Clinical trial NCT03414983
Conditions: Colorectal Cancer
Sponsor: Bristol-Myers Squibb
Start date: 2018-02-20; Completion date: 2022-12-28
Enrollment: 196 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This purpose of this study is to evaluate nivolumab (BMS-936558) in combination with standard of care (SOC) chemotherapy with bevacizumab for the treatment of first-line metastatic colorectal cancer (mCRC).

Detailed description:

Arms: arm 1: Nivo + SOC arm 2: SOC
Interventions: intervention 1: Nivolumab intervention 2: Oxaliplatin intervention 3: Leucovorin intervention 4: Fluorouracil intervention 5: Bevacizumab
Intervention descriptions: intervention 1: Specified dose on specified days intervention 2: Specified dose on specified days intervention 3: Specified dose on specified days intervention 4: Specified dose on specified days intervention 5: Specified dose on specified days

Protocol documents:
Prot_000.pdf: 
Official Title of Study: 
An Open-Label Exploratory Phase 2/3 Study of Nivolumab with Standard of Care Therapy vs 
Standard of Care Therapy for First-Line Treatment of Metastatic Colorectal Cancer 
(CheckMate 9X8: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 9X8) 
 
NCT Number: NCT03414983 
Document Date (Date in which document was last revised): November 13, 2020 


Page:
1
Protocol Number:
CA2099X8
IND Number:
119,381
EUDRACT Number:
2017-003662-27
Date:
13-Oct-2017
Revised Date:
13-Nov-2020
Clinical Protocol CA2099X8
An Open-Label Exploratory Phase 2/3 Study of Nivolumab with Standard of Care Therapy vs 
Standard of Care Therapy for First-Line Treatment of Metastatic Colorectal Cancer 
(CheckMate 9X8: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 9X8)
Protocol Amendment 07
Incorporates Administrative Letter 05
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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 
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within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Protocol Amendment No.: 07
Date: 13-Nov-2020
2
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO).
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CA2099X8
BMS-936558
nivolumab
Protocol Amendment No.: 07
Date: 13-Nov-2020
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol
Amendment 07
13-Nov-2020
Administrative 
Letter 05
28-Sep-2020
Revised Protocol 
06
02-Jun-2020
Major change: Clarifies study treatment duration for standard of care 
(SOC)
SOC may continue, after the maximum treatment duration of 24 months 
for nivolumab, until progression, unacceptable toxicity, withdrawal of 
consent, or the end of the study, whichever comes first.
Revised Protocol 
05
19-Dec-2019
This revised protocol removes Interim Analysis 2 (IA2).
Revised Protocol 
04
07-Dec-2018
Clarifies the infusion days for fluorouracil, updates Appendix 3, and 
aligns Appendix 4 with contraceptive guidance for nivolumab and other 
components of study treatment.
Revised Protocol 
03
13-Sep-2018
Incorporates Administrative Letter 03, and reinstates exclusion criteria 
2j.
Administrative 
Letter 03
11-Sep-2018
Adding Appendix 11 back into the document
Revised Protocol 
02
06-Aug-2018
Incorporates Administrative Letter 02 and updates to be consistent with 
SmPC and label information. Revises prohibited and/or restricted 
treatments; laboratory tests, assessments, and other analyses; dose 
modification criteria; urinalysis
 sample collection 
requirements. 
 clarifies 
eligibility criteria. 
 
 Minor changes and corrections including revisions to reflect the 
most recent language for BMS studies.
Administrative 
Letter 02
23-Apr-2018
Revised Protocol 
01
02-Feb-2018
Incorporates Administrative Letter 01, revisions to laboratory tests 
exclusion criteria, revisions to dose modification criteria, urinalysis 
 
 sample collection requirements. 
 
 Addition of a definition of 
DILI for participants with elevated liver function tests at baseline. 
Updated rationale for the 2-year treatment duration, in addition of a 
number of other minor changes and corrections.
Administrative 
Letter 01
07-Dec-2017
Original Protocol
13-Oct-2017
Not applicable
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TABLE OF CONTENTS
TITLE PAGE................................................................................................................
DOCUMENT HISTORY ..............................................................................................
SUMMARY OF KEY CHANGES OF PROTOCOL AMENDMENT 07 ..................
TABLE OF CONTENTS..............................................................................................
1 SYNOPSIS.................................................................................................................
2 SCHEDULE OF ACTIVITIES..................................................................................
3 INTRODUCTION .....................................................................................................
3.1.1 Research Hypothesis ................................................................................ 
4 OBJECTIVES AND ENDPOINTS...........................................................................
5 STUDY DESIGN.......................................................................................................
5.1 Overall Design ..................................................................................................
5.1.2 Blinded Independent Central Review ....................................................... 
5.2 Number of Participants .....................................................................................
5.3 End of Study Definition....................................................................................
6 STUDY POPULATION............................................................................................
6.1 Inclusion Criteria ..............................................................................................
6.2 Exclusion Criteria .............................................................................................
6.3 Lifestyle Restrictions ........................................................................................
6.4 Screen Failures..................................................................................................
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6.4.1 Retesting During Screening ..................................................................... 
7 TREATMENT ...........................................................................................................
7.1 Treatments Administered..................................................................................
7.2 Method of Treatment Assignment ....................................................................
7.4 Dosage Modification.........................................................................................
7.4.1 Nivolumab Dose Delay ............................................................................ 
7.4.2 Dose Modification Criteria for Oxaliplatin-Plus-Fluoropyrimidine 
Treatment .................................................................................................... 
7.4.2.1 General Guidance for Dose Modification for Chemotherapy ........ 
7.4.3 Dose Modification Criteria for mFOLFOX6 ........................................... 
7.4.4 Dose Modification Criteria for bevacizumab .......................................... 
7.4.5 Treatment of Infusion-Related Reactions ................................................. 
7.5 Preparation/Handling/Storage/Accountability..................................................
7.6 Treatment Compliance......................................................................................
7.7 Concomitant Therapy........................................................................................
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.3 Permitted Therapy ................................................................................... 
7.7.3.1 Imaging Restriction and Precautions ............................................. 
7.8 Post-Study Drug Access ...................................................................................
8 DISCONTINUATION CRITERIA ...........................................................................
8.1 Discontinuation from Study Treatment ............................................................
8.1.1 Nivolumab Dose Discontinuation ............................................................ 
8.1.2 SOC Dose Discontinuation ...................................................................... 
8.1.3 Criteria to Resume Treatment with Nivolumab ....................................... 
8.1.4 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study........................................................................
8.3 Lost to Follow-Up.............................................................................................
9 STUDY ASSESSMENTS AND PROCEDURES.....................................................
9.1 Efficacy Assessments ........................................................................................
9.1.1 Imaging Assessment for the Study............................................................ 
9.1.1.1 Methods of Measurement ................................................................ 
9.1.1.2 BICR Assessment of Progression .................................................... 
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 ...........................................................................................................
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9.4 Safety ................................................................................................................
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Vital signs................................................................................................. 
9.4.3 Clinical Safety Laboratory Assessments .................................................. 
9.4.4 Imaging Safety Assessment ...................................................................... 
10.2 Populations for Analyses ................................................................................
10.3 Statistical Analyses.........................................................................................
10.3.1 Efficacy Analyses ................................................................................... 
10.3.2 Safety Analyses....................................................................................... 
10.3.4 Interim Analyses ..................................................................................... 
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.....................................................................
DEFINITIONS..............................................................................................................
APPENDIX 5 NIVOLUMAB MANAGEMENT ALGORITHMS .............................
APPENDIX 6 ECOG PERFORMANCE STATUS .....................................................
APPENDIX 7 RECIST 1.1 GUIDELINES
..........
APPENDIX 10 COUNTRY SPECIFIC APPENDIX...................................................
APPENDIX 11 REVISED PROTOCOL SUMMARY OF CHANGE HISTORY......
 
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CA2099X8
BMS-936558
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SYNOPSIS
Protocol Title: An Open-Label Exploratory Phase 2/3 Study of Nivolumab with Standard of 
Care Therapy vs Standard of Care Therapy for First-Line Treatment of Metastatic 
Colorectal Cancer 
(CheckMate 9X8: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 9X8)
Study Phase: 2/3
CA209-9X8 (CHECKpoint pathway and nivoluMAB clinical trial evaluation 9X8) is a Phase 2/3, 
open-label, multi-center trial to evaluate nivolumab in combination with standard of care (SOC) 
therapy (mFOLFOX6) with bevacizumab for the treatment of first-line metastatic colorectal cancer 
(mCRC)1. 
Study Population:
Male and female participants of 18 years of age or more with first-line histologically confirmed 
metastatic colorectal cancer, not amenable to curative resection.
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CA2099X8
BMS-936558
nivolumab
Objectives and Endpoints:
Objectives
Endpoints
Primary
•
To compare the efficacy of nivolumab plus SOC 
chemotherapy with bevacizumab (Nivo+SOC) with 
SOC chemotherapy with bevacizumab (SOC) in 
participants with mCRC
•
Progression Free Survival (PFS) by BICR 
Secondary
•
To evaluate preliminary efficacy in all randomized 
participants
•
ORR, DCR, DoR, TTR by BICR per RECIST 
v1.1
•
ORR, PFS, DCR, DoR, TTR by investigator per 
RECIST v1.1
•
OS
•
To characterize the safety and tolerability of 
nivolumab in combination with standard therapy with 
bevacizumab
•
Safety (including but not limited to): Incidence of 
AEs, SAEs, deaths, and clinical abnormalities per 
CTCAE (Version 4)
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Objectives
Endpoints
AEs, adverse events; BICR, blinded independent central review; DCR, disease control rate; DoR, duration of response; 
 
 
 
 
 
 
OS, overall survival; ORR, objective response rate; 
 
 SOC, standard of care;
 
TTR, time to response; 
. 
Overall Design:
This is a Phase 2/3 open-label, multi-center trial of nivolumab in combination with SOC first-line 
chemotherapy with bevacizumab to evaluate the safety profile and clinical activity of this regimen 
in participants with treatment-naive metastatic colorectal cancer (mCRC).  
In Phase 2, participants will be randomized to treatment with mFOLFOX6 + bevacizumab with or 
without nivolumab. 
 
 
 
Participants will be treated until progression, unacceptable toxicity, withdrawal of consent, or the 
end of the study, whichever comes first. Nivolumab will be given for a maximum of 24 months.
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CA2099X8
BMS-936558
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Figure 1: 
Study Design
DCR, disease control rate; FA; final analysis; IA, interim analysis; ORR, objective response rate; OS, overall survival; 
PFS, progression-free survival.
b Depending on the results at the time of interim analysis (IA), different possible decisions may be made as indicated 
by dashed arrows. If there is not enough evidence of favorable benefit/risk at IA, the Phase 2 study will continue to 
complete with 180 participants unless unacceptable safety concern arises.
One interim analysis (IA) is planned in Phase 2 portion of the study to
 
.
 
 The 
interim results will guide the following decisions:
•
When a strong efficacy signal is observed for all randomized participants, 
 
 is 
observed and no substantial differential effects by subgroups, the study will expand 
 
. 
•
Otherwise, the study continues as planned.
If there are not enough data to support an internal decision at the time of IA, the study will continue 
to 180 randomized participants. 
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Treatment Arms and Duration:
Study treatments: 
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Study Drug for CA2099X8
Medication 
Potency 
IP/Non-IP 
Nivolumab a
Solution for Injection
100 mg (10 mg/ml) and 
40 mg (10 mg/ml)
IP
Oxaliplatin b
various strengths
IP
ቄ
Leucovorin
Calcium Folinateቅb
various strengths
IP
Fluorouracil b
various strengths
IP
Bevacizumab b
various strengths
IP
a May be labeled as either ͆BMS-936558-01͇ or ͆Nivolumab͇
b These products may be obtained by the investigational sites as local commercial products in certain countries if 
allowed by local regulations. 
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
2
SCHEDULE OF ACTIVITIES
Table 2-1:
Screening Procedural Outline (CA2099X8)
Procedurea
Screening 
Visit
Notes
Eligibility Assessments
Informed Consent
X
Register in Interactive Response system to obtain participant number.
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 IRT.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening (re-enrollment if applicable) 
and confirmed prior to randomization.
Medical History
X
All medical history relevant to the disease under study
Baseline Tumor Submission
X
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections (minimum 20 slides from a metastatic site or 25 from a primary colon site), 
obtained within 180 days prior to enrollment and after the last dose of the most recent 
systemic anti-cancer therapy, with an associated pathology report, must be submitted to the 
core laboratory for inclusion. For participants with samples outside of the above criteria, a 
fresh biopsy will be required. 
If the above sample is not from the primary colon tumor, an additional archival sample of at 
least 5 slides must be submitted from the primary colon tumor.  These five slides may be 
submitted after randomization.
Central lab must provide IRT with confirmation of receipt of evaluable tumor tissue prior to 
randomization. Biopsy should be excisional, incisional or core needle. Fine needle 
aspiration is unacceptable for submission.
Baseline Tumor Assessment
X
Must be performed within 28 days prior to first dose. Brain imaging to be performed at 
screening for participants with a history or clinical symptoms of brain metastasis. Bone 
scan may be performed as clinically indicated. See Section 9.1.1
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CA2099X8
BMS-936558
nivolumab
Table 2-1:
Screening Procedural Outline (CA2099X8)
Procedurea
Screening 
Visit
Notes
Safety Assessments
Targeted Physical Examination, Measurements, 
Vital Signs and Performance Status
X
Height, weight, Performance Status (ECOG, see Appendix 6), BP, HR, Temperature. Must 
be collected within 14 days prior to randomization.
ECG
X
Within 14 days prior to randomization.
Assessment of Signs and Symptoms
X
Must be performed within 14 days prior to randomization.
Concomitant Medication Use
X
Must be collected within 14 days prior to randomization.
Vaccine use within 30 days prior to randomization.
SAE Assessment
X
Serious Adverse Event collection from time of consent.
Laboratory Tests
Includes blood and urine samples. 
CBC w/differential, Chemistry, Endocrine, Viral, 
urinalysis
X
CBC, chemistry, urinalysis and endocrine testing must be performed within 14 days prior to 
randomization.  Note: Laboratory tests do not need to be repeated on C1D1 if screening lab 
results are deemed still clinically valid by the treating investigator.
Urinalysis or urine dipstick including protein, glucose, blood, leukocyte esterase, specific 
gravity, pHb
Viral testing to be performed within 28 days prior to randomization. Refer to Section 9.4.3
for list of laboratory tests to conduct.
Pregnancy Test 
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 of study therapy. See Appendix 4
For females under the age of 55, FSH > 40 mIU/mL is required to confirm menopause.
MMR/Microsatellite Status
X
Confirm availability of pathology report for MMR or microsatellite-testing results. Report 
must contain MMR or microsatellite-testing results and should also contain specific results 
per markers tested by IHC or PCR.
Please see inclusion criteria (Section 6.1) 
 for details.
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Clinical Protocol
CA2099X8
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Table 2-1:
Screening Procedural Outline (CA2099X8)
Procedurea
Screening 
Visit
Notes
RAS and BRAF mutation Status
X
Verify RAS and BRAF mutation status, including Kirsten Rat Sarcoma (KRAS) and 
Neuroblastoma Rat Sarcoma (NRAS), based on local testing 
CEA (and CA19-9) Assessment
X
CEA tumor marker will be assessed at screening. If CEA is within normal limits, a CA19-9 
tumor marker will be checked. If the CA19-9 is elevated, this patient will be followed with 
the CA19-9 AND CEA tumor markers. However, if the CA19-9 is within normal limits, 
this patient will be followed with CEA tumor marker only.
BP, blood pressure; CA19-9, cancer antigen 19-9; CBC, complete blood count; CEA, carcino embryonic antigen; HR, heart rate; MMR, mismatch repair; SAEs, 
serious adverse events.
a Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations
b Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required. If urine 
protein is ≥ 2+ from urine dipstick or equivalent from random urinalysis, results from a 24-hour urine collection or urine protein to creatinine ratio (UPCR) are 
required to determine eligibility (refer to exclusion criteria).
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Table 2-2:
On-Treatment Procedural Outline (CA2099X8)
Procedure a
Cycle 1 (1 cycle = 4 weeks)b
Each Subsequent Cycle
(cycle = 4 weeks)
Notes
D1
D2
D15
D16
D1
D2
D15
D16
Safety Assessments
Targeted Physical 
Examination, 
Measurements, Vital 
Signs, Performance Status
X
  
