may be related to both nivolumab and/or ipilimumab and trametinib, both Management 
Algorithms for nivolumab and ipilimumab (Appendix 5) AND trametinib Dose Modification 
guideline (Appendix 6) need to be carefully reviewed and followed. Where toxicity management 
guidelines differ between the two, the most stringent/conservative guideline should be followed. 
Nivolumab in combination with ipilimumab has demonstrated efficacy in multiple tumor types 
including MSI-H CRC, as presented in Table 3.3.1-1. Recent clinical trials have also shown that 
PD-(L)1 inhibition in combination with CTLA-4 inhibition has led to improved survival in MSS 
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CRC.10 Based on current pre-clinical and clinical data, there is scientific rationale (Section 3.1.2) 
to support the theory that a triplet combination of PD-(L)1 inhibition with CTLA-4 and MEK 
inhibition will elicit an improved immunomodulatory effect and improved clinical outcomes in 
MSS CRC.
3.3.1
Summary of Safety and Efficacy in Relevant Clinical Trials
Table 3.3.1-1 below summarizes the high level safety and efficacy data in some relevant clinical 
trials with nivolumab and ipilimumab in combination therapy, and trametinib in monotherapy. 
Study with cobimetinib and atezolizumab in combination therapy is also included for reference.
Table 3.3.1-1:
Summary of Safety and Efficacy in Relevant Clinical Trials
Study
Treatment 
Efficacy
(n. of participants)
Safety
(n. of participants)
Reference
CA209142 in 
MSI-H CRC 
N3 + I1 Q3W (4 
doses) then N3 
Q2W
ORR: 46%
DCR ≥ 12 weeks:66%
DOR: Not Reached
(n=84)
TRAE: 57%
Grade 3/4 TRAE: 24%
TRAE leading to 
discontinuation: 11%
Andre et al. J Clin 
Oncol 35, 2017 
(suppl; abstr 
3531)
CA209012
in NSCLC
N3 Q2W+ I1 
Q12W
ORR: 47%; 
DOR: Not Reached
(n=38)
TRAE: 82%
Grade 3/4: 37%
TRAE leading to 
discontinuation: 5% (n=38)
Nivolumab IB 
(v24Jun2016)
N3 Q2W+ I1 
Q6W
ORR: 39% 
DOR: Not Reached
(n=39)
TRAE: 72%
Grade 3/4: 33%
TRAE leading to 
discontinuation: 8% 
(n=39)
N3 Q2W
ORR: 23%
DOR: Not Reached
(n=52)
TRAE: 72%
Grade 3/4: 19%
TRAE leading to
discontinuation: similar to 
combo
(n=52)
CA209016
in mRCC
N3+I1 Q3W then 
N3 Q2W
ORR: 43%
DOR: 4.1+ to 42.1+ 
weeks
(n=21)
TRAE: 83%
TRAE leading to 
discontinuation: 21%
(n=47)
Nivolumab IB 
(v24Jun2016)
N1+I3 Q3W then 
N3 Q2W
ORR: 48%
DOR: 12.1+ to 35.1 
weeks
(n=23)
TRAE: 94%
TRAE leading to 
discontinuation: 11%
(n=47)
CA209004 in 
Melanoma
N0.3 Q3W + I3 
Q3W then Q12W
ORR: 21%
(n=14)
TEAE: 98%
Nivolumab IB 
(v24Jun2016)
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Table 3.3.1-1:
Summary of Safety and Efficacy in Relevant Clinical Trials
Study
Treatment 
Efficacy
(n. of participants)
Safety
(n. of participants)
Reference
N1 Q3W + I3 
Q3W then Q12W
ORR: 53%
(n=17)
>30% incidence (all grade; 
grade 3-4): rash (55%; 4%), 
pruritus (47%; 0), fatigue 
(38%; 0), diarrhea (34%; 6)
(n=53)
N3 Q3W + I1 
Q3W then 
Q12W--- MTD
ORR: 40%
(n=16)
N3 Q3W + I3 
Q3W then Q12W 
--- Exceeded 
MTD
ORR: 50%
(n=6)
Melanoma 
(BRAF-
Mutated)
Trame 2mg QD
ORR: 22%
DOR: 5.5 mon
(n=214)
TEAE: >99%
>30% incidence (all grade; 
grade 3-4): rash (57%; 8%), 
diarrhea (43%, 0%)
(n=211)
Flaherty et al., 
N Engl J Med. 
2012;367:107–
14.
Melanoma 
(BRAF-
Mutated, 
previously 
treated)
Trame 2mg QD
BRAF inhibitor 
previously treated: 
ORR: 0%; DCR: 28% 
(n=40)
BRAF inhibitor naive: 
ORR: 25%; DCR: 
75% (n=57)
TRAE: 97%
Grade 3/4: 27%
>30% incidence (all grade; 
grade 3): rash/dermatitis 
acneiform (75%; 9%), 
diarrhea (52%, 4%)
(n=97)
Kim et al. J Clin 
Oncol. 
2013;31(4):482-
9.
IMBlaze 370 
mCRC 3rd
line and 
above (up to 
5% MSI-H)
Cobi  60mg (21 
days on/7 days 
off) +atezo 
840mg Q2W
Median OS: 8.87 
months - HR vs 
regorafenib: 1.00 
(95% CI 0.73-1.38) 
Median PFS: 1.91 
months-HR vs 
regorafenib: 1.25 
(95% CI 0.94-1.65)
ORR: 3% 
DCR: 26% 
TRAE: 100%
Grade 3/4 TRAE: 39%
AEs leading to 
discontinuation: 17% (cobi 
only)
Eng et al., 
Lancet Oncol 
2019; 20:849-61
CCTG 
CO.26 Trial:
Advanced 
mCRC (3L+)
Durvalumab 
1500 mg Q4W + 
tremelimumab 
Q4W (For 4 
Cycles)
Median OS: 6.6 
months – HR vs BSC: 
0.72; (90% CI, 0.54-
0.97; p=.07)
HR vs BSC in MSS 
mCRC: 0.66 (CI 90%, 
0.48-0.89, p=0.02)
Median PFS: 1.8 
months – HR vs. BSC: 
TRAE: 100%
Grade 3 / 4 TRAE: 64%
Chen et al., 
JAMA Oncol. 
2020 Jun; 6(6): 
831-838.
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Table 3.3.1-1:
Summary of Safety and Efficacy in Relevant Clinical Trials
Study
Treatment 
Efficacy
(n. of participants)
Safety
(n. of participants)
Reference
1.01 (90% CI, 0.76-
1.34)
Abbreviations: AE, adverse event; atezo: atezolizumab; BSC, best supportive care; CCTG, Canadian Cancer Trials 
Group; CI, confidence interval; cobi: cobimetinib; CRC, colorectal cancer; DCR, disease control rate; DOR, duration 
of response; HR, hazard ratio; I, ipilimumab; IB, Investigator’s Brochure; I1, ipilimumab 1 mg/kg; mCRC,
I3, ipilimumab 3 mg/kg; metastatic colorectal cancer; mRCC, metastatic renal cell carcinoma; MSI-H, microsatellite 
instability high; MSS, microsatellite stable; MTD, maximum tolerated dose; N, nivolumab; N0.3, nivolumab 
0.3 mg/kg; N3, nivolumab 3 mg/kg; NSCLC, nonsmall cell lung cancer; ORR, objective response rate; OS, overall 
survival; PFS, progression-free survival; Q2W, every 2 weeks; Q3W, every 3 weeks; Q4W, every 4 weeks; 
Q6W, every 6 weeks; Q13W, every 13 weeks; QD, once daily; TEAE, treatment-emergent adverse event; TRAE,
treatment related adverse event; trame, trametinib; 3L(+): 3rd line (plus).
3.3.2
Safety Monitoring on Study Treatment
The following safety measures have been employed to ensure safety of the participants in this 
current study:
•
A 3+3 design was used to evaluate safety and dose limiting toxicities (DLT) in both doublet 
and triplet regimens. Safety/DLT evaluation phase was performed to determine the 
recommended Phase 2 dose (RP2D) for metastatic CRC.
•
Intense toxicity monitoring for dose optimization cohorts will help to ensure the participant 
safety, including frequent safety conference calls with investigators and representatives of the 
sponsor and collaborator (as needed).
•
A BMS medical safety team (MST) routinely reviews safety signals across the entire 
nivolumab program, including all ongoing combinations with ipilimumab or other agents like 
MEK-inhibitor that are applicable for this study.
In summary, safety evaluations will be carried out by the Sponsor/BMS Medical Monitor (or 
designee) and investigators throughout the study to determine whether dose modification, 
additional safety measures, or termination of the study treatment combination is required at any 
time. Treatment of AEs will follow institutional guidelines and local prescribing information as 
applicable. Study specific toxicity management guidelines include investigator brochures for each 
study treatment component,90,91 and dose modification and discontinuation guidelines as stated in 
protocol Sections 7.4 and 8.1, and Appendix 5 and Appendix 6. The most stringent toxicity 
management must be applied in cases where the study specific guideline and local treatment 
guideline differ. 
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints: Parts 1 and 1A
Objectives
Endpoints
Primary
•
To characterize the safety and tolerability of 
combination therapies 
•
DLTs in Part 1 and Part 1A, only, observed for 1 
treatment cycle (4 weeks for the doublet regimen 
and 8 weeks for the triplet regimen)
•
To establish recommended dosing regimen for the 
combination (nivolumab plus ipilimumab plus 
trametinib OR nivolumab plus trametinib) 
•
Safety (including but not limited to): AEs, SAEs, 
deaths, and clinical laboratory abnormalities per 
CTCAE (version 4.0)
Secondary
•
To evaluate preliminary efficacy 
•
ORR DCR, DOR, TTR, and PFS by investigator 
per RECIST v1.1
•
OS
AE, adverse event; CTCAE, Common Terminology Criteria for Adverse Events; DCR, disease control rate; 
DLTs, dose limiting toxicities; DOR, duration of response; 
 
; ORR, objective response rate; 
OS, overall survival; PFS, progression free survival; 
; RECIST, Response Evaluation Criteria 
in Solid Tumors; SAE, serious adverse event; TTR, time to response.
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Table 4-2:
Objectives and Endpoints: Parts 1B and 2
Objectives
Endpoints
Primary
•
To evaluate the ORR in all participants treated 
with nivolumab plus ipilimumab and trametinib in 
the 2L and 3L+a setting (Parts 1B and 2, 
respectively) and regorafenib in 3L+a (Part 2 only) 
•
ORR by investigator b
Secondary
•
To evaluate efficacy in all participants treated with 
nivolumab plus ipilimumab and trametinib in the 
2L and 3L+a setting (Parts 1B and 2, respectively); 
and regorafenib in 3L+a (Part 2 only) 
•
BOR, DCR, DOR, TTR, and PFS by investigatorb
•
OS
•
To characterize the safety and tolerability of 
combination therapies
•
Safety (including but not limited to): AEs, SAEs, 
deaths, and clinical laboratory abnormalities per 
CTCAE (version 4.0)
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Table 4-2:
Objectives and Endpoints: Parts 1B and 2
Objectives
Endpoints
AE, adverse event; 
, BOR, best overall response; 
; CTCAE, Common Terminology Criteria for Adverse Events; DCR, 
disease control rate;; DOR, duration of response;
 
 
; ORR, objective response rate; OS, overall survival; PFS, progression free survival; PFS2, 
time to second objective disease progression; 
 
; RECIST, Response Evaluation Criteria in Solid Tumors; SAE, serious adverse event; TTR, time to response; 
; 2L, second line; 3L+, third line plus.
a No more than 4 prior lines of therapy
b Per RECIST v1.1
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 1/2 open-label, multi-center trial of nivolumab in combination with trametinib, 
with or without ipilimumab, to evaluate the safety profile and clinical activity of these regimens 
in participants with metastatic colorectal cancer (mCRC).
Participants were dosed in the dose optimization phases of the study (Parts 1 and 1A) with either 
the doublet (nivolumab + trametinib) or triplet (nivolumab + ipilimumab + trametinib) regimen. 
Decisions regarding dosages of trametinib to be used in Parts 1B and 2 were based on observed 
safety and efficacy signals in Parts 1A and 1. The recommended Phase 2 dose was determined to 
be the triplet regimen for Parts 1b and 2 (nivolumab 6 mg/kg Q4W + ipilimumab 1 mg/kg Q8W + 
trametinib 1.5 mg continuous QD). Assessment of the preliminary benefit/risk based on the safety 
and efficacy profile for the doublet and triplet regimens used in the non-randomized parts of the 
study was reviewed along with additional emerging safety and efficacy data from other relevant 
trials to determine the optimal dose of trametinib to be used in Part 2 and Part 1B in combination 
with nivolumab and ipilimumab (Figure 5.1-1). Participants in each part of the study will be treated 
until progression, unacceptable toxicity, withdrawal of consent, or a maximum of 2 years. 
Maximum treatment duration is not applicable to participants receiving SOC therapy in Part 2, 
Cohort 5, which may be continued until progression of disease or unacceptable toxicity.
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Per Protocol Amendment 04, due to early study closure the last participant last treatment (LPLT) 
date on CA209-9N9 study will occur approximately 9 months after last participant first treatment 
(LPFT); and last participant last visit (LPLV) date will occur approximately 12 months after LPFT. 
When this LPLV date is reached, participants follow-up will be ceased, and all participants will 
complete the study. Any participant still on treatment after LPLT date who continue to demonstrate 
clinical benefit will be eligible to receive treatment outside of this study in accordance with 
Protocol Section 7.8. For Cohort 4 and Cohort 6 participants the total maximum duration of 
treatment will be 2 years, including the treatment duration on CA209-9N9.  For participants in 
Cohort 5, the treatment will be administered as per the local standard of care. In the event 
alternative means of supplying study treatment as described in Section 7.8 is not accessible, the 
study may remain open until such means become available or last participant ends treatment and 
completes follow-up visits 1 and 2 in accordance with Table 2-8, Table 2-9, Table 2-10, and Table 
2-11.
In the initial dose optimization phase of the study, which is now completed, both the doublet 
regimen (Part 1, 3L mCRC) and triplet regimen (Part 1A; 2L mCRC) employed “3+3” design for 
observation of DLT. The dose-limiting toxicities (DLT) observation period was one cycle for both 
treatment regimens, ie, 4 weeks for the doublet regimen; 8 weeks for the triplet regimen. DLT 
observations are described in Section 5.1.1.1. Dose optimization phase of the study (Part 1 and 
Part 1A) has been completed. Enrollment is closed in Part 1 and Part 1A cohorts. No further 
evaluations of DLT will be conducted. 
Participants were allocated to treatment as follows:
•
Part 1: Participants with 3L mCRC were assigned to receive doublet therapy as nivolumab 480 
mg Q4 week plus trametinib 1.5 mg QD (continuous dosing, Cohort 1 Group) 
•
Part 1A: Participants with 2L mCRC were assigned to receive the triplet therapy of either:
−
6 mg/kg nivolumab (Q4W) plus ipilimumab 1 mg/kg (Q8W) plus trametinib 1.5 mg QD 
(continuous dosing, Cohort 2 Group), OR
−
6 mg/kg nivolumab (Q4W) plus ipilimumab 1 mg/kg (Q8W) plus trametinib 1.5 mg QD 
(2 week ON/2 week OFF, Cohort 3 Group)
Only pMMR/MSS participants were enrolled in Part 1 and Part 1A.
Trametinib 1.5 mg QD was the starting dose selected for Cohort 1, 2, and 3 groups. In Part 1, 
trametinib continuous doing regimen were investigated initially in Cohort 1, with dose de-
escalation and escalation scheme built in for trametinib intermittent dosing regimen, 2 week ON/2 
week OFF (Cohort 1 Group). In Part 1A, both trametinib continuous dosing and intermittent dosing 
was investigated initially in two separate Cohort Groups (Cohort 2 Group and Cohort 3 Group). 
Specifications regarding trametinib dosing in dose optimization phase can be found in Section 
5.1.1.
The totality of the safety data was reviewed, and decision on dose escalation, de-escalation or 
discontinuation of a particular dosing regimen were made by the study team in conjunction with 
treating physicians and documented accordingly. 
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•
For 
 
(Part 1B) phase, further evaluations of safety and efficacy will 
be conducted in Part 1B (triplet regimen; 2L pMMR/MSS mCRC) of the study. Participants 
who have failed 1 prior line of therapy will be allocated to: 
−
Part 1B Cohort 6: One cohort will be initiated in Part 1B to further characterize the safety 
and preliminary efficacy profile of the triplet regimen. Participants with 2L pMMR/MSS 
mCRC will be assigned to receive: 6 mg/kg nivolumab (Q4W) plus ipilimumab 1 mg/kg 
(Q8W) plus trametinib 1.5 mg continuous QD (Cohort 6)
•
For
 
(Part 2) phase, the efficacy and safety of the investigational 
triplet regimen versus SOC regimen (regorafenib) in 3L+ (no more than 4 prior lines of 
therapy) pMMR/mCRC will be evaluated in Part 2, the randomized controlled portion of the 
trial. 
−
Participants will be randomized at 2:1 ratio to receive nivolumab 6 mg/kg Q4W plus 
ipilimumab 1 mg/kg Q8W plus trametinib 1.5 mg continuous QD (Cohort 4), OR 
regorafenib in the SOC arm (Cohort 5).
For Part 1B (Cohort 6) and Part 2 (Cohorts 4 and 5), the proportion of participants with RAS 
mutations will be monitored on an ongoing basis. The IRT system will be set up to notify the 
Sponsor once the pre-defined number of RAS mutant participants have been enrolled. The target 
will be approximately 65% mutant, 35% wild type. If accrual diverges significantly from this goal, 
accrual in a cohort may be paused after discussion between the Sponsor and the investigators. 
Patients with BRAF V600 mutation are not eligible for the study.
Interim analysis will be performed to evaluate preliminary safety and efficacy per Section 10.3.7.
The study design schematic is presented in Figure 5.1-1.
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Figure 5.1-1:
Study Design Schematic
Ipi, ipilimumab; mCRC, metastatic colorectal cancer; MSS, microsatellite stable; Nivo, nivolumab; pMMR, proficient mismatch repair, QD, quaque die, once 
daily; Q4W, every 4 weeks; Q8W, every 8 weeks; wk, week; 2L, second line; 3L, third line; 3L+, third line plus.
a See Table 7.2-1 for unique cohort numbers for dose escalation and de-escalation.
b Participants in Part 1A were assigned to each treatment cohort on an alternating basis in IRT (interactive response technology). NOTE: Enrollment is closed in 
Part 1 and Part 1A cohorts. 
NOTE: Participants in each part of the study will be treated until progression, unacceptable toxicity, withdrawal of consent, or a maximum of 2 years. Maximum 
treatment duration is not applicable to standard of care therapy (regorafenib).
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5.1.1
Part 1 and Part 1A: Dose Optimization
The dose optimization phase of the study has completed. Enrollment is closed in all Part 1 
and Part 1A cohorts.
There will be ongoing safety data review, but no further DLT 
evaluations.
The DLT observation period will be one cycle for both treatment regimens, i.e., 4 weeks for the 
doublet regimen (Part 1); 8 weeks for the triplet regimen (Part 1A). 
Following 3+3 design in Part 1 (doublet regimen) and Part 1A (triplet regimen), trametinib dosing 
regimen could be either escalated or de-escalated for the next treatment cohort based on the number 
of DLT’s observed from previous cohort. Table 5.1.1-1 describes dose escalation or de-escalation 
plan for trametinib as a general rule. However, the totality of the safety data observed, not only the 
adverse events that meet the DLT definition, will be considered when making decisions for dose 
escalation or de-escalation. Such decisions will be made and documented in conjunction with 
treating physicians and collaborator at the end of the DLT observation period. 
Table 5.1.1-1:
Dose Escalation and De-Escalation Plan Per 3+3 Design
Number of Participants with 
DLT at a Given Dose Level
Escalation And De-Escalation Plan
0 out of 3, or < 2 out of 6
May Enter 3 additional patients at the next higher dose level.
1 out of 3
Enter 3 additional patients at the same dose level.
2-3 out of 3, or ≥ 2 out of 6
Enter 3 additional patients at the next lower dose level
Part 1 Doublet Regimen, Cohort 1 Group
Trametinib dose levels are detailed below with starting daily dose at 1.5 mg with dose escalation 
and de-escalation scheme following 3 + 3 design for the doublet regimen (Part 1; Table 5.1.1-2). 
(See Table 7.2-1 for cohort identification by trametinib dose level)
Table 5.1.1-2:
Dose Escalation and De-Escalation for Trametinib ONLY in 
Part 1 (DOUBLET Regimen [Nivolumab + Trametinib])a
Trametinib DOSE LEVEL (DL)
Trametinib plus Nivolumab 480 mg Q4W 
1 cycle = 4 weeks
DL+2
2 mg continuous
DL+1
2 mg 2wk on/2wk offb
starting
1.5 mg continuous
DL-1
1.5 mg 2 wk on/2 wk offb
DL-2
1 mg 2 wk on/2 wk offb
a No dose de-escalation for nivolumab is permitted. Dose modification for individual participants during DLT 
observation period is not permitted.  
b Trametinib is administered on Day 1 through Day 14 of each cycle.
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Part 1A Triplet Regimen, Cohort 2 and 3 Groups
Trametinib dose levels are detailed below with starting daily dose at 1.5 mg with dose escalation 
and de-escalation scheme following 3+3 design for the triplet regimens (Part 1A; Table 5.1.1-3). 
No dose escalation or de-escalation for nivolumab or ipilimumab is permitted. Participants with 
2L mCRC will be assigned to treatment cohorts in Part 1A on an alternating basis in IRT. (See 
Table 7.2-1 for Cohort identification by trametinib dose level.)
Table 5.1.1-3:
Dose Escalation and De-Escalation for Trametinib ONLY in Part 
1A (TRIPLET Regimen [Nivolumab + Ipilimumab + Trametinib])a
Trametinib DOSE LEVEL 
(DL)
Trametinib Continuous Dosing Arm 
NIVO (6 mg/kg) Q4W/ IPI (1mg/kg) 
Q8W
1 cycle = 8 weeks
Trametinib Intermittent Dosing 
Arm (2 Week ON/2 week OFF b)
NIVO (6 mg/kg) Q4W/ IPI 
(1mg/kg) Q8W
1 cycle = 8 weeks
DL+1
2 mg cont
2 mg 2wk/2wk off 
starting
1.5 mg cont
1.5 mg 2wk on/2wk off
DL-1
1 mg cont
1 mg 2wk on/2wk off
cont, continuous; DL, Dose Level. 
a No dose escalation or de-escalation for nivolumab or ipilimumab is permitted in either arm.  Dose modification for 
individual participants during DLT observation period is not permitted.  
b Trametinib is administered on Day 1 through Day 14 of each cycle.
Part 1 and Part 1A, All Cohorts: ENROLLMENT CLOSED
All participants will start at the same trametinib dose level and frequency (daily in continuous 
regimen vs. intermittent regimen) within a particular cohort throughout the first cycle (doublet and 
triplet regimens). No dose escalation or de-escalation within a particular cohort is permitted once 
study treatment starts during the first cycle (doublet and triplet regimens) for DLT observation. If 
participants don’t tolerate the study treatment at the pre-specified starting dose during the first 
cycle/DLT observation period, study treatment must be permanently discontinued*. After the DLT 
observation period, the daily dose of trametinib may be modified to manage participants’ adverse 
events (see Section 7.4.4). Modification of trametinib dosing frequency is not permitted throughout 
treatment duration, except dosing delay per dose modification guidelines (Appendix 6).
Toxicities will be considered DLTs only if they occur in Cycle 1 for the doublet and triplet 
regimens. Participants are required to complete Cycle 1 (≥ 50% of the planned cumulative dose) 
to be considered evaluable unless discontinuation occurred due to a DLT. 
DLTs are specified in Section 5.1.1.1 below.
*Under rare circumstances, participants may resume study treatment at a lower dose level for 
trametinib if deemed medically appropriate by investigators. BMS Medical Monitor or designee 
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should be consulted before resuming study treatment. Dose modification should be approved by 
BMS on a case by case basis (refer to Sections 7.4 and 8). Participants will be analyzed based on 
initial cohort assignment regardless of dose modification received.
Part 1B and Part 2: ENROLLMENT CLOSED
Per Revised Protocol 02, Part 2 (
 
