A Phase 2 Clinical Trial of Nivolumab, or Nivolumab Combinations in Recurrent and Metastatic Microsatellite Instability High (MSI-H) and Non-MSI-H Colon Cancer
Phase: PHASE2
Conditions: Microsatellite Unstable Colorectal Cancer, Microsatellite Stable Colorectal Cancer, Mismatch Repair Proficient Colorectal Cancer, Mismatch Repair Deficient Colorectal Cancer
Sponsor: Bristol-Myers Squibb

Official Title of Study:  
 A Phase 2 Clinical Trial of Nivolumab, or Nivolumab Combinations, in Recurrent and 
Metastatic Microsatellite Instability High (MSI-H) and non-MSI-H Colon Cancer 
(CheckMate 142: CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 142) 
 
 
NCT Number:  NCT02060188 
Document Date (Date in which document was last revised): 27-Aug-2021 
 
 
 

Page: 1
Protocol Number: CA209142
IND Number: 119,381
EUDRACT Number 2013-003939-30
Date:18-Nov-2013
Revised Date 27-Aug-2021
CLINICAL PROTOCOLCA209142
A Phase 2 Clinical Trial of Nivolumab, or Nivolumab Combinations, in Recurrent and 
Metastatic Microsatellite Instability High (MSI-H) and non-MSI-H Colon Cancer
(CheckMate 142: CHECKpointpathwayand nivoluMAb clinical Trial Evaluation 142)
Protocol Amendment Number: 09
Clinical Trial Physician-Medical Monitor
Bristol Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648 
Telephone (office): 
email: 
Clinical Scientist-Study Director
Bristol Myers Squibb Company
3401 Princeton Pike
Lawrenceville, NJ 08648 
Telephone:
email: 
24-hr Emergency TelephoneNumber
USA: 
International: 
Bristol-Myers Squibb Research and Development
Route 206 & ProvinceLine Road
Lawrenceville, NJ 08543
Avenue de Finlande 4 B-1420 
Braine-l’ Alleud, Belgium
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing thisdocument, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participatein and/or the performance of the proposed BMS-sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, 
copying, disclosure or dissemination of this information is strictly prohibited unless 
expressly authorized in writing by BMS. Any supplemental information (eg, amendments) 
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that may be added to this document is also confidential and proprietary to BMS and must 
be kept in confidence in thesame manner as the contents of this document. Any person 
who receives this document without due authorization from BMS is requested to return it 
to BMS or promptly destroy it. All other rights reserved. References to BMS in this 
protocol may applyto partners to which BMS has transferred obligations, eg, a Contract 
Research Organization (CRO).
© 2020Bristol-Myers Squibb Company
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DOCUMENT HISTORY
Document
Date of Issue
Summary of Change
Protocol 
Amendment 09
27-Aug-2021
Major changes:
Frequency oftumor assessments has been reduced from 
every 12 weeksto every 24 weeksfor participantswith
disease control meeting specified criteria.
Re-initiated participants with CR were previously 
allowed to stay on treatment untilPD. This was updated 
to a maximum of 24 months of additionaltreatment
following re-initiation.
Added that COVID-19vaccines that are NOT live are 
permitted during the study and after the last dose of IP. 
The efficacy and safety of vaccination in subjects who
are receivingnivolumab, ipilimumab, BMS-986016, 
daratumumab, or combinations are unknown.
Added that study therapy should also be delayed in cases 
of confirmed or suspected SARS-CoV-2infection and in 
the case of priorSARS-CoV-2 infection, symptoms 
should have resolved in order toresume study 
intervention.
Added clarification on study site closuresand 
dissemination of clinical study data.
Updated exploratory endpoints to collect and reportdata 
on participants after re-initiation.
mStage 1/2 and cStage 1/2: Nivolumab monotherapy 
dosing has been updated from 3 mg/kgevery 2 weeks to
480 mg every 4 weeks.
cStage1/2re-initiation: The treatment regimenfor
participants has been amended from nivolumab 480 mg
Q4W to (240 mg nivolumab + ipilimumab 1 mg/kg) 
every 3 weeks for 4 doses followed by480 mg nivolumab 
every 4 weeks.
Cohort3re-initiation:Participants with nivolumab dosing 
previously 240 mg every 2 weeks will now have dosing 
360 mg every 3 weeks.
Participants who are treated beyond progression will be 
able to receive treatmentfor a maximum of 24 additional 
months following initial RECIST 1.1 defined PD.
Updated biomarker sampling schedule for re-initiation 
cohorts to align withupdated dosing schedule.
Removed Patient Reported Outcome collection in re-
initiation phase.
Revised Protocol 08
08-Jun-2020
Major changes:
Changed Medical Monitor and added Study Director 
(IncorporatesAdministrative Letter 08, 29-Aug-2019).
Increased Survival Follow-up from a maximum of 3
years to aminimum of 5years.
Pharmacokinetic and immunogenicity sample collection 
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Document
Date of Issue
Summary of Change
nolongerrequiredafter2yearsoftreatmentorduring
post-treatment Follow-Up Visits 1 & 2. Applicable to 
Arms N, N+I, Cohort C3, and Cohort C6.
Nivolumab infusion duration reduced to 30 minutes for 
Arms Nand N+I.
Revised Protocol07
05-Feb-2019
Major changes:
For MSI-H cohorts only:
Option to discontinue treatment when maximum clinical 
benefit has been achieved per Investigator assessment 
and additional protocol defined criteria. 
Re-initiation of treatment uponprogression forsubjects 
who have discontinued at maximum clinical benefitis 
now an option for MSI-H subjects who meet criteria for 
re-initiation of treatment (See Section 3.1.4.8 and Section 
4.3.9)
Time and Events schedules and biomarker assessment 
tables specific for MSI-H cohorts during re-initiation of 
treatment have been added. 
PK/Immunogenicity assessments will not be collected 
from subjects during re-initiation.
Incorporates Administrative Letters 07,06, and 05.
Administrative 
Letter 07
11-Jan-2018
Correction in Section 1.5 Overall Risk/Benefit Section regarding 
nivolumaband daratumumab infusion sequence.
Administrative 
Letter 06
20-Nov-2017
Changed in Medical Monitor
Administrative 
Letter 05
31-May 2017
Corrected BMS number in Document History described for
Amendment 09.
Revised Protocol 06
19-Apr-2017
IncorporatesAmendment 09 and Administrative Letter 04.
Amendment 09
19-Apr-2017
This purpose of this amendment is to add information to align 
with the daratumumab program standardsand to add clarity to 
various sections of the protocol. 
Changedthe dose of BMS-986016 from 80 mg to 160 mg 
Added language to provide information regarding the 
rationale for the combination of nivolumab and daratumumab
and the overall risk benefit of this combination. 
Added inclusion criteria andthe exclusion of vaccination with 
live vaccines to align with the daratumumab program 
standards. 
Clarified the sequence of the daratumumab, nivolumab, and 
pre-and post-infusion medications for daratumumab.
Added details regarding monitoring vital signs and 
premedicationsto align with the daratumumab program 
standards. 
Minor clarificationswerealso added to several sections. 
Administrative 
Letter 04
26-Jan-2017
Change inMedical Monitor and correction of an error in product 
description removed from Table4.1-1.
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Document
Date of Issue
Summary of Change
RevisedProtocol 05
28-Nov-2016
Incorporates Amendment 08
Amendment 08
28-Nov-2016
This global amendment was written primarily to address the 
following:
Add two new cohorts:
o Cohort C5:Subjects with MSI-Highcolorectal 
cancer receiving nivolumab combined with an
anti-LAG3 agent (BMS-986016) 
o Cohort C6: Subjects with non-MSI-High 
colorectal cancer receivingNivolumab 
combined with daratumumab
Revised Protocol 04
10-Aug-2016
IncorporatesAmendment: 05
Amendment 05
10-Aug-2016
This global amendment was written primarily to address the
following:
Add one new cohort, C3: MSI-High subjects with 
metastatic colorectal cancer receiving nivolumab and 
ipilimumab in the first line settingfor their metastastic 
disease
Addspecificity andclarifications regarding MSI testing 
requirements throughout the protocol
Increase the volume of tumor tissue sample submitted for 
correlative biomarker work, and add a quality control 
step to ensure only subjectswith qualitytumor tissue
samples may be treated with study drug.
Reduce infusion time durations to 30 minutes for 
nivolumab and ipilimumab for Cohort C3 only.
Require confirmatory scan subsequent to an initial scan 
interpreted as PRand/or CRat least 4 weeks after this
initial scan.
Modifymanagement algorithms for toxicities toreflect 
revised nivolumab IB.
Revise contraception language in the protocol and add 
appendix specifying acceptablemethods of contraception 
to reflect revised nivolumab IB.
Administrative 
Letter 03
19-Nov-2015
Reported change in the medical monitor for the study
Administrative 
Letter 02
22-Jan-2015
Required archived tumor tissue obtained prior to the last 
systemic therapy received in the metastatic settingor from an
unresectable site of disease in the event that thesample 
collected is of poor quality.
Revised Protocol 03
10-Jun-2015
Incorporates Amendment: 04
Amendment 04
10-Jun-2015
This global amendment was written primarily to address the 
following:
Add a biomarkercollection schedule forsubjects dosed with 
the combination of nivolumab plus ipilimumab. 
Include an appendix regarding MSI testing panel descriptions 
(PCR and IHC), classification of MSI status, and sample 
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Document
Date of Issue
Summary of Change
prioritization.
In addition to the above changes, other minor changes have 
been made including the following: 
Added a clarification regarding imaging assessments 
indicating confirmation scans for progressive disease do not 
have to be performed.
Clarified inclusion criterion regarding prior treatments.
Clarified exclusioncriterionregarding radiation therapy.
Edited information regarding pregnancy in sectionaddressing 
discontinuation of subjects from treatment.
Edited language addressing weight fluctuations and dose 
recalculations in section addressing selection and timing of 
dosefor subjects.
Clarified information regarding timing for determining safety
laboratoryresults. 
Removed EORTC QLQ-C30 & EQ-5D Questionnaires from 
the Survival Follow-up Visit.
Removed exploratory endpoints utilizing IRRC assessments.
Revised Protocol 02
23-Apr-2014
Incorporates Amendment: 03
Amendment 03
23-Apr-2014
Thisglobalamendmentwaswrittenprimarilytobeconsistentwith
other protocols within the nivolumab program regarding Adverse 
Event Management Algorithms. Accordingly, the existing
Appendix 01 of the protocol has been replaced with the most up-
to-date managementalgorithms.
In addition to the above change, other minor changes have been 
made including: 
The title of the study in the protocol title page was updated to
be specific forMicrosatellite Instability High (MSI-H) Colon 
Cancer population. 
BRAF mutation status is documented at the screening visit in 
order to align with hypotheses that will be addressed by the 
biomarker plan for CA209142.
An oversight regardinga missing ‘X’ in the timeand events
schedule was corrected pertaining to concomitant medication 
information collection at the screening visit.
A table note describing the allowable time window pertaining 
to biomarker sample collections was edited. This change was 
made to ensure consistency with other biomarker sample 
collections across the nivolumab program.
Revised Protocol 01
06-Feb-2014
Incorporates Amendment(s) 01
Amendment 01
06-Feb-2014
 