X
X
  
X
Weight, BP, HR, Temperature and Performance Status
Adverse Events 
Assessment (including 
SAEs)
Continuously
Record at each visit
Concomitant Medication 
Continuously
Record at each visit
Laboratory Tests
Pregnancy Test
X
See notes
Serum or urine pregnancy test to be done within 24 hours 
prior to first dose, and then every 4 weeks (± 7 days) 
regardless of dosing schedule. See Appendix 4.
CBC w/differential, 
Chemistry panel and 
urinalysis
X
X
X
X
Laboratory assessments should be performed within 72 hours 
prior to each infusion.
Urinalysis or urine dipstick including protein, glucose, blood, 
leukocyte esterase, specific gravity, pH to be performed 
within 72 hrs prior to each bevacizumab infusiond.
Refer to Section 9.4.3
Thyroid Testing
X
X
Refer to Section 9.4.3
CEA (and CA19-9)
Assessment
X
See notes
Selected tumor marker(s) at screening (CEA alone or CEA 
and CA19-9) will be assessed every 2 weeks (±7 days) until 
Week 12, then every 8 weeks (±7 days) thereafter, prior to 
each restaging.
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Table 2-2:
On-Treatment Procedural Outline (CA2099X8)
Procedure a
Cycle 1 (1 cycle = 4 weeks)b
Each Subsequent Cycle
(cycle = 4 weeks)
Notes
D1
D2
D15
D16
D1
D2
D15
D16
Efficacy Assessments
Tumor assessments
Imaging will begin at Week 12 (± 7 days) from randomization, 
and then every 8 weeks (± 7 days) thereafter until confirmed 
progression, withdrawal of consent, or the study ends, 
whichever occurs first. This schedule should be followed even if 
treatment delay occurs. 
Brain Imaging 
See Section 9.1.1
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Table 2-2:
On-Treatment Procedural Outline (CA2099X8)
Procedure a
Cycle 1 (1 cycle = 4 weeks)b
Each Subsequent Cycle
(cycle = 4 weeks)
Notes
D1
D2
D15
D16
D1
D2
D15
D16
IRT Vial Assignment
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
Table 2-2:
On-Treatment Procedural Outline (CA2099X8)
Procedure a
Cycle 1 (1 cycle = 4 weeks)b
Each Subsequent Cycle
(cycle = 4 weeks)
Notes
D1
D2
D15
D16
D1
D2
D15
D16
Randomization
X
Randomization after eligibility is confirmed. First treatment 
should occur within 3 calendar days of randomization.
Dispense Study 
Treatment:
Nivolumab 240 mg flat 
dose (Arm A) IV
X
X
X
X
ONLY in ARM A (Nivolumab + SOC) 
Oxaliplatin 85 mg/m2 IV
X
X
X
X
Leucovorin 400 or 350 
mg/m2  IVc
X
X
X
X
Fluorouracil 400 mg/m2
IV
X
X
X
X
Fluorouracil 1200 mg/m2
IVc
X
X
X
X
Continuous infusion over 24 hours. Day 1 (or Day 15) 
through Day 2 (or Day 16) of each cycle (total dose of 
2400 mg/m2 over 48 hours)
OR
Fluorouracil 2400 
mg/m2 IVc
X
X
X
X
Continuous infusion over 46 to 48 hours. Day 1 (or Day 15)
through Day 2 (or Day 16)
Bevacizumab 5 mg/kg IV
X
X
X
X
BP, blood pressure; CA19-9, cancer antigen 19-9; CBC, complete blood count; CEA, carcino embryonic antigen; HR, heart rate;
 IRT, 
interactive response technology; 
SAEs, serious adverse events.
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 regulations
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b If a dose is delayed, the procedures schedule for that same timepoint should also be delayed to coincide with when that timepoint’s dosing actually occurs. If 
dose is delayed, CEA (and CA19-9) schedule should be kept regardless of dosing.
c Regimen for FOLFOX6 may be used as per local standards
d If urine protein is ≥ 2+ from urine dipstick or equivalent from random urinalysis a 24 hour urine collection or UPCR should be performed and results obtained 
before the next treatment with bevacizumab.  See Section 7.4.4 for bevacizumab dose modification criteria.
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Table 2-3:
Follow-up Procedural Outline (CA2099X8)
Procedure a
Safety 
Follow-
up visits 
1 and 2b
Survival
Follow-upc
Notes
Safety Assessments
Targeted Physical Examination, Vital Signs
X
Adverse Events Assessment (including SAEs)
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)
Concomitant Medication Review
X
Review of Subsequent Cancer Therapies
X
X
Additional subsequent cancer therapy details such as regimen, setting of 
the regimen, line of therapy, start date and end date of each regimen, best 
response to the regimen and date of progression after second line therapy 
will be collected.
Laboratory Tests
Pregnancy Test
X
CBC w/differential, Chemistry panel, Thyroid testing, 
and urinalysis
X
To be done at safety follow-up visit 1. To be repeated at safety follow-up 
visit 2 if study related toxicity persists.
FU visit 1 ONLY:  Urinalysis or urine dipstick including protein, glucose, 
blood, leukocyte esterase, specific gravity, pHd
Refer to Section 9.4.3 Clinical Safety Laboratory Assessments for list of 
laboratory tests.
Efficacy Assessments
Tumor assessments
Participants who enter the follow-up period without tumor progression will continue to have tumor 
imaging assessments as per on-treatment schedule (at Week 12 from randomization, and then every 8 
weeks thereafter until confirmed progression, withdrawal of consent, or the study ends, whichever 
occurs first). 
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Table 2-3:
Follow-up Procedural Outline (CA2099X8)
Procedure a
Safety 
Follow-
up visits 
1 and 2b
Survival
Follow-upc
Notes
Brain Imaging 
See Section 9.1.1
Participant Status
Survival status
X
X
Every 3 months after safety follow-up visit 2; may be accomplished by 
visit, phone contact or email, to assess subsequent anti-cancer therapy for 
up to 3 years after completing safety follow up visit in all cohorts.
CBC, complete blood count; SAEs, serious adverse events;
 
.
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 regulations
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 Survival Follow-up visits to occur every 3 months (± 14 days) from Follow-up visit #2. Survival visit may be conducted in person or by telephone. BMS may 
request that survival data be collected on all treated participants outside of the 3 month specified window. At the time of this request, each participant will be 
contacted to determine their survival status unless the participant has withdrawn consent for all contact.
d Urinalysis or urine dipstick. If blood, protein, or leukocytes esterase are positive on the dipstick, microscopic examination of the sediment is required. If urine 
protein is ≥2+ from urine dipstick or equivalent from random urinalysis, 24-hour urine collection or UPCR may be performed if deemed clinically indicated by 
the investigator.
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3
INTRODUCTION
CA209-9X8 (CHECKpoint pathway and nivoluMAB clinical trial evaluation 9X8) is a Phase 2/3,
open-label, multi-center trial to evaluate nivolumab (BMS-936558) in combination with standard 
of care (SOC) chemotherapy (mFOLFOX6) with bevacizumab for the treatment of first-line
metastatic colorectal cancer (mCRC)1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.1.1
Research Hypothesis
Nivolumab plus SOC chemotherapy with bevacizumab (Nivo + SOC) will demonstrate superior 
efficacy (defined as progression-free survival [PFS]) compared to SOC chemotherapy with 
bevacizumab alone in participants with previously untreated mCRC. 
 
 
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4
OBJECTIVES AND ENDPOINTS
Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
Primary
•
To compare the efficacy of nivolumab plus standard of care (SOC)
chemotherapy with bevacizumab (Nivo + SOC) with SOC chemotherapy 
with bevacizumab in participants with mCRC
•
Progression Free Survival
(PFS) by BICR 
Secondary
•
To evaluate preliminary efficacy in all randomized participants
•
ORR, DCR, DoR, TTR by 
BICR per RECIST v1.1
•
ORR, PFS, DCR, DoR, TTR 
by investigator per RECIST 
v1.1
•
OS
•
To characterize the safety and tolerability of nivolumab in combination 
with standard therapy with bevacizumab
•
Safety (including but not 
limited to): incidence of AEs, 
SAEs, deaths, and clinical 
abnormalities per CTCAE 
(Version 4)
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Table 4-1:
Objectives and Endpoints
Objectives
Endpoints
AEs, adverse events; BICR, blinded independent central review; DCR, disease control rate; DoR, duration of response; 
 
 
 
 
 
 
 
 
OS, overall survival; ORR, objective response rate; PFS, progression-free survival; 
 
 SOC, standard of care;
 
TTR, time to response;
. 
5
STUDY DESIGN
5.1
Overall Design
This is a Phase 2/3, randomized, open-label study of nivolumab plus SOC, or SOC alone, in the 
first-line treatment of participants with metastatic CRC. 
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The study design schematic is presented in Figure 5.1-1.
Figure 5.1-1:
Study Design Schematic
DCR, disease control rate; FA; final analysis; IA, interim analysis; ORR, objective response rate; OS, overall survival; 
PFS, progression-free survival.
 
b Depending on the results at the time of interim analysis (IA), different possible decisions may be made as indicated 
by dashed arrows. If there is not enough evidence of favorable benefit/risk at IA, the Phase 2 study will continue to 
complete with 180 participants unless unacceptable safety concerns arise.
One interim analysis (IA) is planned in the Phase 2 portion of the study 
 
.
 
The interim 
results will guide the following decisions:
•
When a strong efficacy signal is observed for all randomized participants, 
 
 is 
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observed and no substantial differential effects by subgroups, the study will expand 
 
. 
•
If the study does not expand at IA, enrollment continues as planned.
If there are not adequate data to support expanding the study at the time of IA, the study will 
continue to 180 randomized participants. 
This study will consist of three phases: screening, treatment, and follow-up. For a complete list of 
study required procedures, please refer to Section 2.
Screening Phase
Screening begins by establishing the participant’s initial eligibility and signing of the informed 
consent (ICF). Participant is enrolled using the Interactive Response Technology (IRT) system.
Participant is assessed for study eligibility according to the inclusion (Section 6.1) and exclusion 
(Section 6.2) criteria.  Completion of screening assessments must be completed in accordance with 
timelines as indicated in Table 2-1. The pathological reports confirming eligibility must be
reviewed, dated, and signed by the investigator prior to randomization.
Participants must submit mandatory baseline tumor sample:
•
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor tissue 
sections (minimum 20 slides from metastatic site or 25 from primary colon tumor), obtained
within 180 days prior to enrollment and after the last dose of the most recent systemic anti-
cancer therapy, with an associated pathology report, must be submitted to the core laboratory 
for inclusion. For participants with samples outside of the above criteria, a fresh biopsy will be 
required. Central lab must provide IRT with confirmation of receipt of evaluable tumor tissue 
prior to randomization. Biopsy should be excisional, incisional or core needle. Fine needle 
aspiration is unacceptable for submission.
•
In addition, at least 5 slides from the primary colon tumor must be submitted if the above 
specimen is from a metastatic site. The 5 slides from the primary tumor may be submitted after 
randomization.
The screening phase either ends with confirmation of full eligibility and randomization for the 
participants, or with the confirmation that the participant is a screen failure. This study permits the 
re-enrollment of a participant that has discontinued the study as a pre-treatment failure prior to 
randomization. If re-enrolled, the participant must be re-consented. A new participant 
identification number will be assigned by IRT at the time of re-enrollment.
Treatment Phase
Following confirmation of eligibility, treatment phase begins with the treatment assignment call 
to the IRT. Participants will be randomized 2:1 to one of the following treatment arms:
•
Arm A: nivolumab plus SOC (Nivo +SOC)
•
Arm B: SOC
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Administration of study treatment is to begin within 3 calendar days of randomization. Participants 
will receive study treatment, until progression, unacceptable toxicity, or withdrawal of consent, or 
the study ends, whichever occurs first. Nivolumab will be given for a maximum of 24 months.
Women of child bearing potential (WOCBP) must have a documented negative pregnancy test 
within 24 hours prior to the start of each dose of the investigational product. On-study vital sign 
assessments should be performed within 72 hours prior to the first dose and then prior to dosing. 
Please refer to Table 2-2. On-study laboratory assessments should be drawn within 72 hours prior 
to dosing and will be assessed at the local laboratory. Please refer to Table 2-2. Tumor assessments 
will occur in accordance with Table 2-2 until confirmed disease progression (by BICR). Each site 
should submit scans on a rolling basis and preferably within 7 days of image acquisition to a central 
vendor and report any pertinent cytology/pathology results for central review by the BICR. If 
progression (defined in Section 9.1.1) is assessed by the investigator, the site will inform the 
radiology vendor so that the BICR assessment/confirmation of progression can be performed.
Please refer to Section 9.1.1.2 for additional details.
•
Participants whose progression is not confirmed by the BICR will be required to continue 
tumor assessments (if clinically feasible) according to the protocol-specified schedule or 
sooner if clinically indicated. Investigators are strongly encouraged to wait for BICR 
confirmation of progression prior to initiating any subsequent therapy. 
 
 
 
Treated participants will be evaluated for progression beginning 
at Week 12 (± 7 days), and then every 8 weeks (± 7 days) during treatment. Following initial 
progression, participants will continue to be followed during safety and survival follow up. 
 
Treatment Phase ends 
when the participant is discontinued from study therapy. Please refer to Section 8.1 for a complete 
list of possible reasons for discontinuation. 
Follow-up Phase
Follow-up Phase begins after the decision is made to discontinue a participant from study therapy 
(eg, due to toxicity, progression, etc.). 
•
Following initial progression, participants will continue to be followed during safety and 
survival follow up. 
 
Participants who enter the follow-up period without tumor progression will continue to have tumor 
imaging assessments per on-treatment schedule: at Week 12 (± 7 days) from randomization and 
then every 8 weeks (± 7 days).
 