 phase for triplet regimen including SOC 
arm) and Part 1B (
 
 for triplet regimen) will be initiated based on the totality 
of safety data observed from this study and relevant ongoing clinical studies. The observed 
benefit/risk profile from Part 1 and 1A has determined a recommended Phase 2 dose to be the 
triplet regimen of nivolumab 6 mg/kg Q4W + ipilimumab 1 mg/kg Q8W + trametinib 1.5 mg 
continuous QD. There will be ongoing safety data review, but no further DLT evaluations.
5.1.1.1
Dose Limiting Toxicity 
As Part 1 and Part 1A are completed, there will be ongoing safety data review, but no further 
DLT evaluations.
For the purpose of guiding dose regimen, DLTs will be defined based on the incidence, duration 
and grade of AEs for which no alternate cause can be identified. Adverse events will be evaluated 
according to the NCI CTCAE (version 4.0). DLT(s) during the first cycle of treatment (the DLT 
evaluation period) will be observed for the first 4 weeks for the doublet regimen and first 8 weeks 
for the triplet regimen. Every attempt must be made to assign relationship to the individual study 
treatment, if possible, or to the combination regimen, nivolumab/ipilimumab/trametinib 
combination or nivolumab/trametinib combination.  To meet criteria for dose limiting toxicity, 
adverse events have to be at least possibly related to study treatment, and not to disease 
progression, be clinically relevant and a clinically relevant shift from baseline.
Participants who withdraw from the study during the DLT evaluation interval for reasons other 
than a DLT may be replaced at the same dose of the study treatment. 
Dose limiting toxicities can include the following adverse events (meeting the preceding criteria):
1) Hepatic DLT
a) Any of the following events will be considered a hepatic DLT (Note that this special 
category of DLT uses ULN rather than Common Toxicity Criteria Grade for definition.): 
i)
For participants with normal baseline AST and ALT values: AST or ALT > 8× ULN
ii) For participants with normal baseline Total bilirubin (TBIL) value: TBIL > 5× ULN
iii) For participants with normal baseline AST and ALT and normal baseline bilirubin 
values: AST or ALT > 3× ULN and concurrent total bilirubin > 2× ULN without initial 
findings of cholestasis (elevated serum alkaline phosphatase ≥2× ULN) or other 
reasons to explain the combination of increased aminotransferases and TBIL 
iv) For participants with abnormal baseline AST or ALT or abnormal baseline bilirubin 
values: [AST or ALT > 2× baseline AND >8× ULN], combined with [TBIL > 2× 
baseline AND > 2× ULN] without initial findings of cholestasis (elevated serum 
alkaline phosphatase ≥2× ULN) or other reasons to explain the combination of 
increased aminotransferases and TB,
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2) Nonhepatic Nonhematologic DLT
a) Any of the following events will be considered a nonhepatic nonhematologic DLT: 
i)
Grade 2 ocular toxicities, including episcleritis, uveitis, iritis, eye pain, or blurred vision 
that does not respond to topical therapy and does not improve to Grade 1 severity within 
2 weeks OR requires systemic treatment
ii) Any clinical evidence of congestive heart failure or ≥ Grade 3 cardiac event that is 
symptomatic or requires medical intervention
iii) Grade 3 pneumonitis, bronchospasm, colitis, neurologic toxicity, hypersensitivity 
reaction, or infusion reaction
iv) Grade 3 hypertension if it persists > 7 days despite optimal anti-hypertensive treatment 
or grade 4 hypertension of any duration
v) Any Grade 3 or greater nondermatologic, nonhepatic, nonhematologic toxicity will be 
considered a DLT with the following specific EXCEPTIONS:
(1) Grade 3 electrolyte or laboratory abnormalities that are not complicated by 
associated clinical adverse experiences, last less than 48 hours, and either resolve 
spontaneously or respond to conventional medical intervention. The maximum 
allowable time limit for correction of electrolyte abnormalities to ≤Grade 1 is 
72 hr.
(2) Grade 3 nausea, vomiting, or diarrhea that lasts less than 48 hours and either 
resolves spontaneously or responds to medical intervention. 
(3) Isolated Grade 3 or Grade 4 elevation of amylase or lipase not associated with 
clinical or radiographic evidence of pancreatitis
(4) Isolated Grade 3 fever not associated with hemodynamic compromise (eg, 
hypotension, clinical or laboratory evidence of impaired end-organ perfusion).
(5) Grade 3 endocrinopathy that is well-controlled by hormone replacement
(6) Grade 3 tumor flare (defined as pain, irritation, or rash that localizes to site of 
known or suspected tumor)
(7) Grade 3 fatigue
(8) Grade 3 infusion reaction that returns to Grade 1 in less than 6 hours
3) Dermatologic DLT
a) Grade 3 rash if no improvement (ie, resolution to ≤Grade 1) after a 2-week dosing delay. 
Participants who have not experienced a Grade 3 drug-related skin AE may resume 
treatment in the presence of Grade 2 skin toxicity.
b) Grade 4 rash of any duration
4) Hematologic DLT
a) Grade 4 neutropenia ≥7 consecutive days in duration
b) Grade 4 thrombocytopenia or Grade 3 thrombocytopenia with bleeding, or any requirement 
for platelet transfusion
c) Grade 4 anemia not explained by underlying disease
d) Grade ≥3 febrile neutropenia for 48 hours
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e) Grade ≥3 hemolysis (ie, requiring transfusion or medical intervention such as steroids) or 
any clinically relevant hemolysis as follows:
i)
Any clinically meaningful laboratory evidence of hemolysis and Grade 2 creatinine
elevation
ii) Any clinically meaningful laboratory evidence of hemolysis and Grade 3 
thrombocytopenia
iii) Any clinically meaningful laboratory evidence of hemolysis with more than a 3gm/dL 
drop in hemoglobin (or CTCAE hemoglobin level ≥ Grade 3).
5) Any toxicity requiring dose delay of study treatment during cycle 1 resulting in: 
a) Delay of > 4 weeks in initiating Cycle 2
b) Participant receives less than 50% of intended total dose of any study drug treatment
c) Participant only receives one dose of nivolumab in the triplet regimen
5.1.1.2
Toxicity Management during DLT Observation
Optimal medical management must be implemented for all participants in this study, including the 
DLT observation phase in Part 1 and Part 1A. As Part 1 and Part 1A are completed, there will be 
ongoing safety data review, but no further DLT evaluations.
Adequate patient education and frequent follow-up with participants by investigator site staff must 
be performed to manage treatment emergent toxicities. Refer to Section 3.3.2 for AE management 
guidelines. Prophylaxis/prevention measures relating to trametinib related skin toxicities and 
diarrhea are described below and in Appendix 6:
•
Rash: Rash prophylaxis/prevention is recommended for the first 6 weeks of study treatment 
with trametinib. Participants who develop rash/skin toxicities should be seen by a qualified 
physician and should receive evaluation for symptomatic/supportive care management. 
•
Diarrhea: Loperamide or other anti-diarrheal treatment should be accessible prior to start of 
study treatment with trametinib so loperamide or other anti-diarrheal administration can begin 
at the first signs of diarrhea, if clinically indicated.
5.1.2
Part 1B: 
 
 The Triplet Regimen
Preliminary safety, efficacy, 
 data from Parts 1 and 1A were analyzed in a 
predetermined interim analysis to select the optimal dosing regimen of nivolumab 6 m/kg Q4W 
plus ipilimumab 1 mg/kg Q8W plus trametinib 1.5 mg continuous QD for Part 1B. Approximately 
80 participants (Cohort 6) will be treated in Part 1B to further assess the safety and preliminary 
efficacy of the combination regimen. The totality of the safety data and preliminary efficacy data 
from Part 1B will be reviewed on an ongoing basis. 
5.1.3
Part 2: 
 the Triplet Regimen and Standard of 
Care Arm
Preliminary safety, efficacy, 
 data from Part 1 and Part 1A were analyzed in a 
predetermined interim analysis to determine the optimal regimen for Part 2. Part 2 of the study for 
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the triplet regimen will consist of 1 cohort (Cohort 4) to investigate the safety and clinical activity 
of nivolumab 6 mg/kg Q4W plus ipilimumab 1 mg/kg Q8W plus trametinib 1.5 mg continuous 
QD. A SOC arm with regorafenib will also be initiated (Cohort 5). Participants will be randomized 
according to a 2:1 ratio (approximately 80 participants to receive the triplet regimen and 40 
participants to receive the SOC therapy, regorafenib).
Participants who have failed at least 2 prior lines of therapy (no more than 4 prior lines) will be 
randomized to receive the triplet regimen OR regorafenib. No crossover will be permitted between 
the 2 treatment arms upon discontinuation of study treatment.
5.1.4
Data Monitoring Committee and Other External Committees
A data monitoring committee (DMC) will not be utilized for this Phase 1/2 study.
5.1.4.1
Blinded Independent Central Review 
A blinded independent central review (BICR) may be utilized in Part 2 and Part 1B of this study 
. Details of BICR procedures will be 
specified in a BICR Charter. Refer to Section 9.1.1 Imaging Assessment for the Study for further 
details.
5.2
Number of Participants
Part 1 and Part 1A followed a 3+3 design, with potential dose escalation and de-escalation based 
on DLT observations, with intention to treat up to approximately 18 and 24 participants, 
respectively. Part 1 and Part 1A (dose optimization phase) have completed. Part 1B, will treat 
approximately 80 participants. Part 2 will randomize approximately 120 participants into 2 arms 
(nivolumab + ipilimumab + trametinib and regorafenib) in a 2:1 ratio. See Section 10.1 for sample 
size determination.
5.3
End of Study Definition
The start of the trial is defined as the first visit for first participant screened. End of trial is defined 
as the last visit or scheduled procedure shown in the schedule of activities (see Section 2) for the 
last participant. Study completion is defined as the final date on which data for the primary 
endpoint is expected to be collected. 
5.4
Scientific Rationale for Study Design
5.4.1
Rationale for 2 year treatment duration for Immunotherapy (Nivolumab 
+ Ipilimumab)
The optimal duration of immunotherapy is an important question and continues to be investigated. 
Clinical trials across different tumor types in the nivolumab and ipilimumab development program 
indicate that most of the responses occur early, with a median time to response of 2 to 4 months, 
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.92 Furthermore, a limited duration of ipilimumab (at doses up to 10 mg/kg), including 
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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.93
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit. CA209-003, a dose-escalation cohort expansion trial evaluating the safety 
and clinical activity of nivolumab in patients with previously treated advanced solid tumors 
(including 129 subjects with NSCLC), specified a maximum treatment duration of 2 years. Among 
16 subjects with NSCLC who discontinued nivolumab after completing 2 years of treatment, 12 
subjects were alive > 5 years and remained progression-free without any subsequent therapy. In 
the CA209-003 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.94 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% to 18% for 
squamous and non-squamous NSCLC, respectively).95
Taken together, these data suggest that treatment beyond 2 years is unlikely to confer additional 
clinically meaningful benefit and that the risk of progression after discontinuing treatment at 
2 years is low.
In contrast, a shorter duration of nivolumab of only 1 year was associated with increased risk of 
progression in previously treated patients with NSCLC, suggesting that treatment beyond 1 year 
is likely needed. In CA209153, patients with previously treated advanced NSCLC who completed
1 year of nivolumab therapy were randomized to either continue or stop treatment, with the option 
of retreatment upon progression. Among 163 patients still on treatment at 1 year and without 
progression, those who were randomized to continue nivolumab had significant improvement in 
progression-free survival (PFS) compared to those who were randomized to stop treatment, with 
median PFS (post-randomization) not reached vs 10.3 months, respectively; HR = 0.42 (95% CI, 
0.25 to 0.71). With a median follow-up of 14.9 months post-randomization, there also was a trend 
for patients on continued treatment to live longer (OS HR = 0.63 [95% CI: 0.33, 1.20]). Of note, 
the PFS curves in both groups plateau approximately 1 year after randomization (ie, 2 years after 
treatment initiation), suggesting that there may be minimal benefit in extending treatment beyond 
a total of 2 years.96
Collectively, these data suggest that there is minimal if any benefit derived from continuing I-O 
treatment beyond two years in advanced tumors. However, even though immunotherapy is well 
tolerated, patients will be at risk for additional toxicity with longer term treatment. Therefore, in 
this study, nivolumab treatment will be given for a maximum of 2 years from the start of study 
treatment.
For these reasons, in study CA2099N9, nivolumab and ipilimumab treatment will be given for up 
to 2 years in the absence of disease progression or unacceptable toxicity for the doublet and triplet 
regimens. There is no maximum treatment duration for the SOC arm (regorafenib) in Part 2, 
Cohort 5, which may be continued until progression of disease or unacceptable toxicity. Please 
refer to Section 7.8.
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5.4.2
Rationale for Choice of Standard of Care Treatment in Part 2
Regorafenib is a standard late line therapy for mCRC patients who have been previously treated 
with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF therapy, 
and anti-EGFR therapy (if KRAS wild type). Regorafenib is approved by regulatory authorities in 
many regions of the world for patients with mCRC who have failed at least 2 prior lines of therapy
(no more than 4 prior lines).
Regorafenib was chosen to be the SOC treatment in Part 2, in accordance with current clinical 
expert guidance that advises that regorafenib may provide benefit when used in the 3L+ setting. 
Prior TAS-102 is allowed as it is often well-tolerated and equally effective whether or not patients 
have received regorafenib.97,98,99,100
5.4.3
Rationale for Stratification in Part 2
Two stratification factors, primary tumor location (right vs left sided tumor) and extended RAS 
mutation status (wild-type vs mutant) were chosen for the evaluation of the triplet regimen 
(nivolumab plus ipilimumab plus trametinib) with SOC therapy (regorafenib) in 3L+ (no more 
than 4 prior lines of therapy) mCRC.
Right vs Left Sided Tumor:
In a systemic review and meta-analysis with more than 1.4 million colon cancer participants, a 
significant prognostic impact of primary tumor location on overall survival (OS) was observed 
with a 20% reduced risk of death for cancers arising on the left side.101 Such a survival benefit 
seen in the left side primary tumor was independent of disease stage (II, III, and IV), and Stage IV 
disease showed a significantly greater survival benefit compared with Stage II and III disease. 
Recent meta-analysis based on data from 6 randomized clinical trials in mCRC (Stage IV), 
CRYSTAL, PRIME, PEAK, FIRE-3, CALGB 80405 and 20050181, also demonstrated predictive 
favorable effect on OS and PFS in patients with left-sided tumors.102 Five of the aforementioned 
studies were in 1L mCRC patient population, and Study 20050181 was in the 2L mCRC patient 
population. 
Thus, the right versus left sided tumor is chosen as one of the 2 stratification factors. Specifically, 
primary tumors originating in the appendix, cecum, ascending colon, hepatic flexure, and 
transverse colon will be classified as right-sided. Primary tumors originating in the splenic flexure, 
descending colon, sigmoid colon, rectosigmoid junction, and rectum will be classified as 
left-sided. If tumors were located in both left-sided and right-sided locations and the origin could 
not be ascribed to either side, these tumors will be stratified as right-sided (Appendix 13).
Participants with unknown primary tumor location or primary tumor located in both sides will be 
stratified to the right-sided stratum. Such participants are not expected to exceed 2% to 5%.
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Extended RAS/BRAF Wild-type vs Mutant:
Extended RAS (KRAS and NRAS) and BRAF mutation status testing is standard practice in 
guiding treatment decisions in mCRC. As discussed in Section 3.2.2, the prognostic value of 
KRAS mutations in mCRC (independent of anti-EGFR therapy) is unclear due to conflicting data 
from various meta-analyses across all disease stages. It is also uncertain which mutation status will 
benefit more from the triplet (nivolumab + ipilimumab + trametinib). Based on current available 
data, preliminary anti-cancer efficacy using PD-L1 antibody in combination with MEKi was 
observed only in KRAS mutant participants, recognizing 20 out of 23 participants treated were 
KRAS mutant (refer to Section 3.1.2 for updated results).103 In addition, the CORRECT45 and 
RECOURSE trial results also indicated that both regorafenib and TAS-102 improved OS over best 
supportive care numerically higher in the KRAS wild-type population than in the KRAS mutant 
population, although not statistically significant. In order to keep balanced distribution of each 
treatment stratum for both cohorts (Cohort 4 and Cohort 5), extended RAS mutation status will 
also be utilized as a stratification factor in Part 2. Coexistence of both RAS and BRAF mutation 
is very rare. Thus participants whose tumors are wild-type for extended RAS vs. participants 
whose tumors are extended RAS mutant will be stratified into 2 groups, RAS wild-type vs mutant. 
Capping for wild-type (extended RAS) status will be implemented per study design (Section 5.1).
BRAF mutations are observed in 5% to 10% of CRC, with 80% to 90% of BRAF mutations being 
V600E.40,104 Given the poor prognosis associated with BRAF V600 mutations, these patients will 
be excluded.40
5.5
Justification for Dose
5.5.1
Rationale for Dose Selection of Nivolumab and Ipilimumab
5.5.1.1
Rationale for Nivolumab Dosing
Nivolumab monotherapy has been extensively studied in multiple tumor types, including 
melanoma, NSCLC, renal cell carcinoma (RCC), classical Hodgkin’s lymphoma (cHL), head and 
neck (H&N) and urothelial carcinoma (UC), using body weight normalized dosing (mg/kg), and 
has been safely administered at doses up to 10 mg/kg Q2W. Nivolumab is currently approved for 
the treatment of various tumors, including melanoma, NSCLC, RCC, cHL, SCCHN, and UC, 
using a regimen of either  nivolumab 240 mg Q2W or nivolumab 3 mg/kg Q2W.
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5.5.1.2
Rationale for Ipilimumab Dosing
In CA209012, ipilimumab 1 mg/kg using Q6W and Q12W schedules were assessed and were 
found to be safe in combination with nivolumab 3 mg/kg Q2W. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.5.2
Rationale for the Dose of Trametinib
The FDA and EMA approved dose of trametinib as single agent and in combination with 
dabrafenib is 2 mg QD for unresectable and metastatic melanoma. 
 