 
 
 
In addition, this amendment provides clarification on the
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Document
Date of Issue
Summary of Change
followingitemsintheprotocol:
Synopsis:
Clarification of EligibilityCriteria for prior treatment for the 
MSI-H Population 
Trial Objectives: 
Clarification of an exploratory endpoint to specify for patients 
treated with nivolumab in combination with ipilimumab inthe 
non MSI-H population 
Edited primary and secondary objectives in synopsis for 
consistency throughout protocol
Trial Conduct:
Clarification that additional treatment after progression could
include nivolumab alone or nivolumab in combination with 
ipilimumab
Modificationregarding post study access to therapy language 
tocorrectly specify Sponsor obligations
Clarification to exclusion criterion regarding hepatitis 
serology testing methodologies to alignwith methodologies 
specified in the Flow Chart/Time and Events Schedule
Clarification throughout the protocolregarding pregnancy 
testing while on study treatment to ensure testing is performed 
every 4weeks (+or –1 week), regardless of dosingschedule.
Clarification that baseline MRI for brain is onlyfor suspected 
or known disease
Clarification regarding on-study local laboratory assessments 
to align with protocol visit schedule
Clarification regarding archived biopsy information in the 
biomarker samplingschedule table to beconsistent with 
language specified in the protocol body 
Changes to nivolumab and ipilimumab immunogenicity 
sampling schedule to collect samples at 6 months (24 weeks) 
and every 6months thereafter (for nivolumab) as this was 
determined to besufficient given the half-life of anti-drug 
antibodies. 
Replace ECOG 1-5 scale with correct 0-5 scale to correctly 
assess subjects
Original Protocol
18-Nov-2013
Not applicable
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OVERALL RATIONALE FOR PROTOCOLAMENDMENT 09:
This study has been revised to simplify studyrelated schedule of activities, including study drug 
administration, and to help reduce participant burden while aligning with current study objectives. 
The key updates include:
Frequency of tumor assessments has been reduced from every 12 weeksto every 24 weeksfor 
participants withdisease control meeting specified criteria.
Re-initiated participants with complete response (CR)were previously allowed to stay on 
treatment until progressive disease (PD). This was updated to a maximum of 24 additional 
months on treatmentfollowing re-initiation.
Added that coronavirus disease 2019(COVID-19)vaccines that are NOT live are permitted 
during the study and after the last dose of investigational product.The efficacy and safety of 
vaccination in subjects who are receiving nivolumab, ipilimumab, BMS-986016, 
daratumumab, or combinations are unknown.
Added that study therapy should also be delayed in cases of confirmed or suspected severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2)infection and in the case of prior 
SARS-CoV-2 infection, symptoms shouldhave resolvedin order to 
resume studyintervention.
Added clarification on study site closuresand dissemination of clinical study data.
Updated exploratory endpoints to collect and report data on participants after re-initiation.
mStage 1/2 and cStage 1/2:Nivolumab monotherapy dosing has been updated from 3 mg/kg
every 2 weeks (Q2W) to 480 mg every 4 weeks(Q4W).
cStage 1/2re-initiation:The treatment regimen for participants has been amended from 
nivolumab 480 mg Q4W to (240mg nivolumab + ipilimumab1 mg/kg)every 3 weeks (Q3W) 
for 4 doses followed by 480 mg nivolumab Q4W.
Cohort 3re-initiation:Participants with nivolumab dosing previously 240 mg Q2W will now 
have dosing 360 mg Q3W.
Participants who are treated beyond progression will be able to receive treatment for a 
maximum of 24 additional months following initial Response Evaluation Criteria In Solid 
Tumors version 1.1 (RECIST 1.1)defined PD.
Updated biomarker sampling schedule for re-initiation cohorts to align with updated dosing 
schedule.
RemovedPatient Reported Outcome collection in re-initiation phase.
Appendices have been updated to align with nivolumab program level updates.
Minor editorial changes were incorporated throughout this protocol to provide clarity and 
consistency.
Protocol Amendment No: 09
Date: 27-Aug-2021
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Title Page
Updated Medical Monitor contact 
information
The following change was made in 
the Document History table for 
Revised Protocol 08:
Nivolumab infusion duration 
reduced to 30 minutes for Arms 
N and N+Iall cohorts and 30-
minute ipilimumab infusion 
durationwill be implemented in 
Cohort C4.
Updated to new clinical 
scientist contact 
information.
This was an error in the 
previous revision
descriptionof change
sectionas only N and 
N+I infusion duration
wereupdatedduring 
Revised Protocol 08.
Synopsis
Updated the synopsis to 
accommodate for the changes made 
throughout the body of the protocol.
Updated for consistency 
across protocol.
Section 1.1.4.8 Rationale 
for Shorter Nivolumab and 
Ipilimumab Infusion Times
Updated “Shortened nivolumab 
infusion times will be implemented 
in all cohorts. Shortened ipilimumab 
infusions will be implemented in 
Cohorts C3 and C4 only”to 
“Therefore, shortened infusion times 
apply to all cohorts receiving 
nivolumab and ipilimumab.”
To clarify that all 
cohorts receiving 
nivolumab and 
ipilimumab should have 
shortened infusion 
times.
Section 1.1.4.9 Rationale 
for Nivolumab Flat Dosing
Updated text to justify nivolumab 
dosing and switching of nivolumab 
dosing and frequency.
Provides justification 
and background for 
nivolumab flat dosing. 
Section 1.1.4.10 Rationale 
for Nivolumab Dose: 240 
mg Q3W (cStage 1/2), 480 
mg Q4W (mStage 1/2 and 
cStage 1/2),and 360 mg 
Q3W (Cohort 3) During 
Re-initiation Treatment
Section 3.1.4.2 MSI-H 
Nivolumab Monotherapy 
(Arm N): mStage 1 and 2
Section 3.1.4.3 MSI-H 
Nivolumab + Ipilimumab 
(Arm N+I): cStage 1 and 2
Updated section title to include all 
nivolumab doses and added text for 
rationale of nivolumab 360 mg Q3W 
treatment for Cohort 3 and clarified 
that nivolumab 480 mg Q4W is for 
mStage 1/2 and cStage 1/2.
Reducesfrequency of 
treatment to help 
mitigate participant 
burdenand provides
rationale for flat dosing
used in treatment 
re-initiation.  
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Date: 27-Aug-2021
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Section 1.5 Overall 
Risk/Benefit Assessment
Section 3.1.5 Review of 
Safety
Changed “medical safety team 
(MST)” to “safety management team 
(SMT).” 
To align with current 
BMS nomenclature.
Section 3.1 Study Design 
and Duration
Removed “On-treatment tumor 
imaging assessments will occur, 
starting 6 weeks after first dose, 
every 6 weeks (±1 week) for the first 
24 weeks, then every 12 weeks 
(±1week) until disease progression 
or treatment is discontinued 
(whichever occurs later).”
To streamline protocol 
andreduce repetition as 
this is already stated in 
Sections3.1.9.1, 5.4,
and Table 5.1-14.
Section 3.1.4.2 MSI-H 
Nivolumab Monotherapy 
(Arm N): mStage 1 and 2
Section 3.1.4.3 MSI-H 
Nivolumab + Ipilimumab 
(Arm N+I): cStage 1 and 2
Section 3.1.4.4 Non-MSI-H 
Safety Cohort (Nivolumab 
+ Ipilimumab)
Section 3.1.4.5 MSI-H C3 
Cohort (No Prior Treatment 
in Metastatic Setting, 
Nivolumab + Ipilimumab)
Section 3.1.4.6MSI-H C5 