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Participants will have 2 follow-up visits (FU1 
and FU2) for safety within approximately 100 days from the last dose of study treatment. Both 
follow-up visits should be conducted in person, according to Table 2-3. Beyond this time period, 
participants will be followed for survival and ongoing treatment-related AEs until these events 
have resolved, returned to baseline or are deemed irreversible. All toxicities will be documented 
for a minimum of 100 days after the last dose of study medication. 
After the Follow-up 2 Visit, all participants will be followed for survival status every 3 months 
(± 14 days) until death, withdrawal of consent, lost to follow-up, or end of study.
•
Survival status may be ascertained by telephone contact if the participant is unable to return to 
the site for a visit. 
•
If new anti-tumor therapy is initiated for either disease progression or a secondary malignancy 
at any time during this period, this and all other pertinent data obtained should be recorded on 
the appropriate Case Report Form (CRF).
5.1.2
Blinded Independent Central Review
A BICR will be utilized in this study for determination of BICR-assessed endpoints. Details of 
BICR procedures will be specified in the BICR Charter. Refer to Section 9.1.1 Imaging 
Assessment for the Study for further details.
5.2
Number of Participants
Approximately 180 (up to 450 depending on IA results) participants will be randomized in a 
2:1 ratio. Approximately 120 participants in the nivolumab + SOC arm (Arm A) and
approximately 60 in the SOC alone arm (Arm B).
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). Study 
completion is defined as the final date on which data for the primary endpoint was or is expected 
to be collected, if this is not the same.
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6
STUDY POPULATION
For entry into the study, the following criteria MUST be met.
6.1
Inclusion Criteria
1) Signed Written Informed Consent
a) Participants 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 confirmed metastatic colorectal cancer, not amenable to curative resection.
b) Available local test results for tumor BRAF, KRAS and NRAS (extended RAS) mutation 
status and Microsatellite/MMR testing in addition to available tumor sample as required 
per protocol (see 2(e))
c) No prior chemotherapy for metastatic colorectal cancer.  
i)
If participant has received adjuvant or neoadjuvant chemotherapy, there must be more 
than 6 months gap (> 6 months) between the completion of that therapy and diagnosis 
of recurrent or metastatic disease.
d) Presence of measurable disease by RECIST 1.1 criteria.
i)
Previously irradiated lesions may not be the target lesion unless there has been 
documented progression in those lesions
e) Adequate tumor tissue available.  Tumor tissue specimens:
i)
Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained tumor 
tissue sections (minimum 20 slides from a metastatic site or 25 from a primary colon 
site), obtained within 180 days prior to enrollment and after the last dose of the most 
recent systemic anti-cancer therapy, with an associated pathology report, must be 
submitted to the core laboratory for inclusion. For participants with samples outside of 
the above criteria, a fresh biopsy will be required. Biopsy should be excisional, 
incisional or core needle. Fine needle aspiration is unacceptable for submission.
ii) If the above sample is not from the primary colon tumor, an additional archival sample 
of at least 5 slides must be submitted from the primary colon tumor. These additional 
5 slides may be submitted after randomization.
iii) Central lab must confirm receipt of evaluable tumor tissue prior to randomization. 
Biopsies of bone lesions that do not have a soft tissue component are also unacceptable 
for submission.
f)
ECOG Performance Status of 0-1. See Appendix 7 for ECOG Performance Status scale.
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g) Re-enrollment: This study permits the re-enrollment of a participant that has discontinued 
the study as a pre-treatment failure (ie, participant has not been treated). If re-enrolled, the 
participant must be re-consented and assigned a new participant number from IRT.
h) All participants will be required to undergo mandatory on-study biopsies. Participants will 
be required to undergo on-study biopsies at acceptable clinical risk as judged by the 
investigator in both arms.
i)
The tumor tissue specimen must be a core needle biopsy, excisional or incisional 
biopsy. Fine needle biopsies, drainage of pleural effusions with cytospins, or punch 
biopsies are not considered adequate 
. Biopsies of bone lesions 
that do not have a soft tissue component or decalcified bone tumor samples are also not 
acceptable. Where possible, the biopsied lesion should be distinct from target lesions 
being evaluated for radiologic response, and when feasible the same lesion should be 
used for both the baseline and on-study sampling.
3) Age and Reproductive Status
a) Males and Females, 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 treatment.
c) Women must not be pregnant or breastfeeding
d) Women of childbearing potential (WOCBP) randomized to the nivolumab + SOC arm must 
agree to follow instructions for method(s) of contraception (Appendix 4) for the duration 
of treatment with study treatment(s) and 6 months after the last dose of study treatment.
e) Males randomized to the nivolumab + SOC arm who are sexually active with WOCBP 
must agree to follow instructions for method(s) of contraception (Appendix 4) for the 
duration of treatment with study treatment(s) 7 months after the last dose of nivolumab. In 
addition, male participants must be willing to refrain from sperm donation during this time. 
f)
Women of childbearing potential (WOCBP) randomized to the SOC arm must agree to 
follow instructions for method(s) of contraception (Appendix 4) for the duration of 
treatment with study treatment(s) and for at least 6 months after the last dose of 
investigational drug.
g) Males randomized to the SOC arm who are sexually active with WOCBP must agree to 
follow instructions for method(s) of contraception (Appendix 4) for the duration of 
treatment with study treatment(s) and for at least 7 months after the last dose of 
investigational drug. In addition, male participants must be willing to refrain from sperm 
donation during this time. 
h) 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.
Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4)
which have a failure rate of < 1% when used consistently and correctly.
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6.2
Exclusion Criteria
1) Target Disease Exceptions
a) 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. Cases should be discussed with the medical monitor. There must also 
be no requirement for immunosuppressive doses of systemic corticosteroids (> 10 mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration.
b) Resectable oligometastastic only disease with multidisciplinary plan for complete resection 
of all disease.
c) Ascites that cannot be controlled with medical therapy alone.
2) Medical Conditions
a) Participants with an active, known or suspected autoimmune disease. Participants with type 
I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders 
(such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not 
expected to recur in the absence of an external trigger are permitted to enroll.
b) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
c) Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured (ie, basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast) and considered to be of low 
risk of recurrence
d) History of interstitial lung disease or pneumonitis.
e) Clinically significant cardiovascular disease. Pre-existing hypertension should be 
adequately controlled to < 140/90 mmHg.
f)
Clinically significant bleeding diathesis or coagulopathy.
g) Deep venous thrombosis, pulmonary embolism, arterial thrombosis or cerebrovascular 
accident within 6 months prior to enrollment.
h) Non-healing wound, ulcer, or bone fracture.
i)
Participants with > Grade 1 peripheral neuropathy.
j)
Prior history of gastrointestinal perforation or abscess.
k) History of hemoptysis of ≥half teaspoon (2.5 mL) of red blood within 3 months prior to
enrollment.
l)
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.
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m) Any other sound medical, psychiatric and/or social reason as determined by the 
investigator.
3) Prior/Concomitant Therapy
a) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-CTLA-4 antibody, or 
any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways.
b) Received cancer-related investigational product(s) (IPs) and/or biologic therapy within 
28 days or 5 half-lives, whichever is longer, prior to randomization.
c) Prior major surgery, open biopsy or significant traumatic injury within 28 days prior to 
randomization. Any wound-related AE(s) must have resolved at least 28 days prior to 
randomization.
d) Prior focal palliative radiotherapy must have been completed at least 14 days prior to 
randomization.
e) 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 randomization/treatment, except with the approval of the Principal 
Investigator. Refer to Section 7.7.1 for prohibited therapies.
f)
Participants who have received a live / attenuated vaccine within 30 days of first treatment.
4) Physical and Laboratory Test Findings
a) WBC < 2000/μL
b) Neutrophils < 1500/μL
c) Platelets < 100×103/μL
d) Hemoglobin < 9.0 g/dL
e) PT/INR and PTT > 1.5 ×ULN
f)
Serum creatinine > 1.5 ×ULN, unless creatinine clearance ≥40 mL/min (measured or 
calculated using the Cockroft-Gault formula)
g) AST/ALT: > 3.0 ×ULN, unless participant has documented liver metastases in which case 
AST/ALT > 5.0× ULN are exclusionary.
h) Total bilirubin > 1.5 ×ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0 ×ULN)
i)
Albumin < 3.0 g/dL
j)
For participants with proteinuria ≥2+ by urine dipstick or urinalysis at baseline, 24-hr urine 
must be collected.  Proteinuria > 1g/24hrs is exclusionary. It is acceptable to estimate urine 
protein to creatinine ratio (UPCR) instead of 24hr urine collection. UPCR > 1000 mg/g is 
exclusionary.
k) Any positive test result for hepatitis B virus or hepatitis C virus indicating presence of 
virus, eg, Hepatitis B surface antigen (HBsAg, Australia antigen) positive, or Hepatitis C 
antibody (anti-HCV) positive (except if HCV-RNA negative).
l)
Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally. See Appendix 10.
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nivolumab
5) Allergies and Adverse Drug Reaction
a) Any contraindications to any of the study drugs of the chemotherapy regimen. Investigators 
should refer to local package insert of the SOC chemotherapy drugs and bevacizumab.
b) History of severe hypersensitivity reaction to any monoclonal antibody.
c) History of allergy or hypersensitivity to study drug components
6) Other Exclusion Criteria
a) Prisoners or participants who are involuntarily incarcerated. (Note: under specific 
circumstances a person who has been imprisoned may be included as a participant. Strict 
conditions apply and Bristol-Myers Squibb approval is required.
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria.
6.3
Lifestyle Restrictions
Not applicable. No restrictions are required. Please also refer to local SOC products labels for 
possible restrictions.
6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but who 
are not subsequently randomized in the study/included in the analysis population. A minimal set 
of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, as applicable, and to respond to queries from regulatory authorities. Minimal 
information includes date of consent, demography, screen failure details, eligibility criteria, and 
any serious AEs.
6.4.1
Retesting During Screening
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized / has not 
been treated). If re-enrolled, the participant must be re-consented.
Retesting of laboratory parameters and/or other assessments within any single Screening or Lead-
in period will be permitted (in addition to any parameters that require a confirmatory value).
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state.
Laboratory parameters and/or assessments that are included in Table 2-1, Screening Procedural 
Outline may be repeated in an effort to find all possible well-qualified participants. Consultation 
with the Medical Monitor may be needed to identify whether repeat testing of any particular 
parameter is clinically relevant.
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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
•
Oxaliplatin
•
Leucovorin 
•
Fluorouracil 
•
Bevacizumab 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form.
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products.
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Table 7-1:
Study treatments for CA2099X8
Product Description 
/ Class and Dosage 
Form
Potency
IP/Non-IMP
Blinded or 
Open Label
Packaging / 
Appearance
Storage 
Conditions
(per label)
Nivolumab
(BMS-936558-01)
Solution for 
Injectiona
100 mg (10 
mg/ml)  and 
40 mg (10
mg/mL)
IP
Open label
Vial and various 
packaging 
configurations
2° to 8°C. 
Protect from 
light and
freezing.
Oxaliplatinb
various
strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the 
label on
container and/or
Pharmacy 
manual.
ቄ
Leucovorin
Calcium Folinateቅb
various
strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the 
label on
container and/or
Pharmacy 
manual.
Fluorouracilb
various
strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the 
label on
container and/or
Pharmacy 
manual.
Bevacizumabb
various
strengths
IP
Open label
Vial and various
packaging 
configurations
Refer to the 
label on
container and/or
Pharmacy 
manual.
Further instructions with regard to the preparation, handling, and storage for above product will be provided to sites 
separately as Pharmacy manual.
a May be labeled as either “BMS-936558-01” or “Nivolumab”
b 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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BMS-936558
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7.1
Treatments Administered
The selection and timing of dose for each participant is as follows:
Table 7.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose strength(s)/Dosage level(s)
Dosage formulation
Frequency of 
Administration
Route of 
Administration
Oxaliplatin
85 mg/m2
Q2W
IV
Leucovorin
400 mg/m2 or 350 mg/m2 as per local 
standards
Q2W
IV
Fluorouracil
Bolus 400 mg/m2
Q2W
IV
Fluorouracil
1200 mg/m2
continuous infusion on Day #1 (or Day #15) 
and 1200 mg/m² continuous infusion on 
Day #2 (or Day #16)
OR
2400 mg/m2 continuous infusion over 46 to 
48 hours Day #1 (or Day #15) through 
Day #2 (or Day #16) as per local standards
Q2W
IV
Bevacizumab
5 mg/kg
Q2W
IV
Nivolumab
240 mg
Q2W
IV
IV, intravenous. 
When study drugs (nivolumab and SOC therapy) are to be administered on the same day, 
nivolumab is to be administered first. Nivolumab infusion must be promptly followed by a saline 
flush to clear the line of nivolumab before starting SOC therapy infusion(s). The second infusion 
will always be the standard of care and will start after the infusion line has been flushed, filters 
changed and the patient has been observed to ensure no infusion reaction has occurred. The time 
between infusions is expected to be approximately 30 minutes but may be more or less depending 
on the situation.
Participants will be treated until progression, unacceptable toxicity, withdrawal of consent, or the 
end of the study, whichever comes first. Nivolumab will be given for a maximum of 24 months.
Participants should receive nivolumab at a dose of 240 mg as a 30 minute infusion on Day 1 of 
each treatment cycle every 2 weeks (± 3 days) for a maximum of 24 months, or until confirmed 
progression, unacceptable toxicity, withdrawal of consent, or the study ends, whichever occurs 
first. Participants should begin study treatment within 3 calendar days of randomization. 
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 12 days from the previous dose during Q2W cycles. Premedications are not 
recommended for the first dose of nivolumab.
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Participants should be carefully monitored for infusion reactions during study drug administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. Resumption of 
treatment should be at the next scheduled time point.
Nivolumab infusion must be promptly followed by a saline flush to clear the line. Instructions for 
dilution and infusion of nivolumab injection may be provided in the clinical protocol, pharmacy 
binder, or pharmacy manual. Care must be taken to assure sterility of the prepared solution as the 
product does not contain any antimicrobial preservative or bacteriostatic agent. 
Where applicable (ex. bevacizumab), dosing calculations should be based on the body weight 
assessed at baseline. It is not necessary to recalculate subsequent doses if the participant weight is 
within 10% of the weight used to calculate the previous dose. All doses should be rounded up to 
the nearest milligram per institutional standard.
Nivolumab plus SOC and bevacizumab arm
Participants assigned to nivolumab plus SOC will receive nivolumab 240 mg administered IV over 
30 minutes first, then followed by bevacizumab administration and finally by the FOLFOX 
administration.
First administration (C1D1) of bevacizumab will be delivered over a 90-min infusion. If well 
tolerated the second administration (C1D15) will be delivered over 60 min; if the 60-min infusion 
is well tolerated, all subsequent infusions will be delivered over 30 min or as per local institutional 
standards.
Bevacizumab administration will then be followed by oxaliplatin 85 mg/m2, leucovorin 
400 mg/m2, and fluorouracil 400 mg/m2 will be administered IV on Day 1 of each treatment cycle 
every 2 weeks, and fluorouracil 1200 mg/m2 IV continuous infusion on Day 1 and on Day 2 or 
2400 mg/m² over 46 to 48 hours of each treatment cycle every 2 weeks (see Table 7.1-1). Dosing 
windows for subsequent mFOLFOX doses should adhere to recommendations in the prescribing 
information or local standards, where indicated.
Premedication may be administrated per local standard, but are not recommended for the first dose 
of nivolumab.
SOC and bevacizumab arm
Participants assigned to SOC will receive bevacizumab first, followed by FOLFOX administration.
First administration (C1D1) of bevacizumab will be delivered over a 90-min infusion. If well 
tolerated the second administration (C1D15) will delivered over 60 min; if the 60-min infusion is
well tolerated, all subsequent infusions will be delivered over 30 min or as per local institutional 
standards.
Bevacizumab administration will then be followed by oxaliplatin 85 mg/m2, leucovorin 
400 mg/m2, and fluorouracil 400 mg/m2 administered IV on Day 1 of each treatment cycle, and 
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fluorouracil 1200 mg/m2 IV continuous infusion on Day 1 and on Day 2 or 2400 mg/m² over 46 to 
48 hours of each treatment cycle, every 2 weeks (see Table 7.1-1). Dosing windows for subsequent 
FOLFOX doses should adhere to recommendations in the prescribing information or local 
standards, where indicated.
Premedication may be administrated per local standard.
7.2
Method of Treatment Assignment
CA2099X8 is a randomized, open-label study. After the participant’s initial eligibility is 
established and informed consent has been obtained, the participant must be enrolled into the study 
by using an Interactive Response Technology (IRT) to obtain the participant number. Every 
participant that signs the informed consent form must be assigned a participant number using IRT. 
Specific instructions for using IRT will be provided to the investigational site in a separate 
document.
All participants will be centrally randomized using an Interactive Response Technology (IRT). 
Before the study is initiated, each site user will receive log in information and directions on how 
to access the IRT. The investigator or designee will register the participant for enrollment by 
following the enrollment procedures established by BMS.
The following information is required for enrollment:
•
Date that informed consent was obtained
•
Date of birth, where applicable by local regulations
•
Gender at birth
Once enrolled in IRT, enrolled participants who have met all eligibility criteria will be ready to be 
randomized through IRT. The following information is required for participant randomization:
•
Participant number
•
Date of birth, where applicable per local regulations
•
Tumor sidedness (left, right, transverse or unknown)
•
Prior oxaliplatin-based adjuvant chemotherapy (yes or no)
•
Confirmation that evaluable tumor tissue has been received at the central lab.
Participants meeting all eligibility criteria will be randomized in a 2:1 ratio to nivolumab + SOC 
or SOC arms stratified by tumor sidedness and prior oxaliplatin-based adjuvant chemotherapy. 
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2). 
The exact procedures for using the IRT will be detailed in the IRT manual.
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7.4
Dosage Modification
There are no dose modifications allowed for nivolumab, except treatment delay. 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.
•
For adverse events that are deemed to be related to mFOLFOX6 + bevacizumab ONLY by the 
treating physician, dose modification criteria for SOC must be followed as described in 
Sections 7.4.2 and 7.4.3.
•
For adverse events that are deemed to be related to nivolumab ONLY by the treating physician, 
dose modification criteria for nivolumab must be followed as described in Section 7.4.1 and 
Appendix 5.
•
For 
adverse 
events 
that 
are 
possibly 
related 
to 
the 
combination 
regimen 
(nivolumab + mFOLFOX6 + bevacizumab), the most conservative toxicity management 
guidelines must be followed.
•
If there is a delay in administration of study drug(s) due to toxicity, treatment with the other 
study agent(s) should continue as scheduled.  Resumption of treatment should be at the next 
scheduled time point.
7.4.1
Nivolumab Dose Delay
Nivolumab administration should be delayed for the following:
•
Grade 2 non-skin, drug-related AE, with the exception of fatigue
•
Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities
•
Grade 3 skin, drug-related AE
•
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 should be re-evaluated weekly or more frequently if 
clinically indicated and resume nivolumab dosing when re-treatment criteria are met.  If there is a 
delay or modification in administration of study drug(s) due to toxicity, treatment with the other 
study agent(s) should continue as scheduled. If clinically appropriate, the investigator can delay 
all treatment components up to a maximum of 7 days to allow synchronized administration of all 
agents.
7.4.2
Dose Modification Criteria for Oxaliplatin-Plus-Fluoropyrimidine 
Treatment
Dose modifications of oxaliplatin, leucovorin and fluorouracil are permitted according to local 
standards or local package inserts.
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7.4.2.1
General Guidance for Dose Modification for Chemotherapy
•
Treatment for the first cycle should only commence if all the inclusion criteria are met and the
participant has been enrolled. For subsequent cycles, dose delay/modification is permitted per
local standard.
•
Doses of any study drug omitted for toxicity are not replaced or restored; instead, the patient 
should resume the planned treatment cycles. Supportive care (for example, colony-stimulating 
factors [CSFs], blood and blood products, etc. can be administered in accordance with the latest 
American Society of Clinical Oncology (ASCO) or other equivalent guidelines.
•
Dose modification, for non-serious and non-life-threatening toxicities like alopecia, altered 
taste or nail changes may not be required and the final decision is left to the discretion of the 
treating investigator.
•
In situations where concomitant toxicities of varying severity exist, dose modification will be 
tailored for the toxicity with highest CTCAE grading.
•
If there is a delay or modification in administration of study drug(s) due to toxicity, treatment 
with the other study agent(s) should continue as scheduled. If clinically appropriate, the 
investigator can delay all treatment components up to a maximum of 7 days to allow 
synchronized administration of all agents. 
If toxicity related to any component of chemotherapy does not resolve in the same treatment cycle, 
the administration of that component can be delayed up to 6 weeks. If the toxicity does not resolve 
within 6 weeks, that component will be discontinued unless it is determined by the treating 
investigator that the patient might benefit from continuation of the component.
7.4.3
Dose Modification Criteria for mFOLFOX6
Recommended dose modifications of FOLFOX are provided in Table 7.4.3-1 and Table 7.4.3-2.  
Modifications may be made as per local standards.
Table 7.4.3-1:
Recommended Dose Modifications of FOLFOX
Drug
Starting Dose
Dose Modification
Dose Level - 1
Dose Level - 2
Oxaliplatin
85 mg/m2
70 mg/m2
50 mg/m2
5-FU
Bolus 5-FU: 400 mg/m2
Leucovorin: 400 mg/m2  Infusion 
5-FU: 2400 mg/m2/ continuous 
infusion over 46-48 hours
Bolus 5-FU: 300 mg/m2
Leucovorin: 300 mg/m2  Infusion 
5-FU: 2000 mg/m2/ continuous 
infusion over 46-48 hours
Bolus 5-FU: 200 mg/m2
Leucovorin: 200 mg/m2 Infusion 
5-FU: 1600 mg/m2/ continuous 
infusion over 46-48 hours
5-FU: 5-fluorouracil.
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Table 7.4.3-2:
Dose Modifications of FOLFOX
Toxicity 
Definition
During a course of 
therapy
Dose adjustment for next 
treatments
Neutropenia
Grade 3 or greater
Interrupt until resolved to 
Grade 2
Dose level -1
*If treatment delayed for 
4 consecutive weeks, discontinue all 
treatment
Thrombocytopenia
Grade 2
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 2 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1 
Grade 3
Interrupt until resolved to 
Grade 1
Dose level -1
*If Grade 3 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Grade 4
Interrupt until resolved to 
Grade 1
Dose level -2
*If Grade 4 persists > 7 days, 
oxaliplatin reduced by 2 dose levels 
when platelets improve to Grade 1
Neurologic toxicity
Grade 2 peripheral 
sensory neuropathy
Interrupt until resolved to 
Grade 1 or management as 
per institutional standard
Oxaliplatin dose -1
Continue 5-FU and leucovorin
*If oxaliplatin delayed for 
neurologic toxicity for 4 
consecutive weeks, discontinue
oxaliplatin, continue 5-FU and 
leucovorin
Grade 3 or greater 
peripheral sensory 
neuropathy
Discontinue oxaliplatin
Continue 5-FU and leucovorin
Gastrointestinal 
toxicities
Grade 2 or greater 
diarrhea
Interrupt until resolved to 
Grade 1
Dose level -1
If dose delayed for diarrhea for 
4 consecutive weeks, discontinue all 
treatment
For toxicities not listed above, dose modifications are permitted per local standards. 
Participants may also discontinue oxaliplatin following multiple cycles if, in the investigator’s 
judgment, cumulative toxicity is likely to increase over time.
7.4.4
Dose Modification Criteria for bevacizumab
Dose modifications or delay for bevacizumab are allowed per institutional standards.  
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Table 7.4.4-1:
Recommended Guidelines for Management of Proteinuria
Grade
Description
Management
Grade 1
1+ protein on urinalysis, or 
0.15 to 1g of protein in 
24hrs urine collection, or
150 to 1000 mg/g if UPCR 
is used to assess the 
proteinuria
Continue Bevacizumab
Grade 2
2+ or 3+, or
1 to 3.4g/24hrs, or
1000 to 3400 mg/g
Give Bevacizumab and collect 
24 hour urine or test UPCR 
before the next cycle
Resume Bevacizumab only if 
<2g/24hours, or < 2000 mg/g
If not <2g/24h, or < 2000 mg/g
for 3 months, discontinue 
Bevacizumab
Grade 3
Urinary protein 
≥3.5 g/24hrs, or
≥3500 mg/g
Discontinue Bevacizumab
UPCR, urine protein to creatinine ratio
7.4.5
Treatment of Infusion-Related Reactions 
If an infusion-related reaction should 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) 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):
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•
Stop the study treatment infusion, begin an IV infusion of normal saline, and treat the 
participant 
with 
diphenhydramine 
50 
mg 
IV 
(or 
equivalent) 
and/or 
acetaminophen/paracetamol 325 to 1000 mg; remain at bedside and monitor participant until 
resolution of symptoms. Corticosteroid and/or bronchodilator therapy may also be 
administered as appropriate. If the infusion is interrupted, then restart the infusion at 50% of 
the original infusion rate when symptoms resolve; if no further complications ensue after 
30 minutes, the rate may be increased to 100% of the original infusion rate. Monitor participant 
closely. If symptoms recur, then no further study treatment 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 infusion. 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 treatment. Begin an IV infusion of normal saline 
and treat the participant as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Study treatment will be 
permanently discontinued. 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).
7.5
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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Study treatment not supplied by BMS will be stored in accordance with the package insert.
Investigational product documentation (whether supplied by BMS or not) must be maintained that 
includes all processes required to ensure drug is accurately administered. This includes 
documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets).
Further guidance and information for final disposition of unused study treatment are provided in 
Appendix 2 and Pharmacy Manual.  
7.6
Treatment Compliance
Study treatment compliance will be periodically monitored by drug accountability. Drug 
accountability should be reviewed by the site study staff at each visit to confirm treatment 
compliance. 
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, 
extensive, non-palliative 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.
•
Ongoing treatment with aspirin (>325 mg per day) or other medications known to predispose 
participants to gastrointestinal ulceration is prohibited for participants receiving bevacizumab.
•
Also refer to local institutional guidelines and/or product labels of SOC components for 
possible prohibited and/or restricted treatments.
•
Any live / attenuated vaccine (eg varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) during treatment and until 100 days post last dose.
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 
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randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
7.7.3
Permitted Therapy
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.
7.7.3.1
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. 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.
7.8
Post-Study Drug Access
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS supplied study treatment for the maximum treatment duration 
specified in protocol Section 7.1. 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 the nivolumab 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 
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consent for any further contact with him/her or persons previously authorized by participant to 
provide this information
•
Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the participant
•
Termination of the study by Bristol-Myers Squibb (BMS)
•
Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness
•
Documented radiographic disease progression per RECIST v1.1.
•
Criteria listed Section 8.1.1 and 8.1.2
Refer to the Schedule of Activities (see Section 2) for data to be collected at the time of treatment 
discontinuation and follow-up and for any further evaluations that can be completed.
In the case of pregnancy, the investigator must immediately notify the Sponsor or designee of this 
event and study treatment must immediately be stopped. In most cases, the study drug will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for participant 
safety). Please contact the Sponsor or designee within 24 hours of awareness of the pregnancy. If 
the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug (ie, allowing restart of study treatment if participant chose to terminate the pregnancy), 
a discussion between the investigator and the Sponsor or designee must occur so permission may 
be granted.
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.
8.1.1
Nivolumab Dose Discontinuation
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
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•
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 will be permanently 
discontinued. If the investigator determines a possible favorable benefit/risk ratio that warrants 
continuation of study treatment, a discussion between the investigator and the 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.
•
Any event that leads to delay in dosing lasting > 6 weeks from the previous dose requires 
discontinuation, with the following exceptions:
−
Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed. 
−
Dosing delays lasting > 6 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the BMS Medical Monitor (or designee). 
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Prior to re-initiating treatment in a participant with a dosing delay lasting > 6 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 6 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
SOC Dose Discontinuation
Except where specified below, the medications in the SOC chemotherapy regimen should be 
discontinued for any of the following:
•
Any Grade ≥4 drug-related peripheral neuropathy requires discontinuation of oxaliplatin.
•
In case of persistent Grade 3 drug-related paraesthesia, oxaliplatin should be discontinued.
•
Any Grade ≥3 drug-related mucocutaneous reaction possibly attributable to leucovorin 
requires permanent discontinuation.
•
Grade ≥3 drug-related thrombocytopenia associated with clinically significant bleeding, all 
treatment should be held until resolved to ≤Grade 1. Subsequent dose reduction of any SOC 
medications or discontinuation of oxaliplatin will be at the discretion of the treating 
investigator.
•
Any drug-related liver function test (LFT) abnormality that meets the following criteria
requires discontinuation:
−
AST or ALT > 5-10 ×ULN for > 2 weeks
−
AST or ALT > 10 ×ULN
−
Total bilirubin > 5 ×ULN
−
Concurrent AST or ALT > 3 ×ULN and total bilirubin > 2 ×ULN
•
Any oxaliplatin-related decrease in creatinine clearance to < 30 mL/min (using the Cockroft 
Gault formula) requires discontinuation of oxaliplatin.
•
Any drug-related AE which recurs after 2 prior dose reductions for the same drug-related AE 
requires discontinuation of the drug(s) which was/were previously dose reduced.
•
Any Grade ≥3 drug-related hypersensitivity reaction or infusion reaction requires 
discontinuation of the drug(s) felt to be causing the reaction. The drug not felt to be related to 
the hypersensitivity reaction or infusion reaction may be continued.
•
Any Grade 4 drug-related AE which the investigator deems is inappropriate to be managed by 
dose reduction(s) requires discontinuation of the drug(s) felt to be causing the event. The drug 
not felt to be related to the event may be continued.
•
If any drug-related toxicity does not resolve within 42 days, that component will be 
discontinued unless it is determined by the treating investigator that the participant might 
benefit from continuation of the component.
•
In case of unexplained drug-related respiratory symptoms such as non-productive cough, 
dyspnea, crackles, or radiological pulmonary infiltrates, oxaliplatin should be discontinued 
until further pulmonary investigation excludes interstitial lung disease or pulmonary fibrosis.
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Treatment with bevacizumab must be permanently discontinued according to the updated 
bevacizumab package insert including the following: 
•
Grade 4 drug-related hypertension including hypertensive encephalopathy
•
Grade 3-4 drug-related hemorrhage 
•
Grade 4 drug-related non-pulmonary or non-CNS hemorrhage
•
Grade ≥1 drug-related pulmonary or CNS hemorrhage
•
Drug-related arterial thromboembolic event (any grade)
•
Any grade of drug-related congestive heart failure
•
Grade 3 drug-related proteinuria
•
Participants who develop drug-related gastrointestinal perforation, tracheoesophageal fistula 
or any Grade 4 fistula.  Discontinue in patients with fistula formation involving any internal 
organ 
•
Participants who develop a drug-related severe ATE
•
Grade 4 drug-related VTE, including pulmonary embolism
•
Drug-related wound dehiscence (any grade –requiring medical or surgical therapy)
•
Drug-related reversible posterior leukoencephalopathy (any grade,- confirmed by MRI)
•
Other unspecified bevacizumab related AE’s (Grade 4)
For toxicities not listed above, the treating investigators can decide to discontinue any individual 
chemotherapy agent or all chemotherapy agents if it is not the best interest in the participant per 
the local standards.
Post-treatment study follow-up is critically important and is essential to preserving participant 
safety and the integrity of the study. Participants who discontinue study treatment will continue to 
be followed for collection of tumor surveillance assessments, safety, 
 