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5.5.3
Rationale for Shorter Infusion Time
Long infusion times place a burden on patients and treatment centers. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.5.4
Rationale for Dose Selection of Regorafenib in 3rd line MSS/mCRC
Recommended starting dose for regorafenib is selected based on approved product labels across 
various regions. Local product label and institutional guidelines for regorafenib starting dose can 
be considered in consultation with BMS Medical Monitor/designee (see Table 7.1.4.2-1).  
6
STUDY POPULATION
For entry into the study, the following criteria MUST be met. As of 30-Nov-2022, enrollment into 
this study was closed.
6.1
Inclusion Criteria 
1) Signed Written Informed Consent
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
participant care.
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
laboratory tests, tumor biopsies, and other requirements of the study.
2) Type of Participant and Target Disease Characteristics
a) Histologically or cytologically confirmed previously treated metastatic colorectal cancer 
with adenocarcinoma histology and in Stage IV per American Joint Committee on Cancer 
(Edition 7.0) at study entry. 
b) Microsatellite status should be performed per local standard of practice, IHC and/or PCR. 
If IHC results are equivocal, PCR is required for determining microsatellite status, MSS or 
MSI-H.
i)
Not applicable per Protocol Amendment 03: Part 1 (3L setting), Part 1A and Part 1B 
(2L setting) and Part 2 (3L setting): only participants with pMMR/MSS mCRC are 
eligible
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ii) No longer applicable per Revised Protocol 02. Part 2 (≥ 3L setting): Both participants 
with pMMR/MSS and dMMR/MSI-H mCRC are eligible. dMMR/MSI-H enrollment 
will be capped at 5% in each treatment arm. 
iii) Part 1 (3L setting), Part 1A and Part 1B (2L setting) and Part 2 (3L+ setting): only 
participants with pMMR/MSS mCRC are eligible.
c) KRAS and NRAS (extended RAS) and BRAF mutation status should be verified based on 
available local testing results as part of medical history prior to study treatment. Refer to 
Appendix 10 for local testing methodology permitted by the study. Participants with 
colorectal cancers that are RAS wild-type or mutant may be enrolled.
i)
In Parts 1B and 2, the proportion of participants with RAS mutations and wild-type
will be monitored on an ongoing basis, as specified in Section 5.1.
d) Prior lines of therapies:
i)
Not applicable per Protocol Amendment 03: Participants with 3L mCRC in Part 1
and Part 2 must have progressed or been intolerant to two prior lines of chemotherapy 
in the metastatic disease setting, which must include at least a fluoropyrimindine and 
oxaliplatin- and irinotecan-containing regimens.  
ii) Participants with 2L mCRC in Part 1A and 1B must have progressed or been intolerant 
to one prior line of chemotherapy in the metastatic disease setting, which must include 
at least a fluoropyrimindine and oxaliplatin- or irinotecan-containing regimens.  
iii) For participants who received systemic therapy in the adjuvant or neoadjuvant setting, 
progression must occur at least 6 months after the last dose of the adjuvant or 
neoadjuvant therapy, except for Part 2.  
iv) Adjuvant/neoadjuvant therapy or maintenance therapy will NOT be considered as one
line of prior therapy for study entry. See criterion below for Part 2 on 
adjuvant/neoadjuvant therapy.
v) Not applicable per Protocol Amendment 03: Participants who received FOLFOXIRI 
(or equivalent) in the 1L setting may be considered for enrollment in the third line 
setting (Part 1 or Part 2) but not the second-line setting (Part 1A or Part 1B).
vi) Prior therapies containing anti-VEGF agents and/or anti-EGFR agents are permitted.
vii)No longer applicable per Revised Protocol 02. Participants with ≥ 3L mCRC in Part 
2 must have progressed or been intolerant to at least 2 prior lines of chemotherapy in 
the metastatic setting, which must include at least a fluoropyrimindine and oxaliplatin-
and irinotecan-containing regimens. 
viii)
Not applicable per Protocol Amendment 03: Participants with 3L mCRC in Part 
2 disease recurrence within 6 months after the last dose of the adjuvant/neoadjuvant 
therapy is permitted and will be considered as 1 line of prior therapy for study entry. 
Disease recurrence beyond 6 months after the last dose of the adjuvant/neoadjuvant 
therapy is also permitted but will NOT be considered as 1 line of prior therapy for study 
entry. 
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ix) Not applicable per Protocol Amendment 03: Participants with 3L mCRC in Part 2:
disease progression must have occurred during or within 3 months following the last 
dose of approved standard therapies.
x) Participants with 3L mCRC in Part 1 and 3L+ mCRC in Part 2 must have progressed 
or been intolerant to 2 prior lines or at least 2 prior lines (no more than 4 prior lines) of 
therapy, respectively, in the metastatic disease setting, which must include at least a 
fluoropyrimindine and oxaliplatin- and irinotecan-containing regimens. 
xi) Participants who received FOLFOXIRI (or equivalent) in the 1L setting may be 
considered for enrollment in the 3L setting (Part 1) or 3L+ setting (Part 2) but not the 
second line setting (Part 1A or Part 1B).
xii)Participants with 3L+ mCRC in Part 2: disease recurrence within 6 months after the 
last dose of the adjuvant/neoadjuvant therapy is permitted and will be considered as 1 
line of prior therapy for study entry. Disease recurrence beyond 6 months after the last 
dose of the adjuvant/neoadjuvant therapy is also permitted but will NOT be considered 
as 1 line of prior therapy for study entry. 
xiii)
Participants with 3L+ mCRC in Part 2: disease progression must have occurred 
during or within 3 months following the last dose of approved standard therapies.
e) Participants must have measurable disease per RECIST 1.1 (Appendix 8). 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.
g) ECOG Performance Status of 0-1 at screening and on C1D1. See Appendix 7 for ECOG 
Performance Status scale.
h) Re-enrollment: This study permits the re-enrollment of a participant who 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 from IRT. 
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3) Age and Reproductive Status
a) Men and women, ages ≥18 years of age.
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 drug.
c) Women must not be pregnant or breastfeeding.
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception for the duration of study treatment and 5 months after the last 
dose of study treatment {i.e., 30 days (duration of ovulatory cycle) plus the time required 
for the investigational drug to undergo approximately five half-lives. See Appendix 4. For 
participants randomized to treatment with regorafenib (Part 2: Cohort 5) institutional 
guidelines apply.
e) Not Applicable per Protocol Amendment 03: Males who are sexually active with 
WOCBP must agree to follow instructions for method(s) of contraception for the duration 
of study treatment and 7 months after the last dose of study treatment (ie, 90 days [duration 
of sperm turnover] plus the time required for the investigational drug to undergo 
approximately five half-lives.) In addition, male participants must be willing to refrain 
from sperm donation during this time. See Appendix 4. For participants  randomized to 
treatment with regorafenib (Part 2: Cohort 5) institutional guidelines apply.
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 this section.
g) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of study treatment and 4 months after the last 
dose of study treatment {i.e., 90 days (duration of sperm turnover) plus the time required 
for the investigational drug to undergo approximately five half-lives.} In addition, male 
participants must be willing to refrain from sperm donation during this time. See 
Appendix 4. For participants randomized to treatment with regorafenib (Part 2: Cohort 5) 
institutional guidelines apply.
Investigators shall counsel WOCBP and male participants who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise WOCBP and male participants who are sexually active with WOCBP 
on the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% per year when used consistently and correctly.
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At a minimum, participants must agree to use one highly effective method of contraception. See 
Appendix 4 for recommended methods of contraception. 
6.2
Exclusion Criteria 
1) Target Disease Exceptions
a) Participants with BRAF V600 mutant colorectal cancer are NOT eligible for this study.  
i)
Verify BRAF V600 mutation status based on available local testing results as part of 
medical history prior to study treatment. Refer to Appendix 10 for local testing 
methodology permitted by the study. All other BRAF variants, except V600, are 
eligible for this study.
b) Active brain metastases or leptomeningeal metastases. Participants with brain metastases 
are eligible if these have been treated and there is no magnetic resonance imaging (MRI 
except where contraindicated in which CT scan is acceptable) evidence of progression for 
at least 8 weeks after treatment is complete and within 28 days prior to first dose of study 
drug administration. 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.
2) Medical History and Concurrent Diseases
a) 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.
b) Not applicable per Protocol Amendment 03: Prior malignancy active within the previous 
3 years except for locally curable cancers that have been apparently cured, such as basal or 
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, 
cervix, or breast.
c) 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.
d) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 
14 days of study drug administration. Inhaled or topical steroids and adrenal replacement 
doses > 10 mg daily prednisone equivalents are permitted in the absence of active 
autoimmune disease.
e) 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.
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f)
All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE [version 4.0]) or baseline before administration of 
study drug. Participants with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after platinum 
based therapy, are permitted to enroll.
g) Toxicities from the prior anti-cancer treatment have not been resolved to Grade 1 (NCI 
CTCAE version 4.0) at the time of study entry or participants have not completed prior 
treatment as specified below:
i)
Received chemotherapy and other approved SOC within 14 days prior to first dose
ii) Received investigational product(s) (IPs) within 28 days or 5 half-lives prior to first 
dose
iii) Prior major surgery within 28 days prior to first dose. Any surgery-related AE(s) must 
have resolved at least 14 days prior to first dose.  
iv) Received radiation therapy with curative intent within 28 days prior to first dose. Prior 
focal palliative radiotherapy must have been completed at least 14 days prior to first 
dose.
h) Current use of a prohibited medication. Treatment with botanical preparations (eg, herbal 
supplements or traditional Chinese medicines) intended for general health support or to 
treat the disease under study within 2 weeks prior to first dose of study treatment. Refer to 
Section 7.7 for prohibited therapies.
i)
Prior treatment with any MEK inhibitor
j)
History of interstitial lung disease or pneumonitis.
k) Inability to take oral medication or significant nausea and vomiting, malabsorption, 
external biliary shunt, significant bowel resection that would preclude adequate absorption 
of oral medication.
l)
Psychological, familial, or sociological condition potentially hampering compliance with 
the study protocol and follow-up schedule. 
m) Additional criteria for Part 2 only: Note: criterion vii) below applies to both Part 1b and 
Part 2: 
i)
Prior treatment with regorafenib 
ii) Severe hepatic impairment (Child-Pugh C)
iii) Any evidence of active bleeding, or hemorrhage or bleeding event ≥ NCI-CTCAE
version 4.0 Grade 3 within 4 weeks prior to the start of study medication
iv) Prior or current gastrointestinal perforation or fistula
v) Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism 
within 6 months before the start of study medication (except for adequately treated 
catheter-related venous thrombosis occurring more than 1 month before the start of 
study medication)
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vi) Non-healing wound, non-healing ulcer, or non-healing bone fracture
vii)Active infection (ie, body temperature ≥38°C due to infection): Applies to Parts 1B 
and Part 2.
n) Participants who have received a live/attenuated vaccine within 30 days of randomization 
(eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles, mumps, rubella 
[MMR]).
o) Prior malignancy active within the previous 2 years prior to randomization except for 
locally curable cancers that have been apparently cured, such as basal or squamous cell 
skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or 
breast.
3) Physical and Laboratory Test Findings 
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100×103/μL
d) Hemoglobin < 9.0 g/dL
e) PT/INR and PTT > 1.5 ×ULN
f)
Serum creatinine  > 1.5 ×ULN,  unless creatinine clearance > 50 mL/min (measured or 
calculated using the Cockcroft-Gault formula)
g) AST and/or ALT: > 3.0 ×ULN
i)
Part 2 ONLY: Participants with documented liver metastases with AST and ALT > 5.0
×ULN will be excluded. 
h) Total bilirubin > 1.5 ×ULN
i)
Participants with Gilbert’s Syndrome who have a total bilirubin level of > 3.0 ×ULN 
will be excluded.
i)
Albumin < 3.0 g/dL
j)
Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, e.g. Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
k) History or evidence of cardiovascular risk including any of the following: 
i)
LVEF <LLN or < 50%, whichever is lower by ECHO (preferred) or MUGA.  NOTE: 
same method used at baseline must be used throughout the study.
ii) A QT interval corrected for heart rate using the Bazett’s formula (QTcB) ≥ 480 msec;
iii) History or evidence of current clinically significant uncontrolled arrhythmias
iv) Clarification: Participants with atrial fibrillation controlled for > 30 days prior to dosing 
are eligible. 
v) History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to dosing.
vi) History or evidence of current ≥ Class II congestive heart failure as defined by New 
York Heart Association (NYHA; Appendix 11).
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vii)Treatment refractory hypertension defined as a blood pressure of systolic >140mmHg 
and/or diastolic > 90 mm Hg, which cannot be controlled by anti-hypertensive therapy
viii)
Participants with intra-cardiac defibrillators.
l)
Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally. Please see Appendix 12. 
m) Participants with serous retinopathy or retinal vein occlusion (RVO) noted on 
ophthalmological evaluation, or participants with a history of serous retinopathy or retinal 
vein occlusion.
Note: Study required laboratory testing results (refer to Table 2-1) should be obtained within 28
days prior to first dose, and reviewed to confirm eligibility. Screening laboratory values must meet 
the above criteria without continuous supportive treatment such as growth factor administration, 
blood transfusion, coagulation factors and/or platelet transfusion, or albumin transfusion.
4) 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.
c) Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).
5) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: Under specific 
circumstances, and only in countries where local regulations permit, a person who has been 
imprisoned may be included as a participant. Strict conditions apply and BMS approval is 
required.)
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
Specific information regarding warnings, precautions, contraindications, AEs, and other pertinent 
information on the study treatment(s) that may impact participant eligibility is provided in the most 
recent Investigator Brochure for each study treatment components (nivolumab, ipilimumab, 
trametinib). Refer to local product label and institutional guidelines for regorafenib.
6.3
Lifestyle Restrictions
Not applicable for nivolumab, ipilimumab, or trametinib. Refer to local product label and 
institutional guidelines for regorafenib.
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6.4
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 or 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.
6.4.1
Retesting During Screening 
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a screen failure. If re-enrolled, the participant must be re-consented and 
assigned a new participant number from IRT. 
Retesting of laboratory parameters and/or other assessments within Screening will be permitted 
(in addition to any parameters that require a confirmatory value).
The most current result prior to enrollment is the value by which study inclusion will be assessed, 
as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor/designee may be needed to identify whether repeat testing of any 
particular parameter is clinically relevant.
7
TREATMENT
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation.
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP) and can consist of the following:
•
Nivolumab
•
Ipilimumab
•
Trametinib
•
Regorafenib
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.
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Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:
Study treatments for CA2099N9
Product Description / 
Class and Dosage Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage Conditions
(per label)
Nivolumab
Solution for Injection
100 mg (10 mg/mL) 
IP
Open label
Vial
Refer to the label on 
container and/or 
pharmacy manual.
Ipilimumab
Solution for Injection
200 mg
50 mg
(5 mg/mL)
IP
Open label
Vial
Refer to the label on 
container and/or 
pharmacy manual.
Trametinib Tableta
0.5 mg and various 
strengths
IP
Open label
Various packing 
configurations
Refer to label on 
container or package 
insert/summary of product 
characteristics
Regorafenib Tableta
40 mg and various 
strengths
IP
Open label
Various packing 
configurations
Refer to label on 
container or package 
insert/summary of product 
characteristics
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 (SmPCs). 
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7.1
Treatments Administered
7.1.1
Nivolumab and Ipilimumab Infusion
There will be no dose escalations or reductions of nivolumab or ipilimumab allowed in any part 
of the study. Participants should begin study treatment within 3 calendar days of treatment 
assignment. There is ± 3 day window for dose administration subsequent to the first dose. 
Premedications are not recommended for the first dose of nivolumab and ipilimumab.
Participants should be carefully monitored for infusion reactions during nivolumab and 
ipilimumab administration. If an acute infusion reaction is noted, participants should be managed 
according to Section 7.4.2.
When study drugs (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 study drug and will start after the infusion line has been flushed, filters 
changed, and participant has been observed to ensure no infusion reaction has occurred. The time 
in between infusions is expected to be approximately 30 minutes but may be more or less 
depending on the situation.
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.
Please refer to the current versions of the nivolumab or ipilimumab Investigator Brochures and/or 
pharmacy manual for complete storage, handling, dispensing, and infusion information for 
nivolumab and ipilimumab.
7.1.2
Trametinib Dosing 
Trametinib should be taken as follows:
•
Trametinib should be administered under fasted conditions, either 1 hr before or 2 hrs after a 
meal with approximately 120-240 mL of water.
•
Participants should be instructed to take trametinib in the morning, at approximately the same 
time every day. 
•
On visits when participants are to receive nivolumab and/or ipilimumab, participants should 
bring their trametinib to scheduled visit and withhold until after medical assessments.  After 
participants are confirmed to be eligible to continue with study treatment, participants should 
take trametinib first, then receive infusion.
•
If a participant vomits after taking trametinib, the participant should be instructed not to retake 
the dose and wait for the next scheduled dose. The occurrence and frequency of any vomiting 
during a treatment cycle must be noted in the AE section of the eCRF.
•
If a participant misses a dose, he/she should be instructed not to double the next regularly 
scheduled dose. However, participant may take the missed dose immediately if the next 
scheduled dose is at least 12 hours later for trametinib. Participant may then take the next dose 
at the scheduled time.
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nivolumab
7.1.3
Part 1 (Completed) (Doublet Regimen, Cohort 1 Group: Enrollment
Closed)
Participants should receive nivolumab at a dose of 480 mg as a 30-minute infusion on Day 1 of 
each treatment cycle, in combination with trametinib 1.5 mg QD (starting dose for the initial/first 
cohort) until progression, unacceptable toxicity, withdrawal of consent, completion of 2 years of 
treatment, or the study ends, whichever occurs first. Participants should begin study treatment 
within 3 calendar days of treatment assignment. 
Table 7.1.3-1:
Dose Schedule of Nivolumab and Trametinib in Part 1 (Cohort 1 
Group)
Trametinib Dosing 
Regimen
Study Treatment
Every Cycle until End of Treatment
(28 day/4 week per cycle)
Trametinib Continuous 
Nivolumab 480mg IV
+ Trametinib 1.5 mg POa
Nivolumab on Day 1 only; 
Trametinib QD Day 1 through Day 28
Trametinib Intermittent 
(2 weeks on/2 weeks 
off)b
Nivolumab 480mg IV
+ Trametinib 1.5mg POa
Nivolumab on Day 1 only; 
Trametinib QD Day 1 through D14 only
a Trametinib 1.5 mg is the starting dose for the initial/first cohort. Refer to Section 5.1.1 for trametinib daily dose 
to be administered in Cohort 1 Group.
b Trametinib intermittent regimen will be initiated for the next new cohort in case of dose de-escalation.
Treatment cycles should be given every 4 weeks. Following first nivolumab dose, subsequent 
nivolumab dosing will be based on the actual date of administration of the previous dosing. 
Participants may be dosed within a ± 3-day window of scheduled dose due to scheduling conflict. 
A treatment cycle is complete if nivolumab infusion has been administered and the next cycle is 
triggered by the next infusion. Maintain dosing regimen for trametinib and capture the dosing in 
the appropriate treatment cycle anchored by nivolumab infusion. In case of trametinib dosing 
delay, synchronize re-initiation of trametinib dosing to fit in the treatment cycle whenever possible 
if deemed medically appropriate by the investigator.
Participants are not permitted to continue with only one of the study treatment components if either 
nivolumab or trametinib needs to be discontinued.  
See Section 8.1 Discontinuation Criteria for further detail.
Initiation of the Next Treatment Cycle: 
•
Infusion with nivolumab initiates Day 1 of the next cycle. If nivolumab is delayed, the cycle 
is delayed.  Maintain trametinib dosing regimen during the current cycle. Cycle is not skipped, 
only delayed.  
•
If a decision is made to permanently discontinue nivolumab, trametinib must be permanently 
discontinued as well.
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BMS-936558
nivolumab
7.1.4
Part 2 (Triplet Regimen, Cohort 4 and Standard of Care (SOC) Arm, 
Cohort 5) Enrollment Closed
In Part 2 
 
, 2 cohorts of participants will be enrolled.
7.1.4.1
Cohort 4 Triplet Regimen
In Cohort 4, participants should receive nivolumab at a dose of 6 mg/kg as an approximately 30-
minute IV infusion on Day 1 and Day 29 of each treatment cycle (every 4 weeks). If needed, flush 
the IV line with an appropriate amount of diluent (eg, 0.9% sodium chloride or 5% dextrose in 
water) to ensure that the complete dose is administered over approximately 30 minutes.
Ipilimumab should be administered at a dose of 1 mg/kg as about a 30-minute IV infusion on Day 
1 of each treatment cycle (every 8 weeks), plus trametinib 1.5 mg continuous QD until progression, 
unacceptable toxicity, withdrawal of consent, completion of 2 years of treatment, or the study ends, 
whichever occurs first. Participants should begin study treatment within 3 calendar days of 
treatment randomization. 
Table 7.1.4.1-1:
Dose Schedule of Nivolumab + Ipilimumab and Trametinib in 
Part 2 (Cohort 4)
Study Treatment
Every Cycle until End of Treatment
(56 day/8 week per cycle)
Nivolumab 6 mg/kg IV + 
Ipilimumab 1 mg/kg IV + 
Trametinib1.5 mg PO
Nivolumab on Day 1 and Day 29; Ipilimumab on Day 1 only;
Trametinib QD Day 1 through Day 56
Treatment cycles should be given every 8 weeks. Following first nivolumab dose, subsequent 
nivolumab dosing will be based on the actual date of administration of the previous dosing. 
Participants may be dosed within a ± 3 day window of scheduled dose due to scheduling conflict. 
Following, the first ipilimumab dose, subsequent ipilimumab dosing will be synchronized with the 
first dosing of nivolumab in the next cycle. For weight-based dosing, dosing calculations should 
be based on the body weight assessed at baseline. It is not necessary to re-calculate subsequent 
doses if the participant’s weight is within 10% of the weight used to calculate the previous dose. 
All doses should be rounded up or to the nearest milligram per institutional standard. Participants 
should begin study treatment within 3 calendar days of treatment assignment.
A treatment cycle is complete if 2 nivolumab infusions have been administered, OR, 1 nivolumab 
infusion has been administered and at least 8 weeks have passed from the first infusion to the next 
infusion, whichever occurs earlier. Maintain dosing regimen for trametinib and capture the dosing 
in the appropriate treatment cycle anchored by nivolumab infusion. If any of the investigational 
drugs of the triplet regimen (nivolumab, ipilimumab, or trametinib) need to be permanently 
discontinued, then the patient should discontinue all study treatment.
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nivolumab
Initiation of the Next Treatment Cycle: 
•
The next treatment cycle starts if 2 nivolumab infusions have been administered or the next 
infusion is at least 8 weeks apart from the first infusion, whichever is shorter in duration. Cycle 
is not skipped, only delayed.
•
When study treatments 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 study treatment and will start after the infusion 
line has been flushed, filters changed, and the participant has been observed to ensure no 
infusion reaction has occurred.  
•
When nivolumab and ipilimumab are scheduled to be dosed on the same day, if dosing is 
delayed, both nivolumab and ipilimumab must be delayed together. If dosing is resumed after 
a dose delay, both nivolumab and ipilimumab must be resumed on the same day if the next 
scheduled day includes both nivolumab and ipilimumab administration.
7.1.4.2
Cohort 5 Regorafenib 
In Cohort 5, participants will receive regorafenib at the approved dose per local product label 
until progression, unacceptable toxicity, withdrawal of consent, whichever occurs first. 
Participants should begin study treatment within 3 calendar days of treatment randomization. 
Table 7.1.4.2-1:
Recommended Dose of Regorafenib in Part 2 (Cohort 5)
Study Treatment
Every Cycle till the End of Treatment
(28 day/4 week per cycle)
Regorafenib 160 mg a
Orally, once daily for the first 21 days of each 28-day cycle
a The recommended dose of regorafenib is 160 mg. Refer to local product label and institution guidelines.
7.1.4.3
Regorafenib Dosing 
Please refer to local product label and institutional guidelines for further details.
The recommended dose of regorafenib is 160 mg (four 40 mg tablets) taken orally once daily for 
the first 21 days of each 28-day cycle. Continue treatment until disease progression, unacceptable 
toxicity, withdrawal of consent, or the study ends, whichever occurs first.
The participant should take regorafenib at the same time each day. Swallow tablet as a whole with 
water after a low-fat meal that contains less than 600 calories and less than 30% fat. The participant 
should not take 2 doses of regorafenib on the same day to make up for a missed dose from the 
previous day. Any missed doses reported by the participant should be recorded in the participant’s 
source documents and in the participant’s diary. 
Initiation of the Next Treatment Cycle:
•
The next cycle will be initiated every 4 weeks with regorafenib dosing as specified in Table 
7.1.4.2-1.
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•
If regorafenib dosing is delayed, the next cycle will start if at least 4 weeks have passed from 
the first dose in the current cycle to dosing re-initiation.
•
The next treatment cycle may be initiated within a ± 3-day window of scheduled dose due to 
scheduling conflict.
7.1.5
Part 1A Completed (Triplet Regimen, Cohort 2 Group and Cohort 3 
Group: Closed for Enrollment)
The dose optimization phase of the study (Parts 1 and 1A) are completed. Enrollment is 
closed in Part 1 and Part 1A cohorts.
In Part 1A, participants should receive nivolumab at a dose of 6 mg/kg as an approximately 30-
minute IV infusion on Day 1 and Day 29 of each treatment cycle (every 4 weeks). If needed, flush 
the intravenous line with an appropriate amount of diluent (eg, 0.9% sodium chloride or 5% 
dextrose in water) to ensure that the complete dose is administered over approximately 30 minutes.
Ipilimumab should be administered at a dose of 1 mg/kg as about a 30-minute IV infusion on Day 
1 of each treatment cycle (every 8 weeks), plus trametinib 1.5 mg QD (starting dose for the 
initial/first cohorts, either continuously, or 2 week on/2 week off dosing) until progression, 
unacceptable toxicity, withdrawal of consent, the study ends or up to a maximum of 2 years
whichever occurs first (see Table 7.1.5-1). Dosing calculations should be based on the body weight 
assessed at baseline. It is not necessary to re-calculate subsequent doses if the participant weight 
is within 10% of the weight used to calculate the previous dose. All doses should be rounded up 
or to the nearest milligram per institutional standard. Participants should begin study treatment 
within 3 calendar days of treatment assignment. 
Table 7.1.5-1:
Dose Schedule of Nivolumab, Ipilimumab and Trametinib in Part 
1A (Cohort 2 Group and Cohort 3 Group)
Trametinib Dosing 
Regimen
Study Treatment
Every Cycle till End of Treatment
(56 day/8 week per cycle)
Cohort 2 Group: 
Trametinib 
Continuous 
Nivolumab
6 mg/kg IV + 
Ipilimumab 1 mg/kg IV + 
Trametinib1.5 mg POa
Nivolumab on Day 1 and Day 29; 
Ipilimumab on Day 1 only;
Trametinib QD Day 1 through Day 56
Cohort 3 Group: 
Trametinib
Intermittent 
(2 weeks on/2 
weeks off)
Nivolumab
6 mg/kg IV + 
Ipilimumab 1 mg/kg IV + 
Trametinib1.5 mg POa
Nivolumab on Day 1 and Day 29; 
Ipilimumab on Day 1 only;
Trametinib QD Day 1 through D14; Day 29 through 
Day 42
a Trametinib 1.5 mg is the starting dose for the initial/first cohorts. Refer to Section 5.1.1 for trametinib daily dose to 
be administered in Cohort 2 and 3.
Treatment cycles should be given every 8 weeks. Following first nivolumab dose, subsequent 
nivolumab dosing will be based on the actual date of administration of the previous dosing. 
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nivolumab
Participants may be dosed within a ± 3 day window of scheduled dose due to scheduling conflict. 
Following first ipilimumab dose, subsequent ipilimumab dosing will be synchronized with the first 
dosing of nivolumab in the next cycle. A treatment cycle is complete if two nivolumab infusions 
have been administered, OR, one nivolumab infusion has been administered and at least 8 weeks 
have passed from the first infusion to the next infusion, whichever occurs earlier. Maintain dosing 
regimen for trametinib and capture the dosing in the appropriate treatment cycle anchored by 
nivolumab infusion. In case of trametinib dosing delay, synchronize re-initiation of trametinib 
dosing to fit in the treatment cycle whenever possible if deemed medically appropriate by the 
investigators. If any of the investigational drugs of the triplet regimen (nivolumab, ipilimumab, or 
trametinib) need to be permanently discontinued, then the participant should discontinue all study 
treatment.
Initiation of the Next Treatment Cycle: 
•
The next treatment cycle starts if two nivolumab infusions have been administered or the next 
infusion is at least 8 weeks apart from the first infusion, whichever is shorter in duration. Cycle 
is not skipped, only delayed.
•
When study treatments 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 study treatment and will start after the infusion 
line has been flushed, filters changed, and the participant has been observed to ensure no 
infusion reaction has occurred.  
•
When nivolumab and ipilimumab are scheduled to be dosed on the same day, if dosing is 
delayed, both nivolumab and ipilimumab must be delayed together. If dosing is resumed after 
a dose delay, both nivolumab and ipilimumab must be resumed on the same day if the next 
scheduled day includes both nivolumab and ipilimumab administration.
7.1.6
Part 1B (Triplet Regimen, Cohort 6) Enrollment Closed
In Part 1B of the study, participants will receive nivolumab at a dose of 6 mg/kg as an 
approximately 30-minute IV infusion on Day 1 and Day 29 of each treatment cycle (every 4 
weeks). If needed, flush the intravenous line with an appropriate amount of diluent (eg, 0.9% 
sodium chloride or 5% dextrose in water) to ensure that the complete dose is administered over 
approximately 30 minutes. Ipilimumab should be administered at a dose of 1 mg/kg as about a 30-
minute IV infusion on Day 1 of each treatment cycle (every 8 weeks), plus trametinib 1.5 mg QD, 
until progression, unacceptable toxicity, withdrawal of consent, the study ends, or up to a 
maximum of 2 years, whichever occurs first (see Table 7.1.6-1). For weight-based dosing, dosing 
calculations should be based on the body weight assessed at baseline. It is not necessary to re-
calculate subsequent doses if the participant’s weight is within 10% of the weight used to calculate 
the previous dose. All doses should be rounded up or to the nearest milligram per institutional 
standard. Participants should begin study treatment within 3 calendar days of treatment 
assignment.
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BMS-936558
nivolumab
Table 7.1.6-1:
Dose Schedule of Nivolumab, Ipilimumab, and Trametinib in Part 
1B (Cohort 6)
Nivolumab Dosing 
Regimen
Study Treatment
Every Cycle till End of Treatment
(56 day/8 week per cycle)
Cohort 6: 
Nivolumab weight-
based dosing
Nivolumab
6 mg/kg IV + 
Ipilimumab 1 mg/kg IV + Trametinib1.5 mg
Nivolumab on Day 1 and Day 29; 
Ipilimumab on Day 1 only
Trametinib 1.5 mg QD (continuous)
Treatment cycles should be given every 8 weeks. Following first nivolumab dose, subsequent 
nivolumab dosing will be based on the actual date of administration of the previous dosing. 
Participants may be dosed within a ± 3-day window of scheduled dose due to scheduling conflict. 
Following the first ipilimumab dose, subsequent ipilimumab dosing will be synchronized with the 
first dosing of Nivolumab in the next cycle. A treatment cycle is complete if two nivolumab 
infusions have been administered, OR, one nivolumab infusion has been administered and at least 
8 weeks have passed from the first infusion to the next infusion, whichever occurs earlier.  
Maintain dosing regimen for trametinib and capture the dosing in the appropriate treatment cycle 
anchored by nivolumab infusion.  In case of trametinib dosing delay, synchronize re-initiation of 
trametinib dosing to fit in the treatment cycle whenever possible if deemed medically appropriate 
by the investigators.
Initiation of the Next Treatment Cycle:
•
The next treatment cycle starts if two nivolumab infusions have been administered or the next 
infusion is at least 8 weeks apart from the first infusion, whichever is shorter in duration. Cycle 
is not skipped, only delayed.
•
When study treatments 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 study treatment and will start after the infusion 
line has been flushed, filters changed, and the participant has been observed to ensure no 
infusion reaction has occurred.  
•
When nivolumab and ipilimumab are scheduled to be dosed on the same day, if dosing is 
delayed, both nivolumab and ipilimumab must be delayed together. If dosing is resumed after 
a dose delay, both nivolumab and ipilimumab must be resumed on the same day if the next 
scheduled day includes both nivolumab and ipilimumab administration.
7.2
Method of Treatment Assignment
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
All participants must be assigned a participant number upon providing signed written informed 
consent. For Part 1 and 1A, contact Sponsor for treatment allocation authorization before 
registering participants in IRT (Parts 1 and 1A are now closed for enrollment). The Sponsor will 
implement an IRT to assign participant numbers, study treatment group and dose level, as well as 
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manage treatment supply. During the screening visit, the investigative site will register the 
participant by an IRT designated by BMS for assignment of a 5-digit participant number that will 
be unique across all sites.
The participant identification number (PID) will ultimately be composed of the site number and 
participant number. For example, the first participant screened (eg, enrolled) at site number 1, will 
have a PID 
. For Parts 1, and 1A, the digit 
 will be dependent on which cohort 
group the participant has been screened to (see Table 7.2-1). Specific instructions for using the 
IRT will be provided to the investigational sites in a separate instruction manual.
Unique cohort numbers are assigned to individual treatment arms and trametinib dose levels. See 
Table 7.2-1 below.
Table 7.2-1:
Unique Cohort Numbers in Part 1, 1A, 1B and 2
Part 1 and Part 1A (Completed)
Trametinib 
Dose Level 
(DL)
Trametinib Dose in 
Doublet Regimena --
Cohort Number
Trametinib Dose in Triplet 
Regimenb- Continuous 
Dosing --- Cohort Number
Trametinib Dose in Triplet 
Regimenb 
Intermittent Dosing ---
Cohort Number
DL+2
2 mg continuous in Part 1--
- Cohort 1D
NA
NA
DL+1
2 mg 2 wk on/2 wk off in 
Part 1----Cohort 1B
2 mg continuous in Part 1A -
--Cohort 2B
2mg 2wk/2 wk off in Part 1A 
--- Cohort 3B
starting
1.5 mg continuous in Part 1 
--Cohort 1
1.5 mg continuous in Part 1A 
---Cohort 2
1.5 mg 2 wk on/2 wk off in 
Part 1A --- Cohort 3
DL-1
1.5 mg 2 wk on/2 wk off in 
Part 1--- Cohort 1A
1 mg continuous in Part 1A -
--Cohort 2A
1 mg 2 wk on/2 wk off in 
Part 1A --- Cohort 3A
DL-2
1 mg 2 wk on/2 wk off in 
Part 1 ---Cohort 1C
NA
NA
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Table 7.2-1:
Unique Cohort Numbers in Part 1, 1A, 1B and 2
Part 1 and Part 1A (Completed)
Trametinib 
Dose Level 
(DL)
Trametinib Dose in 
Doublet Regimena --
Cohort Number
Trametinib Dose in Triplet 
Regimenb- Continuous 
Dosing --- Cohort Number
Trametinib Dose in Triplet 
Regimenb 
Intermittent Dosing ---
Cohort Number
Parts 2 and 1B 
Trametinib 
Dose Level 
(DL)
Regorafenib
Trametinib Dose in Triplet Regimenb- Continuous Dosing 
--- Cohort Numbers
N/A
Part 2 1.5 mg continuous --- Cohort 4
Part 1B 1.5 mg continuous --- Cohort 6
SOC without 
trametinib
Part 2 with regorafenib ---
Cohort 5
NA
DL= dose level; SOC=standard of care; wk=week.
a Doublet regimen: nivolumab + trametinib. Refer to Section 7.1.3 and 7.1.4 for nivolumab dosing. 
b Triplet regimen: nivolumab + ipilimumab + trametinib. Refer to Sections 7.1.5 and 7.1.6 for nivolumab and 
ipilimumab dosing.
Part 2 is a randomized open-label study with 2 treatment arms, nivolumab + ipilimumab + 
trametinib versus regorafenib. Enrollment is closed for Part 2.
•
Once enrolled in IRT, participants who have met all eligibility criteria for Part 2 will be 
randomized in a 2:1 ratio to nivolumab + ipilimumab + trametinib (Cohort 4) or regorafenib
(Cohort 5). The following stratification factors will be applied:
−
Primary tumor sidedness (left vs right) (Appendix 13). Participants with unknown primary 
tumor location or primary tumor located in both sides will be allocated to the right sided 
stratum. Such participants are not expected to exceed 2% to 5%.
−
Extended RAS mutation status (wild-type vs mutant). Please refer to Section 5 for details 
on proportion of participants with RAS mutation status monitoring. Patients with unknown 
RAS/BRAF status will not be eligible. Patients with BRAF V600 mutation are not eligible
for the study.
7.3
Blinding
This is an open label Phase 1/2. However, Part 2 of the study is randomized/ open-label, and the 
specific treatment to be taken by a participant will be assigned using an IRT. Access to treatment 
codes will be restricted from select BMS personnel prior to database lock.
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Part 1B is non-randomized, open-label. The site will contact the IRT prior to the start of study 
treatment administration for each participant in Part 1B. The site will record the treatment 
assignment on the applicable case report form, if required. Part 1B is now closed to enrollment. 
Part 1 and 1A are closed to enrollment.
For Part 2, designated staff of BMS Research & Development may obtain the randomization codes
prior to database lock to facilitate the bioanalytical analysis 
 