Cohort (2L in Metastatic 
Setting, Nivolumab + BMS-
986016)
Section 3.1.4.7 non-MSI-H 
C6 Cohort (Nivolumab + 
Daratumumab)
Removed RECIST 1.1 evaluation of 
response bullets. 
Tostreamline protocol 
language andreduce 
repetition as this is 
already stated in 
multiple sections.
Section 3.1.4.3 MSI-H 
Nivolumab + Ipilimumab 
(Arm N+I): cStage 1 and 2
Clarified that questionnaires will be 
completed for all subjects except for 
those enrolled in the non-
Microsatellite Instability High 
(MSI-H)Safety Cohort.
Updated for 
clarification.
Section 3.1.4.8 Treatment 
Options Upon Progression 
after Treatment
Added “inclusive of treatment 
beyond progression” and removed 
exception for re-initiated subjects 
Accumulating data 
suggest that 24 months 
of programmed death 
Protocol Amendment No: 09
Date: 27-Aug-2021
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Discontinuation At 
Maximum Clinical Benefit
Section 4.3.1 Re-initiation 
Dose Schedules
with CR to be able to stay on 
treatment until PD.
receptor-1 checkpoint 
inhibitor treatment is
sufficient for long-term 
benefit.
Section 3.1 Study Design 
and Duration
Updated Figure 3.1-1 Study Design 
Schematic (Arm N and Arm N+I) 
and Non-MSI-H Safety Cohort to 
include updated language of
“Survival Follow-up” to “Follow-up 
For Survival.”
Updated to clarify that 
follow-up for 
participants will 
continue for a minimum 
of 5 years from first 
treatment.
Section 3.1.9.1 Follow-up 
for all Cohorts After Initial 
Study Treatment
Added instructions for the 
investigators to reduce scan 
frequency for participants having 
disease control 3 years after the first 
dose.
Removed duration and frequency of 
survival follow-up.
Added to reduce 
participant burden.
To maintain clarity and 
consistency.
Section 3.1.10 End of Study 
Definition
Updated study conclusion definition 
to include a minimum of 5 years of 
follow-up fromfirst treatment for 
the last participant, or until survival 
follow-up is concluded for all 
subjects, whichever occurs first.
Addedlanguage on study 
completion and study site closure, 
reasons for early site closure, and 
what to do in the case of premature 
study termination or suspension.
Added to clarify that 
follow-up for 
participants will 
continue for a minimum 
of 5 years from first 
treatment.
Added to clarify site 
closure and align with 
current standard BMS 
policies regarding site 
closure and end of study 
definition.
Section 3.4.1 Prohibited 
and/or Restricted 
Treatments
Added information regarding 
COVID-19 vaccines.
To explain which 
COVID-19vaccines are 
permitted.  
Section 3.6.2 Lost to 
Follow-Up
Modified text in this section with 
instructions forwhen a participant 
fails to return to the clinic for a
required study visit.
Updated based on 
current BMS policies 
regarding lost to follow-
up.
Protocol Amendment No: 09
Date: 27-Aug-2021
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Section 4.1.3.2 Ipilimumab
Updated text for ipilimumab 
infusion time to approximately 
30minutes.
To align with current
ipilimumab standard 
infusion times.
Section 4.3 Selection and 
Timing of Dose for Each 
Subject
Section 5.1 Flow 
Chart/Time and Events 
Schedule
Updateddosing windows for Q2W, 
Q3W,Q4W, and Q6W dosing 
cycles.
Updated doses and dosing schedules 
in respective tables.
The efficacydose
(cStage1/2) was 
determined to be 
3mg/kg nivolumab + 
1mg/kg ipilimumab 
Q3W for 4 doses.
Reduced dosing 
frequency to reduce 
participant burden.
Dosing windows were 
updated to align with 
dosing frequencies.
Section 4.3.1 Re-initiation 
Dose Schedules
Updated treatmentsand treatment 
schedulesupon re-initiation in Table 
4.3.1-1.
To reduce unnecessary 
participant burden and 
to allow cStage 1/2 
participants to reinitiate 
treatment with 
combinationregimen.
Section 4.3.3 Dose Delay 
Criteria
Added “Study therapy should also 
be delayed in cases of confirmed or 
suspected SARS-CoV-2 infection, 
regardless of the severity.”
Standard SARS-CoV-2 
requirement.
Section 4.3.5Criteria to 
Resume Treatment
Added “In the case of prior
SARS-CoV-2 infection, symptoms 
should have resolved in order to 
resume study treatment and there 
should be no sequelae that would 
place the participant at a higher risk 
of receiving study intervention.”
Standard SARS-CoV-2 
requirement.
Section 4.3.8Treatment 
Beyond Disease Progression
Added that subjects will be 
permitted to continue treatment for 
up to 24 months beyond initial 
RECIST 1.1 defined PD, as assessed 
by the investigator, and clarifiedthat 
subjects who progress following re-
initiation of treatment have the 
option to be treated beyond 
For consistency with 
24-month maximum 
treatment duration 
allowed for subjects 
who re-initiate treatment 
and alignment with
nivolumabessential 
Protocol Amendment No: 09
Date: 27-Aug-2021
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
progression for a cumulative 
maximum of 24 months from 
re-initiation dose.
Added that treatment beyond 
progression may be administered 
during or after localized 
interventions.
Added “For subjects with timepoint 
response of progression being 
treated beyond progression, scans 
should be repeated every 12weeks 
or earlier,as clinically indicated,to 
assess furtherdiseaseprogression.”
protocol elements 
(EPE).
Updated to clarify when 
treatment beyond 
progression may be 
administered.
To clarify that 
Investigator has 
flexibility to monitor 
progression withearlier 
scans ifclinically 
indicated
Section 4.3.9 Treatment Re-
initiation Inclusion Criteria: 
MSI-H Cohorts
Added “Inclusion Criteria” to 
section title.
Added to clarify that the 
section listsinclusion 
criteria for subjects in 
order to re-initiate 
treatment.
Section 5.1 Flow 
Chart/Time and Events 
Schedule 
Removed “For MSI-H subjects 
only” and added “except for those 
enrolled in the non-MSI-H Safety 
Cohort” from EORTC QLQ-C30 
andEQ-5D Questionnaires row of 
Table 5.1-2and Table 5.1-3.
Removed “through Week 23 visit 
and every alternate dosethereafter” 
from laboratory tests row ofTable 
5.1-2 and Table 5.1-3.
Added troponin testing for Cohort 
C5 only in Table 5.1-7and Table 
5.1-13.
Added “To Be Performed at Each 
Dosing Visit” to header in Table 
5.1-9 and Table 5.1-10.
Fixing previous mistake.
Every alternate dose was 
removed as planned 
sampling timelines are 
now aligned with dosing 
schedule.
Consistency with 
relatlimab EPE.
Added to clarify when 
assessments will be 
performed and for 
consistency across 
tables.
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Removed stool sample rows from 
Table 5.1-9 through Table 5.1-12.
Removed “Note: Only Nivolumab 
will be administered during 
Re-initiation” from title of Table 
5.1-10. Removed Nivolumab 480 
mg Q4W treatment heading and 
footnotefrom Table 5.1-10.
Updated dosing regimens and 
schedulesin Tables 5.1-2, 5.1-3, 
5.1-10, 5.1-11, and 5.1-12.
Removed table note and added 
reference to Table 5.1-14 in Tables
5.1-2through 5.1-5,Table5.1-7, and 
Tables5.1-9through 5.1-13for 
clarity, as further tumor imaging 
assessment is required for all 
participants who go off treatment 
without having progressed.
Removed the outcomes research 
assessmentquestionnaires from the 
re-initiation tables, Table 5.1-9 
throughTable 5.1-13.
Removed “MSI-H Cohorts at” from 
title of Table 5.1-13.
Removed to correct 
previous error and align 
with current biomarker 
schedules.
Not applicable as re-
initiation regimen for 