 as per protocol.
8.1.3
Criteria to Resume Treatment with Nivolumab
Participants may resume treatment with study treatment when the drug-related AE(s) resolve to 
Grade ≤1 or baseline value, with the following exceptions:
•
Participants may resume treatment in the presence of Grade 2 fatigue
•
Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity
•
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 (or designee).
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•
Participants with drug-related endocrinopathies adequately controlled with only physiologic 
hormone replacement may resume treatment after consultation with the BMS Medical Monitor 
(or designee). Adrenal insufficiency requires discontinuation regardless of control with 
hormone replacement.
•
Resumption of treatment should be at the next scheduled time point.
8.1.4
Post Study Treatment Study Follow-up
In this study, overall survival is a key endpoint of the study. Post study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study.
BMS may request that survival data be collected on all treated/randomized participants outside of 
the protocol defined window (see Section 2, Schedule of Activities table). At the time of this 
request, each participant will be contacted to determine their survival status unless the participant
has withdrawn consent for all contacts or is lost to follow-up
8.2
Discontinuation from the Study
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information. 
•
Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible.
•
The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page.
•
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
•
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
8.3
Lost to Follow-Up
•
All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant.
•
Lost to follow-up is defined by the inability to reach the participant after a minimum of three
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records.
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•
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 (see Section 2). 
•
Protocol waivers or exemptions are not allowed.
•
All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment.
•
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (see Section 2), is essential and required for study conduct.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities (see Section 2).
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on-site/local 
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.
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 
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assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
9.1
Efficacy Assessments
9.1.1
Imaging Assessment for the Study
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA2099X8 Imaging Manual to be provided by the core lab. 
Baseline imaging, including CT of the chest, CT/MRI of the abdomen, pelvis, and all known sites 
of disease should be performed within 28 days prior to first dose. 
At Baseline, MRI of the brain without and with contrast is required for participants with known or 
suspected brain metastases. Participants with a history of brain metastasis should have surveillance 
MRI approximately every 12 weeks, or sooner if clinically indicated
First tumor assessment post-baseline should be performed at Week 12 (± 7 days) after 
randomization and then every 8 weeks (± 7 days) thereafter until confirmed progression, 
withdrawal of consent, or the study ends, whichever occurs first. If the investigator finds
progression that is not confirmed by BICR, additional CT of the chest, CT/MRI of the abdomen, 
pelvis, and all known sites of disease should be performed 4 weeks later, prior to subsequent 
therapy.
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.
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled timepoints and/or at an outside institution) should be collected for 
RECIST v1.1 tumor assessment and submitted to the BICR.
Assessments of PR and CR must be confirmed at least 4 weeks after initial response. A Best 
Response of SD can only be made after the participant is on-study for a minimum of 42 days from 
the date of randomization. Investigators will also report the number and size of new lesions that 
appear while on study. The time point of tumor assessments will be reported on the eCRF based 
on the investigator’s assessment. 
9.1.1.1
Methods of Measurement
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. 
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Should a participant have contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.   
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained. 
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable.
CT and MRI scans should be acquired with slice thickness of 5 mm or less with no intervening 
gap (contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging time points. 
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 dedicated diagnostic contrast enhanced CT scans for anatomically-based RECIST 
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.
Participants with a history of bone metastasis may have a bone scan, if clinically indicated.
9.1.1.2
BICR Assessment of Progression
Sites should submit all scans to a BICR, preferably within 7 days of scan acquisition, throughout 
the duration of the study. BICR will review scans, and remain blinded to treatment arm and 
investigator assessment of submitted scans. When progression per RECIST 1.1 criteria is assessed 
by the investigator, the site will inform the imaging core lab, so that the BICR assessment of 
progression can be expedited in a manner that does not unnecessarily alert the BICR team to the 
investigator's assessment. The BICR review will be completed and limited results provided to the 
site.
Participants whose progression is not confirmed by the BICR should perform an additional CT of 
the chest, CT/MRI of the abdomen, pelvis, and all known sites of disease 4 weeks after initial 
progression, prior to subsequent therapy. Also, if participants discontinue treatment without 
radiographic progression, tumor assessments will continue according to the protocol-specified 
schedule, as noted in until progression has been confirmed by BICR.
All study treatment decisions will be based on the investigator’s assessment of tumor images and 
not on the BICR assessment. The BICR assessment of progression is only relevant for determining 
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when tumor assessments for a given participant are no longer required to be submitted to the 
imaging vendor.
 
9.2
Adverse Events
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3.
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
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exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
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
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). Nonserious AE information should 
also be collected from the start of a placebo lead-in period or other observational period intended 
to establish a baseline status for the participants.
Sections 5.6.1 and 5.6.2 in the Investigator Brochure (IB) represent the Reference Safety 
Information to determine expectedness of serious adverse events for expedited reporting. 
Following the participant’s written consent to participate in the study, all SAEs, whether related 
or not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures.
All SAEs must be collected 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 randomization.
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure.
•
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF module.
•
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3. 
•
The investigator will submit any updated SAE data to the sponsor or designee within 24 hours 
of this updated information being available.
Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor.
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3.
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9.2.2
Method of Detecting AEs and SAEs
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. Care should be taken not to introduce bias when 
collecting AE and/or SAEs.  Inquiry about specific AEs should be guided by clinical judgement 
in the context of known adverse events, when appropriate for the program or protocol.
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 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 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3).
Further information on follow-up procedures is given in Appendix 3.
9.2.4
Regulatory Reporting Requirements for SAEs
•
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 
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to BMS Designee within 24 hours of awareness of the event and in accordance with SAE reporting 
procedures described in Appendix 3.
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study treatment, or re-initiation of study treatment, a discussion between the investigator and the 
BMS Medical Monitor/designee must occur. If, for whatever reason, the pregnancy has ended, 
confirmed by negative serum pregnancy test, treatment may be resumed (at least 3 weeks and not 
greater than 6 weeks after the pregnancy has ended), following approvals of participant /sponsor 
/IRB/EC, as applicable.
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 within 24 
hours of awareness of the pregnancy.
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.
•
Any laboratory test result that is clinically significant or meets the definition of an SAE 
•
Any laboratory test result abnormality that required the participant to have study treatment
discontinued or interrupted
•
Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
9.2.7
Potential Drug Induced Liver Injury (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 Appendix 3 for reporting details).
Potential drug induced liver injury is defined as: 
1) AT (ALT or AST) elevation > 3 ×ULN
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AND
2) Total bilirubin > 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.
For participants with elevated AST or ALT or Total bilirubin at baseline, potential DILI is defined 
as: 
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.
9.2.8
Other Safety Considerations
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.
9.3
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Overdoses that meet the regulatory 
definition of SAE will be reported as an SAE (see Appendix 3). 
9.4
Safety
Planned time points for all safety assessments are listed in the Schedule of Activities (see 
Section 2).
9.4.1
Physical Examinations
Refer to Schedule of Activities (see Section 2).
9.4.2
Vital signs
Refer to Schedule of Activities (see Section 2).
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9.4.3
Clinical Safety Laboratory Assessments
Investigators must document their review of each laboratory safety report.
Hematology - CBC
Hemoglobin
Hematocrit
Total leukocyte count, including differential
Platelet count
Chemistry
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total bilirubin
Alkaline phosphatase (ALP)
Lactate dehydrogenase (LDH)
Creatinine
Blood Urea Nitrogen (BUN) or serum UREA
Glucose (fasting or not)
PT/INR – screening and as clinically 
indicated during bevacizumab treatment
PTT - screening
Albumin - screening only
Sodium
Potassium
Chloride
Calcium
Phosphorus
TSH, free T3 and free T4 - screening 
TSH, with reflexive fT3 and fT4 if TSH is 
abnormal - on treatment 
Urinalysis
Urinalysis or urine dipstick including protein, glucose, blood, leukocyte esterase, specific 
gravity, pH. 24hr urine collection or UPCR required if a protein urine dipstick reading is ≥2+.
Serology
Hepatitis B/C, (HBV sAG, HCV antibody or HCV RNA), - screening only. If anti-HCV test is 
positive, then HCV RNA is mandatory.
Other Analyses
CEA (and CA19-9) Assessment
Pregnancy test (WOCBP only: minimum sensitivity 25 IU/L or equivalent units of HCG).
Follicle stimulating hormone (FSH) screening -only required to confirm menopause in women 
< age 55) 
9.4.4
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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10.2
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who signed an informed consent form and were registered 
into the IRT system
Randomized
All participants who were randomized to any treatment arm in the study.
This is the primary population for analyses of efficacy.
Treated (Safety)
All participants who received at least one dose of study treatment 
(nivolumab or SOC).
10.3
Statistical Analyses
The statistical analysis plan will be developed and finalized before database lock and will describe 
the selection of participants to be included in the analyses, and procedures for accounting for
missing, unused, and spurious data. Below is a summary of planned statistical analyses of the 
primary 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
Endpoint
Statistical Analysis Methods
Primary
Progression-free survival (PFS) is defined as the time from randomization date
to the date of the first documented tumor progression, as determined by BICR
(per RECIST v1.1), 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 evaluable tumor assessment. 
•
Participants who did not have any on study tumor assessments and did not 
die will be censored on the randomization date.
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Endpoint
Statistical Analysis Methods
•
Participants who started any subsequent anti-cancer therapy without a prior 
reported progression or prior to death will be censored at the last tumor 
assessment prior to initiation of the subsequent anti-cancer therapy.
Further explanation for various censoring scenarios for PFS will be specified in 
SAP.
The distribution of PFS will be compared in the two randomized arms via a 
two-sided, log-rank test stratified by randomization stratification factors of 
tumor sidedness and prior oxaliplatin-based adjuvant chemotherapy at the 
overall significance level of .20 (two-sided).
The hazard ratio (HR) and the corresponding 95% confidence interval (CI) will 
be estimated in a stratified Cox proportional hazards model using the 
randomized arm as a single covariate, stratified by tumor sidedness and prior 
oxaliplatin-based adjuvant chemotherapy.
The PFS curves for each randomized arm will be estimated using the Kaplan-
Meier (KM) product limit method. Median PFS and the corresponding two-
sided 95% CIs using the log-log transformation will be computed. In addition, 
PFS rates at a specified time point (e.g., 12, 24 months), and the corresponding 
two-sided 95% CIs using the log-log transformation, will be computed.
Secondary
Objective Response Rate (ORR) is defined as the number and percentage of 
participants with a best overall response (BOR) of confirmed complete 
response (CR) or partial response (PR). Best overall response (BOR) is defined 
as the best response designation, recorded between the date of randomization
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.
Disease Control Rate (DCR) is defined as the proportion of participants whose 
BOR is CR or PR or SD among all randomized participants.
Time to Response (TTR) is defined as the time from the date of randomization 
to the date of first confirmed CR or PR. TTR will be evaluated for responders 
only.
Duration of objective response (DoR) is defined as the time between the date 
of first confirmed response to the date of the first documented tumor 
progression (per RECIST 1.1), or death due to any cause, whichever occurs 
first. The rules of censoring are the same as PFS. DoR will be evaluated for 
responders (ie, participants with confirmed CR or PR) only.
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Endpoint
Statistical Analysis Methods
The endpoints above will be assessed by both BICR and investigator where 
applicable.
OS is defined as the time from the date of randomization to the date of death. 
A participant who has not died will be censored at last known date alive.
The ORR will be summarized by binomial response rates and their 
corresponding two-sided 95% exact CIs are calculated using the Clopper-
Pearson method.
OS curves will be estimated using KM product-limit methodology. Median OS 
with two-sided 95% CIs using the log-log transformation will be computed. In 
addition, OS rates at a specific time point (e.g., 12, 24 months) with two-sided 
95% CIs using the log-log transformation, will be computed.
Other secondary variables including TTR, DoR, and DCR will be summarized 
in the following ways. Time to event variables will be analyzed in a similar 
way as OS. Binary variables will be summarized in a similar way as ORR.
Quantitative variables will be summarized using the mean, median, minimum 
and maximum values, and standard deviation. Categorical variables will be 
summarized using tables presenting counts and percentages for each category. 
10.3.2
Safety Analyses
Endpoint
Statistical Analysis Methods
Secondary
The safety analysis will be performed in all participants who have received at 
least 1 dose of study treatment. Descriptive statistics of safety will be presented 
using CTCAE (Version 4) by treatment arm. Adverse events, treatment-related 
AEs, SAEs and treatment-related SAEs will be tabulated using worst grade per 
CTCAE (Version 4) by system organ class and preferred term. On-study 
clinical laboratory abnormalities will be summarized using worst grade per 
CTCAE (Version 4).
10.3.4
Interim Analyses 
One interim analysis (IA) is planned in the Phase 2 portion of the study 
 