. A bioanalytical scientist in the Bioanalytical Sciences department of BMS
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. Part 2 is now closed to enrollment. 
7.4
Dosage Modification
For participants in Part 1 and Part 1A who complete DLT observation period (first cycle), and 
participants in Part 1B and Part 2, study treatment may be modified to manage toxicity. Adverse 
events should be graded and managed according to NCI CTCAE (version 4.0) guidelines. There 
are no dose modifications for nivolumab or ipilimumab, except treatment delay. Trametinib dosing 
will be adjusted as described in Section 7.4.4. If adverse events 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, nivolumab/ipilimumab/trametinib combination 
or nivolumab/trametinib combination.
•
For adverse events that are deemed to be related to trametinib ONLY by the treating physician, 
dose modification criteria for trametinib must be followed as described in Section 7.4.4 and 
Appendix 6
•
For adverse events that are deemed to be related to nivolumab or nivolumab in combination 
with ipilimumab ONLY by the treating physician, dose modification criteria for 
nivolumab/ipilimumab must be followed as described in Section 7.4.1 and Appendix 5
•
For adverse events that are possibly related to the combination regimen, either nivolumab + 
trametinib or nivolumab + ipilimumab + trametinib, the most conservative toxicity 
management guidelines must be followed. Refer to Section 7.4.3 and Appendix 6 for 
trametinib, and Section 7.4.1 and Appendix 5 for nivolumab + ipilimumab.
•
For adverse events that are deemed to be related to regorafenib by the investigator, refer to 
local product label and institution guidelines for further detail in addition to the 
recommendation provided in Section 7.4.6.
7.4.1
Nivolumab/Ipilimumab Dose Delay 
Nivolumab or ipilimumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related adverse event, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT, and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related adverse event
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•
Grade 3 drug-related laboratory abnormality, with the following exceptions: 
−
Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay
−
Grade ≥3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1.1)
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Participants who require delay of nivolumab/ipilimumab should be re-evaluated weekly or more 
frequently if clinically indicated and resume nivolumab/ipilimumab dosing when re-treatment 
criteria are met.
Further detail on immune related adverse event management algorithm is described in Appendix 5 
for the following categories:
•
GI Adverse Event
•
Renal Adverse Event
•
Pulmonary Adverse Event
•
Hepatic Adverse Event
•
Endocrinopathy Management
•
Skin Adverse Event
•
Neurological Adverse Event
•
Myocarditis Adverse Event
7.4.2
Criteria to Resume Treatment with Nivolumab or Ipilimumab
Participants may resume treatment with study drug when the drug-related AE(s) resolve to Grade 
≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue;
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity;
•
For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete;
•
Drug-related pulmonary toxicity, diarrhea or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by BMS Medical Monitor/designee;
•
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical 
Monitor/designee. Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.
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7.4.3
Treatment of Nivolumab- or Ipilimumab-related Infusion Reactions
Since nivolumab and ipilimumab contains only human immunoglobulin protein sequences, it is 
unlikely to be immunogenic and induce infusion or hypersensitivity reactions. However, if such a 
reaction were to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, 
arthralgias, 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/designee 
and reported as an SAE if it meets the criteria. Infusion reactions should be graded according to 
NCI CTCAE (version 4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate:
For Grade 1 symptoms (mild reaction; infusion interruption not indicated; intervention not 
indicated):
•
Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 
(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations.
For Grade 2 symptoms: (moderate reaction required therapy or infusion interruption but responds 
promptly to symptomatic treatment (eg, 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 
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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 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms.
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids).
7.4.4
Trametinib Dose Delay/Modifications
7.4.4.1
General Guidelines for Trametinib Related Toxicities
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to trametinib are provided in Table 7.4.4.1-1. The 
severity of adverse events will be graded utilizing the CTCAE v 4.0. Guidelines for specific 
trametinib related toxicities as listed in Section 7.4.4.2 are provided in Appendix 6.
Table 7.4.4.1-1:
Dose Delay and Modification for Events Considered Related to 
Trametinib (excluding pyrexia)
CTCAE Grade
Action and Dose Modification 
Grade 1
•
Continue trametinib at current dose level 
•
Monitor closely 
•
Provide supportive care according to institutional standards 
Grade 2
•
Interrupt trametinib if clinically indicated 
•
Monitor closely 
•
Provide supportive care according to institutional standards 
•
When toxicity resolves to Grade 1 or baseline, restart trametinib at current dose level 
Grade 3
•
Interrupt trametinib if clinically indicated 
•
Monitor closely 
•
Provide supportive care according to institutional standards 
•
When toxicity resolves to Grade 1 or baseline, restart trametinib reduced by one dose 
level 
•
If the Grade 3 toxicity recurs, interrupt trametinib 
•
When toxicity resolves to Grade 1 or baseline, restart trametinib reduced by another 
dose level 
Grade 4
•
Interrupt trametinib 
•
Monitor closely 
•
Provide supportive care according to institutional standards 
•
If event resolves to Grade 1 or baseline discuss potential continuation of trametinib 
with the Medical Monitor/designee; if continuation of treatment agreed then restart 
trametinib at dose reduced by one dose level 
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Table 7.4.4.1-1:
Dose Delay and Modification for Events Considered Related to 
Trametinib (excluding pyrexia)
CTCAE Grade
Action and Dose Modification 
•
If event does not resolve permanently discontinue trametinib 
Note: Approval from the Medical Monitor/designee is required to restart study treatment after ≥21 days of 
interruption. 
Note: In participants who experience retinal vein occlusion, trametinib treatment should be permanently 
discontinued.
7.4.4.2
Guidelines for Specific Trametinib-related Toxicities
Trametinib dose modification guidelines for specific clinically significant toxicities and common 
toxicities that may be related to trametinib are outlined in Appendix 6: 
•
Rash
•
Diarrhea
•
Ejection fraction changes
•
Hypertension 
•
Pneumonitis
•
Visual changes
•
Liver chemistry elevation.
•
Hand and foot syndrome
•
Pyrexia
Refer to the relevant sections of Appendix 6 for dose modification guidelines for these specific 
adverse events as listed above.
7.4.4.3
Dose Modification for Trametinib
Table 7.4.4.3-1 describes the dose /schedule to be used for any necessary dose modifications for 
trametinib. 
•
For Grade 2 or 3 laboratory abnormalities that are considered unrelated to the study treatment 
or those that are reversible in <48 hrs (except for liver enzymes) such as electrolyte 
abnormalities may continue without dose reductions. Modification of trametinib dosing 
frequency is not permitted, except dose delay to manage toxicity per dose modification 
guideline (Appendix 6).
•
A maximum of 2 trametinib dose level reductions are allowed for Part 1 and Part 1A. For Parts 
1B and 2, a maximum of 1 trametinib dose level reduction is allowed If a third dose 
level/frequency reduction is required for Part 1 or Part 1A, second for Parts 1B and 2, treatment 
will be permanently discontinued. 
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•
If a dose reduction of trametinib is required (Parts 1B and 2), but the toxicity resolves and no 
additional toxicities are seen after 4 weeks of treatment, the dose of trametinib may be re-
escalated but should not exceed 1.5 mg once a day or the dose determined from dose 
optimization evaluation, whichever is lower. Dose re-escalation may NOT be permitted for 
specific toxicities as described in Appendix 6.
•
The minimum daily dose of trametinib that is permissible on study is 1.0 mg. If participants 
require a dose reduction below 1.0 mg, they should be permanently discontinued from 
trametinib.
Table 7.4.4.3-1:
Potential Trametinib Dose Levels in Part 1B and Part 2
Daily Dose Level
Dose/Day
Maximum 
1.5 mg once a day 
Minimum
1.0 mg once a day 
7.4.5
Criteria to Resume Treatment with Trametinib
Treatment with trametinib may be delayed for up to 21 days to allow resolution of toxicity, or 
based on investigator discretion (eg, scheduling issues). If the investigator and the Medical 
Monitor/designee conclude that continued treatment will benefit a participant who has experienced 
a treatment delay > 21 days, then the participant may continue treatment with the approval of the 
Medical Monitor/designee. If a dose delay continues for 10 weeks or more, then trametinib should 
be permanently discontinued for toxicities considered related to study drug.
7.4.6
Dose Modification for Regorafenib
If dose modifications are required, reduce the dose in 40 mg (1 tablet) increments; the lowest 
recommended daily dose of regorafenib is 80 mg daily. The following dose modification is 
provided as a recommendation. Local product labels and/or institutional guidelines should be 
followed if they are more conservative than the recommendations below.
Interrupt regorafenib for the following:
•
Grade 2 hand-foot skin reaction (HFSR) [palmar-plantar erythrodysesthesia (PPES)] that is 
recurrent or does not improve within 7 days despite dose reduction; interrupt therapy for a 
minimum of 7 days for Grade 3 HFSR (refer to Table 7.4.6-2 for additional requirements)
•
Symptomatic Grade 2 hypertension
•
Any Grade 3 or 4 adverse reaction
•
Worsening infection of any grade
•
Reduce the dose of regorafenib to 120 mg:
−
For the first occurrence of Grade 2 HFSR of any duration (refer to Table 7.4.6-2 for 
additional requirements)
−
After recovery of any Grade 3 or 4 adverse reactions except infection
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−
For Grade 3 AST/ALT elevation, only resume if the potential benefit outweighs the risk of 
hepatotoxicity (refer to Table 7.4.6-1 for additional requirements)
Reduce the dose of regorafenib to 80 mg:
•
For re-occurrence of Grade 2 HFSR at the 120 mg dose (refer to Table 7.4.6-2 for additional 
requirements). After recovery of any Grade 3 or 4 adverse reaction at the 120 mg dose (except 
hepatotoxicity or infection)
Table 7.4.6-1:
Recommended Measures and Dose Modifications in Case of Drug-
related Liver Function Test Abnormalities
Observed Elevations of 
ALT and/or AST
Occurrence
Recommended Measures and Dose Modification
≤ 5 times ULN 
(maximum Grade 2)
Any occurrence
Continue regorafenib treatment. 
Monitor liver function weekly until transaminases return to 
< 3 times ULN (Grade 1) or baseline.
> 5 times ULN ≤ 20 times 
ULN (Grade 3)
1st occurrence
Interrupt regorafenib treatment. 
Monitor transaminases weekly until they return to < 3 times 
ULN or baseline.
Restart: If the potential benefit outweighs the risk of 
hepatotoxicity, re-start regorafenib treatment, reduce dose 
by 40 mg (1 tablet), and monitor liver function weekly for 
at least 4 weeks. 
Re-occurrence
Discontinue treatment with regorafenib permanently.
> 20 times ULN (Grade 4)
Any occurrence
Discontinue treatment with regorafenib permanently.
> 3 times ULN (Grade 2 or 
higher) with concurrent 
bilirubin > 2 times ULN
Any occurrence
Discontinue treatment with regorafenib permanently. 
Monitor liver function weekly until resolution or return to 
baseline. 
Exception: Patients with Gilbert’s syndrome who develop 
elevated transaminases should be managed as per the above 
outlined recommendations for the respective observed 
elevation of ALT and/or AST.
Source: Modified from Table 2 of regorafenib SmPC
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Table 7.4.6-2:
Recommended Dose Modifications and Measures for HFSR
Skin Toxicity Grade
Occurrence
Recommended Dose Modification and Measures
Grade 1
Any
Maintain dose level and immediately institute supportive 
measures for symptomatic relief. 
Grade 2
1st occurrence
Decrease dose by 40 mg (1 tablet) and immediately 
institute supportive measures.
If no improvement occurs despite dose reduction, interrupt 
therapy for a minimum of 7 days, until toxicity resolves to 
Grade 0-1. 
A dose re-escalation is permitted at the discretion of the 
physician.
No improvement within 
7 days or 2nd occurrence
Interrupt therapy until toxicity resolves to Grade 0-1.
When re-starting treatment, decrease dose by 40 mg 
(1 tablet). 
A dose re-escalation is permitted at the discretion of the 
physician.
3rd occurrence
Interrupt therapy until toxicity resolves to Grade 0-1.
When re-starting treatment, decrease dose by 40 mg 
(1 tablet). 
A dose re-escalation is permitted at the discretion of the 
physician.
4th occurrence
Discontinue treatment with regorafenib permanently.
Grade 3
1st occurrence
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves to 
Grade 0-1. 
When re-starting treatment, decrease dose by 40 mg 
(1 tablet). 
A dose re-escalation is permitted at the discretion of the 
physician. 
2nd occurrence
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves to 
Grade 0-1. 
When re-starting treatment, decrease dose by 40 mg 
(1 tablet).
3rd occurrence
Discontinue treatment with regorafenib permanently.
Source: Modified from Table 1 of regorafenib SmPC
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.
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Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
For study drugs not provided by BMS and obtained commercially by the site, storage should be in 
accordance with the product label.
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, and review of 
dosing diary cards. Drug accountability should be reviewed by the site study staff at each visit to 
confirm treatment compliance. Sites should discuss discrepancies with the participant at each on-
treatment study visit. 
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 7.7.3)
•
Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy, or standard or investigational agents for treatment of CRC)
•
Any botanical preparation (eg herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care. Use of marijuana and its derivatives 
for treatment of symptoms related to cancer or cancer treatment are permitted if obtained by 
medical prescription or if its use (even without a medical prescription) has been legalized 
locally. 
•
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) within 100 days post last dose of nivolumab without or with 
ipilimumab.
•
Non-live Coronavirus Disease 2019 (COVID-19) vaccination is considered a simple 
concomitant medication within the study. However, the safety and efficacy of non-live 
vaccines (including non-live COVID-19 vaccines) in participants receiving nivolumab, 
ipilimumab, or trametinib are unknown.
The potential for overlapping toxicities with radiotherapy and nivolumab with or without 
ipilimumab in combination with trametinib is not known currently. Therefore, radiotherapy is not 
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permitted while receiving study treatment. If radiotherapy is required, participants should 
discontinue study treatment. Palliative radiotherapy for participants in the SOC arm receiving 
regorafenib may be administered per local product label and institutional guidelines. 
•
Refer to local product labels/institution guidelines for additional prohibited and/or restricted 
treatments for participants receiving regorafenib.
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 treatment 
assignment/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.
Any prescription or herbal product which is not prescribed by the investigator or licensed physician 
for treatment of a specific clinical condition is prohibited.
•
Refer to local product labels/institution guidelines for additional restrictions and precautions 
for participants receiving regorafenib.
7.7.2.1
Imaging Restriction and Precautions
It is the local imaging facility’s responsibility to determine, based on participant attributes 
(eg. allergy history, diabetic history and renal status), the appropriate imaging modality and 
contrast regimen for each participant. Imaging contraindications and contrast risks should be 
considered in this assessment. Participants with renal insufficiency should be assessed as to 
whether or not they should receive contrast and if so, what type and dose of contrast is appropriate. 
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest and 
a contrast enhanced MRI of the abdomen and pelvis may be obtained.
Specific to MRI, participants with severe renal insufficiency (ie, estimated glomerular filtration 
rate (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. In addition, participants are excluded 
from MRI if they have tattoos, metallic implants, pacemakers, etc. The ultimate decision to 
perform MRI in an individual participant in this study rests with the site radiologist, the 
investigator and the standard set by the local Ethics Committee.
7.7.3
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. Regular concomitant use 
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of bisphosphonates and RANK-L inhibitors for prevention or reduction of skeletal-related events 
in participants with bone metastases is allowed if initiated prior to first dose of study treatment.  
Hormone replacement therapy: Participants may continue to receive hormonal replacement 
therapy if initiated prior to treatment assignment/randomization. 
Supportive Care: For participants receiving regorafenib, follow local product label, institutional 
guidelines, or relevant regional guidelines (eg, ASCO or ESMO) to manage expected toxicities. 
Supportive care includes, but is not limited to, hematologic support and management of diarrhea, 
nausea/vomiting, skin toxicities, as well as prophylactic or therapeutic administration of 
appropriate therapies.
7.8
Treatment After the End of the Study
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration 
specified in protocol Section 5.4.1. 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 study drugs 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. Adverse events should be graded and managed according to NCI 
CTCAE (version 4.0) guidelines.
•
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, and only in countries where local regulations permit, a participant who 
has been imprisoned may be permitted to continue as a participant. Strict conditions apply and 
BMS approval is required.)
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•
Documented radiographic disease progression per RECIST v1.1. 
−
Note: For 2L and 3L+ mCRC participants in Cohorts 4 and 6, treatment beyond progression 
is permitted. See Section 8.1.5.
•
Criteria listed in Section 8.1.1 thru 8.1.4.
•
Requiring treatment as listed in Section 7.7.
Any criteria leading to the discontinuation of nivolumab, ipilimumab, or trametinib as part of the 
triplet investigative regimen in Parts 1B and 2 will require discontinuation of the entire regimen.
Discontinuation of the study treatment for abnormal liver tests should be considered by the 
investigator when a participant meets one of the conditions outlined in the protocol (Section 8.1, 
Appendix 5, and Appendix 6) or if the investigator believes that it is in best interest of the 
participant.
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.
In the case of pregnancy, the investigator must immediately, within 24 hours of awareness of the 
pregnancy, notify the BMS Medical Monitor/designee of this event. In most cases, the study 
treatment will be permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for participant safety). Refer to Section 9.2.5 Pregnancy.
All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness).
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page.
The assessment for discontinuation of nivolumab should be made separately from the assessment 
made for discontinuation of ipilimumab. Although there is overlap among the discontinuation 
criteria, if discontinuation criteria are met for ipilimumab but not for nivolumab, treatment with 
nivolumab may continue if ipilimumab is discontinued.
If a participant in any of the nivolumab/ipilimumab combination arms meets criteria for 
discontinuation and 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.
Participants are permitted to continue with nivolumab in combination with trametinib if deemed 
medically appropriate by the treating physician to manage toxicity, and in consultation with 
Medical Monitor/designee. Continuation with ipilimumab in combination with trametinib is not 
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permitted. For participants in Part 1A or Part 1, changes in study treatment are not permitted during 
the DLT observation period. See Section 7.1.2 trametinib dosing for further detail.
8.1.1
Nivolumab Dose Discontinuation (Part 1 Only)
For participants who receive nivolumab without ipilimumab, nivolumab treatment should be 
permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related AE lasting > 7 days, or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
neurologic toxicity, hypersensitivity reactions, infusion reactions, and endocrinopathies:
−
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
myocarditis, hypersensitivity reaction, or infusion reaction of any duration requires 
discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
♦Concurrent AST or ALT > 3 ×ULN and total bilirubin > 2 ×ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment (s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
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respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor/designee.
•
Any event that leads to delay in dosing lasting > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events
are allowed. 
−
Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor/designee. 
−
Prior to re-initiating treatment in a participant with a dosing delay lasting >10 weeks, the 
BMS Medical Monitor (or/designee) must be consulted. Tumor assessments should 
continue as per protocol even if dosing is delayed. Periodic study visits to assess safety and 
laboratory studies should also continue every 4 weeks or more frequently if clinically 
indicated during such dosing delays.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing.
8.1.2
Nivolumab and Ipilimumab Dose Discontinuation
For participants who receive nivolumab in combination with ipilimumab and trametinib, study 
treatment should be permanently discontinued for the following:
•
Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment
•
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, or recurs, with the 
following exceptions for laboratory abnormalities, diarrhea, colitis, neurologic toxicity, drug-
related uveitis, pneumonitis, bronchospasm, hypersensitivity reactions, infusion reactions, and 
endocrinopathies:
−
Grade 3 drug-related diarrhea, colitis, neurologic toxicity, uveitis, pneumonitis, 
bronchospasm, myocarditis, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation
−
Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement. 
−
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except:
♦Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
♦Any drug-related liver function test (LFT) abnormality that meets the following criteria 
require discontinuation:
o
Grade ≥3 drug-related AST, ALT or Total Bilirubin requires discontinuation*
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o
Concurrent AST or ALT > 3× ULN and total bilirubin > 2× ULN
* In most cases of Grade 3 AST or ALT elevation, study treatment(s) will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment(s), a discussion between the investigator and the BMS Medical 
Monitor/designee must occur.
•
Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation:
−
Grade 4 neutropenia ≤7 days
−
Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase
−
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset
−
Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor/designee.
•
Any event that leads to delay in dosing lasting > 10 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events
are allowed. 
−
Dosing delays lasting > 10 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor/designee. Prior to 
re-initiating treatment in a participant with a dosing delay lasting > 10 weeks, the BMS 
Medical Monitor/or designee must be consulted. Tumor assessments should continue as 
per protocol even if dosing is delayed. Periodic study visits to assess safety and laboratory 
studies should also continue every 4 weeks or more frequently if clinically indicated during 
such dosing delays.
•
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued nivolumab 
+ ipilimumab dosing.
Any criteria leading to the discontinuation of nivolumab, ipilimumab, or trametinib as part of the 
triplet investigative regimen in Parts 1B and 2 will require discontinuation of the entire regimen.
8.1.3
Trametinib Dose Discontinuation 
A maximum of 2 trametinib dose level reductions are allowed for Part 1 and Part 1A. Only 1 dose 
level reduction is permitted for Parts 1B and 2. If a third dose level reduction is required for Part 
1 or 1A, or dose reduction below 1.0 mg per day is required, study treatment should be permanently 
discontinued. In addition, discontinue trametinib permanently for the following:
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•
Any event that leads to delay in dosing for > 10 weeks from the previous dose requires 
discontinuation with the following exception:
−
Dosing delays > 10 weeks that occur for non-drug-related reasons may be allowed if 
approved by the BMS Medical Monitor. Prior to re-initiating treatment in a subject with a 
dosing delay lasting > 10 weeks, the BMS Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued treatment
Any criteria leading to the discontinuation of nivolumab, ipilimumab, or trametinib as part of the 
triplet investigative regimen in Parts 1B and 2 will require discontinuation of the entire regimen.
Refer to Appendix 6 for additional dose discontinuation criteria.
8.1.4
Regorafenib Dose Discontinuation
Discontinue regorafenib permanently for any of the following (local product label and 
institutional guidelines should be followed if they are more conservative):
•
Failure to tolerate 80 mg dose
•
Any occurrence of AST or ALT > 20× ULN
•
Any occurrence of AST or ALT > 3× ULN with concurrent bilirubin > 2× ULN, except in 
participants with Gilbert’s syndrome
•
Re-occurrence of AST or ALT > 5× ULN despite dose reduction to 120 mg
•
Gastrointestinal perforation or fistula
•
Severe or life-threatening hemorrhage
•
Reversible posterior leukoencephalopathy syndrome
•
Wound dehiscence
•
For any Grade 4 adverse reaction; only resume if the potential benefit outweighs the risks
•
Any event that leads to delay in dosing for > 10 weeks from the previous dose requires 
discontinuation with the following exception:
−
Dosing delays > 10 weeks that occur for non-drug-related reasons may be allowed if
approved by the BMS Medical Monitor. Prior to re-initiating treatment in a subject with a
dosing delay lasting > 10 weeks, the BMS Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed.
•
Any AE, laboratory abnormality, or intercurrent illness which, in the judgment of the 
investigator, presents a substantial clinical risk to the subject with continued treatment
8.1.5
Treatment Beyond Progression 
Participants in Cohorts 4 and 6 only, will be permitted to continue treatment beyond initial 
RECIST 1.1 defined progressive disease (PD), as assessed by the investigator, as long as the 
following criteria are considered:
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•
Investigator-assessed clinical benefit
•
Tolerance of study drug
•
Stable performance status
•
Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases)
•
Participant provides written informed consent prior to receiving additional treatment with the 
investigational study drug regimen. All other elements of the main consent including 
description of reasonably foreseeable risks or discomforts, or other alternative treatment 
options will still apply.
•
Approval by Medical Monitor/designee. 
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.
If the investigator feels that the participant continues to achieve clinical benefit by continuing 
treatment, the participant should remain on the trial and continue to receive monitoring according 
to the Schedule of Activities, presented in Section 2.
For the participants who continue study therapy beyond progression, further progression is defined 
as an additional 10% increase in tumor burden with a minimum 5 mm absolute increase from time 
of initial PD. This includes an increase in the sum of diameters of all target lesions and/ or the 
diameters of new measurable lesions compared to the time of initial PD. It is recommended that 
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 
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.
8.1.6
Post Study Treatment Study Follow-up
Post study treatment follow-up is of critical importance and is essential to preserving participant 
safety and the integrity of the study. Participants who discontinue study treatment must continue 
to be followed until the LPLV on the study.
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
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•
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.
•
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 evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before treatment assignment/randomization. The 
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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.
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.90
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
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
9.1.1
Imaging Assessment for the Study
9.1.1.1
Methods of Measurements
•
Tumor assessment with contrast-enhanced computed tomography (CT) scans acquired on 
dedicated CT equipment is preferred for this study. Contrast-enhanced CT of the chest, 
abdomen, pelvis, and other known/suspected sites of disease should be performed for tumor 
assessments.
•
Should a participant have a contraindication for CT IV contrast, a non-contrast CT of the chest 
and a contrast enhanced MRI of the abdomen and pelvis and other known/suspected sites of 
disease may be obtained. 
•
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.
•
PET alone will not be considered for the disease assessment. Complementary CT and/or MRI 
or biopsy must be performed in such cases. Note: Use of CT component of a PET/CT scanner: 
Combined modality scanning, such as with FDG-PET/CT, is increasingly used in clinical care 
and is a modality/technology that is in rapid evolution; therefore, the recommendations 
outlined here may change rather quickly with time. At present, low-dose or attenuation 
correction CT portions of a combined FDG-PET/CT are of limited use in anatomically-based 
efficacy assessments, and it is, therefore, suggested that they should not be substituted for 
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dedicated diagnostic contrast enhanced CT scans for anatomically-based RECIST 1.1 
(Appendix 8) measurements. However, if a site can document that the CT performed as part 
of a FDG PET/CT is of identical diagnostic quality to a diagnostic CT (with IV and oral 
contrast), then the CT portion of the FDG-PET/CT can be used for RECIST 1.1 measurements. 
Note, however, that the FDG-PET portion of the CT introduces additional data which may bias 
an investigator if it is not routinely or serially performed. 
•
CT and MRI scans should be acquired with slice thickness of 5 mm or less with no intervening 
gap (continuous).
•
Every attempt should be made to image each participant using an identical acquisition protocol 
on the same scanner for all imaging time points. 
Table 9.1.1.1-1:
Acceptable Imaging Assessment Methods for Different Anatomical 
Areas
Anatomic Region
Preferred 
Method
Alternative Methods
Chest, abdomen, 
and pelvis
Note: Scan must 
cover lung apices to 
diaphragm, 
diaphragm through 
entire liver, and to 
below the pubic 
symphysis
CT with IV 
contrast
For chest:
• CT without contrast can be used only if the participant has a clinical 
contraindication 
for 
iodine-based 
IV 
contrast 
(e.g., 
hypersensitivity, renal insufficiency)
For abdomen and pelvis:
• MRI with gadolinium-based IV contrast is the first alternative 
method if the participant has a clinical contraindication for iodine-
based IV contrast
• CT without contrast can be used as the second alternative method 
only if the participant has a clinical contraindication for both 
contrast-enhanced CT and MRI.
Brain
MRI with IV 
contrast
•
CT with IV contrast is the first alternative method if IV gadolinium 
is clinically contraindicated. 
•
MRI without contrast can be used as a second alternative method 
if a participant has clinical contraindications for both contrast-
enhanced CT and MRI
Notes:
1. CT scans must be performed with slice thickness of ≤5 mm. The reconstruction interval should be equal to slice 
thickness to avoid gap. 
2. The same modality for a given anatomical coverage and the same scanning procedure (most importantly: 
reconstruction slice thickness, anatomic coverage, use of IV contrast) should be consistent between baseline and 
all subsequent follow-up scanning. If possible, the same scanner or an equivalent scanners should be used 
throughout the study. 
3. For abdomen and pelvis CT scans, oral contrast is recommended as per institutional standards. 
4. MRI should include T1 and T2-weighted sequences with T1-weighted at both pre- and post-contrast. 
5. All scans generated should be exportable in electronic format (DICOM) to enable secure and rapid electronic 
transmission to the designated central imaging laboratory. 
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9.1.1.2
Imaging Schedule and Assessment 
Baseline imaging, including CT of the chest, abdomen, pelvis, and all known/suspected sites of 
disease should be performed within 28 days prior to first treatment.
At Screening, MRI of the brain without and with contrast will be performed for participants with 
a history or clinical symptoms of brain metastasis. Participants with history or clinical symptoms 
of brain metastasis should have surveillance MRI per local SOC (approximately every 12 weeks) 
or sooner if clinically indicated.
First imaging assessment post-baseline should be performed Week 8 (± 7 days) following date of 
first dose. Subsequent assessments should include chest, abdomen, pelvis, and all known sites of 
disease and should use the same imaging method as was used at baseline. Irrespective of whether 
subsequent treatment is given, held, or discontinued, imaging assessment should occur for all 
participants who have received at least one dose of study treatment at every 8 weeks (± 7 days)
until whichever of the following occurs first:
•
Radiological disease progression
•
Withdrawal of consent 
•
Death
•
End of Trial
For all participants who continue treatment beyond initial progression (Section 8.1.5), scans should 
continue at every 8 weeks until treatment discontinuation criteria are met (Section 8).
Bone scan, PET scan, or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions. Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by cross sectional imaging techniques such as CT or MRI can 
be considered as measurable lesions if the soft tissue component meets the definition of 
measurability described above.
9.1.1.3
Tumor Assessment by Investigator Sites 
Investigator sites must review baseline images to confirm the participant has measurable disease 
using RECIST (Response Evaluation Criteria in Solid Tumor) 1.1 criteria (Appendix 8). Tumor 
assessments for ongoing study treatment decisions will be completed by the local investigator sites 
using RECIST 1.1 criteria. Tumor assessments are to continue for all participants on the protocol 
schedule irrespective of whether treatment is given, held, or discontinued. Study treatment 
decisions should be made by the investigator based on local read results and clinical assessment.
Per RECIST 1.1, partial or complete response should be confirmed by a repeat tumor imaging 
assessment, preferably at the next scheduled imaging visit, and not less than 4 weeks from the date 
the response was first documented. A Best Overall Response (BOR) of SD requires a minimum of 
49 days from first dose (Day 1) to the date of the first imaging assessment.
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 may undergo blinded independent 
central review (BICR) at any time during the study. Prior to 
 first participant, sites should 
be qualified and understand the 
 