cStage 1/2was updated.
Updated to monotherapy 
flat dosing 480 mg Q4W 
schedule for mStage 1/2 
and cStage 1/2. Updated 
nivolumabdosing from 
240mgQ2W to 360mg 
Q3W for re-initiation of 
Cohort 3to helpreduce 
visits/mitigate 
participant burden.
Added reduction in scan 
frequencyto reduce 
participant burden and 
help optimize 
participant safety.
Removed to reduce 
participant burden.
There are only 
re-initiation participants 
in MSI-H cohorts so all 
re-initiated participants 
are MSI-H.
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Added Table 5.1-14aStandard 
Tumor Imaging Assessment and 
Table 5.1-14b Reduced Tumor 
Imaging Assessment.
Added table to help 
streamline protocol.
Table 5.1-14b was 
added to decrease 
participant burdenand 
help improve safety.
Section 5.3.1 Imaging 
Assessment for the Study
Added “Collect any additional 
imaging that may demonstrate tumor 
response or progression (including 
scans performed at unscheduled time
points and/or at an outside 
institution) for RECIST 1.1 tumor 
assessment and submit to the 
BICR.” 
Align with nivolumab 
EPE and clarify current 
unscheduled scan 
collection requirement, 
therebyhelping to
ensure accuracy of 
tumor response 
assessments.
Section 5.4 Efficacy 
Assessments
Added “Subjects with a history of 
brain metastasis should have 
surveillance MRI approximately 
every 12 weeks, or sooner if 
clinically indicated.” 
Added “Confirmation of PR and/or 
CR is required after at least 4 weeks 
from the initial scan reporting 
response. Confirmation of 
progression is not required.” 
Added rationale and criteria for 
subjects to qualify for reduced scan 
frequency.
Removed repetitive 
language from Section 
3.1 and added to 
appropriate section for 
clarity and 
consolidation.
Reduce participant 
burden and help 
optimize participant 
safety
Section 5.6.8Tumor 
Samples
Removed biomarker sampling 
schedules for subjects in cStage 1/2 
and Cohort 3from Table 5.6.8-4.
Changed biomarker sampling 
schedules for subjects in Cohort 5 to 
subjects in cStage 1/2 and Cohort 3
who re-initiate treatmentin Table 
5.6.8-5.
Added Table 5.6.8-6for biomarker 
sampling schedule for subjects in 
Cohort 5who re-initiate treatment.
Due to the changes in 
dosing schedules, 
subjects in cStage 1/2 
and Cohort 3 moved 
from Day 1 Week5 
biomarker sampling to 
Day 1 Week 4 
biomarker sampling, so 
the tables were split into 
2 different tables to 
accommodate this 
change.
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Section 5.7 Outcomes 
Research Assessments
Removed “and for those subjects 
who re-initiate treatment in Cohorts 
N, N+I, and Cohorts 3 and 5.”
Added “If exceptional circumstances 
preclude the continued 
administration of measures using 
plannedmodalities, then alternate 
administration methods may be 
required, after consultation with 
Sponsoror the Sponsor’s 
representative.”
Removed to reduce 
participant burden.
Added to allow 
collection of data on 
patient-reported 
outcomes via alternative 
administration methods.
Section 6.4 Pregnancy
Removed text on reporting
pregnancy for female partners of
male study subjects.
To align with the 
removal of contraceptive 
requirements for male 
subjects, no longer 
necessitating reporting 
of pregnancy for female 
partner of male study
subject.
Section 8.3.3 Exploratory 
Endpoint(s)
Updated BOR2, ORR2, TTR2, 
DOR2, and PFS2 to BOR-R, ORR-
R, TTR-R, DOR-R and PFS-R.
To align with language 
in the statistical analysis 
plan.
Section 9.1.2 Monitoring
Added language explaining that 
monitoring details describing 
strategy are provided in the 
monitoring plan.
Added to clarify remote 
monitoring and align 
with current standard 
BMS policies regarding 
remote monitoring.
Section 9.4 Dissemination 
of Clinical Study Data
Added language about BMS making 
information available to the public 
and where study information may be 
posted.
Added to align with 
current BMS policy on 
prevision of study 
results.
Appendix 3Response 
Evaluation Criteria in Solid 
Tumors Guidelines (Version 
1.1) with BMS 
Modifications 
Updated to current RECIST 1.1 
language.
Updated to 
accommodate 
BMS-specific RECIST 
1.1 criteria.
Appendix 5 Women of 
Childbearing Potential 
Definition of “woman of 
childbearing potential”was added.
Changes were made to 
be consistent with 
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SUMMARY OF KEY CHANGES FORPROTOCOLAMENDMENT09
Section Number & Title
Description of Change
Brief Rationale
Definitions and Methods of 
Contraception
End of relevant systemic exposure 
time point was updated.
Methods of Contraception section 
was updated with more details for 
the following sections:
Highly Effective Contraceptive 
Methods That Are User 
Dependent
Highly Effective Methods That 
Are User Independent
Sexual Abstinence
Less than Highly Effective 
Contraceptive Methods That Are 
User Dependent 
current BMS protocol 
standards and policies.
Throughout
Removed BMS-936558 from all 
nivolumab referencesexcept the first 
mention.
Minor editorial and typographical 
changes were made.
Updated for consistency 
when referring to 
nivolumab.
Updated for editorial 
and grammatical 
purposesto provide 
clarity and consistency.
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SYNOPSIS
Clinical ProtocolCA209142
Protocol Title: A Phase 2 Clinical Trial of Nivolumab, or Nivolumab Combinations,in Recurrent and 
Metastatic Microsatellite Instability High (MSI-H) and non-MSI-H Colon Cancer
(CheckMate 142:CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 142)  
Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational 
Product(s):  
Nivolumab monotherapy administered IV over 30minutes at 3 mg/kg every 2 weeks untildiscontinuation of 
study therapy for reasons described in Section 3.1.4.1 Study Treatment Discontinuation.
Nivolumab administered IV over 30minutes at 1 mg/kg combined with ipilimumab administered IV over 
90minutes at 3 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 30minutes at 
3mg/kg every 2 weeks until progression
Nivolumab administered IV over 30minutesat 3 mg/kg combined with ipilimumab administered IV over 
90minutes at 1 mg/kg every 3 weeks for 4 doses followed by nivolumab administered IV over 30minutes at 
3mg/kg every 2 weeks until discontinuation of study therapy for reasons described in Section 3.1.4.1 Study 
Treatment Discontinuation.
Nivolumab administered IV over 30minutes at 3 mg/kg every 2 weeks combined with ipilimumab administered 
IV over 30minutes at 1 mg/kg every 6 weeks until discontinuation of study therapy for reasons described in 
Section 3.1.4.1 Study Treatment Discontinuation.(Cohort C3)
Nivolumab administered IV over 30 minutes at 240 mg every 2 weekscombined with BMS-986016 160mg 
administered IV every two weeksuntil discontinuation of study therapy for reasons described in Section 3.1.4.1 
Study Treatment Discontinuation.(CohortC5)
Nivolumab240 mg every two weeks starting on Week 3, and 480 mg every four weeks starting from Week25; 
combined with daratumumab 16 mg/kg weekly from Week 1-8, every two weeks from Week 9-24, and every 
fourweeks starting on Week 25 (Cohort C6) 
Nivolumab 480 mg every 4 weeks administered IV over 30 minutes until discontinuation of study therapy for 
reasons described in Section 3.1.4.1(mStage 1/2 and cStage 1/2)
Nivolumab 360 mg every 3 weeks and ipilimumab1mg/kgevery 6 weeks