. The decision flow is described in Section 5.1.
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The Statistical Analysis Plan will further describe the planned interim analysis.
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12
APPENDICES
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APPENDIX 1
ABBREVIATIONS AND TRADEMARKS
Term
Definition
5-FU
5-Fluorouracil
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BICR
blinded independent central review
BMS
Bristol-Myers Squibb
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
CBC
complete blood count
CEA
Carcinoembryonic Antigen
CFR
Code of Federal Regulations
CI
confidence interval
CNS
Central nervous system
CR
complete response
CRC
colorectal cancer
CRF
Case Report Form, paper or electronic
CTAg
Clinical Trial Agreement
DCR
disease control rate
dL
deciliter
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)
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Term
Definition
FDA
Food and Drug Administration
FFPE
formalin-fixed paraffin embeded
FSH
follicle stimulating hormone
g
Gram
GCP
Good Clinical Practice
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCG 
human chorionic gonadotrophin
HCV
hepatitis C virus
HIV
Human Immunodeficiency Virus
HR
heart rate
ICH
International Conference on Harmonisation
ie
id est (that is)
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IMP
investigational medicinal products
IND 
Investigational New Drug Exemption
I-O
Immuno-oncology
IP/IMP
investigational product/investigational medicinal product
IRB
Institutional Review Board
IRT
interactive response technology
IU
International Unit
IV
intravenous
kg
kilogram
L
Liter
LDH
lactate dehydrogenase
LFT
Liver function tests
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Term
Definition
mCRC
metastatic colorectal cancer
mg
milligram
mg
microgram
min
minute
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 stability
N/A
not applicable
NCCN
national comprehensive cancer network
ORR
objective response rate
OS
overall survival
PD-L1
program cell death ligand 1
PFS
progression-free survival
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Term
Definition
PR
partial response
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SOP
Standard Operating Procedures
TSH
Thyroid stimulating hormone
TTR
time to response
ULN
Upper limit of normal
US
united states
WBC
white blood cell
WOCBP
women of childbearing potential
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APPENDIX 2
STUDY GOVERNANCE CONSIDERATIONS
The term ‘Participant’ is used in the protocol to refer to a person who has consented to participate 
in the clinical research study.  The term ‘Subject’ used in the eCRF is intended to refer to a person 
(Participant) who has consented to participate in the clinical research study.
REGULATORY AND ETHICAL CONSIDERATIONS
GOOD CLINICAL PRACTICE
This study will be conducted in accordance with:
•
Good Clinical Practice (GCP), 
•
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 breach of 
the conditions and principles of Good Clinical Practice (GCP) (occurring in any country) in 
connection with that trial or the protocol related to the trial which is likely to affect to a significant 
degree the safety or physical or mental integrity of 1 or more subjects of the trial or the scientific 
value of the trial. 
Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, participant recruitment materials (eg, 
advertisements), and any other written information to be provided to subjects. The investigator or 
BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product labeling 
information to be provided to subjects and any updates. 
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The investigator, Sponsor or designee should provide the IRB/IEC with reports, updates and other 
information (eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures.
COMPLIANCE WITH THE PROTOCOL AND PROTOCOL REVISIONS
The investigator should not implement any deviation or change to the protocol without prior 
review and documented approval/favorable opinion of an amendment from the IRB/IEC (and if 
applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study participants. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to:
•
IRB/IEC
•
Regulatory Authority(ies), if applicable by local regulations (per national requirements)
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from 
participants currently enrolled in the study if they are affected by the amendment; and (3) the new 
form must be used to obtain consent from new participants prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
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 participants are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer to 
participate. 
In situations where consent cannot be given to participants, their legally acceptable representatives 
(as per country guidelines) are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which the participant volunteers to participate. 
Sponsor or designee will provide the investigator with an appropriate (ie, Global or Local) sample
informed consent form which will include all elements required by ICH, GCP and applicable
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regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki.
Investigators must:
•
Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood. 
•
Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study.
•
Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion. 
•
Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the participants, prior to the beginning of the study, 
and after any revisions are completed for new information.
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant.
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented. 
The confidentiality of records that could identify participants must be protected, respecting the 
privacy and confidentiality rules applicable to regulatory requirements, the participants' signed 
ICF and, in the US, the participants’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to participant records. 
Participants unable to give their written consent (e.g., stroke or participants with or severe 
dementia) may only be enrolled in the study with the consent of a legally acceptable representative. 
The participant must also be informed about the nature of the study to the extent compatible with 
his or her understanding, and should this participant become capable, he or she should personally 
sign and date the consent form as soon as possible. The explicit wish of a participant who is unable 
to give his or her written consent, but who is capable of forming an opinion and assessing 
information to refuse participation in, or to be withdrawn from, the clinical study at any time should 
be considered by the investigator.
The rights, safety, and well-being of the study participants are the most important considerations 
and should prevail over interests of science and society.
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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), 
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.
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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 treatment integrity in accordance with 
requirements applicable under law and the 
SOPs/standards of the sourcing pharmacy. 
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
CASE REPORT FORMS
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
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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 participants must be protected, respecting the 
privacy and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task.  For electronic CRFs, review and approval/signature is completed electronically through the 
BMS electronic data capture tool.  The investigator must retain a copy of the CRFs including 
records of the changes and corrections.
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS electronic data capture tool using the unique user 
account provided by Sponsor or designee. User accounts are not to be shared or reassigned to other 
individuals
MONITORING
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records. 
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable .Certain CRF pages and/or electronic files may serve as the source 
documents:
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS audit reports will be kept confidential.
The investigator must notify BMS promptly of any inspections scheduled by regulatory authorities, 
and promptly forward copies of inspection reports to 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 
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investigator (or head of the study site in Japan) must contact BMS prior to destroying any records 
associated with the study.
BMS or designee will notify the investigator (or head of the study site in Japan) when the study 
records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS or designee. 
RETURN OF STUDY TREATMENT
For this study, study treatments (those supplied by BMS, a vendor or sourced by the investigator) 
such as partially used study treatment containers, vials and syringes may be destroyed on site. 
If..
Then
Study treatments supplied by BMS (including 
its vendors
Any unused study treatments supplied by BMS 
can only be destroyed after being inspected 
and reconciled by the responsible Study 
Monitor unless study treatments containers 
must be immediately destroyed as required for 
safety, or to meet local regulations (eg, 
cytotoxics or biologics).
If study treatments will be returned, the return 
will be arranged by the responsible Study 
Monitor.
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 
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method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
•
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers.
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS, is solely the responsibility of the investigator 
or designee.
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:
•
National Coordinating Investigator
•
Participant recruitment (eg, among the top quartile of enrollers)
•
Regional representation (eg, among top quartile of enrollers from a specified region or country)
•
Other criteria (as determined by the study team)
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.
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APPENDIX 3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING
ADVERSE EVENTS
Adverse Event Definition:
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study treatment 
and that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study treatment, whether or 
not considered related to the study treatment.
Events Meeting the AE Definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
results from other safety assessments (eg, ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically significant 
in the medical and scientific judgment of the investigator. Note that abnormal lab tests or 
other safety assessments should only be reported as AEs if the final diagnosis is not 
available. Once the final diagnosis is known, the reported term should be updated to be the 
diagnosis.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. Overdose, as a verbatim term (as reported by the investigator), 
should not be reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of sequelae and 
should specify "intentional overdose" as the verbatim term
Events NOT Meeting the AE Definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
DEFINITION OF SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met.
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SERIOUS ADVERSE EVENTS
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose:
Results in death
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe)
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below)
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
•
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
•
elective surgery, planned prior to signing consent
•
admissions as per protocol for a planned medical/surgical procedure
•
routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy)
•
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
•
admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason)
•
admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols)
Results in persistent or significant disability/incapacity
Is a congenital anomaly/birth defect
Is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.) 
Pregnancy and potential drug induced liver injury (DILI) must follow the same transmission timing 
and processes to BMS as used for SAEs (see section 9.2.5 for reporting pregnancies).
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EVALUATING AES AND SAES
Assessment of Causality
•
The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE.
•
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
•
The investigator will use clinical judgment to determine the relationship.
•
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.
•
The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
•
For each AE/SAE, the investigator must document in the medical notes that he/she has
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment.
•
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study treatment or if new 
information becomes available, the SAE report must be updated and submitted within 24 hours 
to BMS (or designee) using the same procedure used for transmitting the initial SAE report.
All SAEs must be followed to resolution or stabilization.
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REPORTING OF SAES TO SPONSOR OR DESIGNEE
•
SAEs, whether related or not related to study treatment, and pregnancies must be reported 
to BMS (or designee) immediately within 24 hours of awareness of the event.
•
SAEs must be recorded on the SAE Report Form.
−
The required method for SAE data reporting is through the eCRF.
−
The paper SAE Report Form is only intended as a back-up option when the electronic 
data capture (EDC) system is unavailable/not functioning for transmission of the eCRF 
to BMS (or designee).
♦In this case, the paper form is transmitted via email or confirmed facsimile (fax) 
transmission
♦When paper forms are used, the original paper forms are to remain on site
•
Pregnancies must be recorded on a paper Pregnancy Surveillance Form and transmitted via email or 
confirmed facsimile (fax) transmission 
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list
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APPENDIX 4
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION
DEFINITIONS
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
•
Premenarchal
•
Premenopausal female with 1 of the following:
−
Documented hysterectomy
−
Documented bilateral salpingectomy
−
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
−
A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 40 
mIU/mL to confirm menopause.
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 6 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 
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Progestogen-only hormonal contraception associated with inhibition of ovulationb 
−
oral 
−
injectable 
Highly Effective Methods That Are User Independent
•
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb
•
Intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)c
•
Bilateral tubal occlusion
•
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used. 
•
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
•
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
•
WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2. 
•
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence 
NOTES: 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized. 
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness
Unacceptable Methods of Contraception*
•
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
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•
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).
•
Spermicide only
•
Lactation amenorrhea method (LAM)
* Local laws and regulations may require use of alternative and/or additional contraception 
methods.
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL.
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure.
•
Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator.
•
Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment.
•
Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant.
•
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment. 
•
Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment.
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting
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APPENDIX 5
NIVOLUMAB MANAGEMENT ALGORITHMS
These general guidelines constitute guidance to the Investigator and may be supplemented by 
discussions with the Medical Monitor representing the Sponsor. The guidance applies to all 
immuno-oncology agents and regimens.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.
Corticosteroids are a primary therapy for immuno-oncology drug-related adverse events. The oral 
equivalent of the recommended IV doses may be considered for ambulatory patients with low-
grade toxicity. The lower bioavailability of oral corticosteroids should be taken into account when 
switching to the equivalent dose of oral corticosteroids.
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the immuno-oncology agent or regimen being used.
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APPENDIX 6
ECOG PERFORMANCE STATUS 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and 
prognosis. They are included here for health care professionals to access. 
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
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APPENDIX 7
RECIST 1.1 GUIDELINES 
1
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline 
.1
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or ≥2x slice thickness if 
greater than 5mm.
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm).
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis ≥10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
1.2
Non-Measurable
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with ≥10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions.
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1.3
Special considerations regarding lesion measurability
1.3.1
Bone lesions
•
Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions. 
•
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above.
•
Blastic bone lesions are non-measurable.
1.4
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded).
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected.
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease.
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’).
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2
RESPONSE CRITERIA
2.1
Evaluation of Target Lesions
•
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm.
•
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.
•
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression).
•
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.
•
Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above. 
2.1.1
Special Notes on the Assessment of Target Lesions
2.1.1.1
Lymph nodes
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions.
2.1.1.2
Target lesions that become ‘too small to measure’
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
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small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’.
2.2
Evaluation of Non-Target Lesions
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol.
•
Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis). 
•
Non-CR/Non-PD: Persistence of one or more non-target lesion(s)
•
Progressive Disease (PD): Unequivocal progression of existing non-target lesions.
2.2.1
Special Notes on Assessment of Progression of Non-Target Disease
The concept of progression of non-target disease requires additional explanation as follows:
2.2.1.1
When the patient also has measurable disease
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
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disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial.
2.2.2
New Lesions
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
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2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD.
2.3
Response Assessment
2.3.1
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement.
2.3.2
Time Point Response
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (± Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
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Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response, PD = progressive disease and NE = inevaluable
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
≥4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (± 7 days) for a particular 
protocol, a Best Response of SD can only be made after the participant 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 participant is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF).
Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
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Table 2.3.3-1:
Best Overall Response (Confirmation of CR and PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
Best Overall Response
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD provided minimum criteria for SD duration met, otherwise, 
PD
PR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
NE
NE
NE
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR.
2.3.4
Confirmation Scans
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR (eg, 
CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of a
previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation.
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the participant is considered to not have 
progressive disease.
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APPENDIX 10
COUNTRY SPECIFIC APPENDIX
Table 1:
Criteria for exclusion of HIV-positive participants in Germany and
other countries as applicable
Section 6.2 Exclusion Criteria,
Exclusion criterion 4) Physical and Laboratory Test 
Findings, l)
“Known history of positive test 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- Laboratory
Tests
Add “HIV” to the list of laboratory tests
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APPENDIX 11
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
 Revised Protocol 06, 02-Jun-2020
 
 
 
 
 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 06
Section Number & 
Title
Description of Change
Brief Rationale
•
Synopsis: Overall 
Design 
•
Section 5.1 Overall 
Design 
•
Section 5.1 Overall 
Design, Treatment Phase
•
Section 7.1 Treatments 
Administered
Text has been added to clarify that
treatment with SOC may continue, 
after the maximum treatment duration 
of 24 months for nivolumab, until 
progression, unacceptable toxicity, 
withdrawal of consent, or the end of 
the study, whichever comes first.
Clarification for study sites that 
treatment with SOC may continue, 
after the maximum treatment duration 
of 24 months for nivolumab, until 
progression, unacceptable toxicity, 
withdrawal of consent, or the end of the 
study, whichever comes first, which is 
consistent with NCCN guidelines for 
1L treatment for mCRC.
Throughout 
Minor editorial or format changes that 
do not change content.
Clarify text. 
 Revised Protocol 05, 19-Dec-2019
 
 
SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 05
Section Number & 
Title
Description of Change
Brief Rationale
Synopsis; Section 5, Overall 
Study Design
Updated Figure and footnotes, and 
description of analyses to remove 
reference of IA2.
As described in the overall rationale.
Section 2, Schedule of 
Activities, Table 2-2, On-
Treatment Procedural 
Outline, CEA (and CA19-9) 
Assessment
Collection window (± 7 day) added.
This collection is intended to align with 
tumor assessments, therefore the 7 day 
window as added as clarification.
Section 10.3.4, Interim 
Analyses
Updated to remove reference to IA2.
As described in the overall rationale
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SUMMARY OF KEY CHANGES OF REVISED PROTOCOL 05
Section Number & 
Title
Description of Change
Brief Rationale
Appendix 5
Management Algorithms Updated. 
Myocarditis Algorithm added.
Algorithms have been updated to 
contain the most recent version from 
the 27-Jun-2019 IB. The only update to 
the algorithms in the latest IB is 
addition of the myocarditis algorithm.
 Revised Protocol 04, 07-Dec-2018
 
 
Summary of key changes of Revised Protocol 04
Section Number 
& Title
Description of Change
Brief Rationale
Section 2, Schedule 
of Activities, Table 
2-2, On-Treatment 
Procedural Outline 
(CA2099X8), IRT 
Vial Assignment, 
Fluorouracil 1200 mg 
and 2400 mg 
infusions
Revised Notes regarding schedule of fluorouracil 
infusion.
To clarify the fluorouracil 
infusion days.
Section 7.1, 
Treatments 
Administered, Table 
7.1-1, Section and 
Timing of Dose, 
Fluorouracil 1200 mg
and 2400 mg 
infusions; 
paragraph e, under 
Nivolumab plus SOC 
and bevacizumab 
arm; and paragraph 2 
under SOC and 
bevacizumab arm.
Revised text regarding schedule of fluorouracil 
infusion.
To clarify the fluorouracil 
infusion days.
Section 7.1, 
Treatments 
Administered
Paragraph 8 was revised and paragraph 9 was 
removed.
Detailed text regarding 
treatment administration of 
nivolumab is addressed in the 
Pharmacy Manual.
Appendix 3
Revised text in the following sections: Events 
Meeting the AE Definition, Events Not Meeting the 
Updated to reflect the most 
recent language for BMS 
studies.
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Summary of key changes of Revised Protocol 04
Section Number 
& Title
Description of Change
Brief Rationale
AE Definition, Definition of SAE, and Follow-up of 
AEs and SAEs.
Appendix 4
Removed text regarding women treated with 
hormone replacement therapy. 
Revised text regarding highly effective methods of 
contraception that are user independent and 
unacceptable methods of contraception. 
Update to Appendix 4 in the 
previous version was incorrect. 
The current version has been 
updated to align with 
contraceptive guidance for 
participants being treated with 
nivolumab and other 
components of study treatment.
 Revised Protocol 03, 13-Sep-2018
 
Summary of key changes of Revised Protocol 03
Section Number & 
Title
Description of Change
Brief Rationale
Section 6.2, Exclusion 
Criteria, 2), j)
Exclusion criteria removed in 
Revised Protocol 02, has been 
returned to the document. 
Feedback from 
 requested we reinstate 
exclusion criteria 2j, due to concerns of GI 
perforation highlighted in the Avastin black box 
warning.
 Revised Protocol 02, 06-Aug-2018
 
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 2, Schedule of Activities, 
Table 2-1;  Section 5.1, Overall 
Design, Screening Phase, 
Participants must submit mandatory 
baseline tumor sample, bullet 
Regarding baseline tumor submission, 
text was deleted regarding tissue 
submission from a resected primary 
tumor, archival tissue from an 
endoscopic biopsy, or baseline tumor 
Language removed to clarify 
that tissue from the primary 
tumor will be required in order 
to enroll in this study, without 
exception.
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Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
2;Section 6.1, Inclusion Criteria 
2) Type of Participant and Target 
Disease Characteristics e) ii)
submission that occurred 6 or more 
years prior to randomization.
Section 2, Schedule of Activities, 
Table 2-1
Regarding laboratory tests, a note was 
added stating that laboratory tests do 
not need to be repeated on C1D1 if 
screening laboratory results are 
deemed still clinically valid by the 
treating investigator.
In alignment with other 
protocols, to provide reasonable 
flexibility to sites and subjects 
in terms of timing of lab test 
blood draws 
Section 2, Schedule of Activities, 
Table 2-1, Footnote b; Table 2-2, 
Footnote d, and Table 2-3, 
Footnote d.
Footnote was revised to allow for 
urine protein to creatinine ratio 
(UPCR) in place of the 24-hour urine 
collection.
Urine protein to creatinine ratio 
is an acceptable method to 
assess and manage proteinuria 
and less cumbersome as a 24-hr 
urine collection.
Section 2, Schedule of Activities, 
Table 2-2
Regarding IRT vial assignment, timing 
of fluorouracil was revised.
To clarify the schedule of 5-FU 
infusion.
Section 2, Schedule of Activities, 
Table 2-2
Table footnote b includes revised dose 
delay information. 
 