 provided by the central imaging vendor.
For Part 1B and Part 2, tumor assessment scans should be submitted to the vendor within 14 days 
of acquisition.
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9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study. 
Contacts for SAE reporting specified in Appendix 3
Immune-Mediated Adverse Events
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Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Trametinib Adverse Event of Special Interest
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which are 
ones of scientific and medical concern specific to the sponsor’s product or program, for which 
ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and understand 
them. Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the Investigator Brochure, and a list of Medical Dictionary 
for Regulatory Activities (MedDRA) preferred terms to flag as AESI’s will be included in the Data 
Presentation plan.
AESI for trametinib include:
•
Skin related toxicities
•
Ocular events
•
Cardiac related events
•
Hepatic disorders
•
Pneumonitis/interstitial lung disease
•
Bleeding events
•
Hypertension
•
Hypersensitivity
•
Venous thromboembolism
Warnings and Precautions for Regorafenib 
Refer to local product labels for safety profile, including Warnings and Precautions.
9.2.1
Time Period and Frequency for Collecting AE and SAE Information
The collection of nonserious AE information should begin at initiation of study treatment until the 
time points specified in the Schedule of Activities (Section 2). 
Sections 5.6.1 and 5.6.2, in the 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 that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (eg, a follow-up skin biopsy).
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For participants assigned to treatment and never treated with study drug, SAEs should be collected 
for 30 days from the date of treatment assignment.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
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 section.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AEs and/or SAEs. Inquiry about specific AEs should be guided by clinical judgement 
in the context of known AEs when appropriate for the program or protocol.
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 Section 9.2.4 and 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 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
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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 Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements. 
9.2.5
Pregnancy
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 5 half-
lives after product administration, the investigator must immediately notify the 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.
In most cases, the study treatment will be permanently discontinued in an appropriate manner (eg, 
dose tapering if necessary for participant safety). Please call the BMS Medical Monitor/designee 
within 24 hours of awareness of the pregnancy (see Section 8.1).
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant.
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form.
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
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.
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•
Any laboratory test result that worsens from baseline and is clinically significant or meets the 
definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted/delayed, or dose reduced
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy or intervention
•
Any clinically significant safety assessments that are associated with the underlying disease, 
unless judged by the investigator to be more severe than expected for the participant's 
condition, are not to be reported as AEs or SAEs.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (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 9.2.4 and Appendix 3 for reporting 
details).
For participants with normal ALT, AST, and Total bilirubin at baseline, potential DILI is defined 
as: 
1) AT (ALT or AST) elevation > 3 times upper limit of normal (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.
For participants with elevated AST or ALT or Total bilirubin at baseline, potential DILI is defined 
as (Appendix 6): 
1) AT (ALT or AST) elevation > 2× baseline AND 3× ULN; OR
AT elevation 8 times ULN
AND
2) Total bilirubin > 2× baseline AND >2× 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.
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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 
9.3.1
Nivolumab or Ipilimumab Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2.4). 
9.3.2
Trametinib Overdose
In the event of a trametinib overdose, defined as administration of more than 3.0 mg once daily, 
the investigator should contact the Medical Monitor/designee immediately and closely monitor the 
participant for AEs/SAEs and laboratory abnormalities. There is no specific treatment 
recommended by the marketing authorization holder for trametinib overdose. The investigator will 
use clinical judgment to treat any overdose. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor/designee based on the clinical evaluation of the participant. 
 
 
Information regarding the quantity of the excess dose as well as the duration of the overdosing should 
be documented in the eCRF.
9.3.3
Regorafenib Overdose
Refer to local product label.
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (see 
Section 2).
9.4.1
Physical Examinations
Refer to Schedule of Activities in Section 2.
9.4.2
Vital signs
Refer to Schedule of Activities in Section 2.
9.4.3
Ophthalmic Examination 
Participants are required to have a standard ophthalmic examination conducted by an 
ophthalmologist at screening prior to randomization (7-day window does not apply at C1D1), 
Week 4/Month 1 (within 7 days prior to study treatment.), Month 6 from the first dose date, then 
annually thereafter unless clinically indicated sooner on treatment. In addition, there will be an 
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exam at follow-up visit 1. Ophthalmic examination will be performed at the time points indicated 
in the Schedule of Activities in Section 2. The exam will include visual acuity (best corrected), 
tonometry (intraocular pressure measurement), visual field examination, slit lamp biomicroscopy 
of the anterior segment (with special attention to inflammation) and the posterior segment, and 
indirect fundoscopic examination with special attention to possible retinal abnormalities. Optical 
coherence tomography is strongly recommended at scheduled visits, with special attention to 
retinal abnormality that are predisposing factors for Retinal Vein Occlusion (RVO) or Central 
Serous Retinopathy (CSR). In participants with clinical suspicion of RVO or CSR, additional color 
fundus photographs, as well as fluorescein angiography and/or optical coherence tomography were 
recommended, if clinically indicated.
Ophthalmic examination during treatment and Follow-Up periods is not required for Cohort 5 
participants, unless clinically indicated.
9.4.4
Electrocardiograms
Refer to Schedule of Activities in Section 2.
9.4.5
Echocardiogram/MUGA
Decreases of the LVEF have been observed in participants receiving trametinib. Echocardiograms 
(ECHOs) will be performed to assess cardiac ejection fraction and cardiac valve abnormalities. 
ECHOs will be performed at the time points indicated in the Schedule of Activities in Section 2.
The evaluation by the echocardiographer should include an evaluation for LVEF and an 
assessment of the right and left-sided heart valves. The procedure (ECHO) to document the 
participant’s baseline LVEF status must be used consistently throughout the study. If possible, it 
is also preferred that interpretation of LVEF status be performed consistently by the same reviewer 
throughout the study.
9.4.6
Clinical Safety Laboratory Assessments
Local laboratories are being utilized to analyze clinical safety samples. Investigators must 
document their review of each laboratory safety report. 
Results of clinical laboratory tests performed at screening must be available and meet eligibility 
criteria prior to first dosing. For subsequent infusion, clinical laboratory tests must be performed 
within 72 hours prior to next infusion (with results available to support continuation with study 
treatment). Continuation of trametinib dosing will be also assessed within 72 hours prior to 
initiation of the subsequent cycle, and as needed throughout the cycle.
For participants with normal or clinically stable thyroid function results from previous test, study 
treatment can resume with pending laboratory results if participants meet all other requirements 
for continuing study treatment. Results must be reviewed promptly once available to confirm 
dosing decision and medical management. 
See Schedule of Activities (Section 2).
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9.4.7
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. 
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9.9
Health Economics OR Medical Resource Utilization and Health 
Economics
In addition to the aforementioned 
, health care resource utilization data 
will be collected for Part 2 participants using an internal case report form eCRF developed for use 
in previous trials. The form, which is completed by study staff, records information about hospital 
admissions, including number of days spent in various wards and discharge diagnosis, as well as 
non-protocol specified visits related to study therapy, including date of visit, reason for visit, and 
type of visit. The health care resource utilization data will be used to support subsequent economic 
evaluations.
10
STATISTICAL CONSIDERATIONS
10.1
Sample Size Determination
This study will consist of multiple cohorts/parts for different target populations with different 
treatment regimens and the sample size for each part has been provided as below.
10.1.1
mCRC 3rd line Participants: Part 1 Dose Optimization Cohorts
Sample size at each dose level depends on the observed toxicity and is not based on statistical 
considerations. Three to 6 participants will be evaluated at each dose level. Administration of 
treatment regimen to 6 participants at a dose level provides ~82% probability of observing at least 
one occurrence of any adverse event if there is a 25% incidence in the population from which the 
sample is drawn. Approximately 3 to 18 participants are estimated to be treated in these dose
optimization cohorts. The total sample size for this part ranges from 3 to 18 participants.
10.1.2
mCRC 3rd line Plus Participants: Part 2 
 
Cohort
The purpose of Part 2 is to gather tolerability and preliminary efficacy, for nivolumab in 
combination with ipilimumab and trametinib or SOC (regorafenib) in pMMR/MSS 3L+ (no more 
than 4 prior lines of therapy) mCRC, including 
 
 for combination therapy with immune checkpoint inhibitor(s) and MEK 
inhibitor. Approximately 120 participants will be randomized in 2:1 ratio to receive nivolumab 
plus ipilimumab plus trametinib continuous dosing (Cohort 4), or SOC (regorafenib, Cohort 5). 
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10.1.3
mCRC 2nd line Participants: Part 1A Dose Optimization Cohorts
Sample size at each dose level depends on the observed toxicity and is not based on statistical 
considerations. Three to 6 participants will be evaluated at each dose level. Administration of 
treatment regimen to 6 participants at a dose level provides ~82% probability of observing at least 
one occurrence of any adverse event that would occur with a 25% incidence in the population from 
which the sample is drawn. Approximately 3 to12 participants are estimated to be treated for each
of two dose optimization cohorts (nivolumab + ipilimumab + continuous trametinib dosing and 
nivolumab + ipilimumab + intermittent trametinib dosing). The total sample size for this part 
ranges from 6 to 24 participants.
10.1.4
mCRC 2nd line Participants: Part 1B
 
Cohorts
The safety and efficacy of the triplet combination regimen has been initially explored in the 2L 
setting. An additional 
 
 cohort will be initiated for the 2L participants to 
further optimize the patient selection strategy. Approximately 80 participants will be treated to 
establish expanded experience with the triplet regimen of nivolumab plus ipilimumab plus 
trametinib continuous dosing. 
10.2
Populations for Analyses
For purposes of analysis, the following populations are defined below. The population definition 
will apply to all cohorts unless specified otherwise:
Population
Description
Enrolled 
All participants who sign informed consent and were registered into IRT.
Randomized
All participants who are randomized to any treatment in Part 2 (primary efficacy 
analysis population for Part 2 and outcome research assessment analysis 
population for Part 2).
Treated 
All participants who take at least 1 dose of study medication. 
Response-evaluable
All treated (randomized for Part 2) participants with measurable disease at 
baseline and at least one post-baseline tumor assessment.
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Population
Description
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before the first 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. Part 1A/1B, Part 1 and Part 2 will be analyzed 
independently. Below is a summary of planned statistical analyses of the primary and secondary 
endpoints.
A description of the participant population will be included in the statistical output reported, 
including subgroup of age, gender, and race.
10.3.1
Efficacy Analyses
The primary efficacy analyses will be performed on the treated population for all cohorts, except 
for Part 2 where the primary efficacy analyses will be performed on the randomized population. 
Efficacy in subgroups of interest will be evaluated in Part 2 and in Part 1B. 
 