Treatment for maximum clinical benefit subjectsin MSI-Hcohorts who meet criteria for re-initiation (Section 3.1.4.8) 
ispresented below: 
Cohort
Treatment upon Re-initiation
mStage 1/2
Nivolumab 480 mg Q4W
cStage 1/2
Nivo 240 mg + Ipi 1 mg/kg Q3W for 4 doses
followed by Nivo480mgQ4W
C3 (1L)
Nivo 360mg Q3W + Ipi 1mg/kg Q6W
C5 (BMS-986016 /anti-LAG3)
Nivo 240mg Q2W + BMS-986016 (LAG3) 
160mg Q2W 
Abbreviations: Ipi = ipilimumab;LAG3 = lymphocyte activation gene-3; Nivo = nivolumab; Q2W = every 2 weeks; 
Q3W = every 3 weeks; Q4W = every 4 weeks; Q6W = every 6 weeks.
Treatment duration after re-initiation, inclusive of treatment beyond progression,will be a maximum of 24 months.
Time and events schedules for study procedures duringre-initiation screening, treatment and follow-up are presented 
in Section 5.1. PK and immunogenicity samples will not be collected at any time during re-initiated treatment. 
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nivolumab
Study Phase:  2
Research Hypothesis:  Treatment with nivolumab monotherapy, nivolumab combined with ipilimumab,nivolumab 
combined with anti-LAG-3 antibody (BMS-986016), or nivolumab combined with daratumumabwill have clinical 
activity in subjectswith recurrent or metastatic CRC.
Objectives:  
Primary Objective
To evaluate the investigator-assessedobjective response rate (ORR) of nivolumab monotherapy and nivolumab in 
combination with either ipilimumab, or 
anti-LAG-3 antibody (BMS-986016) in dMMR/microsatellite 
instability high 
(MSI-H)mCRC; the ORR of nivolumab combined with ipilimumab in subjectswith metastatic non-MSI-H (pMMR) 
CRC; and, the ORR of nivolumab combined with daratumumab therapy in  subjectswith metastatic non-MSI-H
(pMMR)mCRC.
Secondary Objectives
To evaluate the IRRC-assessed objective response rate (ORR) of nivolumab monotherapy and nivolumab in 
combination with either ipilimumab or anti-LAG-3 antibody (BMS-986016) in dMMR/MSI-H mCRC; the ORR of 
nivolumab combined with ipilimumab in subjectswith metastatic non-MSI-H (pMMR) CRC; and, the IRRCORR of 
nivolumab combined with daratumumab therapy in subjectswith metastatic non-MSI-H(pMMR)mCRC.
To evaluate the disease control rate (DCR) of nivolumab monotherapy or combined with the above agents in subjects
with metastatic mCRC.
Exploratory Objectives
Listed in protocol Section 1.3.3.
Study Design:  CA209142 is a Phase 2 open-label, multi-centertrial of nivolumab monotherapy(Cohort N) or in 
combination therapy(Cohort N + I)to estimate the response rate in MSI-H CRC and non-MSI-H CRC. CA209142 
completed a safety cohort of subjectswith non-MSI-H CRC to assess the safety and tolerability of nivolumab in 
combination with ipilimumab in subjectswith non-MSI-H CRC in preparation for an analogous 2-stage assessment 
of the response rate for the combination in MSI-H CRC. 
As described in Figure 1, subjectswith recurrent or metastatic CRC received nivolumab or nivolumab with 
ipilimumab,depending on the response rate in the monotherapy MSI-H cohort andtolerability of the nivolumab 
combined with ipilimumab combination in the non-MSI safety cohort.
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Figure 1:
Study Design Schematic
mStage = 
monotherapy Stage; cStage 
= combination Stage; Arm N = Nivolumab monotherapy; ArmN+I=nivolumab 
in combination with ipilimumab; nMSI-H N+I = non-MSI-H nivolumab in combination with ipilimumab
Two Stage Design: Both Arms N and N+I will follow a two-stage design to test whether nivolumab monotherapy or 
nivolumab combined with ipilimumab yields an objective response rate (ORR) that is of clinical interest in MSI-H 
metastatic colorectal cancer mCRC. On treatment stages that meet an ORR threshold will proceed from Stage 1 to 
Stage2 (same for both m and cStage). Table 1contains the efficacy criteria decisions.
Table1:
EfficacyCriteriatoProceedfromStage1toStage2
mStage 1 Efficacy Criteria
Next Step
7/19 subjectshave confirmed CR or PR
Go into mStage 2
3-6/19 subjectshave confirmed CR or PR
Close mStage 1 & open cStage 1
2/19 subjectshave confirmed CR or PR
Close Trial
cStage 1 Efficacy Criteria
7/19 subjectshave confirmed CR or PR
Go into cStage 2
< 7/19 subjectshave confirmed CR or PR
Close Trial
Note: Confirmed responses are documented by a second scan performed 4 weeks after first scan reporting response
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The decision to enter cStage 1 will be based not only on the activity of the mStage 1, but the safety seen in the non-MSI 
Independent Safety Sub-Trial;thus the decision to start the combo in MSI-H will take into account both efficacy and 
safety. If 2/19 subjectsin mStage 1 (ie, an approximate ORR of 10%), the absolute lower bound indicating "no 
activity" will be declared and the protocol will close to further enrollment.
Dose-escalating Safety Evaluation Phase for Combination Arm: Although the regimen currently used in the Phase3 
melanoma study, nivolumab 1 mg/kg IV + ipilimumab 3 mg/kg, is expected to also be tolerable in mCRC, an initial 
dose-escalating safety evaluation for the combination arms will be conducted.
Enrollment to mStage 1 for Arm N will occur in parallel to the safety evaluation for Arm N+I.
Per Revised Protocol 07, for the monotherapy mStage 1/2 and the combination therapy cStage 1/2,the option to 
discontinue treatment at maximum clinical benefit as assessed by the Investigator and defined in Sections 3.1.4.1has 
been incorporated. Re-initiation of treatment upon progression after discontinuationat maximum clinical benefitis an 
option for eligible MSI-H subjects as described in Section 3.1.4.8. 
The CA209-142 study also includesthe C3 cohortas described below inFigure 2. The C3cohort will enroll 30 MSI-
H subjectswho have not had prior therapy for their metastatic disease.  Per Revised Protocol 07, for Cohort C3,the 
option to discontinue treatment at maximum clinical benefit as assessed by the Investigator and defined in Sections 
3.1.4.1 has been incorporated. Re-initiation of treatment upon progression after discontinuation at maximum clinical 
benefit is an option for eligible MSI-H subjects as described in Section 3.1.4.8.
Figure 2:
Study Schematic for Cohort 3
The CA209-142 study includes aC5 cohortas described below in Figure 3. The C5 cohort will enroll 40 previously-
treatedMSI-Hsubjectswho have not had prior anti-PD-1 therapy for their metastatic CRC disease. 
Per Revised Protocol 07, for Cohort C5, the option to discontinue treatment at maximum clinical benefit as assessed 
by the Investigator and defined in Sections 3.1.4.1 has been incorporated. Re-initiation of treatment upon progression 
after discontinuation at maximum clinical benefit is an option for eligible MSI-H subjects as described in Section 
3.1.4.8.
Figure 3:
Study Schematic for Cohort 5 
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The CA209142 study includes a C6 cohort as described below inFigure 4. The C6 cohort will enroll 40 previously-
treatednon-MSI-H subjects.
Figure 4:
Study Schematic for Cohort 6 
Study Population:  
Key Inclusion Criteria (See protocol Section 3.3.1 for full list of criteria)
1. Men 
and women 18 years of age with an Eastern Cooperative Oncology Group (ECOG) performance status 
of 0-1 
2. Subjectswith histologically confirmed, recurrent or metastatic CRC
3. Microsatellite instability expression detected by an accredited laboratory per local regulations.
a. Subjectswith MSI-H tumors will enroll in the MSI-H Cohort (Cohort N and Cohort N+ I) (mStage and 