 
 Added 
text to clarify that CEA and 
CA19-9 should be collected on 
schedule regardless of dose 
delays.
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Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Section 6.1, Inclusion Criteria, 2) c) 
i
Revised language for time gap 
between the completion of adjuvant or 
neoadjuvant chemotherapy and 
diagnosis of recurrent or metastatic 
disease.
Clarification of eligibility 
criteria.
Section 6.1, Inclusion Criteria, 2) h
Criterion was added to require that all 
participants will be required to 
undergo on-treatment biopsies.
Added with the addition of 
mandatory on-treatment 
biopsies.
Section 6.1, Inclusion Criteria, 3) d) 
and f 
Revised the time from last dose of 
investigation drug
Updated to reflect the most 
recent language for BMS 
studies.
Section 6.2, Exclusion Criteria, 2) 
Medical Conditions
Criterion g was revised to within 6 
months of enrollment.
Criterion j is no longer applicable.
Modified to align with clinical 
practice.
Section 6.2, Exclusion Criteria, 
3) Prior/Concomitant Therapy
Revised criterion c.
To align with current 
bevacizumab label.  The current 
label states that bevacizumab 
should be discontinued at least 
28 days prior to surgery, and 
should be held for at least 28 
days after surgery.
Section 6.2, Exclusion Criteria, 
3) Prior/Concomitant Therapy
Added criterion 3f to exclude 
participants who have received a live / 
attenuated vaccine within 30 days of 
first treatment.
Alignment with current BMS 
standards for studies using 
nivolumab.
Section 6.2, Exclusion Criteria, 
Physical and laboratory test 
findings; and Section 9.4.3, Clinical 
Safety Laboratory Assessments 
Criterion 4j revised to include a 
statement to allow for urine protein to 
creatinine ratio in place of the 24-hour 
urine collection
Urine protein to creatinine ratio 
is an acceptable method to 
assess and manage proteinuria 
and less cumbersome as a 24-hr 
urine collection
Section 7, Treatment; Table 7.1-1; 
section on Nivolumab plus SOC and 
bevacizumab arm
Added text regarding dosing 
calculations to Table 7.1-1; 
paragraph 3 under the section titled, 
Nivolumab plus SOC and 
To clarify the dose and the 
schedule of 5-FU infusion.
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BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
bevacizumab arm; and paragraph 3 
under the section titled, SOC and 
bevacizumab arm.
Section 7, Treatment
Below paragraph 8, a paragraph was 
added regarding dosing calculations
for bevacizumab administration.
To clarify that weight based 
dosing does not need to be 
recalculated if the patient’s 
weight is within 10% of the 
weight used to calculate the 
previous dose.
Section 7.4.4, Table 7.4.4-1
Revisions were made to the 
recommended guidelines for 
management of proteinuria.
To include information on urine 
protein to creatinine ratio  
Section 7.7.1, Prohibited and/or 
Restricted Treatments
Added a new bullet to prohibit 
administration of any live / attenuated 
vaccine (eg varicella, zoster, yellow 
fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) 
during treatment and until 100 days 
post last dose. 
Alignment with current BMS 
standards for studies using 
nivolumab.
Section 8.1.1, Nivolumab Dose 
Discontinuation
Myocarditis added to the list of drug-
related events requiring 
discontinuation.
Update to be consistent with 
SmPC and the label for 
nivolumab. 
Section 8.1.2, SOC Dose 
Discontinuation
Revised bullet items for bevacizumab
discontinuations.
To align with current 
bevacizumab label.
Section 9.2.5, Pregnancy
Added paragraph regarding possible 
pregnancy.
Updated to reflect the most 
recent language for BMS 
studies. 
Section 9.3, Overdose
Revised reporting text.
Updated to reflect the most 
recent language for BMS 
studies.
Section 9.4.3, Clinical Safety 
Laboratory Assessments, Other 
Analyses
Added CEA and CA19-9 testing
To be consistent with section 2, 
schedule of activity. 
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Date: 13-Nov-2020
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CA2099X8
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 02
Section Number & Title
Description of Change
Brief Rationale
Appendix 2, Study Governance 
Considerations
Minor revisions to language Good 
Clinical Practice potential serious 
breach reporting.
Deleted return of study treatment 
language that specified study 
treatments supplied by BMS or its 
vendors.
Updated to reflect the most 
recent language for BMS 
studies.
Appendix  3, Adverse Events and 
Serious Adverse Events: Definitions 
and Procedures for Recording, 
Evaluating, Follow Up and 
Reporting
Added sections: Events Meeting the 
AE Definitions and Events NOT 
Meeting the AE Definition; and 
Definition of SAE 
Revised text regarding pregnancy and 
potential drug induced liver injury.
Revised text for the following: 
Evaluating AEs and SAEs, 
Assessment of Causality, Follow-up of 
AE and SAEs; Reporting of SAEs to 
Sponsor or Designee.
Updated to reflect the most 
recent language for BMS 
studies.
Appendix 4, Women of 
Childbearing Potential Definitions 
and Methods of Contraception
Added note regarding women treated 
with hormone replacement therapy.
Revised the definition relevant 
systemic exposure.
Revised text regarding highly effective 
methods of contraception that are user 
independent.
Revised section on unacceptable 
methods of contraception to include 
section on less than highly effective 
contraceptive methods that are user 
dependent.
Updated to reflect the most 
recent language for BMS 
studies.
Appendix 5, Hepatic Adverse Event 
Management Algorithm
Footnote *, regarding delay of I-O 
therapy was deleted.
Hepatic algorithm updated to 
align with most recent guidance 
in the IB.
Appendix 10, Country Specific 
Appendix
Added additional countries as 
applicable.
Updated to reflect the most 
recent language for BMS 
studies.
All
Minor formatting and typographical 
corrections.
Minor, therefore have not been 
summarized
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Clinical Protocol
CA2099X8
BMS-936558
nivolumab
 Revised Protocol 01, 02-Feb-2018
 
 
 
 
 
 
 
 
Summary of key changes of Revised Protocol 01
Section 
Number & Title
Description of Change
Brief Rationale
2, Schedule of 
Activities, Tables 2-
1, 2-2, 2-3
Addition of urinalysis requirements
To ensure assessment of proteinuria at 
screening and management of 
proteinuria during and after treatment 
6.1 Inclusion 
Criteria, 2) Type of 
Participant and 
Target Disease 
Charact.eristics
Inclusion criteria 2.b rephrased
Inclusion criteria reworded for better 
clarity
6.1 Inclusion 
Criteria, 2) Type of 
Inclusion criteria 2.c.i updated
Inclusion criteria updated to allow 
participants who had neoadjuvant 
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BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section 
Number & Title
Description of Change
Brief Rationale
Participant and 
Target Disease 
Charact.eristics
chemotherapy to be eligible, if > 6 
months have elapsed since completion 
of that therapy and diagnosis of 
recurrent or metastatic disease
6.1 Inclusion 
Criteria, 2) Type of 
Participant and 
Target Disease 
Charact.eristics
Inclusion criteria 2.e rephrased
Sentence added to specify that adequate 
tumor tissue must be available for 
eligibility
6.2 Exclusion 
Criteria, 2) Medical 
Conditions
Exclusion criteria 2 k updated
Clarifies half-teaspoon volume
6.2 Exclusion 
Criteria, 2) Physical 
and Laboratory Test 
Findings
Exclusion criteria 4.g and 4.j updated
Clarifies AST/ALT exclusion criteria 
for participants with  liver metastases 
and eligibility requirements for 
proteinuria
6.3 Lifestyle 
Restrictions
Lifestyle restrictions updated
Specifies that there may be restrictions 
associated to the SOC components
7.4 Dosage 
Modification
4th bullet added
Bullet added to specify that if there is a 
delay in administration of study drug(s) 
due to toxicity, treatment with the other 
study agent(s) should continue as 
scheduled and resumption of treatment 
should be at the next scheduled time 
point
7.4.1 Nivolumab 
Dose Delay
Last paragraph updated with guidelines on what 
to do with other study agents in case of 
nivolumab dose delay
Clarifies what to do with other study 
agents in case of nivolumab delay.
7.4.4 Dose 
Modification 
Criteria for 
bevazicumab
Dose modification criteria updated with 
recommended guidelines for the management 
of proteinuria
Bevacizumab may be discontinued 
without other study drugs needing to be 
discontinued. 
7.7.1 Prohibited 
and/or Restricted 
Treatment
Restrictions on botanical preparation updated 
with conditions of use of marijuana and its 
derivatives
Under certain conditions use of 
marijuana and its derivatives will be 
permitted in this protocol as per latest 
BMS standards
7.7.1 Prohibited 
and/or Restricted 
Treatment
Ongoing treatment with aspirin (>325 mg/day) 
or other medications known to predispose 
participants to gastrointestinal ulceration and 
reference to local institutional standards and 
product labels of SOC components added to the 
list of prohibited/restricted treatments
Restriction on aspirin treatment or 
medications known to predispose 
participants to gastrointestinal 
ulceration added specifically for 
bevacizumab treatment. Reference to 
institutional standards or product labels 
added for clarity.
Protocol Amendment No.: 07
Date: 13-Nov-2020
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CA2099X8
BMS-936558
nivolumab
Summary of key changes of Revised Protocol 01
Section 
Number & Title
Description of Change
Brief Rationale
8.1 Discontinuation 
from Study 
Treatment
Third paragraph related to discontinuation 
guidelines in case of pregnancy revised
Updated as per latest BMS standard 
language. In case of pregnancy, study 
treatment must be discontinued. 
Conditions to restart study treatment 
have been clarified.
8.1.2 SOC Dose 
Discontinuation
Discontinuation criteria list for SOC drugs 
updated
Clarifies that certain criteria for 
discontinuation must be drug related 
and list of bevacizumab discontinuation 
criteria updated to better align with 
bevacizumab label
8.1.3 
Last bullet added to specify when to resume 
treatment
Last bullet specifies that resumption of 
treatment should be at the next 
scheduled time point
9.2.7 Potential Drug 
Induced Liver 
Injury (DILI)
Section updated with definition of DILI for 
participants with elevated AST, ALT or Total 
Bilirubin at baseline
Definition of DILI updated in order to 
take into account potential participants 
enrolled with elevated liver function 
tests
9.4.3 Clinical Safety 
Laboratory 
Assessments
Glucose fasting status updated, coagulation 
testing (PT/INR) updated to be performed if 
clinically indicated, urinalysis testing updated 
as per updated schedule of activities (section 2)
Fasting status for glucose clarified as 
not mandatory, coagulation testing may 
be performed during bevacizumab 
treatment if clinically indicated, 
urinalysis testing requirements updated 
for proteinuria assessment and 
management
Throughout 
protocol
Typographical, formatting and wording updates
Typographical, formatting and wording 
updates
Protocol Amendment No.: 07
Date: 13-Nov-2020
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SAP_001.pdf: 
Official Title of Study: 
An Open-Label Exploratory Phase 2/3 Study of Nivolumab with Standard of Care Therapy vs 
Standard of Care Therapy for First-Line Treatment of Metastatic Colorectal Cancer 
(CheckMate 9X8: CHECKpoint pathway and nivoluMab clinical Trial Evaluation 9X8) 
 
NCT Number: NCT03414983 
Document Date (Date in which document was last revised): March 18, 2021 


STATISTICAL ANALYSIS PLAN
FOR CLINICAL STUDY REPORT
AN OPEN-LABEL EXPLORATORY PHASE 2/3 STUDY OF NIVOLUMAB WITH 
STANDARD OF CARE THERAPY VS STANDARD OF CARE THERAPY FOR FIRST-
LINE TREATMENT OF METASTATIC COLORECTAL CANCER
(CHECKMATE 9X8: CHECKPOINT PATHWAY AND NIVOLUMAB CLINICAL TRIAL 
EVALUATION 9X8)
PROTOCOL CA2099X8
VERSION # 4.0
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TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT ...................................1
TABLE OF CONTENTS............................................................................................................2
LIST OF TABLES......................................................................................................................5
LIST OF FIGURES ....................................................................................................................6
1
BACKGROUND 
......................................................................7
2
STUDY DESCRIPTION ..........................................................................................8
2.1
Study Design ............................................................................................................8
2.2
Treatment Assignment............................................................................................10
2.3
Blinding and Unblinding.........................................................................................10
2.4
Protocol Amendments.............................................................................................10
2.6
Blinded Independent Review Committee (BICR)....................................................11
3
OBJECTIVES ........................................................................................................12
3.1
Primary...................................................................................................................12
3.2
Secondary...............................................................................................................12
4
ENDPOINTS..........................................................................................................12
4.1
Primary Endpoint....................................................................................................12
4.2
Secondary Endpoints ..............................................................................................15
4.2.1
Progression-Free Survival (PFS)............................................................................15
4.2.2
Objective Response Rate (ORR)..............................................................................15
4.2.3
Duration of Response (DoR)...................................................................................16
4.2.4
Disease Control Rate (DCR)...................................................................................16
4.2.5
Time to Response (TTR)..........................................................................................16
4.2.6
Overall Survival (OS) .............................................................................................16
4.2.7
Safety Endpoints.....................................................................................................16
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS 
FOR ANALYSES ..................................................................................................22
6.1
Study Periods..........................................................................................................22
6.2
Treatment Regimens...............................................................................................22
6.3
Populations for Analyses ........................................................................................22
7
STATISTICAL ANALYSES..................................................................................23
7.1
General Methods ....................................................................................................23
7.1.1
General Methods: Efficacy .....................................................................................23
7.2
Study Conduct........................................................................................................24
7.2.1
Accrual...................................................................................................................24
7.2.2
Relevant Protocol Deviations..................................................................................24
7.3
Study Population ....................................................................................................25
7.3.1
Subject Disposition.................................................................................................25
7.3.2
Demographics and Other Baseline Characteristics.................................................25
7.3.2.1
Demographics ........................................................................................................25
7.3.2.2
CRC disease Characteristics...................................................................................26
7.3.2.3
Other Baseline Characteristics ...............................................................................26
7.3.3
Medical History......................................................................................................26
7.3.4
Prior Cancer Therapy.............................................................................................26
7.3.5
Baseline Examinations............................................................................................27
7.3.5.1
Discrepancies Between IRT and CRF Stratification Factors ...................................27
7.4
Extent of Exposure .................................................................................................27
7.4.1
Administration of Study Therapy.............................................................................27
7.4.2
Modifications of Study Therapy ..............................................................................29
7.4.2.1
Dose delays ............................................................................................................29
7.4.2.2
Infusion Interruptions and Rate Changes................................................................29
7.4.2.3
Dose Reductions.....................................................................................................30
7.4.3
Concomitant Medications.......................................................................................30
7.4.4
Subsequent Therapy................................................................................................30
7.5
Efficacy..................................................................................................................30
7.5.1
Primary Efficacy Endpoint......................................................................................31
7.5.1.1
Primary Analysis ....................................................................................................31
7.5.1.2
Sensitivity Analyses.................................................................................................31
7.5.2
Secondary Efficacy Endpoints.................................................................................32
7.5.2.1
Objective Response Rate and Related Endpoints.....................................................32
7.5.2.2
Sensitivity Analyses for ORR...................................................................................33
7.5.2.3
PFS and OS............................................................................................................33
7.5.2.4
Participants Follow-up...........................................................................................33
7.5.2.5
Consistency of Treatment Effect in Subsets .............................................................34
7.5.2.6
ORR Subgroups......................................................................................................35
7.6
Safety.....................................................................................................................35
7.6.1
Deaths ....................................................................................................................35
7.6.2
Serious Adverse Events...........................................................................................35
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy.................................35
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7.6.4
Adverse Events Leading to Dose Modification........................................................35
7.6.5
Adverse Events .......................................................................................................36
7.6.6
Select Adverse Events .............................................................................................36
7.6.7
Immune Modulating Medication .............................................................................36
7.6.8
Multiple Events.......................................................................................................36
7.6.9
Other Events of Special Interest..............................................................................36
7.6.10
Immune Mediated Adverse Events...........................................................................36
7.6.11
Clinical Laboratory Evaluations.............................................................................36
7.6.12
Vital Signs ..............................................................................................................36
7.6.14
Pregnancy ..............................................................................................................36
7.6.15
Adverse Events by Subgroup...................................................................................36
7.11
Interim Analysis .....................................................................................................39
8
CONTENT OF REPORTS .....................................................................................40
8.1
Interim Analysis .....................................................................................................40
9
CONVENTIONS....................................................................................................40
10
CONTENT OF REPORTS .....................................................................................41
11
DOCUMENT HISTORY........................................................................................42
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LIST OF TABLES
Table 2.4-1:
Protocol Amendments ............................................................................10
Table 4.1-1:
Censoring Scheme Used in Primary Analysis of PFS..............................13
Table 7.4.1-1:
Selection and Timing of Dose.................................................................28
Table 7.4.1-2:
Administration of Study Therapy - Definition of Parameters ..................28
Table 7.5.1.2-1:
Censoring Scheme - PFS Sensitivity Analysis ........................................32
Table 11-1:
Document History ..................................................................................42
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LIST OF FIGURES
Figure 2.1-1:
Study Design Schematic...........................................................................9
Figure 4.1-1:
Graphical Representation of the Primary PFS Definition ........................14
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1
BACKGROUND 
CA2099X8 (CHECKpoint pathway and nivoluMab clinical trial evaluation 9X8) is a Phase 2/3, 
randomized 2:1, open-label, multi-center trial to evaluate nivolumab (BMS-936558) in 
combination with standard of care (SOC) chemotherapy (mFOLFOX6) with bevacizumab for the 
treatment of first-line metastatic colorectal cancer (mCRC)1. 
Research Hypothesis:  
Nivolumab plus SOC chemotherapy with bevacizumab (Nivo + SOC) will demonstrate superior 
efficacy (defined as progression-free survival [PFS]) compared to SOC chemotherapy with 
bevacizumab alone in participants with previously untreated mCRC. 
 
 
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Schedule of Analyses:
In this study, one interim analysis (IA) and one final analysis (FA) are planned.
 
 
 
 
 
 
 
This document describes statistical analyses and outputs for CA2099X8 final analysis. At the time 
of this SAP update, one interim analysis was performed per previous version of SAP. Final analysis 
will be performed per this SAP
 
2
STUDY DESCRIPTION
2.1
Study Design
This is a Phase 2/3, randomized, open-label study of nivolumab plus SOC, or SOC alone, in the 
first-line treatment of participants with metastatic CRC. 
The study design schematic is presented in Figure 2.1-1.
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Figure 2.1-1:
Study Design Schematic
DCR, disease control rate; FA; final analysis; IA, interim analysis; ORR, objective response rate; OS, overall survival; 
PFS, progression-free survival.
b Depending on the results at the time of the IA, different possible decisions may be made as indicated by dashed 
arrow from  IA. If there is not enough evidence of favorable benefit/risk at IA, the Phase 2 study will continue to 
compete with 180 participants unless unacceptable safety concern arises.
One IA is planned in this Phase 2 study 
 
.
Enrollment and randomization will continue during the planned IA. The IA will only be based on 
the planned number of randomized participants. The study team/statistician will remain blinded to 
the additional participants who are not included in the IA. As such, when the study expends to a 
phase III cohort, these additional randomized participants will be included in the phase III cohort. 
 
 
 
 
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If the study does not expand at IA, enrollment will continue as planned to approximately180 
randomized participants. 
2.2
Treatment Assignment
CA2099X8 is a randomized, open-label study. After the participant’s initial eligibility is 
established and informed consent has been obtained, the participant must be enrolled into the study 
by using an Interactive Response Technology (IRT) to obtain the participant number. Every 
participant that signs the informed consent form must be assigned a participant number using IRT. 
All participants will be centrally randomized using the IRT. 
Participants meeting all eligibility criteria will be randomized in a 2:1 ratio to nivolumab + SOC 
or to SOC arm. Randomization will be stratified by tumor sidedness (Left, Right, Transverse, and 
Unknown) and prior oxaliplatin-based adjuvant chemotherapy (Yes, No). The exact procedures 
for using the IRT will be detailed in the IRT manual.
2.3
Blinding and Unblinding
The trial is open label however no analyses or summaries generated by randomized treatment arms 
or treated arms for all randomized participants will be produced during the conduct of the study 
by the Sponsor.
At time of planned interim analysis, only the planned number of randomized participants will be 
unblinded to the study team. Decision of expanding to Phase III part of the study or continuing
enrollment of Phase II part of the study will based on the results from these unblinded Participants. 
In addition, the Blinded Independent Review Committee (BICR) will perform the central imaging 
review without knowledge of the treatment group assignment. At time of planned interim analysis, 
BICR data from the planned number of randomized participants will be transferred to the Sponsor 
and included for interim analysis.
2.4
Protocol Amendments
Global amendments incorporated in the protocol are described in Table 2.4-1.
Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Change
Protocol Amendment 
07
13-Nov-2020
Administrative Letter 
05
28-Sep-2020
Revised Protocol 06
02-Jun-2020
Major change: Clarifies study treatment duration for standard of care 
(SOC)
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Table 2.4-1:
Protocol Amendments
Document
Date of Issue
Summary of Change
SOC may continue, after the maximum treatment duration of 24 
months for nivolumab, until progression, unacceptable toxicity, 
withdrawal of consent, or the end of the study, whichever comes first. 
Revised Protocol 05
19-Dec-2019
Removed interim analysis 2 (IA2). 
Revised Protocol 04
07-Dec-2018
Clarified the infusion days for fluorouracil, updated Appendix 3, and 
aligned Appendix 4 with contraceptive guidance for nivolumab and 
other components of study treatment.
Revised Protocol 03
13-Sep-2018
Incorporates Administrative Letter 03, and reinstates exclusion criteria 
2j.
Administrative Letter 
03
11-Sep-2018
Adding Appendix 11 back into the document
Revised Protocol 02
06-Aug-2018
Incorporates Administrative Letter 02 and updates to be consistent 
with SmPC and label information. Revises prohibited and/or restricted
treatments; laboratory tests, assessments, and other analyses; dose 
modification criteria; urinalysis;
 sample collection 
requirements. 
 clarifies 
eligibility criteria. 
 