 Other subgroups (e.g., the stratification factor of 
tumor sidedness, etc.) will be described in the Statistical Analysis Plan (SAP). Details on censoring 
scheme on time-to-event endpoints such as DOR, PFS, and OS and additional analyses will be 
described in the SAP. In Part 2, no crossover will be permitted between the two treatment arms 
upon discontinuation of study treatment.
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Endpoint
Statistical Analysis Methods
Best Overall Response (BOR) for a participant will be 
assessed per RECIST 1.1 as applicable per investigator 
(primary endpoint).
BOR is defined as the best response designation,
recorded between the first dosing date (randomization 
date, for Part 2) and the date of the initial objectively 
documented tumor progression per RECIST v1.1 or the 
date of subsequent therapy, whichever occurs first. For 
participants without documented progression or 
subsequent therapy, all available response designations 
will contribute to the BOR determination. 
ORR is defined as the proportion of all treated 
(randomized, for Part 2) participants whose BOR is 
either confirmed complete response (CR) or confirmed 
partial response (PR).
The disease control rate (DCR) is defined as the 
proportion of participants whose BOR is either 
confirmed CR or confirmed PR or stable disease (SD)
•
Estimate of ORR/DCR and corresponding two-
sided exact 95% CI using the Clopper-Pearson 
method by treatment 
DOR and TTR (per investigator)
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, whichever occurs first. The rules of censoring 
are the same as for PFS.
Time to response (TTR) is defined for participants who 
had a confirmed CR or PR as the time from the first 
dosing date (randomization date, for Part 2) to the date 
of first documented CR or PR per RECIST 1.1.
•
Estimate of median DOR/TTR using the Kaplan-
Meier method and corresponding two sided 95% 
CI (using log-log transformation) by treatment
Progression Free Survival PFS (per investigator) and 
overall survival OS
PFS for a participant is defined as the time from the 
first dosing date (randomization date for Part 2) 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 first dosing date 
(randomization date, for Part2).
•
Participants who started any subsequent anti-
cancer therapy without a prior reported 
progression or prior to death will be censored 
•
Estimate of median and rates at fixed time points
by the Kaplan-Meier method and corresponding 
two sided 95% CI using log-log transformation 
(for median) and Greenwood formula (for rates) 
by treatment
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nivolumab
Endpoint
Statistical Analysis Methods
at the last tumor assessment prior to initiation 
of the subsequent anticancer therapy.
•
Further explanation for various censoring 
scenarios for PFS will be specified in the 
SAP.
OS for a participant is defined as the time from the first 
dosing date (randomization date for Part 2) to the date 
of death due to any cause. A participant who has not 
died will be censored at last known date alive.
•
10.3.2
Safety Analyses
All safety analyses will be performed on the Treated population.
Endpoint
Statistical Analysis Methods
Incidence of DLTs, AEs, SAEs, AEs leading to 
discontinuation, deaths
AEs will be graded according to CTCAE ( version
4.0).
DLT rate by dose level; Frequency distribution of treated 
participants with AE using the worst CTC grade. 
Participants will only be counted (1) once at the preferred 
term (PT) level, (2) once at the system organ class (SOC) 
level, and (3) once in the ‘Total participant’ row at their 
worst CTC grade, regardless of SOC or PT.
Deaths will be summarized using frequency distribution
Laboratory abnormalities
Laboratory values will be graded according to 
CTCAE (version 4.0) 
Laboratory abnormalities will be summarized.
Lab shift table using the worst CTC grade on treatment per 
participant.
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10.3.6
Outcomes Research Analyses 
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10.3.6.3
Other Analyses 
Not Applicable
10.3.7
Interim Analyses 
Data were reviewed during the dose escalation/de-escalation evaluation phase (Part 1 and Part 1A) 
to determine the proposed combination regimens for Part 2 and Part 1B. Comprehensive analyses 
for Part 1 including safety, 
, and preliminary efficacy data were conducted to support 
dose selection for Part 2 (RP2D) as appropriate.
An interim analysis (IA) of Part 2 and Part1B cohorts will be conducted after an overall total of 
approximately 100 treated participants (including approximately 60 treated participants from Part 
2) have a minimum of 4 months of follow-up after the first treatment (corresponding to at least 2 
tumor assessments). The objectives of this IA will be a review of the safety data and to provide 
preliminary efficacy. 
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11
REFERENCES
1
Ohrling K, Edler D, Hallstrom M, et al: Mismatch repair protein expression is an independent 
prognostic factor in sporadic colorectal cancer. Acta Oncol. 2010;49.
2
Koopman M, Kortman G, Mekenkamp L, et al. Deficient mismatch repair system in patients 
with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266-73.
3
Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N 
Eng J Med 2015. 372:2509-20.
4
Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab ± ipilimumab in treatment (tx) of 
patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite 
instability (MSI-H): CheckMate-142 interim results. Poster presented at 2016 ASCO Annual 
Meeting. J Clin Oncol 34, 2016. 
5
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proceedings of the National Academy of Sciences. 2010; 107: 4275-80.
6
CA209012: Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin, 
Pemetrexed/Cisplatin, 
Carboplatin/Paclitaxel, 
Bevacizumab
Maintenance, 
Erlotinib, 
Ipilimumab or as Monotherapy in First-Line or in Switch Maintenance in Participants With 
Stage IIIB/IV Non-small Cell Lung Cancer (NSCLC) (CheckMate 012). NCT01454102.
7
CA209016: Nivolumab (BMS-936558; MDX-1106) in Combination With Sunitinib,
Pazopanib, or Ipilimumab in Participants With Metastatic Renal Cell Carcinoma (RCC)
(CheckMate016). NCT01472081.
8
Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in 
untreated melanoma. N Engl J Med. 2015;372:2006-17.
9
CA209067: Phase 3 Study of Nivolumab or Nivolumab Plus Ipilimumab Versus Ipilimumab
Alone in Previously Untreated Advanced Melanoma (CheckMate-067). NCT01844505.
10 Chen EX, Jonker DJ, Loree JM, et al. Effect of combined immune checkpoint inhibition vs. 
best supportive care alone in patients with advanced colorectal cancer, JAMA Oncol. 
2020;6:831-8.
11 Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus 
ipilimumab in DNA mismatch repair–deficient/microsatellite instability–high metastatic 
colorectal cancer. Clin Oncol. 2018; 36:773-9.
12 Salmon H, Idoyaga J, Rahman A, et al: Expansion and Activation of CD103+ Dendritic Cell
Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF
Inhibition. Immunity. 2010;44:924-38.
13 Ebert Peter JR, Cheung J, Yang Y, et al: MAP Kinase Inhibition Promotes T Cell and antitumor 
Activity in Combination with PD-L1 Checkpoint Blockade. Immunity. 2016;44:609-21.
Protocol Amendment No.: 04
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nivolumab
14 Hoeflich KP, Merchant M, Orr C, et al: Intermittent Administration of MEK Inhibitor GDC-
73 plus PI3K Inhibitor GDC-0941 Triggers Robust Apoptosis and Tumor Growth Inhibition. 
Cancer Research. 012;72:210-9.
15 Sumimoto H, Imabayashi F, Iwata T, et al: The BRAF–MAPK signaling pathway is essential
for cancer-immune evasion in human melanoma cells. J Exper Med.2006;203:1651-6.
16 Rinehart J, Adjei AA, LoRusso PM, et al: Multicenter Phase II Study of the Oral MEK 
Inhibitor, CI-1040, in Patients With Advanced Non-Small-Cell Lung, Breast, Colon, and 
Pancreatic Cancer. J Clin Oncol. 2004;22:4456-62.
17 Infante JR, Fecher LA, Falchook GS, et al: Safety, pharmacokinetic, pharmacodynamic, and 
efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet 
Oncol. 2012; 13:773-81.
18 Liu L, Mayes PA, Eastman S, et al: The BRAF and MEK Inhibitors Dabrafenib and 
Trametinib: Effects on Immune Function and in Combination with Immunomodulatory 
Antibodies Targeting PD-1, PD-L1, and CTLA-4. American Association for Cancer Research 
21:1639-51, 2015.
19 Eng C, Kim TW, Bendell J, et al. Atezolizumab with or without cobimetinib versus regorafenib 
in previously treated metastatic colorectal cnacer (IMblaze370): a multicentre, open-label, 
phase 3, randomised, controlled trial. Lancet Oncol 2019;20:849:61.
20 Ferlay J, Shin HR, Bray F, et al. 2018 Globocan data base: Global Cancer Facts & Figures 4th 
Edition
21 Siegel RL, Miller KD, Saurer AG, et al. Colorectal Cancer Statistics, 2020. CA Cancer J Clin.
2020;70:145-164.
22 Cutsem, EV. Cervantes A, Nordlinger B. Metastatic colorectal cancer: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 (sup 3); iii1-iii9.
23 NCCN. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf accessed on 13 Sept 
2013.
24 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.
25 Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with 
fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-
line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010 Nov 
1;28(31):4706-13.
Protocol Amendment No.: 04
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nivolumab
26 Tabernero J, Van Cutsem E, Lakomy R, et al: Results from VELOUR, a phase 3 study of
aflibercept versus placebo in combination with FOLFIRI for the treatment of patients with 
previously treated metastatic colorectal cancer. 2011 European Multidisciplinary Congress. 
Abstract 6LBA. Presented September 25, 2011.
27 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125085s267lbl.pdf accessed 13 
Sept 2013.
28 Tabernero J, Yoshino T, Cohn AL, et al: Ramucirumab versus placebo in combination with 
second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during 
or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a 
randomised, double-blind, multicentre, phase 3 study. The Lancet Oncology. 2015;16:499-
508. 
29 http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/125418s000lbl.pdf accessed 13 
Sept 2013.
30 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125084s242nd 
Linebl.pdf 
accessed 13 Sept 2013.
31 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203085s001lbl.pdf accessed on 13 
Sept 2013.
32 Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, et al. 
Randomized Trial of TAS-102 for Refractory Metastatic Colorectal Cancer. N Engl J Med. 
2015;372(20):1909-19.
33 Schubbert S, Shannon K, Bollag G. Hyperactive Ras in developmental disorders and cancer. 
Nat Rev Cancer 2007; 7:295-308.
34 Morris VK, Lucas FA, Overman MJ, et al. Clinicopathologic characteristics and gene 
expression analyses of non-KRAS 12/13, RAS-mutated metastatic colorectal cancer. Ann 
Oncol 2014; 25:2008-14.
35 Bos JL, Fearon ER, Hamilton SR, et al. Prevalence of ras gene mutations in human colorectal 
cancers. Nature 1987; 327:293-7.
36 Vaughn CP, Zobell SD, Furtado LV, Baker CL, Samowitz WS. Frequency of KRAS, BRAF, 
and NRAS mutations in colorectal cancer. Genes Chromosomes Cancer 2011; 50:307-12.
37 Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, ESMO Guidelines Working Group. 
Metastatic colorectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and 
follow-up. Ann Oncol 2014; 25(suppl 3):iii1-9.
38 Waring P, Tie J, Maru D et al. RAS mutations as predictive biomarkers in clinical management 
of metastatic colorectal cancer. Clinical Colorectal Cancer. 2015;15(2):95-103. 
39 Larki P, Gharib E, Yaghoob M. Coexistence of KRAS and BRAF Mutations in Colorectal 
Cancer: A Case Report Supporting the Concept of Tumor Heterogeneity. Cell Journal. 
2017;19(1):113-117.
Protocol Amendment No.: 04
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nivolumab
40 Barras D. BRAF Mutation in Colorectal Cancer: An Update. Biomarkers in Cancer. 
2015;7(S1): 9-12. 
41 Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in Combination with Oxaliplatin, 
Fluorouracil, and Leucovorin (FOLFOX4) for Previously Treated Metastatic Colorectal 
Cancer: Results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 
2007; 25(12):1539-44.
42 Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in 
metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013; 
14(1):29-37.
43 Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, 
leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with 
metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin 
Oncol, 2012; 30(28):3499-506.
44 Peeters M, Price TJ, Cervantes A, et al. Randomized phase III study of panitumumab with 
fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-
line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010; 28(31):4706-
13.
45 Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated 
metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-
controlled, phase 3 trial. Lancet. 2013; 381(9863):303-12.
46 Aaltonen LA, Salovaara R, Kristo P, et al. Incidence of hereditary nonpolyposis colorectal
cancer and the feasibility of molecular screening for the disease. N Engl J Med
1998;338:1481-7.
47
Popat S, Hubner R, Houlston RS. Systematic review of microsatellite instability and colorectal 
cancer prognosis. J Clin Oncol 2005;23:609-18.
48 NCCN current version March 2017.
49 Pawlik TM, Paut CP, Rodriguez-Bigas MA. Colorectal carincogenesis: MSI-H versus MSI-L. 
Disease Markers. 2004;20:99-206. 
50 Gruber SB and Vilar E. Microsatellite instability in colorectal cancer-the stable evidence. Nat 
Rev Clin Oncol 2010;7:153-62.
51 Rajagopalan H, Bardelli A, Lengauer C, et al. Tumorigenesis: RAF/RAS oncogenes and 
mismatch-repair status. Nature 2002;418:934.
52 Oliveira C, Pinto M, Duval A, et al. BRAF mutations characterize colon but not gastric cancer 
with mismatch repair deficiency. Oncogene 2003;22:9192-6.
53 Greenson JK, Bonner JD, Ben-Yzhak O, et al. Phenotype of microsatellite unstable colorectal 
carcinomas: Well-differentiated and focally mucinous tumors and the absence of dirty necrosis 
correlate with microsatellite instability. Am J Surg Pathol 2003;27:563-70.
Protocol Amendment No.: 04
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nivolumab
54 Dolcetti R, Viel A, Doglioni C, et al. High prevalence of activated intraepithelial cytotoxic T 
lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with 
microsatellite instability. Am J Pathol 1999;154:1805–13.
55 Guidoboni M, Gafa` R, Viel A, et al. Microsatellite instability and high content of activated 
cytotoxic lymphocytes identify colon cancer patients with a favorable prognosis. Am J Pathol 
2001;159: 297–304.
56 Duval A, Rolland S, Compoint A, et al. Evolution of instability at coding and non-coding 
repeat sequences in human MSI-H colorectal cancers. Hum Mol Genet 2001;10:513–8.
57 Kammertoens T, Blankenstein T. Making and circumventing tolerance to cancer. Eur J 
Immunol 2009;39:2345–53.
58 Schwitalle Y, Kloor M, Eiermann S, et al. Immune response against frameshift-induced 
neopeptides in HNPCC patients and healthy HNPCC mutation carriers. Gastroenterology 
2008;134:988–97.
59 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.
60 Alexander J, Watanabe T, Wu TT, et al. Histopathological identification of colon cancer with 
microsatellite instability. Am J Pathol 2001;158:527–35.
61 Banerjea A, Ahmed S, Hands RE, et al. Colorectal cancers with microsatellite instability 
display mRNA expression signatures characteristic of increased immunogenicity. Mol Cancer 
2004;3:21.
62 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.
63 Guinney, J., Dienstmann, R., Wang, X. et al. The consensus molecular subtypes of colorectal 
cancer. Nat Med 2015;21:1350-6.
64 Piskol R, Huw L, Sergin I, et al. Clinically applicable gene expression classifier reveals 
intrinsic and extrinsic contributions to consensus molecular subtypes in primary and metastatic 
colon cancer. Clinical Cancer Research 2019;25:4431-42.
65 Eide, P.W., Bruun, J., Lothe, R.A. et al. CMScaller: an R package for consensus molecular 
subtyping of colorectal cancer pre-clinical models. Sci Rep 2017;25:4431-42.7
66 Teufel M, Schwenke S, Seidel H, et al. Molecular subtypes and outcomes in regorafenib-
treated patients with metastatic colorectal cancer (mCRC) enrolled in the CORRECT trial. J 
Clin Oncol 2015;33(Suppl 15):3558.
67 Lenz HJ, Ou FS, Venook AP, et al. Impact of Consensus Molecular Subtype on Survival in 
Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). 
J Clin Oncol 2019;37:1876-1885.
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nivolumab
68 Stintzing S, Wirapati P, Lenz HJ, et al. Consensus molecular subgroups (CMS) of colorectal
cancer (CRC) and first-line efficacy of FOLFIRIs cetuximab or bevacizumab in the FIRE3 
(AIO KRK-0306) trial. Ann Oncol 2019;30:1796-1803.
69 Johnson B, Thomas JV, Dasari A, et al. A phase II study of durvalumab (MEDI4736) (anti-
PD-L1) and trametinib (MEKi) in microsatellite stable (MSS) metastatic colorectal cancer 
(mCRC). J Clin Oncol 2020;38, 152.
70 Lee MS, Selitsky SR, Parker, JS, et al. Association of consensus molecular subtypes (CMS) 
with time to progression (TTP), progression free survival (PFS), and overall survival (OS) with 
second-line FOLFIRI ± regorafenib in metastatic colorectal cancer (mCRC). J Clin Oncol 
2019;37(Suppl 4):597.
71 Pardoll D. Does the immune system see tumors as foreign or self? Annu Rev Immunol. 
2003;21:807-39.
72 Zitvogel L, Tesniere A, Kroemer G. Cancer despite immunosurveillance: immunoselection 
and immunosubversion. Nat Rev Immunol. 2006;6:715-27.
73 Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to 
tumor escape. Nat Immunol. 2002;3:991-8.
74 Greenwald RJ, Freeman GH, Sharpe AH. The B7 family revisited. Annu Rev Immunol.
2004;23:515-48.
75 Freeman FJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a 
novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 
2000; 192(7): 1027-34.
76 Sharpe AH, Wherry EJ, Ahmed R, et al. The function of programmed cell death 1 and its 
ligands in regulating autoimmunity and infection. Nature Immunol. 2007;8:237-45.
77 Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412-20.
78 Nivolumab Clinical Study Report: CA209-016 December 2016.
79 BMS Clinical Study Report CA209004, December 2014.
80 Wolchok JD, Kluger H, Callahan MK et al. Nivolumab plus Ipilimumab in Advanced
Melanoma. N Engl J Med 2013;369:122-33.
81 Nivolumab Investigator Brochure.
82 Andre T, Lonardi S, Wong MK-Y et al. Combination of nivolumab (NIVO) + ipilimumab (IPI) 
in the treatment of patients (pts) with deficient DNA mismatch repair (dMMR)/high 
microsatellite instability (MSI-H) metastatic colorectal cancer (mCRC): CheckMate 142 
Study.  Poster presented at the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, IL USA. 
83 Chen, et al. CD38 as a novel immune checkpoint and a mechanism of resistance to the blockade
of the PD-1/PD-L1 axis. J Clin Oncol 2017; 35: suppl 7S, abstract 79.
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84 Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al: Updated results from a phase III trial of
nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with
advanced melanoma (MEL) (CheckMate 067). ASCO Meeting Abstracts 34:9505, 2016.
85 Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical Impact of Different Classes of Infiltrating
T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal Cancer; 
Cancer Res February 15 2011;(71)(4):1263-71.
86 Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and 
receptors. Leuk.Res. 2001;25:1-12.
87 Vaisitti T, Aydin S, Rossi D et al. CD38 increases CXCL12-mediated signals and homing of
chronic lymphocytic leukemia cells. Leukemia 2010;24:958-69.
88 Malavasi F, Deaglio S, Damle R et al. CD38 and chronic lymphocytic leukemia: a decade later. 
Blood. 2011;118:3470-8.
89 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.
90 Ipilimumab Investigator Brochure.
91 Trametinib Investigator Brochure.
92 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). 2016 Annual 
Meeting of the European Association of Dermato-Oncology; 2016 August 31-September 3; 
Vienna, Austria.
93 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.
94 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. 2017 April 1-5; Washington, DC, USA.
95 Felip 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. 2017 Sep 8-12; Madrid, Spain. Poster 1301PD.
96 Spigel DR, McLeod M, Hussein MA, et al. Randomized results of continuous vs 1-year fixed 
duration in patients with advanced non-small cell lung cancer. Oral presentation at the 
European Society of Medical Oncology Annual Meeting. 2017 Sep 8-12; Madrid, Spain.
97 Mayer RJ, Van Cutsem E, Falcone A et al. Randomized trial of TAS-102 for refractory 
metastatic colorectal cancer. N Engl J Med 2015; 372:1909-19.
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98 Shitara K, Arita S, Shirakawa T, et al. REVERCE: randomized phase II study of regorafenib 
followed by cetuximab versus the reverse sequence for metastatic colorectal cancer patients 
previously treated with fluoropyrimidine, oxaliplatin, and irinotecan. J Clin Oncol 2019; 
36:557.
99 Arita S, Shirakawa T, Matsushita Y, et al. Efficacy and safety of TAS-102 in clinical practice 
of salvage chemotherapy for metastatic colorectal cancer. Anti-cancer Res 2016; 36:1959-66.
100 Bekaii-Saab T, Kim R, Kim TW, et al. Third- or later-line therapy for metastatic colorectal 
cancer: reviewing best practice. Clin Colorectal Cancer 2019;18:e117-e129.
101 Petrelli F, Tomasello G, Borgonovo K, et al. Prognostic survival associated with left-sided vs. 
right-sided colon cancer: a systematic review and meta-analysis. JAMA Oncol. 2017;3(2)-211-
9.
102 Arnold D, Lueza B, Douillard J.Y. et al. Prognostic and predictive value of primary tumor side 
in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and 
EGFR directed antibodies in six randomized trials. Ann Onocol 2017;28:1713-29.
103 Desai J, Hong YS, Kim J, et al. Efficacy and Safety of Cobimetinib and Atezolizumab in an 
Expanded Phase 1b Study of Microsatellite-Stable (MSS) Metastatic Colorectal Cancer 
(mCRC). Eur Soc Med Oncol 2016;Poster 470P.
104 Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature
2002; 417:949-54.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
1L
first line
2L
second line
3L
third line
3L+
third line plus
5-FU
5-fluorouracil
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
AST
aspartate aminotransferase
AT
aminotransaminases
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BSA
body surface area
BSC
best supportive care
BUN
blood urea nitrogen
C
Celsius
C1
chloride
Ca
calcium
CBC
complete blood count
CEA
carcinoembryonic antigen
CFR
Code of Federal Regulations
cHL
classical Hodgkin’s lymphoma
CI
confidence interval
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Term
Definition
CMS
consensus molecular subtype
CNS
central nervous system
COVID-19
Coronavirus Disease 2019
CR
complete response
CRC
colorectal cancer
CRF
Case Report Form, paper or electronic
CSR
Central Serous Retinopathy
DCR
disease control rate
dL
deciliter
DLT
dose limiting toxicity
dMMR
deficient mismatch repair
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
eg
exempli gratia (for example)
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
g
gram
GCP
Good Clinical Practice
h
Hour
H&N
head and neck 
HBsAg
hepatitis B surface antigen
HCG 
human chorionic gonadotrophin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
HRT
hormone replacement therapy
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Term
Definition
ICH
International Conference on Harmonisation
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IL
interleukin
 
IMP
investigational medicinal products
IND 
Investigational New Drug Exemption
I-O
Immuno-oncology
IP
investigational product
IRB
Institutional Review Board
irPR
immune-related partial response
irSD
immune-related stable disease
IRT
interactive response technology
IU
International Unit
IV
intravenous
K
potassium
kg
kilogram
L
Liter
LDH
lactate dehydrogenase
LFT
Liver function tests
LLN
lower limit of normal
LPFT
last patient first treatment
LPLV
last patient last visit
LVEF
left ventricular ejection fraction
MAPK 
mitogen activated protein kinase
mCRC
metastatic colorectal cancer
MEK
mitogen-activated protein kinase enzymes
mg
milligram
μg
microgram
Mg
magnesium
min
minute
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Term
Definition
mL
milliliter
mmHg
millimeters of mercury
MMR
mismatch repair (of DNA)
mOS
median overall survival
MRI
magnetic resonance imagining 
MSI
microsatellite instability
MSI-H
microsatellite instability high
MSS
microsatellite stable
MST
medical surveillance team
MTD
maximum tolerated dose
MUGA
multigated acquisition scan
N
number of subjects or observations
Na
sodium
NCCN
national comprehensive cancer network
ng
nanogram
NSCLC
nonsmall cell lung cancer
ORR
objective response rate
OS
overall survival
PD
pharmacodynamic
PD-L1
program cell death ligand 1
PE
physical examination
PFS
progression-free survival
pMMR
proficient mismatch repair
PPES
Palmar-planta erythrodysesthesia
PO 
per os (by mouth route of administration)
PR
partial response
QD, qd
quaque die, once daily
RCC
renal cell carcinoma
RP2D
Recommended Phase 2 dose
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Term
Definition
RVO
retinal vein occlusion
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOP
Standard Operating Procedures
STAT3
Signal transducer and activator of transcription 3
TBD
to be decided
TEAE
treatment-emergent adverse event
Treg
T-regulatory cell
TSH
thyroid stimulating hormone
TTR
time to response
UC
urothelial carcinoma
ULN
upper limit of normal
US
United States
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the 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 Union Directive 2001/20/EC
•
United States Code of Federal Regulations, Title 21, Part 50 (21CFR50) 
•
applicable local requirements.
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the participant informed consent will receive approval/favorable opinion by Institutional 
Review Board/Independent Ethics Committee (IRB/IEC), and regulatory authorities according to 
applicable local regulations prior to initiation of the study.
All potential serious breaches must be reported to Sponsor or designee immediately. A serious
breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity 
of the subjects of the study or the scientific value of the study.
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (e.g., 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 (e.g., 
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 (e.g., 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 for 
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
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 (i.e., 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. 
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator.
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
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BMS COMMITMENT TO DIVERSITY IN CLINICAL TRIALS
The mission of BMS is to transform patients’ lives through science by discovering, developing, 
and delivering innovative medicines that help them prevail over serious diseases. 
BMS is committed to doing its part to ensure that patients have a fair and just opportunity to 
achieve optimal health outcomes.
BMS is working to improve the recruitment of a diverse participant population with the goal that 
the clinical trial becomes more reflective of the real-world population and the people impacted by 
the diseases studied.
DATA PROTECTION, DATA PRIVACY, AND DATA SECURITY
BMS collects and processes personal data of study participants, patients, health care providers, 
and researchers for biopharmaceutical research and development to advance innovative, high-
quality medicines that address the medical needs of patients. BMS ensures the privacy, protection, 
and confidentiality of such personal data to comply with applicable laws. To achieve these goals, 
BMS has internal policies that indicate measures and controls for processing personal data. BMS 
adheres to these standards to ensure that collection and processing of personal data are limited and 
proportionate to the purpose for which BMS collects such personal data. This purpose is clearly 
and unambiguously notified to the individual at the time of collection of personal data. In the true 
spirit of science, BMS is dedicated to sharing clinical trial information and data with participants, 
medical/research communities, the media, policy makers, and the general public. This is done in a 
manner that safeguards participant privacy and informed consent while respecting the integrity of 
national regulatory systems. Clinical trial data, health-related research, and pharmacovigilance 
activities on key-coded health data transferred by BMS across national borders is done in 
compliance with the relevant data protection laws in the country and GCP requirements.
BMS protects Personal Information with adequate and appropriate security controls as indicated 
under the data protection laws. To align with the recommended security standards, BMS has 
adopted internal security standards and policies to protect personal data at every stage of 
its processing.
To supplement these standards, BMS enters into Clinical Trial Agreements (CTAgs) with 
confidentiality obligations to ensure proper handling and protection of personal data by third 
parties accessing and handling personal data.
SOURCE DOCUMENTS
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 
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adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records).
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original. 
STUDY TREATMENT RECORDS
Records for study treatments (whether supplied by BMS, its vendors, or the site) must substantiate 
study treatment integrity and traceability from receipt, preparation, administration, and through 
destruction or return. Records must be made available for review at the request of BMS/designee 
or a Health Authority.
If
Then
Supplied by BMS (or its vendors):
Records or logs must comply with applicable 
regulations and guidelines and should include:
•
amount received and placed in storage 
area
•
amount currently in storage area
•
label identification number or batch 
number
•
amount dispensed to and returned by each 
participant, including unique participant 
identifiers
•
amount transferred to another area/site for 
dispensing or storage
•
nonstudy disposition (e.g., lost, wasted) 
•
amount destroyed at study site, if 
applicable
•
amount returned to BMS
•
retain samples for 
bioavailability/bioequivalence, if 
applicable 
•
dates and initials of person responsible for 
Investigational Product 
dispensing/accountability, as per the 
Delegation of Authority Form.
Sourced by site, and not supplied by BMS or 
its vendors (examples include IP sourced from 
the sites stock or commercial supply, or a 
specialty pharmacy)
The 
investigator 
or 
designee 
accepts 
responsibility for documenting traceability and 
study drug integrity in accordance with 
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If
Then
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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requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
In addition, the study may be evaluated by 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 (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (e.g., 
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
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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.
STUDY AND SITE CLOSURE
The Sponsor/designee reserves the right to close the study site or to terminate the study at any time 
for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies have 
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to, the following:
For study termination:
•
Discontinuation of further study intervention development
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For site termination:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
•
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by 
the investigator
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should ensure 
appropriate participant therapy and/or follow-up.
DISSEMINATION OF CLINICAL STUDY DATA
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
CLINICAL STUDY REPORT AND PUBLICATIONS
A Signatory Investigator must be selected to sign the clinical study report. 
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria:
•
External Principal Investigator designated at protocol development
•
National Coordinating Investigator 
•
Involvement in trial design and data interpretation
•
Regional representation (e.g., among top quartile of enrollers from a specified region or 
country)
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTAg) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTAg.
Scientific publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors. No public presentation or publication of any interim results may be made by any 
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Principal Investigator, sub-investigator, or any other member of the study staff without the prior 
written consent of the Sponsor.
Authorship of publications at the Sponsor is aligned with the criteria of the International 
Committee of Medical Journal Editors (ICMJE; www.icmje.org). Authorship selection is based on 
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)
2) Drafting the work or revising it critically for important intellectual content
3) Final approval of the version to be published
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 the 
Sponsor 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.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING,
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug.
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)
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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.) 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 
for reporting pregnancies).
EVALUATING AES AND SAES
Assessment of Causality
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug 
administration and the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship. 
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 drug or if new 
information becomes available, the SAE report must be updated and submitted within 
24 hours to BMS (or designee) using the same procedure used for transmitting the initial 
SAE report.
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All SAEs must be collected that occur during the screening period and within 100 days of 
the last dose of study treatment. For participants randomized/assigned to treatment and 
never treated with study drug, SAEs should be collected for 30 days from the date of 
treatment assignment.
All SAEs must be followed to resolution or stabilization.
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.
REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study drug, and pregnancies must be reported 
to BMS (or designee) within 24 hours of awareness of the event.
•
All SAEs must be collected that occur during the screening period and within 100 days 
of the last dose of study treatment. For participants randomized/assigned to treatment
and never treated with study drug, SAEs should be collected for 30 days from the date 
of treatment assignment.
•
SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy 
Surveillance Form (electronic or paper forms).
•
The preferred method for SAE data reporting collection is through the eCRF.
•
The paper SAE/pregnancy surveillance forms are only intended as a back-up option 
when the eCRF system is not functioning.
−
In this case, the paper forms are to be transmitted via email or confirmed facsimile 
(fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission 
is the required method for reporting. In the event the electronic system is unavailable for 
transmission, paper forms must be used and submitted immediately. When paper forms are 
used, the original paper forms are to remain on site.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
Appendix 4 provides general information and definitions related to women of childbearing 
potential and methods of contraception that can be applied to most clinical trials. For information 
specific to this study regarding acceptable contraception requirements for female and male 
participants, refer to Section 6.1 of the protocol. Only the contraception methods as described in 
Section 6.1 are acceptable for this study.
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
Note: Females treated with hormone replacement therapy (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. Suggested 
guidelines for the duration of the washout periods for HRT types are presented below. Investigators 
should use their judgement in checking serum FSH levels.
•
1-week minimum for vaginal hormonal products (rings, creams, gels) 
•
4-week minimum for transdermal products
•
8-week minimum for oral products 
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Other parenteral products may require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mL at any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure 
End of relevant systemic exposure is the timepoint where the Investigational Medicinal Product 
(IMP) or any active major metabolites have decreased to a concentration that is no longer 
considered to be relevant for human teratogenicity or fetotoxicity. This should be evaluated in 
context of safety margins from the no-observed-adverse-effect level or the time required for 5 half-
lives of the IMP to pass.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months after the end of study 
treatment.*
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly.a
•
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb 
−
oral 
−
intravaginal 
−
transdermal 
•
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 ovulationb 
−
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 b
•
Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
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Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence
•
Periodic abstinence (including, but not limited to, calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method 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 drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male 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
•
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
•
Withdrawal (coitus interruptus).
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Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 4 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 4 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 4 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 4 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 Appendix 3 for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 5
NIVOLUMAB MANAGEMENT ALGORITHMS FOR STUDIES 
UNDER CTCAE VERSION 4.0
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
For adverse events that may be related to both nivolumab and/or ipilimumab and trametinib, both 
Management Algorithms for Nivolumab and Ipilimumab (Appendix 5) AND Trametinib Dose 
Modification guideline (Appendix 6) need to be carefully reviewed and followed.  Where toxicity 
management guidelines differ between the two, the most stringent/conservative guideline should 
be followed.
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APPENDIX 6
TRAMETINIB DOSE MODIFICATION GUIDELINES
For adverse events that may be related to both nivolumab and/or ipilimumab and trametinib, both 
Management Algorithms for Nivolumab and Ipilimumab (Appendix 5) AND Trametinib Dose 
Modification guideline (Appendix 6) need to be carefully reviewed and followed.  Where toxicity 
management guidelines differ between the two, the most stringent/conservative guideline should 
be followed.
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APPENDIX 7
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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APPENDIX 8
RECIST 1.1 GUIDELINES (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:
2
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
•
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ൒2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
3
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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4
SPECIAL considerations REGARDING LESION MEASURABILITY
4.1.1
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.
5
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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6
RESPONSE CRITERIA
6.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
6.1.1
Special Notes on the Assessment of Target Lesions
6.1.1.1
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.
6.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
6.1.1.3
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’.
6.2
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.
6.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
6.2.1.1
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.
6.2.1.2
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: 
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if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
6.2.2
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 
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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.
6.3
Response Assessment
6.3.1
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.
6.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) 
Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
6.3.3
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
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
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
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.
6.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
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APPENDIX 9
MSI/MSS STATUS TESTING 
TESTING PANEL DESCRIPTIONS (PCR AND IHC)
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) is 
required to be submitted for sponsor or representative to review.
1. 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)
•
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:
♦If ≥3 markers of 4 Æ MSI-H
♦If 1 marker of 4 Æ re-amplify
2. Promega MSI Multiplex system version 1.1
•
5 mononucleotide markers:
−
BAT-25
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−
BAT-26
−
NR-21F
−
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 mononucleotide loci
Reference:
Murphy KM et al., “Comparison of the Microsatellite Instability analysis system 
and the Bethesda Panel for the Determination of Microsatellite Instability in Colorectal Cancers” 
Journal of Molecular Diagnostics Vol 8, 2006, p305 
3. 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
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APPENDIX 10
KRAS/NRAS AND BRAF MUTATIONAL TESTING
FDA or other health authority approved testing should be used for local testing.
If not, 
documentation demonstrating validation of the test performance (preferable under CLIA or 
equivalent ex-US) is required to be submitted for sponsor or representative to review.  
For RAS:
DNA sequencing to identify RAS (KRAS and NRAS) mutations in codons 12 and 13 (exon 2), 59 
and 61 (exon 3), and 117 and 146 (exons 4).  
Note: for participants who had received anti-EGFR agents in prior line(s) of therapy, RAS 
mutation testing may be repeated after completing such therapy per local institutional guidelines.  
Participant enrollment will be based on initial testing results 
 