cStage groups), the C3 Cohort, and the C5 Cohort. 
b. Subjectswith phenotypes that are non-microsatellite instability high (non-MSI-H) will enroll in the non-
MSI-H Safety Cohortand the C6 Cohort.
4. For subjectswith recurrent or metastatic MSI-H CRC in the MSI-H Cohort(mStage and cStage groups):
a. Progression during, after, or have been intolerant to 1 line treatment(s) for their metastatic disease, 
which must include at least
i.A fluoropyrimidine, and
ii.Oxaliplatin or irinotecan,
1. Subjectswho received oxaliplatin in an adjuvant setting should have progressed during or 
within 6 months of completion of adjuvant therapy in order for oxaliplatin to count as aprior 
therapy needed for entry
OR 
2. Subjectactively refuses chemotherapy for the treatment of metastatic (Stage IV) or locally 
advanced disease considered 
as standard 
treatment for this disease stage, 
despite being informed 
by the investigator about the treatment options. The subject’s refusal must be thoroughly 
documented. The investigator will discuss each individual subjectrefusing chemotherapy with 
the sponsor’s medical monitor to confirm eligibility.
5. For subjectswith non-MSI-H colon cancer for the non-MSI-H Safety Cohort:
a. Progression during,after, or been intolerant following the last administration of approved standard 
therapies, which must include at minimum a fluoropyrimidineand oxaliplatinoririnotecan, as well as at 
least one of the following agents, if approved or in standard 
national guidelines, bevacizumab, cetuximab 
or panitumumab (if KRAS wild type), and regorafenib.
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OR
b. Subjectactively refuses chemotherapy (including drugs or biologics) for the treatment of metastatic 
(Stage IV) or locally advanced disease considered as standard treatment for this disease stage, despite 
being informed by the investigator about the treatment options. The subject’s refusal must be thoroughly 
documented. The investigator will discuss each individual subjectrefusing chemotherapy with the 
sponsor’s medical monitor to confirm eligibility.
6. For subjectswith metastatic or recurrent CRC in the MSI-H C3Cohort, subjectsmustnothave had treatment 
for their metastatic disease.
7. For subjectswith metastatic or recurrent CRC in the C6 Cohort: Progression during, after, or been 
intolerant following the last administration of approved standard therapies, which must include at minimum 
a fluoropyrimidine, and oxaliplatin or irinotecan
8. Subjectsmust have measurable disease per RECIST 1.1 criteria for response assessment. Subjectswith 
lesions in a previously irradiated field as the sole site of measurable disease will be permitted to enroll 
provided the lesion(s) have demonstrated clear progression and can be measured accurately. 
Key Exclusion Criteria (SeeprotocolSection 3.3.2 for full list of criteria)
1. Active brain metastases or leptomeningeal metastases are not allowed. 
2. Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or 
drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
3. Prior malignancy active within the previous 3 years except for locally curable cancers that have been 
apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ 
of the prostate, cervix, or breast.
4. Subjectswith active, known or suspected 
autoimmune disease. Subjectswith vitiligo, 
type I diabetes mellitus, 
residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not 
requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are 
permitted to enroll.
5. Subjectswith a condition requiring systemic treatment with either corticosteroids (>10mg daily prednisone 
equivalents) orother immunosuppressive medications within 14 days of study drug administration. Inhaled 
or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the 
absence of active autoimmune disease.
Re-initiation of Treatment for MSI-H Cohorts 
Subjects in MSI-H cohorts who discontinue study treatment at Maximal Clinical Benefit, (Section 3.1.4.1) are 
permitted to re-initiate treatment, if disease progression defined by RECIST criteria occurs within 1 year (52weeks) 
and protocol-defined criteria(Section 4.3.9) are met. 
Study Assessments:  The primary endpoint of this studyisORR which is based on tumor assessments at baseline and 
then at 6 weeks from first dose which continue every 6 weeks for the first 24 weeks and every 12 weeks thereafter 
until disease progression (investigator-assessed RECIST 1.1-defined progression) or treatment discontinuation, 
whichever occurs later.
Statistical Considerations: 
Sample Size:  This study will consist of 5 cohorts: non-MSI-H safety cohort, MSI-H cohort(Cohort N and Cohort 
N+I), Cohort C3 (MSI-H subjectswho have not had prior therapy for theirmetastatic disease), MSI-H Cohort C5 
Cohort and non-MSI-H Cohort C6. It is expected to treat up to approximately 96 central-pathology-lab-confirmed 
subjects(up to 29 non-MSI-H and up to 67MSI-H) for the initial non-MSI-H and MSI-H cohorts. It is expected to 
treat approximately 30subjectsin cohort C3. It is expected to treat approximately 40 MSI-H subjectsin C5 Cohort 
and 40 non-MSI-H subjectsC6 Cohort.
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Sample size determination for non-MSI-H and MSI-H cohorts:
The MSI-H cohort will include subjectswho are defined as MSI-H based on standard diagnostic testing documented 
in the subject’s medical history and prospectively confirmed inthe current study by repeat testing using a polymerase 
chain reaction (PCR)test.
The non-MSI-H safety cohort will include all subjectstesting non-MSI-H by the repeat PCR test, including those who 
were MSI-H by medical history but not confirmed by repeat testing.
For the non-MSI-H safety cohort, sample size is not based on power considerations and will depend on the observed 
toxicity.
For the MSI-H cohort, a Simon optimal two-stage design will be used to test the null hypothesis that the true ORR is 
30% (not considered clinically compelling) with either nivolumab monotherapy or the combination of 
nivolumab/ipilimumab. In the first stage(mStage 1), 19 subjectswill be treated with nivolumab monotherapy. If there 
are 2 or fewer responses in these first 19 treated subjects, the protocol will be closed to further enrollment. If there are 
more than 2 but less than 7 responses in the first 19treated subjects, accrual to the monotherapy arm will be stopped, 
and the combination arm will be opened for accrual. Otherwise, if there are 7 or more responses in the first 19 treated 
subjects, approximately 29 additional subjectswill be accrued to themonotherapy arm (mStage 2) to target a total of 
48 treated subjects.
If accrual to the combination arm is opened to the MSI-H cohort as specified above, stage I of the Simon two-stage 
design will be initiated in the combination arm with 19 treated subjects(cStage 1). If there are 6 or fewer responses in 
these first 19 treated subjects, accrual to the combination arm will be stopped. Otherwise, approximately 29additional 
subjectswill be accrued to the combination arm (cStage 2) to target a total of 48 subjectstreated with combination 
therapy.
Subjectswhose repeat testing does not confirm MSI-H status will be replaced in order to obtain the required number 
of subjectsin each stage of the Simon design.Note that because of the delay in obtaining the centrally evaluated MSI 
status, more than 48 subjectsmay be treated with monotherapy and combination therapy in these initial cohorts.