 Minor changes and corrections including revisions to reflect 
the most recent language for BMS studies.
Administrative
Letter 02
23-Apr-2018
Revised Protocol 01
02-Feb-2018
Incorporates Administrative Letter 01, revisions to laboratory tests
exclusion criteria, revisions to dose modification criteria, urinalysis 
 sample collection requirements.
Addition of a definition of
DILI for participants with elevated liver function tests at baseline.
Updated rationale for the 2-year treatment duration, in addition of a
number of other minor changes and corrections.
Administrative
Letter 01
07-Dec-2017
Original Protocol
13-Oct-2017
Not applicable
2.6
Blinded Independent Review Committee (BICR)
A BICR will be utilized in this study for determination of BICR-assessed endpoints. Details of 
BICR procedures will be specified in the BICR Charter.
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3
OBJECTIVES
3.1
Primary
•
To compare the efficacy of nivolumab plus standard of care (SOC) chemotherapy plus
bevacizumab (Nivo + SOC) with SOC chemotherapy plus bevacizumab in participants with 
mCRC
3.2
Secondary
•
To evaluate preliminary efficacy in all randomized participants
•
To characterize the safety and tolerability of nivolumab in combination with standard therapy 
with bevacizumab
4
ENDPOINTS
4.1
Primary Endpoint
The primary endpoint is progression-free survival (PFS) that is assessed by BICR in All 
Randomized participants. 
PFS is defined as the time from randomization to the date of the first documented progression, as 
determined by BICR (per RECIST 1.1), or death due to any cause, whichever occurs first. 
•
Participants who die without a reported prior progression per BICR (and die without start of 
subsequent therapy) will be considered to have progressed on the date of death. 
•
Participants who did not have documented progression per BICR and who did not die, will be 
censored at the date of the last tumor assessment on or prior to initiation of the subsequent anti-
cancer therapy, if any. 
•
Participants who did not have baseline tumor assessment will be censored on the date they 
were randomized
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•
Participants who did not have any post baseline tumor assessments and did not die (or died 
after initiation of the subsequent anti-cancer therapy) will be censored at the randomization 
date. 
•
Participants who started any subsequent anti-cancer therapy without a prior reported 
progression per BICR will be censored at the last tumor assessment on or prior to initiation of 
the subsequent anti-cancer therapy.
•
Baseline tumor assessment is defined as tumor scans prior to or on randomization date 
Censoring rules for the primary analysis of PFS are summarized in Table 4.1-1. Further 
explanation for various censoring scenarios are presented in Figure 4.1-1.
Table 4.1-1:
Censoring Scheme Used in Primary Analysis of PFS
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessment
Date of randomization
Censored 
No post baseline tumor assessments 
and no death
Date of randomization
Censored 
Documented progression
Date of the first documented tumor progression
Progressed 
No progression and no death
Date of last tumor assessment
Censored 
Subsequent anti-cancer therapies
Date of last tumor assessment prior to initiation 
of the subsequent therapy
Censored 
Death without progression and without 
initiation of subsequent anti-cancer 
therapy
Date of death
Progressed 
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Figure 4.1-1:
Graphical Representation of the Primary PFS Definition
rand = randomization, subs = subsequent therapy
PFS Primary 
Definition
No: baseline Scan
Censored at rand 
(regardless of 
Death) 
Yes: baseline scan
No: post baseline  
scans
Yes: Death
Death with prior 
subsequent 
therapy
Censored at 
randomization
Death without 
prior subsequent 
therapy
Event at Death 
date
No:Death
Censored at 
randomization
Yes:  post baseline 
scans
No PD, 
No death
Yes: subsequent 
therapy
Censored at max( rand, 
last tumor scan <=the 
subs date)
No: subsequent 
therapy
Censored at last 
tumor scan date
Yes: PD or Death 
or both
Yes: subs < PD or 
death or min (PD, 
death)
Censored at 
max(rand, last tumor 
scan <= subs date)
No: subs < PD or 
death or min (PD, 
death date)
Event at PD or  
death or min (PD, 
death date)
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4.2
Secondary Endpoints
4.2.1
Progression-Free Survival (PFS) 
Progression-free survival by investigator assessment in All Randomized participants is defined the 
same way as for the primary endpoint (per BICR), except that only tumor assessments by 
investigator will be taken into account.
4.2.2
Objective Response Rate (ORR)
ORR as assessed by BICR per RECIST 1.1 in All Randomized participants is defined as the 
number of participants with a best overall response (BOR) of confirmed CR or PR divided by the 
number of randomized participants in a population of interest. BOR is defined as the best response 
designation as determined by BICR per RECIST 1.1, recorded between the date of randomization 
and the date of objectively documented progression per RECIST 1.1 or the date of subsequent anti-
cancer therapy (including tumor-directed radiotherapy and tumor-directed surgery), whichever 
occurs first. For participants without documented progression or subsequent anti-cancer therapy, 
all available response designations will contribute to the BOR determination. 
For a BOR of CR or PR, the initial response assessment must be confirmed by a consecutive 
assessment no less than 28 days later. In the case of stable disease (SD), measurements must have 
met the SD criteria at least 42 days after randomization.
ORR as assessed by investigator in All Randomized participants is defined similarly as the 
endpoint as assessed by BICR, except that only tumor assessments by investigator will be taken 
into account.
In this study, the case report form (CRF) page of BOR will be filled under the following conditions 
when investigators review the tumor scans: 1) a participant has disease progression; 2) a participant 
has complete response; 3) a participant is determined to be not evaluable or off study (for example, 
a participant died before first on-study assessment). Therefore, at the database lock of interim 
analysis, participants who are on treatment or who have response of PR or SD may not qualify to 
complete the BOR CRF page. As such, the following imputation algorithm will be used to 
determine the BOR for participants who have not been ready to complete BOR page in order to 
conduct ORR analysis per investigator assessment.
•
If a participant has PR date (from confirmed PR) reported in the CRF page of investigator best 
overall response date (RECIST 1.1 response criteria) and the BOR page is not filled yet, the 
participant’s investigator BOR will be imputed as PR. This reflects the situation where a PR 
has been determined for the participant but the PR may further become CR at later time points, 
and thus only the PR date is recorded but the BOR page is not filled.
•
If a participant does not have a BOR page but has at least one on-study tumor assessment that 
occurs beyond 42 days after randomization, the participant’s BOR will be imputed as SD.
•
Otherwise, the participant’s investigator BOR will remain missing and not be imputed. This 
reflects a situation where a participant recently randomizes to the study and has not yet reached 
the timing of first scheduled tumor scan.
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4.2.3
Duration of Response (DoR)
Duration of Response (as assessed by BICR and as assessed by investigator) is defined as the time 
between the date of first confirmed response (CR or PR) to the date of the first documented 
progression (per RECIST 1.1) or death due to any cause, whichever occurs first. The rules of 
censoring are the same as PFS. DoR will be evaluated only for participants with confirmed CR or 
PR.
4.2.4
Disease Control Rate (DCR)
DCR is defined as the proportion of participants whose BOR is confirmed CR or confirmed PR or 
SD among All Randomized participants of a population of interest based on BICR-assessed BOR
or investigator-assessed BOR. 
4.2.5
Time to Response (TTR)
TTR is defined as the time from the randomization date to the date of the first confirmed CR or 
PR (as assessed by BICR and as assessed by investigator). TTR is derived for responders only. 
4.2.6
Overall Survival (OS)
OS is defined as the time between the date of randomization and the date of death. For participants
without documentation of death, OS will be censored on the last date the participant was known 
to be alive.
4.2.7
Safety Endpoints
Safety and tolerability objective will be measured by the incidence of adverse events (AEs), serious 
adverse events (SAEs), adverse events leading to discontinuation, adverse events leading to dose 
delays, immune mediated adverse events, select adverse events, deaths, and laboratory 
abnormalities. Toxicities will be graded using the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. See details in the Core Safety 
SAP.
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6
STUDY PERIODS, TREATMENT REGIMENS AND POPULATIONS FOR 
ANALYSES
6.1
Study Periods
Refer to Core Safety SAP13 for definitions of baseline period and post baseline period for AEs and 
evaluations of laboratory tests, and vital signs.
6.2
Treatment Regimens
The treatment group “as randomized” will be retrieved from the IRT system
•
Arm A in the IRT system: Experimental arm: Nivo 240mg + mFOLFOX6 + Bevacizumab all 
Q2W
•
Arm B in the IRT system: Control arm: mFOLFOX6 + Bevacizumab both Q2W
The treatment group “as treated” will be, in general, the same as the arm randomized by IRT. 
However, if a participant received the incorrect drug for the entire period of treatment, the 
participant’s treatment group will be defined as the incorrect drug the participant actually received.
6.3
Populations for Analyses
All analyses will be performed using the treatment group as randomized (intent-to-treat) with the 
exception of extent of exposure (dosing) and safety, for which the treatment group as treated will 
be used. 
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When appropriate, the following definitions of different types of participants will be applied to 
different populations of interest defined as below:
•
Enrolled: Participants who signed an informed consent form and were registered into the IRT 
system. 
•
Randomized: All participants who were randomized to any treatment group in the study. This 
is the primary population for analyses of efficacy.
•
Treated: All participants who received at least one dose of study treatment (nivolumab or 
SOC). This is the primary population for analyses of exposure and safety.
•
Response Evaluable: Randomized participants with 1) a BOR of CR, PR, SD, or PD; 2) target 
lesion(s) assessed at baseline and 3) at least one post-baseline time point with all baseline target 
lesion(s) assessed
7
STATISTICAL ANALYSES
7.1
General Methods
Unless otherwise noted, the bulleted titles in the following subsections describe tabulations of 
discrete variables, by the frequency and proportion of participants falling into each category,
grouped by treatment (with total, as needed). Percentages given in these tables will be rounded 
and, therefore, may not always sum to 100%. Continuous variables will be summarized by 
treatment group (with total, as needed) using the mean, standard deviation, median, minimum and 
maximum values.
7.1.1
General Methods: Efficacy
Stratification Factors
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For all stratified analyses, stratification factors will be based on the randomization factors. 
Specifically, stratification factors used for analyses are as follows:
•
for All Randomized Participants
−
tumor sidedness (left, right, transverse, and unknown)
−
prior oxaliplatin-based adjuvant chemotherapy (yes vs. no)
Unless otherwise specified, stratification factors are used as entered in the IRT.
General Methods for Time-to-event Variables
Time to event distribution (e.g. OS, PFS, DoR) will be estimated using Kaplan-Meier (KM) 
method.
Median along with 95% confidence interval (CI) will be constructed based on a log-log 
transformed CI for the survivor function S(t)14,15. Rates at fixed timepoints (e.g. OS at 6 months) 
will be derived from the KM estimate and corresponding CI will be derived based on Greenwood 
formula16 for variance derivation and on log-log transformation applied on the survivor function 
S(t)17.
Unless otherwise specified, the stratified log-rank test (for primary endpoint of PFS) will be 
performed to test the comparison of time to event distributions between two treatment groups. The 
stratified hazard ratio (HR) between two treatment groups along with CI will be obtained by fitting 
a stratified Cox model (using randomization stratification factors specified above) with the 
treatment group variable as unique covariate. 
General Methods for binomial proportion variables
Confidence intervals for binomial proportions will be derived using the Clopper-Pearson 
method18. The difference in rates (e.g., ORR) between the two treatment groups along with their 
two-sided 95% CI will be estimated using Cochran-Mantel-Haenszel (CMH) method of 
weighting19, adjusting for the stratification factors.
7.2
Study Conduct
7.2.1
Accrual
The accrual pattern will be summarized by country, investigational site and per month for all 
enrolled participants. Randomization date, first dosing date, country, investigational site will be 
presented in a by participant listing of accrual.
7.2.2
Relevant Protocol Deviations
The relevant Protocol Deviations will be summarized for all randomized participants, by treatment 
group and overall. The following programmable deviations will be considered as relevant protocol 
deviations. Non-programmable relevant eligibility and on-treatment protocol deviations, as well 
as significant (both programmable and nonprogrammable) eligibility and on-treatment protocol 
deviations will be reported via other approach.
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At Entrance
•
Participants who have received prior chemotherapy for metastatic colorectal cancer
−
For participants who have received adjuvant or neo-adjuvant chemotherapy, there is no 
more than 6 months gap (< 6 months) between the completion of that therapy and diagnosis
of recurrent or metastatic disease.
•
Participants with baseline ECOG performance status > 1.
•
Participants without any measurable disease per investigator by RECIST 1.1 criteria at 
baseline.
On-study
•
Participants treated differently as randomized (participants who received the wrong treatment
consistently, excluding the never treated). 
A participant listing will also be produced.
7.3
Study Population
7.3.1
Subject Disposition
The total number of participants enrolled (randomized or not randomized) will be presented along 
with the reason for not being randomized.
Number of participants randomized but not treated along with the reason will be tabulated by 
treatment group as randomized. This analysis will be performed on all randomized participants.
Number of participants who discontinued study treatment along with corresponding reason will be 
tabulated by treatment group as treated. This analysis will be performed on all treated participants. 
A participant listing for all treated participants will be provided showing the participant’s 
randomization date, first and last dosing date, off treatment date and reason for going off treatment.
A participant listing for all enrolled participants will also be provided, showing the participant’s 
race, gender, age, consent date and reason for not being randomized.
7.3.2
Demographics and Other Baseline Characteristics
Descriptive statistics will be summarized for the following baseline characteristics for all 
randomized participants by treatment as randomized. All baseline presentations will identify 
participants with missing measurements. Listings will also be provided.
7.3.2.1
Demographics
•
Age (descriptive statistics)
•
Age categories (<65, ≥65 and <75, ≥75 years)
•
Gender (male, female)
•
Race/Ethnicity
•
Region (US/Canada vs. Europe vs. Rest of World)
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•
Baseline ECOG Performance Status (0, 1, >1, Not reported)
•
Weight (descriptive statistics)
7.3.2.2
CRC disease Characteristics
•
Tumor sidedness (Left, Right, Transverse, and Unknown) (stratification factor)
•
Prior oxaliplatin-based chemotherapy (Yes, No) (stratification factor)
•
Time from initial disease Diagnosis to Randomization (< 3month, 3month-< 6months, 
6months -< 1 year, 1-< 2 years, 2 - < 3 years, 3 -< 4 years, 4 - < 5 years, ≥ 5 years)
•
Time from Initial Metastatic Disease Diagnosis to Randomization (< 3month, 3month-< 
6months, 6months -< 1 year, 1-< 2 years, 2 - < 3 years, 3 -< 4 years, 4 - < 5 years, ≥ 5 years)
•
Disease diagnosis: initial diagnosis (Stage, classification, Location, cell type), initial metastatic 
(stage, location) and study entry (stage)
•
TNM classification at initial diagnosis:
−
Tumor (Tx, T0, T1, T2, T3, T4a, T4b)
−
Nodes (Nx, N0, N1a, N1b, N1c, N2a, N2b)
−
Metastasis (M0, M1a, M1b, M1c)
•
All lesions (Investigator and BICR Tumor Assessments at Baseline): organ of lesion, 
•
Target Lesions (Investigator and BICR Tumor Assessments at Baseline): Presence of target 
lesions, organ of target lesion, summary of diameters of target lesions 
7.3.2.3
Other Baseline Characteristics
•
Smoking Status
•
Alcohol use
7.3.3
Medical History
•
General medical history will be listed by participant and pretreatment events will be tabulated. 
7.3.4
Prior Cancer Therapy
•
Prior anti-cancer therapy will be summarized:
•
Prior surgery related to current cancer (yes or no).
•
Prior radiotherapy (yes or no).
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•
Prior systemic therapy (setting, Time from completion of prior adjuvant/neo-adjuvant therapy 
to randomization(< 6 months, 6 - < 12month, ≥ 12 months), etc)
•
Prior/current non-study medication classified by anatomic and therapeutic classes.
A listing by participant will also be provided. Agents and medication will be reported using the 
generic name.
7.3.5
Baseline Examinations
Participants with abnormal baseline physical examination will be tabulated by examination criteria
and by treatment as randomized for all randomized participants.
7.3.5.1
Discrepancies Between IRT and CRF Stratification Factors
A summary table (cross-tabulation) by treatment group as randomized for stratification factor will 
be provided to show any discrepancies between what was reported through IVRS and CRF data.
7.4
Extent of Exposure
Analyses in this section will be performed in all treated participants by treatment group as treated. 
Listing will include all available exposure data.
7.4.1
Administration of Study Therapy
The following parameters will be summarized by treatment group (descriptive statistics):
•
Relative dose intensity (%) using the following categories: < 50%; 50 - < 70%; 70 - < 90%; 90 
- < 110%; ≥110%. 
•
Number of doses received (summary statistics)
•
Cumulative dose 
•
Duration of treatment: duration of treatment will be presented using a Kaplan-Meier curve 
whereby the last dose date will be the event date for participants who discontinued study 
therapy.  Participants who are still on study therapy will be censored on their last dose date.  
Median duration of treatment and associated 95% CI will be provided.
•
A by-participant listing of dosing of study medication (record of study medication, infusion 
details, and dose change) and a listing of batch number will be also provided.
•
Time from randomization to first dose date (<= 3 days, 4 - 5 days, 6 - 7 days, 8 - 14 days, 15 -
21 days, >21 days)
The selection and timing of dose for each participant is as follows (see details in Protocol Section 
7.1):
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Table 7.4.1-1:
Selection and Timing of Dose
Study Treatment
Unit dose strength(s)/Dosage level(s)
Dosage formulation
Frequency of 
Administration
Route of 
Administration
Oxaliplatin
85 mg/m2
Q2W
IV
Leucovorin
400 mg/m2 or 350 mg/m2 as per local 
standards
Q2W
IV
Fluorouracil
400 mg/m2
Q2W
IV
Fluorouracil
1200 mg/m2
Continuous infusion Day #1 and Day #2
OR
2400 mg/m2 Continuous infusion over 
46 hours Day #1 through Day #2  as per 
local standards
Q2W
IV
Bevacizumab
5 mg/kg
Q2W
IV
Nivolumab
240 mg
Q2W
IV
IV, intravenous. 
Table 7.4.1-2:
Administration of Study Therapy - Definition of Parameters
Parameter
Definition per study medication
Nivolumab
Dosing schedule per protocol
240mg every 2 weeks
Dose
Dose (mg) is defined as the total drug administrated at each dosing date as 
collected on the CRF
Cumulative Dose
The sum of all doses (mg) administered to a participant during the treatment 
period
Relative dose intensity (%)
Cum dose (mg) /[ (Last dose date - Start dose date + 14) x 240 /14 ] x 100
Duration of treatment 
Last dose date - Start dose date +1
Bevacizumab
Dosing schedule per protocol
5 mg/kg every 2 weeks 
Dose
Dose (mg/kg) is defined as total dose administered at each dosing date (mg) 
divided by the most recent weight (kg). Dose administered and weight are 
collected from the CRF.
Cumulative Dose
Cum Dose (mg/kg) is the sum of the doses administered to a participant
during the treatment period.
Relative dose intensity (%)
Cum dose (mg/kg) /[ (Last dose date - Start dose date +14) x 5/14 ] x 100
Duration of treatment 
Last dose date - Start dose date +1 
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Table 7.4.1-2:
Administration of Study Therapy - Definition of Parameters
Parameter
Definition per study medication
Oxaliplatin/ Leucovorin/ Fluorouracil
Dosing schedule per protocol
Every 2 weeks
Dosea
Dose (mg/m2) is defined as the total dose administered (mg) / most recent 
BSA
Cumulative Dose
The sum of all doses (mg/m2) administered to a participant during the 
treatment period
Relative dose intensity (%)
Cumulative dose (mg/m2) / [Last dose date –Start dose date + 14) x ds / 14]
ds is dose level for Oxaliplatin or Leucovorin or Fluorouracil, respectively 
as in Table 7.4.1-1
Duration of treatment 
Last dose date - Start dose date +1 
a * Dose administered in mg at each dosing date and BSA (computed using most recent weight and baseline height) 
are collected on the CRF.
7.4.2
Modifications of Study Therapy  
7.4.2.1
Dose delays
Treatment may be delayed for up to a maximum of 6 weeks from the last dose without approval 
from BMS clinical trial physician. A dose will be considered as actually delayed if the delay is 
exceeding 3 days (i.e., greater than or equal to 4 days from scheduled dosing date). Length of delay 
is defined as (duration of interval from prior dose in days - 14). Dose delays will be divided into 
following categories: 4 - < 8 days, 8 - < 15 days, 15 - < 42 days, ≥42 days. Reason for dose delay 
will be retrieved from CRF dosing pages.
The following parameters will be summarized for Nivolumab, Bevacizumab, Oxaliplatin,
Leucovorin, and Fluorouracil:
•
Number of participants with at least one dose delayed, number of dose delayed per participant, 
Length of Delay and Reason for Dose Delay
7.4.2.2
Infusion Interruptions and Rate Changes
Each study therapy infusion may be interrupted. This information will be retrieved from CRF 
dosing pages. The following parameters will be summarized for Nivolumab, Bevacizumab, 
Oxaliplatin, Leucovorin, and Fluorouracil:
•
Number of participants with at least one dose infusion interrupted along with reason (per 
interruption) for the interruptions and number of infusions interrupted per participant
•
Number of participants with at least one IV infusion rate reduction, number of IV infusion rate 
reduction per participant, and the reason for reduction
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7.4.2.3
Dose Reductions
Per protocol, there will be no dose escalations or reductions of nivolumab. However, for 
bevacizumab and chemotherapy, dose reduction is permitted (as specified in the protocol). This 
information will be retrieved from CRF dosing pages.
For participants treated with chemotherapy, the following will be summarized:
•
Number of participants with at least one dose reduction along with the reason of the dose 
reduction.
7.4.3
Concomitant Medications
Concomitant medications, defined as medications other than study medications which are taken at 
any time on-treatment (i.e. on or after the first day of study therapy and within 100 days following 
the last dose of study therapy), will be coded using the WHO Drug Dictionary.
The following summary tables will be provided: 
•
Concomitant medications (participants with any concomitant medication, participants by 
medication class and generic term).
A by-participant listing will accompany the table.
7.4.4
Subsequent Therapy
•
Number and percentage of participants receiving subsequent therapies will be summarized. 
Categories include: 
•
Immunotherapy including commercial Nivolumab (anti-PD1 agents, anti-PD-L1 agents, anti-
CTLA-4 agents and others) by drug name 
•
Other anti-cancer agents excluding all immunotherapy (approved and investigational) by drug 
name 
•
Surgery for treatment of tumors 
•
Radiotherapy for treatment of tumors
A participant listing of follow-up therapy will also be produced for participants who had any 
subsequent therapy.
7.5
Efficacy
Unless otherwise specified, analyses in this section will be performed in all randomized 
participants by treatment group as randomized. 
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7.5.1
Primary Efficacy Endpoint
7.5.1.1
Primary Analysis
The distribution of PFS as assessed by BICR will be compared between treatment groups using a 
two-sided log rank test, stratified by the stratification factors as specified by
•
Tumor sidedness (left, right, transverse, and unknown)
•
Prior oxaliplatin-based adjuvant chemotherapy (yes vs. no)
A two-sided significance level of 0.2 will be used. 
HR with its associated two-sided 80% and 95% CIs will be estimated via a stratified Cox model 
(using the above randomization stratification factors) with treatment group as the only covariate 
in the model.
PFS curves for each treatment group will be estimated and plotted using the KM product-limit 
method. Median PFS along with two-sided 95% CI will be constructed based on a log-log 
transformed CI for the survival function14,15. In addition, PFS rates at a specified time point 
(e.g., 6, 9, 12, 15, 18, 24 months), and the corresponding two-sided 95% CIs using the log-log 
transformation, will be computed. Minimum follow-up (see definition in Section 7.5.2.4) must be 
longer than a time period to generate a rate.
The status of participants who are censored in the PFS KM analysis will be tabulated for each 
randomized treatment group using the following categories:
1) Censored on randomization date
2) Censored on date of last disease assessment on-study
The source of PFS event (death vs. progression) will be summarized by treatment group.
7.5.1.2
Sensitivity Analyses
Progression-Free Survival
•
Analysis using a 2-sided, un-stratified log-rank test, an un-stratified Cox proportional hazards 
model with treatment as the single covariate
•
Analysis for participants with no relevant deviation. This analysis will be conducted only if 
there are more than 10% participants with relevant protocol deviations.
The above analysis will use the same significance level as the corresponding primary analysis. 
Estimate of the HR, its two-sided 80% and 95% CI and descriptive p-value will be presented.
Sensitivity analyses for PFS to investigate alternative censoring schemes
•
Stratified Analysis (using stratification factors per IRT) accounting for assessment on/after 
subsequent therapy: PFS will be defined similarly to the primary definition except that events 
(progression or death) and disease assessments that occurred on or after subsequent anti-cancer 
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therapy will be considered (no time point truncation) (see censoring scheme in Table 7.5.1.2-
1).  
The above analysis will use the same significance level, stratified by stratification factors as the 
corresponding primary analysis. Estimate of the HR, its two-sided 80% and 95% CI and p-value 
will be presented.
Table 7.5.1.2-1:
Censoring Scheme - PFS Sensitivity Analysis
Situation
Date of Progression or Censoring
Outcome
No baseline tumor assessment 
Date of randomization
Censored 
No post baseline tumor assessments and no death
Date of randomization
Censored 
Documented progression per BICR assessment 
according to RECIST 1.1
Date of the first documented tumor 
progression
Progressed 
No progression and no death 
Date of last tumor assessment
Censored 
Subsequent anti-cancer therapies started without a 
prior reported progression
Date of subsequent anti-cancer therapy 
not considered
None 
Death without progression and without initiation 
of subsequent anti-cancer therapy
Date of death 
Progressed 
Death without progression after initiation of 
subsequent anti-cancer therapy
Date of death
Progressed
7.5.2
Secondary Efficacy Endpoints
7.5.2.1
Objective Response Rate and Related Endpoints
ORR (as assessed by BICR and investigator) will be estimated in each treatment group along with 
the exact 95% CI using Clopper-Pearson method. An estimate of the difference in ORRs and 
corresponding 95% CI will be calculated using CMH methodology and adjusted by the 
stratification factors as specified in Section 7.1.1. The stratified odds ratios (Mantel-Haenszel 
estimator) between the treatments will be provided along with the corresponding two-sided 95% 
CI.
Best Overall Response (as assessed by BICR and by investigator) will be summarized by response 
category for each treatment group. 
Duration of Response (as assessed by BICR and by investigator) in each treatment group will be 
estimated using KM product-limit method for participants who achieve confirmed PR or CR. 
Median values along with two-sided 95% CI will be calculated.
Time to objective response (as assessed by BICR and by investigator): summary statistics will 
be provided for each treatment group for participants who achieve PR or CR. 
Disease control rate: an estimate and corresponding two-sided 95% exact CI will be provided 
using Clopper-Pearson method.
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The following participant-level graphics will also be provided: 
•
For the responders only, time courses of the following events of interest will be graphically 
displayed: first tumor response, tumor progression, last dose received, and death (a.k.a. 
swimming plot).
•
For response evaluable participants, a waterfall plot showing the best reduction from baseline 
in target lesion based on will be produced (excluding assessments after PD and assessments 
after start of subsequent anti-cancer therapy).
•
For response evaluable participants, spider plot of tumor target lesion percent change from 
baseline based on will be produced.
7.5.2.2
Sensitivity Analyses for ORR 
As sensitivity analysis, a summary of BICR-assessed ORR based on response-evaluable 
participants will be presented. In addition, for interim analyses, a summary of both BICR-assessed 
and investigator-provided ORR will be provided on response-evaluable participants among the 
interim analysis participants.
7.5.2.3
PFS and OS
PFS (investigator assessments per RECIST v1.1) and OS will be summarized descriptively for 
randomized participants using the KM product-limit method. Median values of PFS and OS, along 
with two-sided 95% CI (based on the log-log transformation), will also be calculated. 
KM curve of PFS and OS will be generated. PFS and OS rates at specific time points (eg. 6 month)
will be estimated using KM estimates. PFS and OS rates at additional time points (e.g.12, 18 and 
24 months) may also be estimated depending on whether minimum follow-up will be longer than 
time point to generate the rate. Associated two-sided 95% CIs will be calculated using the 
Greenwood’s formula14,15.
Status of Censored Participants
The status of participants who are censored in the PFS (investigator assessment) Kaplan-Meier 
analysis will be tabulated using the same categories as PFS by BICR in Section 7.5.1.1. 
The status of participants who are censored in the OS Kaplan-Meier analysis will be tabulated 
using following categories:
•
On-study (on treatment and not progressed, on-treatment progressed, in follow-up) 
•
Off-study: (lost to follow-up, withdrew consent, other).
Participant listings of PFS and OS will be produced.
7.5.2.4
Participants Follow-up
The minimum follow-up will be reported. The minimum follow-up is defined as the time interval 
between the last participant’s randomization date and the clinical cutoff date.
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The extent of follow-up defined as the time between randomization date and last known date alive 
(for participants who are alive) or death date (for participants who died) will be summarized 
descriptively for all participants randomized.
The currentness of follow-up for OS is defined as the time between last OS contact (i.e., last known 
date alive or death date) and clinical cut-off date. Participants who died and participants with last 
known alive date after data cut-off date will be considered as current for this analysis.
The currentness of follow-up for PFS is defined as the time between last tumor assessment date 
(regardless of initiation of subsequent therapy) and clinical cut-off date. Participants who have a 
PFS event (regardless of initiation of subsequent therapy) and participants with last tumor 
assessment date on or after clinical cut-off will be considered as current for this analysis. 
The currentness of follow-up for OS and PFS will be summarized by treatment group, and will be 
categorized into the following categories: 0 day, 1day - 3 months, 3-6 months, 6-9 months, 9-12 
months, and > 12 months.
7.5.2.5
Consistency of Treatment Effect in Subsets
To assess consistency of treatment effects in different subsets, a “forest” plot of PFS/OS 
unstratified HR (and 95% CI) will be produced for the following subgroups.
•
Age category (< 65, ≥ 65 and < 75, ≥ 75)
•
Gender (male, female)
•
Race (white, black, Asian, and other)
•
Region(Us/Canada, Europe, Asia, Rest of world)
•
ECOG (0, 1, >1 if exist)
•
Tumor sidedness (Left, Right, Transverse, and Unknown) (stratification factor--IRT)
•
Disease stage at initial diagnosis (Stage I, Stage II, Stage III, Stage IV)
•
Disease site at initial diagnosis (Colon vs. Rectum)
•
Disease classification at initial diagnosis (Gx, G1, G2, G3, G4)
•
Disease cell type
at initial diagnosis (adenocarcinoma, cribriform comedo-type 
adenocarcinoma, medullary, micropapillary, colloid carcinoma, serrated adenocarcinoma, 
signet ring cell)
•
Time from Initial Disease Diagnosis to Randomization (< 1 year, 1 - < 3 years, ≥ 3 years)
•
Time from Initial Metastatic Disease Diagnosis to Randomization (< 3month, 3month-
<6monther, >=6month)
•
Metastatic disease location(liver, lung, etc)
•
Number of organs with metastases at baseline (≤1 vs. ≥2)
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Prior curative surgery (Yes, No)
•
Prior radiotherapy (Yes, No)
•
Prior adjuvant/neoadjuvant chemotherapy (Yes, No)
•
Prior oxilaplatin use (Yes, No ) (stratification factor-IRT)
If subset category has less than 10 participants per treatment group, HR will not be 
computed/displayed. Number of events and median PFS/OS along with 95% CI will be displayed 
for each treatment group.
7.5.2.6
ORR Subgroups
To assess consistency of ORR, ORR per BICR will be summarized for the subgroups
 