. For Part 2, stratification of RAS mutation status 
is based on initial local testing results.
For BRAF:
DNA sequencing to identify BRAF mutation, including but not limited to V600.
BRAF mutation status is required for participants for eligibility and stratification purposes.
References: 
Misale S, Yaeger R, Hobor S, et al. Emergence of KRAS mutations and acquired resistance to 
anti-EGFR therapy in colorectal cancer. Nature. 2012 June; 486:532-536. 
Knickelbein K and Zhang L. Mutant KRAS as a critical determinant of the therapeutic response 
of colorectal cancer. Genes Dis. 2015 March; 2(1): 4–12.
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APPENDIX 11
NYHA FUNCTIONAL CLASSIFICATION
NYHA Class
Patients with Cardiac Disease 
(Description of HF Related Symptoms)
Class I (Mild)
Patients with cardiac disease but without resulting in limitation of physical activity. 
Ordinary physical activity does not cause undue fatigue, palpitation (rapid or 
pounding heart beat), dyspnea (shortness of breath), or anginal pain (chest pain).
Class II (Mild)
Patients with cardiac disease resulting in slight limitation of physical activity. They 
are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain
Class III (Moderate)
Patients with cardiac disease resulting in marked limitation of physical activity. 
They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, 
dyspnea, or anginal pain.
Class IV (Severe)
Patients with cardiac disease resulting in the inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
may be present even at rest. If any physical activity is undertaken, discomfort is 
increased.
Reference: The Criteria Committee of the New York Heart Association. Nomenclature and 
Criteria for Diagnosis of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 
1994:253-256.
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APPENDIX 12
COUNTRY SPECIFIC APPENDIX
Criteria for exclusion of HIV-positive subjects in Argentina, Czech Republic, Germany, and Any 
Other Countries Where Exclusion of HIV Positive Participants Is Locally Mandated
Section 6.2 Exclusion
Criteria, Exclusion criterion 3.l
“Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiencysyndrome (AIDS)”to be replaced
with “Positive test for HIV”.
Section 2 FlowChart/Time and Events Schedule,
Table 2- 1:Screening Assessments- LaboratoryTests
Add “HIV” to the list of laboratory tests
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 
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.”
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APPENDIX 13
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 CA209-9N9:
Right Sided
•
Cecum
•
Ascending Colon 
•
Hepatic Flexure
•
Transverse Colon
•
Unknown OR Both-Sided locations
Left Sided
•
Splenic Flexure
•
Descending Colon
•
Sigmoid Colon
Please note that the location of the primary tumor (not a metastatic site) should be used to define 
the sidedness.
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APPENDIX 14
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for the Protocol amendment 03; 17-Dec-2021
The main reasons for Protocol Amendment 03 for CA2099N9 are to expand the eligibility criteria 
of Part 2 to include participants who have received at least 2 (no more than 4) prior lines of therapy, 
 
; 
 
 Additional updates include removal of the 
40 mg (10 mg/mL) potency of nivolumab solution for use moving forward, 
 
 clarification of nivolumab intravenous (IV) administration procedure, and 
clarification of treatment discontinuation requirements. Administrative Letters 04 and 05 are also 
incorporated.
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated staff/contact information for the 
Clinical Trial Physician.
Provided current study contact 
information.
Synopsis: 
Rationale
Study Population
Objectives and Endpoints: 
Parts 1B and 2
Study Schematic
 
(Part 2) phase
Section 3.1: Study Rationale
Table 4-2: Objectives and 
Endpoints: Parts 1B and 2
Section 5.1: Overall Design
Section 5.1.3: Part 2: 
 
 for 
the Triplet Regimen and 
Standard of Care Arm
Section 5.4.2: Rationale for 
Choice of Standard of Care 
Treatment in Part 2
Section 5.4.3: Rationale for 
Stratification in Part 2
Updated to include participants in Part 2 
who have received at least 2 (no more 
than 4) prior lines of therapy.
Expanded the eligibility criteria to 
be more representative of the later 
line microsattelite stable (MSS) 
metastaic colorectal cancer 
(mCRC) patient population.
Protocol Amendment No.: 04
Date: 03-May-2023
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v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Section 6.1: Inclusion Criteria
Section 8.1: Discontinuation 
from Study Treatment
Section 10.1.2: mCRC 3rd line 
Plus Participants: Part 2 
 
 
Cohort
Criterion 2) b) i) was noted as “Not 
applicable per Protocol Amendment 03” 
and a new criterion 2) b) iii) was added to 
include 3L+.
Criterion 2) d) i) was noted as “Not 
applicable per Protocol Amendment 03” 
and a new criterion 2) d) x) was added to 
include 3L+.
Criterion 2) d) v) was noted as “Not 
applicable per Protocol Amendment 03” 
and a new criterion 2) d) xi) was added to 
include 3L+.
Criterion 2) d) viii) was noted as “Not 
applicable per Protocol Amendment 03” 
and a new criterion 2) d) xii) was added 
to include 3L+.
Criterion 2) d) ix) was noted as “Not 
applicable per Protocol Amendment 03” 
and a new criterion 2) d) xiii) was added 
to include 3L+.
Updated to state 3L+ mCRC participants 
in Cohorts 4 and 6 were permitted to 
receive treatment beyond progression.
Updated to include participants in Part 2 
who have received 2 (no more than 4) 
prior lines of therapy.
Synopsis: Study Drug for 
CA2099N9 
Table 7-1: Study treatments for 
CA2099N9
Removed the 40 mg (10 mg/mL) potency 
of nivolumab solution for injection for 
use moving forward.
Removed to be in accord with 
nivolumab updated guidance. 
Protocol Amendment No.: 04
Date: 03-May-2023
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2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Protocol Amendment No.: 04
Date: 03-May-2023
250
5.0
Approved
930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Table 2-1: Screening 
Procedural Outline 
(CA2099N9)
Updated the timing of the following 
assessments from within 14 days prior to 
first dose to within 28 days prior to first 
dose:
•
ECOG status
•
Safety assessment of signs and 
symptoms
•
Echocardiogram or MUGA
•
ECG
•
Local laboratory tests
Updated to assist with sites ability 
to effectively pre-screen 
participants.
Table 2-3: On-Treatment 
Assessments (Part 2 mCRC 
3rd line, Triplet, 
 
 CA2099N9 
Cohort 4)
Incorporated Administrative Letter 
04.
Section 3.2.5: Nivolumab
Mechanism of Action
Added two additional paragraphs at the 
end of the section.
Updated to reflect the latest 
available medical data and 
literature.
Section 3.2.6: Ipilimumab 
Mechanism of Action
Replaced text with updated information.
Updated to reflect the latest 
available medical data and 
literature.
Section 3.2.7: Nivolumab 
Combined with Ipilimumab 
Clinical Activity
Added a summary paragraph at the 
beginning of the section.
Added to be in accord with 
nivolumab and ipilimumab 
updated BMS guidance.
Section 3.2.8: Trametinib 
Mechanism of Action and 
Clinical Activity
Removed “monotherapy” from the 
following:
A comparable safety profile has 
been observed for trametinib in 
combination studies.
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
“Across all completed monotherapy 
studies for trametinib at the 
recommended dose of 2 mg daily, the 
most common AEs were rash, diarrhea, 
fatigue, edema peripheral, nausea, 
dermatitis acneiform, vomiting, 
constipation, anemia, pruritus, alopecia, 
hypertension, decreased appetite, 
dyspnea and dry skin.”
Section 5.4.1: Rationale for 2 
year treatment duration for 
Immunotherapy (Nivolumab + 
Ipilimumab)
Deleted text that referred to 
Keynote-010 and Keynote-006 data.
The text was updated to align with 
BMS guidance as pembrolizumab 
analyses suggested higher 
progression rates after completing 
2 years of treatment; however, 
overall, published data are 
supportive of a 2-year treatment 
duration. 
Section 5.4.2: Rationale for 
Choice of Standard of Care 
Treatment in Part 2
Updated text on regorafenib to confirm 
that the drug may provide benefit in the 
3L+ setting, and that prior TAS-102 is 
allowed.
Updated based on more recent 
available information.
Section 6.1: Inclusion Criteria
Criterion 2) a) was updated from version 
4.0 to Edition 7.0 for the American Joint 
Committee on Cancer.
Updated to reflect the latest 
available version of the American 
Joint Committee on Cancer.
Section 6.1: Inclusion Criteria
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception
Noted Criterion 3) e) as “Not applicable 
per Protocol Amendment 03” and a new 
criterion was added, 3) g).
Updated contraception requirements for 
male participants with partner(s) of 
childbearing potential to specify that 
contraception was required for 4 months 
after the last dose of study treatment.
As the use of contraception by 
male participants treated with 
nivolumab is no longer applicable, 
the period for contraception use 
after the last dose of study 
treatment was updated from 
7 months to 4 months, which is 
approximately 5 half-lives for 
trametinib.
Section 6.2: Exclusion Criteria
Noted Criterion 2) b) as “Not applicable 
per Protocol Amendment 03” and a new 
criterion was added, 2) o).
Updated exclusion of participants 
with prior malignancy active 
within the previous 3 years to 
within the previous 2 years per 
United States Food and Drug 
Administration (FDA) guidance 
“Cancer Clinical Trial Eligibility 
Criteria: Patients with Organ 
Dysfunction or Prior or 
Concurrent Malignancies 
Guidance for Industry” issued 
July 2020. This is to allow for 
participants with prior cancers 
whose natural history or treatment 
does not have the potential to 
interfere with the safety or efficacy 
Protocol Amendment No.: 04
Date: 03-May-2023
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v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
assessment of 
nivolumab/ipilimumab or study 
drugs. 
Section 7.1.4.1: Cohort 4 
Triplet Regimen
Section 7.1.5: Part 1A 
Completed (Triplet Regimen, 
Cohort 2 Group and Cohort 3 
Group: Closed for Enrollment)
Section 7.1.6: Part 1B (Triplet 
Regimen, Cohort 6)
Updated text to clarify:
•
Nivolumab IV infusion is 
approximately 30 minutes
•
The line can be flushed to ensure the 
complete nivolumab dose is 
administered over the approximately 
30-minute infusion
•
When nivolumab and ipilimumab are 
administered on the same day, 
nivolumab is to be administered first 
followed promptly by a flush of 
diluent to clear the line of nivolumab 
before starting the ipilimumab 
infusion. The second infusion will 
always be ipilimumab treatment and 
will start after the infusion line has 
been flushed, filters changed, and the 
participant has been observed to 
ensure no infusion reaction has 
occurred
Updated to reflect the most recent 
guidance from BMS.
Table 7.4.4.1-1: Dose Delay 
and Modification for Events 
Considered Related to 
Trametinib (excluding pyrexia)
Section 7.4.4.2: Guidelines for 
Specific Trametinib-related 
Toxicities
Appendix 6: Trametinib Dose 
Modification Guidelines
Updated the table title to clarify that dose 
delay and modification guidelines for 
events considered to be related to 
trametinib did not apply to pyrexia.
Added the following note to the table:
“In participants who experience retinal 
vein occlusion, trametinib treatment 
should be permanently discontinued.”
Added pyrexia to the list of toxicities that 
may be related to trametinib and included 
the event in the dose modification 
guidelines in Appendix 6.
Updated to align with the latest 
trametinib Investigator’s Brochure 
and safety information.
Section 7.7.1: Prohibited 
and/or Restricted Treatments
Added the following text:
“Non-live Coronavirus Disease 2019 
(COVID-19) vaccination is considered a 
simple concomitant medication within 
the study. However, the safety and 
efficacy of non-live vaccines (including 
non-live COVID-19 vaccines) in 
Added to be in accord with 
nivolumab and ipilimumab 
updated BMS guidance.
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
participants receiving nivolumab, 
ipilimumab, or trametinib are unknown.”
Section 8.1: Discontinuation 
from Study Treatment
Section 8.1.2: Nivolumab and 
Ipilimumab Dose 
Discontinuation
Section 8.1.3: Trametinib Dose 
Discontinuation
Added the following text:  
“Any criteria leading to the 
discontinuation of nivolumab, 
ipilimumab, or trametinib as part of the 
triplet investigative regimen in Parts 1B 
and 2 will require discontinuation of the 
entire regimen.”
Added to clarify treatment 
discontinuation requirements.
Section 9.4.3: Ophthalmic 
Examination
Added note for ophthalmic examination 
at screening that 7-day window does not 
apply at Cycle 1 Day 1.
Added to clarify timing of 
ophthalmic examinatin at 
screening.
Protocol Amendment No.: 04
Date: 03-May-2023
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v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of Key Changes of Protocol Amendment 03
Section Number & Title
Description of Change
Brief Rationale
Appendix 2: Study 
Governance Considerations
The following modifications were made:
•
Updated first paragraph of
Monitoring section to further 
describe that details on monitoring 
can be found in the monitoring plan.
•
Added section for Dissemination of 
Clinical Study Data.
These changes were made to:
•
Clarify expectations for
monitoring.
•
Provide details on how
clinical study information will 
be made available.
Appendix 4: Women of 
Childbearing Potential 
Definitions and Methods of 
Contraception
Updated to include:
•
An introductory paragraph
•
Guidance for females treated with 
hormone replacement therapy
•
Description of end of relevant 
systemic exposure
•
Combined (estrogen- and 
progestogen-containing) hormonal 
contraception and progesterone-only 
hormonal contraception as highly 
effective methods that are user 
dependent
•
Clarification that periodic sexual 
abstinence, withdrawal, spermicides 
only, and lactational amenorrhea 
method are not acceptable methods 
Updated to reflect the most recent 
BMS guidance.
Appendix 5: Nivolumab
Management Algorithms for 
Studies Under CTCAE 
Version 4.0
Updated the appendix title to clarify that 
the management algorithms were specific 
to CTCAE version 4.0 and updated the 
guidance for each of the algorithms to the 
latest version.
Updated to reflect the most recent 
management algorithms for 
CTCAE version 4.0.
All
Minor formatting and typographical 
corrections.
These changes are minor and, 
therefore, have not been 
summarized.
Overall Rationale for the Revised Protocol 02, 06-Oct-2020
CA2099N9 has been revised to further optimize patient selection for the triplet combination 
therapy with immune checkpoint blockage (nivolumab with ipilimumab) and mitogen-activated 
protein kinase enzymes (MEK) inhibitor (trametinib) in MSS mCRC. Protocol Revision 01 was 
finalized in March 2018; however, it was not implemented due to emerging data from Phase 3 
IMblaze 370 released at ESMO World GI in June 2018. As IMblaze370 did not demonstrate 
enhanced efficacy with the doublet combination therapy (program cell death ligand 1 [PD-L1] 
blockage and MEK inhibitor), CA2099N9 has been revised to enroll patients only to the triplet 
regimen in the 2L and 3L setting (Parts 1B and 2, respectively). The sample size was increased to 
approximately 120 patients (2:1 randomization to triplet regimen or regorafenib) in Part 2 and 
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
approximately 80 patients to be treated in Part 1B (triplet regimen) to allow for further assessment 
of clinical safety, efficacy, and 
 
 in MSS mCRC. 
In addition, Administrative Letters 02 and 03, described in the document history, have been 
incorporated.
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Updated Information for the Clinical 
Trial Physician and Clinical Scientist. 
Alignment with current BMS protocol 
study team structure. 
Throughout the protocol
The dose optimization part of the study 
(Part 1 and Part 1A) has completed. 
Enrollment is closed in Part 1 and Part 
1A cohorts. Throughout the protocol, 
text has been added to indicate tables, 
sections, and text with procedures now 
completed or cohorts where enrollment 
has closed.
Part 1 and Part 1A text and tables 
remain in the protocol to reflect the 
dose optimization phase of the  
protocol, which has now completed. 
Per Revised Protocol 02, regorafenib is 
the SOC option in the study (Part 2 
[Cohort 5]) as described in Section 
5.4.2. All information connected to 
TAS-102 as a SOC treatment in this 
study has been deleted (text, tables, and 
appendices). 
Align protocol with revised study 
design. 
NCI-CTCAE version 4.0 has been 
specified as the correct NCI-CTCAE 
version to be used in this study.
Clarification. 
• Synopsis, Study Rationale 
• Section 3.1, Study 
Rationale 
• Section 3.1.1, Research 
Hypothesis
Text added or changed to specify the 
following:
•
2L and 3L pMMR/MSS patients 
will be enrolled in Part 1B and Part 
2, respectively.  
•
Triplet regimen dose, determined 
in the dose optimization phase of 
the study, is nivolumab 6 mg/kg 
Q4W + ipilimumab 1 mg/kg Q8W 
+ trametinib 1.5 mg continuous 
QD. 
•
Goal of study: further assessment 
of clinical safety, efficacy, and 
 in MSS 
mCRC. 
Align with revised study design.
• Synopsis, Number of 
Participants
• Section 5.2 Number of 
Participants 
Specification for participant enrollment 
in Parts 1B and 2. Approximately 200 
participants will be enrolled in Parts 2 
and 1B. 
Aligned with new study design. 
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
• Synopsis, Objectives and 
Endpoints
• Section 4, Objectives and 
Endpoints, Table 4-2, 
Objectives and Endpoints 
Parts 1B and 2
•
All objectives updated to align with 
change in study design for Parts 1B 
and Part 2.
•
Primary endpoint is ORR: changed 
from OS (Part 2) and safety (Part 
1B). 
•
Best Overall Response (BOR), and 
Overall Survival included in list of 
secondary endpoints.
•
Additional secondary objective and 
endpoint added to evaluate efficacy 
in Consensus Molecular Subtypes 
(CMS).
•
 
 
 
 
. 
•
Footnote added to specify RECIST 
v1.1 for response criteria 
Objectives and endpoints revised to 
align with new study design. 
• Synopsis, Overall Design 
and Figure 1-1
• Section 5.1, Overall 
Design and Figure 5.1-1 
Part 1B and Part 2 will enroll 2L and 
3L pMMR/MSS mCRC patients, 
respectively, to treatment with triplet 
regimen or standard of care (Part 2 
only). The recommended Phase 2 dose 
for Parts 2 and 1B triplet regimen, 
determined in the dose optimization 
phase of the study, is nivolumab 
6 mg/kg Q4W + ipilimumab 1 mg/kg 
Q8W + trametinib 1.5 mg continuous 
QD.
Data from IMblaze370 did not 
demonstrate enhanced efficacy with the 
doublet combination therapy (PD-L1 
blockage and MEK inhibitor), 
CA2099N9 has been revised to enroll 
patients only to the triplet regimen in 
the 2L and 3L setting (Parts 1B and 2, 
respectively).
The proportion of participants with 
RAS mutations enrolled into Part 1B 
and Part 2 cohorts will be monitored on 
an ongoing basis. The target will be 
approximately 65% mutant, 35% wild 
type. If accrual diverges significantly 
from this goal, accrual in a cohort may 
be paused after discussion between the 
sponsor and the investigators.
This cap will be to ensure that 
sufficient numbers of RAS wild-type 
patients as well as RAS mutant patients 
are enrolled to allow appropriate 
interpretation of results.  
Synopsis, Number of 
Participants 
Specification for enrollment goal in 
Parts 1B and 2.
Alignment with revision to study 
design.
Section 2.0, Schedule of 
Activities 
Procedures with notable revisions 
include:
Schedule of Activities Tables aligned 
with updated study design and revised 
to include clarifications for the study 
sites. 
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Table 2-1, Screening 
Procedural Outline 
()(CA2099N9)
•
Medical History: Appendix 13 has 
been added as reference for tumor 
sidedness. 
•
BRAF Mutation Status:  BRAF 
V600 mutant participants are not 
eligible for this study.
•
 
 
. 
•
Participant Registration and 
Treatment Assignment: Refer to 
Section 7.2 for stratification factors 
now included. 
 