The null hypothesis will be rejected if 20 or more responses are observed in 48 treated subjectsin the remaining open 
arm (nivolumab monotherapy or nivolumab/ipilimumab combination).
Within a given treatment arm, this design yields a one-sided type I error rate of 5% and power of 90% when the true 
response rate is 52%
Sample size determination for Cohort C3:
The sample size determination for Cohort C3was not based on power consideration but to provide precision on 
estimation of ORR. Saltz et al
1reported ORR of 49% and 38% to in chemotherapy group, per investigator assessment 
and per independent response review committee assessment, respectively in this patient population. Table 2presents 
the 95% CI for ORR ranging from 45% to 65%, which are considered meaningful clinical outcome, with a sample 
size of 30 subjects.
Table2:
IntervalEstimationandCoverageProbability,Clopper-Pearson
Method,95% Confidence Interval
Sample size
Number of 
responses
Response rate
Confidence interval
30
13
0.43333
(0.2546, 0.6257)
30
14
0.46667
(0.2834, 0.6567)
30
15
0.50000
(0.3130, 0.6870)
30
16
0.53333
(0.3433, 0.7166)
30
17
0.56667
(0.3743, 0.7454)
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Table2:
IntervalEstimationandCoverageProbability,Clopper-Pearson
Method,95% Confidence Interval
Sample size
Number of 
responses
Response rate
Confidence interval
30
18
0.60000
(0.4060, 0.7734)
30
19
0.63333
(0.4386, 0.8007)
30
20
0.66667
(0.4719, 0.8271)
Sample size determination for Cohort C5:
The sample size determination for Cohort C5 was not based on power consideration but to provide precision on 
estimation of ORR. The table below shows the precision of the estimation of ORR based on the two sided 95% exact 
CI using Clopper Pearson methods based on 4, 8, 12, 16 and 20 responders out of 40 subjects. With 40 subjects, the 
95% CI of observed 16 responders will be (24.9%, 56.7%), which has the lower bound excluding the 23% background 
ORR from previous interim results.
Table3:
Two-sided95% exactCIusingClopper-Pearsonmethodbasedonthenumberof
observed responses out of 40 subjects(For C5 Cohort)
The number of 
observed 
responses
4
8
12
16
20
Observed 
Response Rate
4/40 (10.0%)
8/40 (20.0%)
12/40 (30.0%)
16/40 (40.0%)
20/40 (50.0%)
95% exact CI
(2.8%, 23.7%)
(9.1%, 35.6%)
(16.6%, 46.5%) (24.9%, 56.7%)
(33.8%, 66.2%)
Sample size determination for Cohort C6:
The sample size determination for Cohort C6 was not based on power consideration but to provide precision on 
estimation of ORR. The table below shows the precision of the estimation of ORR based on the two sided 95% exact 
CI using Clopper Pearson methods based on 6, 7, 8, 9, and 12 responders out of 40 subjects. With 40 subjects, the 
95% CI of observed 6 responders will be (5.7%, 29.8%), which has the lower bound excluding the 5% background 
ORR.
Table4:
Two-sided95% exactCIusingClopper-Pearsonmethodbasedonthenumberof
observed responses out of 40 subjects(For C6 Cohort)
The number of 
observed 
responses
6
7
8
9
12
Observed 
Response Rate
6/40 (15.0%)
7/40 (17.5%)
8/40 (20.0%)
9/40 (22.5%)
12/40 (30.0%)
95% exact CI
(5.7%, 29.8%)
(7.3%, 32.8%)
(9.1%, 35.6%)
(10.8%, 38.5%) (16.6%, 46.5%)
Endpoints:
The primary endpoint is investigator-assessed ORR in each cohort. It is defined as the number of subjectswith a best 
overall response (BOR) of confirmed CR or PR, according to RECIST 1.1 criteria, divided by the number of treated 
subjectsin the related cohort.The secondary endpoint is IRRC-assessed ORR in each cohort. It is defined as the 
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number of subjectswith a best overall response (BOR) of confirmed CR or PR, according to RECIST1.1 criteria, 
divided by the number of treatedsubjectsin the related cohort.
Analyses:
In each cohort, the investigator-assessed ORR will be further characterized by the investigator assessed duration of 
response (DOR) and 
rate of complete response (CR). A 
response 
rate estimate and corresponding two-sided 95% exact 
CI will be provided. The method proposed by Atkinson and Brown will be used to estimate the CI. This confidence 
interval takes into account the group sequential nature of the two-stage Simon design,where applicable. The method 
of Clopper-Pearson will be used otherwiseif more subjectswere treated beyond the sample size per the original 
Simon’s 2-stage design. Within each cohort, ORR will be further characterized by the duration of response (DOR) 
and rate of complete response (CR). DOR will be summarized for subjectswho achieve confirmed PR or CR using 
the Kaplan-Meier (KM) product-limit method. Median values of DOR, along with two-sided 95% CI (based on the 
log-log transformation), will also be calculated. Investigator-assessed CR willbe summarized by cohort and by 
treatment (monotherapy and combination therapy, if applicable). An estimate of complete response rate (CRR) and 
corresponding two-sided 95% exact CI will be provided using Clopper-Pearson method.
ORR based on IRRC assessmentwill be summarizedsimilarly as above and will be characterized by IRRC-assessed 
DOR and IRRC-assessed CRR similarly as above.
Safety analyses will be performed in all treated subjectsby cohort (MSI-H,non-MSI-H, and C3) and treatment 
(monotherapy and combination therapy, if applicable). Descriptive statistics of safety will be presented using NCI 
CTCAE version 4.0. On-study AEs will be tabulated using worst grade per NCI CTCAE v4.0 criteria by system organ 
class and MedDRA preferred term. On-study lab parameters including hematology, chemistry, liver function, thyroid 
function, and renal function will be summarized using worst grade per NCI CTCAE v4.0 criteria.
REFERENCES
1 Saltz LB, Clarke S, Díaz-Rubio E, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-
line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013-2019.
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TABLE OF CONTENTS 
TITLEPAGE................................................................................................................
DOCUMENTHISTORY..............................................................................................
OVERALLRATIONALEFORPROTOCOLAMENDMENT09:............................
SUMMARYOFKEYCHANGESFORPROTOCOLAMENDMENT09................
SYNOPSIS....................................................................................................................
TABLEOFCONTENTS..............................................................................................
1INTRODUCTIONANDSTUDYRATIONALE.....................................................
1.1StudyRationale.................................................................................................
1.1.1ColonCancerBackgroundandTreatmentOptions................................
1.1.2MicrosatelliteInstability..........................................................................
1.1.3MSITesting..............................................................................................
1.1.4RationaleforCA209142StudyDesign....................................................
1.1.4.1RationaleforNivolumabMonotherapy..........................................
1.1.4.2RationaleforNivolumabCombinedwithIpilimumab....................
1.1.4.3 Rationale for Nivolumab and Ipilimumab in Treatment-Naive 
dMMRmCRC:CohortC3....................................................................
 