 as defined in the Section 7.5.2.5. BICR-
assessed ORR will be computed for each treatment as randomized along with the exact 95% CI 
using the Clopper-Pearson method. 
The ORR subgroup analyses will also be presented for response-evaluable participants from the 
interim analysis participants for interim analyses.
7.6
Safety
In general, safety presentation will use the all treated population (presented as treated) and will 
follow the Core Safety SAP13. 
7.6.1
Deaths
See Core Safety SAP
7.6.2
Serious Adverse Events
See Core Safety SAP
7.6.3
Adverse Events Leading to Discontinuation of Study Therapy
See Core Safety SAP
7.6.4
Adverse Events Leading to Dose Modification
See Core Safety SAP
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7.6.5
Adverse Events
See Core Safety SAP
7.6.6
Select Adverse Events
See Core Safety SAP
7.6.7
Immune Modulating Medication
See Core Safety SAP
7.6.8
Multiple Events
See Core Safety SAP
7.6.9
Other Events of Special Interest
See Core Safety SAP
7.6.10
Immune Mediated Adverse Events
See Core Safety SAP
7.6.11
Clinical Laboratory Evaluations
See Core Safety SAP
7.6.12
Vital Signs
See Core Safety SAP
7.6.14
Pregnancy
See Core Safety SAP
7.6.15
Adverse Events by Subgroup
See Core Safety SAP
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7.11
Interim Analysis
No multiplicity control of type I error rate for planned IA (and no formal statistical test will be 
performed). Strong type I error control will apply to the phase III expansion cohort, if decision is 
made to expand to Phase III part of the study.
The following analyses will be performed for the IA (if applicable). 
Study Conduct and Study Population
•
relevant protocol deviations
•
Demographic and baseline disease characteristics
•
Disposition: frequency table of participants who discontinued treatment and reasons for
discontinuation
•
Disposition: frequency table of participants who were randomized but not treated and reasons
for not treated
•
Baseline Physical Measurements Summary
•
Prior cancer therapy summary
•
discrepancy in stratification factor between IRT and CRF
Extent of exposure
•
Time from randomization to first dose of study therapy
•
Summary of administration of study therapy
•
Summary of dose delays for all study therapies
•
Summary of infusion interruptions or rate reduction for all study therapies
•
Summary of dose reductions for bevacizumab and chemotherapy
•
Efficacy Analyses:
•
Summary of ORR (per BICR and investigator) 
•
Summary of ORR (per BICR and investigator) within subgroups (as defined in Section 7.5.2.5) 
by treatment groups as randomized. 
•
Summary of ORR (per BICR and investigator) on all response-evaluable participants 
•
Summary of ORR (per BICR and investigator) with subgroups on all response-evaluable 
participants 
•
TTR and DOR (per BICR and investigator)
•
Spider plot
•
Waterfall plot
•
Swimmer plot
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•
Kaplan Meier plot of PFS (per BICR and investigator).
•
Kaplan Meier plot of OS
•
Summary of PFS (per BICR and investigator) and OS using the KM product-limit method. 
Median values of PFS and OS, along with two-sided 95% CI (based on the log-log 
transformation), PFS and OS rate at specific timepoint
Safety Analyses:
•
Death summary
•
Summary of Any Adverse Events by worst CTC Grade
•
Summary of Drug-Related Adverse Events by worst CTC Grade
•
Summary of Serious Adverse Events by worst CTC Grade
•
Summary of Drug-Related Serious Adverse Events by worst CTC Grade
•
Summary of Adverse Events leading to discontinuation by worst CTC Grade
•
Summary of Drug-Related Adverse Events leading to discontinuation by worst CTC Grade
•
Summary of Adverse Events Leading to dose delay and dose reduction
•
Summary of Any Select Adverse Events by worst CTC Grade
•
Summary of Drug-Related Select Adverse Events by worst CTC Grade and by Category
•
summary of Immune-Mediated Adverse Event 
•
Summary of Laboratory Parameter Changes from Baseline Grade (US unit only)
•
Summary of laboratory parameter worst grade (US unit only)
•
Summary of Abnormal Liver Test
•
Summary of abnormal Thyroid Test
8
CONTENT OF REPORTS
8.1
Interim Analysis
Please refer to Section 7.11.
9
CONVENTIONS
The following conventions may be used for imputing partial dates for analyses requiring dates:
For missing and partial adverse event onset dates, imputation will be performed using the Adverse 
Event Domain Requirements Specification20. Missing and partial Non-Study Medication Domain 
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dates will be imputed using the derivation algorithm described in BMS Non-Study Medication 
Domain Requirements Specification21.
For death dates, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day. The imputed date will be compared to the last known alive date and the maximum will be 
considered as the death date.
•
If the month or the year is missing, the death date will be imputed as the last known alive date 
•
If the date is completely missing but the reason for death is present the death date will be 
imputed as the last known alive date
For date of progression, the following conventions will be used for imputing partial dates:
•
If only the day of the month is missing, the 1st of the month will be used to replace the missing 
day.
•
If the day and month are missing or a date is completely missing, it will be considered as 
missing.
•
In case, the date of death is present and complete, the imputed progression date will be 
compared to the date of death. The minimum of the imputed progression date and date of death 
will be considered as the date of progression.
For other partial/missing dates, the following conventions will be used:
•
If only the day of the month is missing, the 15th of the month will be used to replace the 
missing day.
•
If both the day and the month are missing, “July 1” will be used to replace the missing 
information.
•
If a date is completely missing, it will be considered as missing.
The following conversion factors will be used to convert days to months or years: 1 month = 
30.4375 days and 1 year = 365.25 days.
Duration (e.g. time from first diagnosis to first dosing date, duration response, and time to 
response) will be calculated as follows:
Duration = (Last date - first date + 1)
 
10
CONTENT OF REPORTS
All analyses described in the SAP will be included in the Clinical Study Report(s) except where 
otherwise noted. Refer to the Data Presentation Plan for mock-ups of all tables, figures and listings
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11
DOCUMENT HISTORY
Table 11-1:
Document History
Version Number
Author(s)
Description
1.0
Initial version 07-Nov-2018
2.0
Removed IA2 related text (per protocol revision 05); 
updated protocol amendment section.
2.1
Updated PFS2 censoring rule (section 4.3.3) to be 
consistent with program level PFS2 derivation
3.0
•
Improved resolution of Figure 2.1-1.
•
Updated protocol amendment section. 
•
Added Table 5.1-1.
•
Minor clarifications and updates in section
7.2.2, 7.3.5.1, 7.4.2.1 and 7.5.1.1. 
4.0
•
Added Section 8 to clarify analyses conducted 
prior to this revision.
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Signatures
Document: CA2099X8 CSR Statistical Analysis Plan Version 4
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