 
 
 
 
 
• Section 2.0, Schedule of 
Activities: Table 2-3 On-
Treatment Assessments 
(Part 2 mCRC 3rd line, 
Triplet 
 
 CA2099N9) 
Cohort 4
• Section 2.0, Schedule of 
Activities: Table 2-6 On-
Treatment Assessments 
(Part 1B mCRC 2nd line, 
Triplet 
 
, CA2099N9 
[Cohort 6]) 
Table titles and column headers 
updated to reflect change in study 
design, which includes updated 
regimen, assessment days, and cohort 
numbers.
Procedures with notable revisions 
include:
•
Laboratory Tests: Schedule of 
assessments revised (including 
CEA) and instruction on creatinine 
clearance and TSH revised for 
clarity. 
•
 
•
 
 
•
Body Imaging: Note includes 
instructions on scans to vendor. 
•
Outcomes Research Assessment: 
Notes rewritten for clarity and with 
corrected naming of assessment 
tool. 
•
Clinical Drug Supply: Added line 
for administration of ipilimumab 
(Table 2-3 only) and notes revised 
for each part of triplet regimen. 
•
Table footnotes updated.
Schedule of Activities Tables aligned 
with updated study design and revised 
to include clarifications for the study 
sites. 
 
 
 
 
 
 
Section 2.0, Schedule of 
Activities: Table 2-4 On-
Treatment Assessments 
(Part 2 mCRC 3rd line, 
Regorafenib, 
 
Table title and column header updated 
to include updated regimen, assessment 
schedule, and cohort number.
Procedures with notable revisions 
include:
Schedule of Activities Tables aligned 
with updated study design and revised 
to include clarifications for the study 
sites. 
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
 CA2099N9) 
Cohort 5
•
Laboratory Tests: Schedule of 
assessments revised (including 
CEA) and instruction on creatinine 
clearance and TSH revised for 
clarity. 
•
 
 
•
Body Imaging; Note includes 
instructions on scans to vendor. 
•
Outcomes Research Assessment: 
Notes rewritten for clarity and with 
corrected naming of assessment 
tool. 
•
Clinical Drug Supply: Regorafenib 
note revised.
•
Table footnotes updated. 
 
 
 
 
 
 
Section 2.0 Schedule of 
Activities: Table 2-7: 
Follow-Up Period (All 
treatment cohorts) 
(CA2099N9)
Procedures with notable revisions 
include:
•
Review of Subsequent Cancer 
Therapies: Note includes 
instructions on information to be 
collected for subsequent therapies. 
•
Laboratory Tests: instruction on 
creatinine clearance and TSH 
revised. 
•
Body Imaging; Note includes 
instructions on scans to vendor. 
•
Outcomes Research Assessment: 
Notes rewritten for clarity and with 
corrected naming of assessment 
tool. 
•
Footnote c has been updated to 
reflect a 14 day window rather than 
7 days for Survival Follow-Up 
Visits. 
Schedule of Activities Tables aligned 
with updated study design and revised 
to include clarifications for the study 
sites.  Change in window for follow-up 
reflects alignment with study treatment 
standard. 
Section 3.1.2, Rationale for 
the Combination of 
Nivolumab and Ipilimumab 
with Trametinib in MSS 
CRC Population 
Section 3.1.3, Rationale for 
Adding Ipilimumab to 
Nivolumab and Trametinib
Section 3.1.3 was revised to include 
updated clinical data to support triplet 
regimen in light of lack of clinical 
efficacy of the doublet treatment 
regimen of PD-(L)1 inhibition in 
combination with MEK inhibition as 
reported in the recent IMblaze370 
Phase 3 trial. Revisions to this section 
addressed content in Section 3.1.3, 
which was previously deleted. 
Updated to reflect most recently 
reported clinical data.
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 3.2.4, Consensus 
Molecular Structure 
New section to provide background on 
CMS subtypes and to support study 
objective to evaluate efficacy in CMS 
subtypes. Includes Table 3.2.4-1:  
2l+ Clinical Data in Consensus 
Molecular Subtypes (CMS) of mCRC
Updated to provide context for CMS 
subtyping 
 
  
Section 3.3, Overall Benefit 
Risk
New paragraph added to address 
addition of Parts 1B and 2 to study 
design. 
Included to further detail potential 
benefit of the triplet regimen.
Section 3.3.1, Summary of 
Safety and Efficacy in 
Relevant Clinical Trials: 
Table 3.3.1-1 
Table updated with summary of clinical 
data regarding 3L + mCRC.
Updated to reflect most recently 
reported clinical data.
• Section 3.3.2 Safety 
Monitoring on Study 
Treatment
• Section 5.1.4 Data 
Monitoring Committee 
and Other External 
Committee
• Section 5.1.4.2, Data 
Monitoring Committee
Data monitoring committee will not be 
utilized for this Phase1/2 study as 
indicated in Section 5.1.4.  
Section 5.1.4.2 was removed.
Safety was established in Part 1 and 
Part 1A cohorts.
• Section 5.1.2, Part 1B: 
 
 
for Triplet Regimen 
• Section 5.1.3, Part 2: 
 
 
for Triplet Regimen and 
Standard of Care 
• Arm
These sections describe Part 1B and 
Part 2.
Aligns with new study design.
Section 5.1.4.1, Blinded 
Independent Central Review 
 
 
 
 
 
Section 5.4.2, Rationale for 
Choice of Standard of Care 
(SOC) Treatment in Part 2
Regorafenib addressed as standard of 
care choice. 
Regorafenib is the standard of care 
option for this study: Cohort 5 (Part 
1B).
Section 5.4.3, Rationale for 
Stratification in Part 2
Two stratification factors, primary 
tumor location (right vs left sided 
tumor) and extended RAS status (wild-
type vs mutant) were chosen to 
compare for the evaluation of the triplet 
regimen.
Clinical data support primary tumor 
location as having significant 
prognostic impact.
Extended RAS (KRAS and NRAS) 
testing is standard practice in guiding 
treatment decisions in mCRC. 
Protocol Amendment No.: 04
Date: 03-May-2023
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Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 5.5.1.1, Rationale 
for Nivolumab Dosing
New paragraph to address nivolumab 
dose in this revision.  
Text added to support Phase 2 
nivolumab dose for Parts 1B and 2.
Section 5.5.2, Rationale for 
the Dose of Trametinib 
Updated to include rationale for dose of 
trametinib to be used in Parts 1B and 2. 
The recommended Phase 2 dose of 
trametinib in the triplet regimen for 
Parts 2 and 1B will be 1.5 mg 
continuous QD, which is based on the 
initial safety, efficacy, 
 
data observed from Parts 1 and 1A.
Section 5.5.4, Rationale for 
Dose Selection of 
Regorafenib in 3rd line 
MSS/mCRC
Section updated to address choice of 
regorafenib as standard of care option.
Dose of regorafenib is based on 
approved labels across various regions. 
Section 6.1, Inclusion 
Criteria
2) b) i): Addition of Part 2 (third line 
setting) to inclusion for MSS status
2) b) ii) Criterion is no longer 
applicable: ie, eligibility of participants 
with pMMR/MSS and dMMR/MSI-H 
mCRC 
2) c) i) Note that in Part 2 and Part 1B 
proportion of participants with RAS 
mutation and wild type will be 
monitored. 
2) d) i) added Part 2 to inclusion 
criteria specifying number of lines of 
prior therapy
2) d) v) Participants who received 
FOLFOXIRI (or equivalent) in the 
first-line setting may now be 
considered for enrollment in the 3L 
setting (Part 1 or Part 2) but not the 2L 
setting (Part 1A or Part 1B
2) d) vii) Per revised protocol 02, 
criterion no longer applies.
 
.
3)d) and 3)e) contraception requirement 
for participants randomized to standard 
of care arm now addressed. 
Alignment with updates to study design 
and on study population to be enrolled 
in Part 1B and Part 2. 
Section 6.2, Exclusion 
Criteria
1) a) All parts of the study require 
verification of BRAF mutation status; 
therefore reference to study parts was 
removed. 
2) m) vii: exclusion criterion is noted to 
apply to both potential participants in 
Part 1B and Part 2.
Clarification for mutation testing and 
alignment with current standards for 
study treatments.
Protocol Amendment No.: 04
Date: 03-May-2023
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2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
2(n) Participants who have received a 
live/attenuated vaccine within 30 days 
of randomization are now excluded.
5)a) Added qualifier that in countries 
where permitted prisoners or 
participants are involuntarily 
incarcerated may be eligible. 
Section 7 Treatment, Table 
7-1 Study treatments for 
CA2099N9
50 mg added to Ipilimumab Solution 
for Injection.
Alignment to reflect updated 
availability in ipilimumab vial sizes.  
• Section 7.1.4, Part 2 
(Triplet Regimen, Cohort 
4 and Standard of Care 
Arm (Cohort 5) including 
Table 7.1.4.1, Dose 
Schedule of Nivolumab + 
Ipilimumab and 
Trametinib in Part 2 
(Cohort 4) 
• Section 7.1.4.1 Cohort 4 
Triplet regimen
• Section 7.1.4.2, Cohort 5 
Regorafenib including 
Table 7.1.4.2-1, 
Recommended Dose of 
Regorafenib Part 2 
(Cohort 5) 
• Section 7.1.6, Part 1B 
(Triplet Regimen, Cohort 
6) including Table 7.1.6-1, 
Dose Schedule of 
Nivolumab, Ipilimumab, 
and Trametinib in Part 1B 
(Cohort 6) 
These sections have been revised to 
reflect changes in Part 2 and Part 1B 
Cohorts per Revised Protocol 02, 
including dose schedules for the triplet 
regimen and treatment with 
regorafenib. Weight-based dosing 
information added. 
Updated to align with revisions for Part 
2 and Part 1B cohorts. 
Section 7.2, Method of 
Treatment Assignment 
including Table 7.2-1 
Unique Cohort Numbers in 
Parts 1, 1A, 1B, and 2.
Updated to include cohort numbering 
and dosing for Parts 1B and 2. 
Test added to support stratification. 
Align with changes in the study design. 
Section 7.3, Blinding 
As Part 2 is randomized/open label, 
access to treatment codes is restricted 
from all BMS personnel prior to 
database lock. 
Aligned with current protocol standard.
Section 7.4.1, 
Nivolumab/Ipilimumab 
Dose Delay 
Myocarditis added to list of 
management algorithms. 
Alignment with current standard for 
treatment with immuno-oncology 
agents. 
Protocol Amendment No.: 04
Date: 03-May-2023
262
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930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
• Section 7.4.4.2, 
Guidelines for Specific 
Trametinib Related 
Toxicities
• Appendix 6, Trametinib 
Dosing Modifications
QTc prolongation removed as toxicity 
related to trametinib.
QTc prolongation is no longer 
considered as trametinib related 
toxicity.
• Section 7.4.4.3, Dose 
Modification for 
Trametinib
Table 7.4.4.3-1: 
Potential Trametinib 
Dose Levels in Part 1B 
and Part 2
• Section 8.1.3, Trametinib 
Dose Discontinuation
Text and table changes for dose 
modifications and discontinuation for 
trametinib.  
Adjusted for study population. 
Section 7.7.1, Prohibited 
and/or Restricted 
Treatments
Section 7.7.3, Permitted 
Therapies
Text added to Section 7.7.1: Any 
live/attenuated vaccine (eg, varicella, 
zoster, yellow fever, rotavirus, oral 
polio and measles, mumps, rubella 
[MMR]) within 100 days post last dose 
of nivolumab without or with 
ipilimumab.
Similar information deleted from 
Section 7.7.1.
Alignment with standard language for 
participants enrolled in studies with 
immuno-oncology treatment. 
Section 8.1, Discontinuation 
from Study Treatment 
Treatment beyond progression is 
allowed for participants in Cohort 4 and 
Cohort 6.
Language regarding notification of 
pregnancy updated. 
Revised for study population and to 
align with current standard for 
reporting pregnancy. 
• Section 8.1.1, Nivolumab 
Dose Discontinuation 
(Part 1) 
• Section 8.1.2, Nivolumab 
and Ipilimumab Dose 
Discontinuation
•
Section titles changed.
The following note was removed from 
both sections: **Consideration can be 
given to participants with abnormal 
baseline AST or ALT or abnormal 
baseline bilirubin values.  If the 
investigator determines a possible 
favorable benefit/risk ratio that 
warrants continuation of study 
treatment(s), a discussion between the 
investigator and the BMS Medical 
Monitor/designee must occur.
Titles were changed to reflect revised 
study design.  
Paragraph was removed as sufficient 
guidance is provided within the section. 
Protocol Amendment No.: 04
Date: 03-May-2023
263
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5.0
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Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 8.1.5, Treatment 
Beyond Progression 
Language in this section has been 
updated to align with standard for 
clinical trials with immuno-oncology 
agents and to specify that treatment 
beyond progression is permitted in 
Cohorts 4 and 6. 
Alignment with current standard 
imaging language and particulars for 
this study. 
Section 8.1.6, Post Study 
Treatment Study Follow-up
Text added to address sponsor request 
for survival language outside of 
protocol-defined window. 
Aligned with current standard protocol 
language.
Section 9.1.1.2, Imaging 
Schedule and Assessment
Language added to specify imaging 
schedule for participants treated beyond 
progression. 
Section aligned with revised study 
design.
Section 9.1.1.3, Tumor 
Assessment by Investigator 
Sites 
Language updated to imaging standard 
for sending of scans to the vendor. 
Instructions to site for Part 1B and Part 
2 included.
Language added for BOR of stable 
disease (SD) requiring minimum of 49 
days from first dose to date of first 
imaging assessment.
Clarification and alignment with 
current protocol standard.
Section 9.2, Adverse Events
Change in Trametinib Adverse Events 
of Special Interest:
Deletion: Diarrhea, Edema
Addition: Venous Thromboembolism 
Revised per current Investigator 
Brochure (IB) for trametinib. 
Section 9.2.1, Time Period 
and Frequency for 
Collecting AE and SAE 
Information
Language not relevant to this study was 
deleted.
Text added for reporting of SAEs for 
participants assigned to treatment but 
not treated. 
Correction and updated to current 
protocol standard. 
Section 9.2.2, Method of 
Detecting AEs and SAEs.
Section updates to align with current 
standard language for immuno-
oncology treatments.
Alignment with program-wide 
standard.
Section 9.2.4, Regulatory 
Reporting Requirements for 
SAEs
Redundant text removed. 
Alignment with current protocol 
standard. 
Section 9.4.3, Ophthalmic 
Examination
Ophthalmic examination during 
treatment and Follow-Up periods is not 
required for Cohort 5 participants, 
unless clinically indicated.
Ophthalmic examination is required for 
all participants treated with trametinib. 
Protocol Amendment No.: 04
Date: 03-May-2023
264
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Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 9.9, Health 
Economics OR Medical 
Resource Utilization and 
Health Economics 
Updated to specify that data will be 
collected for participants in Part 1B and 
Part 2.
Aligned with addition of 
 
 cohorts. 
Protocol Amendment No.: 04
Date: 03-May-2023
265
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930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
Section 10.1.2, mCRC 3rd 
line Participants: Part 2 
 
 
Cohort,
 
 
 
Aligns with revised study design and 
study objectives.
Section 10.1.4, mCRC 2nd 
line Participants: Part 1B 
 
Cohorts
 
Section 10.2, Populations 
for Analyses
Revised definitions to include 
randomized cohorts from Part 2.
Section 10.3.1, Efficacy 
Analyses
Updated to support study design 
revisions including efficacy in 
subgroups of interest, which are 
specified. 
Detailed revision for efficacy endpoints 
(eg, to include randomized cohorts 
from Part 2 or new endpoints)  and 
statistical methods. 
Section 10.3.2, Safety 
Analyses
Minor revisions. 
Section 10.3.7, Interim 
Analyses 
An interim analysis of Part 2 and Part 
1B cohorts has been defined and the 
section has been updated. 
Section 11, References
Updated to include references to support new text in background sections. 
Appendix 5, Nivolumab 
Management Algorithms 
Updated to current management 
algorithms, which includes algorithm 
for myocarditis. 
Aligned with current Management 
Algorithms for all immuno-oncology 
agents. 
Appendix 10, KRAS/NRAS 
and BRAF Mutational 
Testing
Participant enrollment will be based on 
initial testing results 
 
 
Confirmation of enrollment status. 
Protocol Amendment No.: 04
Date: 03-May-2023
266
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5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & 
Title
Description of Change
Brief Rationale
 
 
Appendix 12, Country 
Specific Appendix 
France, Spain, and Italy have been 
deleted from the countries that require 
criteria for exclusion of HIV-positive 
subjects. 
Pregnancy added as a reason for 
permanent discontinuation from study 
treatment in Czech Republic and any 
Other Countries Where Locally 
Mandated.
Correction of regulatory requirements 
for the Czech Republic, France, Spain, 
and Italy. 
Appendix 13, Guidance to 
Sites on Tumor Location 
and Sidedness 
Replaces previous Appendix 13 with 
new on Specifications for Tumor 
Sidedness.
Specifications for stratification factor 
(tumor sidedness) for participants in 
Part 2.
Appendix 14, Revised 
Protocol Summary of 
Change History
The summay of key changes for 
Revised Protocol 01 is included as 
Appendix 14. 
Of note, Revised Protocol 01 was 
approved but was not implemented. 
This appendix is in alignment with 
standard for revised protocols. 
Throughout the protocol
Minor editorial and format changes.
Revised for clarity.
Overall Rationale for the Revised Protocol 01, 01-Mar-2018
The protocol has been amended to include a randomized comparator arm (Cohort 7) for Part 2 
consisting of standard-of-care regimens (regorafenib or TAS-102) per investigator’s choice for 
≥3rd line metastatic colorectal cancer (mCRC). The rationale is to allow a direct comparison of 
safety and efficacy between study treatment and standard of care treatment in a randomized 
controlled trial design (Part 2). In addition, primary endpoint for Part 2 has been changed to Overall 
Survival (OS), which is the standard endpoint for efficacy assessment in oncology trials. The 
demonstration of clinically meaningful improvements in survival compared to current therapies in 
the treatment of later line mCRC as well as manageable safety, provides an opportunity to support 
registration.
Summary of key changes of Revised Protocol 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 2. Schedule of 
Activities
New table (Table 2-4) added.
New table added to detail schedule of activities for 
Cohort 7.
Section 5.1. Overall 
Design
Section 5.1 amended to include 
details relating to the comparator 
arm.
The study design has been amended to include the 
details relating to the addition of the comparator 
arm in Cohort 7.
Protocol Amendment No.: 04
Date: 03-May-2023
267
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5.0
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Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 5.1.4.2. Data 
Monitoring 
Committee for Part 2
New Section (Section 5.1.4.2) 
added.
A Data Monitoring Committee has been 
introduced to ensure participant safety and monitor 
evaluable data for efficacy during Part 2 of the 
study design.
Section 5.2. Number 
of Participants
Number of participants for the 
randomized Part 2 has been 
detailed.
The number of participants to be studied in Part 2 
(based on the sample size justification presented in 
Section 10.1) has been amended to allow for the 
2:1 randomization between Cohorts 4 and 7.
Section 5.4.1 
Rationale for 
Treatment Duration
Rationale updated. No change to 
study conduct. 
Most updated rationale added supporting 
maximum treatment duration of 2 years from first 
dose.
Section 5.4.2. 
Rationale for Choice 
of Comparator 
Treatments in Part 2
New Section (Section 5.4.2) 
added.
Section added to detail the rationale for the choice 
of standard-of-care chemotherapy regimens 
included for comparator purposes in Cohort 7.
Section 5.4.3. 
Rationale for 
Stratification in Part 2
New Section (Section 5.4.3) 
added.
Section added to detail the rationale for the 
stratification factors (right versus left sided tumors 
and RAS/BRAF double wild-type versus mutant 
[RAS or BRAF, or both]) adopted as part of the 
randomization for Part 2 of the study.
Section 5.5.4. 
Rationale for Dose 
Selection of TAS-102 
in ≥ 3rd line mCRC
New Section (Section 5.5.4) 
added.
Section added to detail the rationale for the dose 
selection for TAS-102 to be used in Part 2, Cohort 
7.
Section 5.5.5. 
Rationale for Dose 
Selection of 
Regorafenib in ≥ 3rd 
Line mCRC
New Section (Section 5.5.5) 
added.
Section added to detail the rationale for the dose 
selection for regorafenib to be used in Part 2, 
Cohort 7.
Section 6.1. Inclusion 
Criteria
Prior lines of therapy clarified.
Section 6.1, 2) d) revised to clarify the relevant 
prior lines of therapy for Parts 1 and 2.
Section 6.2. Exclusion 
Criteria
3)
Additional contraindications 
with respect to medical 
history and concurrent 
diseases added.
4)
Botanical washout period 
changed from 4- to 2 weeks 
prior to first dose. Note 
referring to 7.7.1 added. 
5)
Section 6.2 revised to include contra-
indications for treatment with regorafenib and 
TAS-102.
6)
Correction of washout duration to 2 weeks 
prior to first dose. Clarification regarding 
marijuana use added to Section 7.7.1.
Section 7. Treatment
Table 7-1 amended.
Table 7-1 amended to include details pertaining to 
regorafenib and TAS-102.
Section 7.1.1 
Nivolumab and 
Ipilimumab Infusion
Change “saline” to “diluent” for 
line flushing between infusions. 
Change clarifies that the post-nivolumab infusion 
may be done with diluent not only saline.
Protocol Amendment No.: 04
Date: 03-May-2023
268
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930117593
5.0
v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number 
& Title
Description of Change
Brief Rationale
Section 7.1.4.2. 
Cohort 7 Regorafenib 
or TAS-102, Section 
7.1.4.3. Regorafenib 
Dosing in Part 2, and 
Section 7.1.4.4. TAS-
102 Dosing in Part 2
New Sections (Sections 7.1.4.2, 
7.1.4.3, and 7.1.4.4) added.
Sections added to detail the treatments assigned 
and starting doses in Cohort 7.
Section 7.2. Method of 
Treatment Assignment
Table 7.2-1 modified to include 
Cohort Number in 7.
Table 7.2-1 modified to include details for 
Cohort 7.
Section 7.2. Method of 
Treatment Assignment
Section 7.2 revised to include 
stratification details relating to 
treatment assignment for Cohorts 
4 and 7. 
Section revised to detail the stratification factors 
(right versus left sided tumors and RAS/BRAF 
double wild-type versus mutant [RAS, or BRAF, 
or both]) adopted as part of the randomization for 
Part 2 of the study.
Section 7.4. Dosage 
Modification
Section 7.4 revised to include 
details regarding dose 
modifications for regorafenib 
(Section 7.4.6) and TAS-102
(Section 7.4.7).
Section revised to provide initial guidance on dose 
modifications for the additional study treatments 
introduced with this protocol amendment.
Section 7.7.1 
Prohibited and/or 
Restricted Treatments
Clarification added regarding 
marijuana.
Marijuana may not be prohibited if medically 
prescribed or locally legal. 
Section 7.7.3. 
Permitted Therapies
Section amended to include 
reference to supportive care.
As supportive care is routine for regorafenib and 
TAS-102, suitable reference to this has been 
included.
Sections 8.1.1 
Nivolumab Dose 
Discontinuation and 
8.1.2 Nivolumab and 
Ipilimumab Dose 
Discontinuation
Myocarditis added to the list of 
events that require 
discontinuation. 
Addition aligns discontinuation with SmPC and 
USPI. 
Section 8.1.4. TAS-
102 Dose 
Discontinuation
New Section (Section 8.1.4) 
added.
Section added to detail instances requiring 
discontinuation of TAS-102.
Section 8.1.5. 
Regorafenib Dose 
Discontinuation
New Section (Section 8.1.5) 
added.
Section added to detail instances requiring 
discontinuation of regorafenib.
Section 8.1.6 
Treatment Beyond 
Progression
Added that treatment beyond 
progression may continue to a 
maximum of 2 years from first 
dose. 
Clarification of maximum duration of treatment.
Section 9.9. Health 
Economics OR 
Medical Resource 
Details regarding healthcare 
resource utilization data capture 
included.
Healthcare resource utilization data will be 
collected for Part 2.
Protocol Amendment No.: 04
Date: 03-May-2023
269
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930117593
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v
Approved
2.0
v

Clinical Protocol
CA2099N9
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section Number 
& Title
Description of Change
Brief Rationale
Utilization and Health 
Economics
Section 10.1.2. mCRC 
≥ 3rd line Participants: 
Part 2 Dose Expansion 
Cohort
New Section (Section 10.1.2) 
added.
Section added to detail the sample size 
determination for Part 2, based on the primary 
efficacy of OS, and to detail the plans for interim 
analyses in this part of the study.
Section 10.3.1. 
Efficacy Analyses
Details regarding OS added to 
Endpoints and Statistical Methods
Details regarding OS (primary efficacy endpoint 
for Part 2) included.
Section 10.3.7. Interim 
Analyses
New Section (Section 10.3.7) 
added.
Interim analyses prospectively detailed for the 
efficacy comparison in Part 2 between Nivolumab 
+ Trametinib and Regorafenib/TAS-102.
Protocol Amendment No.: 04
Date: 03-May-2023
270
5.0
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930117593
5.0
v
Approved
2.0
v