1.1.4.4LAG-3andTCellExhaustion.........................................................
1.1.4.5 Rationale for Combination Nivolumab/Anti-LAG-3 Antibody (BMS-
986016)TherapyinMSI-HmCRC(CohortC5)...................................
 
1.1.4.6DoseandSchedulingRationale(NivolumabandIpilimumab)......
1.1.4.7 Rationale for Treatment Duration and Introducing Re-Initiation in 
MSI-H/dMMRCohorts..........................................................................
 
1.1.4.8RationaleforShorterNivolumabandIpilimumabInfusionTimes.
1.1.4.9RationaleforNivolumabFlatDosing.............................................
1.1.4.10 Rationale for Nivolumab Dose: 240 mg Q3W (cStage 1/2), 480 mg 
Q4W (mStage 1/2 and cStage 1/2), and 360 mg Q3W (Cohort 3) During 
Re-initiationTreatment.........................................................................
1.1.5 Rationale to Support Dose/Schedule of Nivolumab Combined with BMS-
986016(CohortC5)....................................................................................
 
1.1.6 Rationale for Nivolumab plus Daratumumab Combination Therapy 
(CohortC6).................................................................................................
 
1.1.7 Rationale to Support Dose/Schedule of Nivolumab Combined with 
Daratumumab(CohortC6).........................................................................
 
1.1.8RationaleforObjectiveResponseRate....................................................
1.1.9RationaleforBiomarkerAnalyses...........................................................
1.2ResearchHypothesis.........................................................................................
1.3Objectives(s).....................................................................................................
1.3.1PrimaryObjectives..................................................................................
1.3.2SecondaryObjectives...............................................................................
1.3.3ExploratoryObjectives............................................................................
1.4ProductDevelopmentBackground...................................................................
1.4.1NivolumabandIpilimumabMechanismsofAction.................................
1.4.2SummaryofResultsfromtheIpilimumabandNivolumabPrograms.....
1.4.2.1SummaryofSafety...........................................................................
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1.4.2.2SummaryofClinicalActivity..........................................................
1.4.3NivolumabCombinedwithBMS-986016(CohortC5)............................
1.4.3.1 Nonclinical Pharmacology Studies utilizing Murine Anti-PD-1 and 
Anti-LAG-3Antibodies..........................................................................
 
1.4.3.2ClinicalPharmacologyBMS-986016.............................................
1.4.3.3 Clinical Safety Combination Therapy (Nivolumab plus BMS-
986016).................................................................................................
 
1.4.4Daratumumab..........................................................................................
1.4.4.1MechanismofAction.......................................................................
1.4.4.2SummaryofDaratumumabClinicalPharmacology.......................
1.4.4.3SummaryofDaratumumabClinicalActivity..................................
1.5OverallRisk/BenefitAssessment.....................................................................
2ETHICALCONSIDERATIONS...............................................................................
2.1GoodClinicalPractice......................................................................................
2.2InstitutionalReviewBoard/IndependentEthicsCommittee.............................
2.3InformedConsent..............................................................................................
3INVESTIGATIONALPLAN....................................................................................
3.1StudyDesignandDuration...............................................................................
3.1.1MismatchRepair/MicrosatelliteInstabilityTesting................................
3.1.2Non-MSI-HSubjects(IndependentSafetySub-Trial)..............................
3.1.2.1 Dose Escalating Safety Evaluation for Nivolumab in Combination 
withIpilimumabinnon-MSI-HSubjects..............................................
 
3.1.2.2 Evaluation of Risk/Benefit for Doses that Do Not Meet Tolerable 
Criteria..................................................................................................
 
3.1.3Screening..................................................................................................
3.1.4Treatment.................................................................................................
3.1.4.1StudyTreatmentDuration(MSI-HCohortsOnly).........................
3.1.4.2MSI-HNivolumabMonotherapy(ArmN):mStage1and2...........
3.1.4.3MSI-HNivolumab+Ipilimumab(ArmN+I):cStage1and2........
3.1.4.4Non-MSI-HSafetyCohort(Nivolumab+Ipilimumab)..................
3.1.4.5 MSI-H C3 Cohort (No Prior Treatment in Metastatic Setting, 
Nivolumab+Ipilimumab)....................................................................
 
3.1.4.6 MSI-H C5 Cohort (2L in Metastatic Setting, Nivolumab + BMS-
986016).................................................................................................
 
3.1.4.7non-MSI-HC6Cohort(Nivolumab+Daratumumab)...................
3.1.4.8 Treatment Options Upon Progression after Treatment 
DiscontinuationAtMaximumClinicalBenefit.....................................
 
3.1.5ReviewofSafety.......................................................................................
3.1.6Treatmentbeyondprogression................................................................
3.1.7IntrasubjectDoseReductions..................................................................
3.1.8MandatoryAvailabilityofTumorMaterial.............................................
3.1.9Followup.................................................................................................
3.1.9.1Follow-upforallCohortsAfterInitialStudyTreatment...............
3.1.9.2Follow-upforRe-initiatedSubjectsinMSI-HCohorts..................
3.1.10EndofStudyDefinition..........................................................................
3.2PostStudyAccesstoTherapy...........................................................................
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3.3StudyPopulation...............................................................................................
3.3.1InclusionCriteria.....................................................................................
3.3.2ExclusionCriteria....................................................................................
3.3.3WomenofChildbearingPotential...........................................................
3.4ConcomitantTreatments...................................................................................
3.4.1Prohibitedand/orRestrictedTreatments.................................................
3.4.2OtherRestrictionsandPrecautions.........................................................
3.4.2.1SurgicalResectionFollowingInitialResponse..............................
3.4.2.2BloodTyping(C6CohortOnly).....................................................
3.4.2.3HerpesZosterVirusAntiviralProphylaxis(C6CohortOnly).......
3.4.3PermittedTherapy...................................................................................
3.5DiscontinuationofSubjectsfromTreatment....................................................
3.6PostTreatmentStudyFollowup.......................................................................
3.6.1WithdrawalofConsent............................................................................
3.6.2LosttoFollow-Up....................................................................................
4TREATMENTS.........................................................................................................
4.1StudyTreatments..............................................................................................
4.1.1InvestigationalProduct............................................................................
4.1.2Non-investigationalProduct....................................................................
4.1.3HandlingandDispensing........................................................................
4.1.3.1Nivolumab.......................................................................................
4.1.3.2Ipilimumab......................................................................................
4.1.3.3NivolumabandIpilimumabCombination.......................................
4.1.3.4NivolumabandBMS-986016Combination....................................
4.1.3.5NivolumabandDaratumumabCombination..................................
4.1.4 Guidelines for Prevention and Management of Infusion Reactions 
(DaratumumabandNivolumab+DaratumumabCombination)...............
 
4.1.4.1Pre-infusionMedicationforDaratumumab...................................
4.1.4.2Post-InfusionMedicationforDaratumumab..................................
4.2MethodofAssigningSubjectIdentification.....................................................
4.3SelectionandTimingofDoseforEachSubject...............................................
4.3.1Re-initiationDoseSchedules...................................................................
4.3.2AntiemeticPremedications......................................................................
4.3.3DoseDelayCriteria.................................................................................
4.3.3.1ManagementAlgorithmsforImmuno-OncologyAgents................
4.3.4DoseModifications..................................................................................
4.3.5CriteriatoResumeTreatment..................................................................
4.3.6DiscontinuationCriteria..........................................................................
4.3.7TreatmentofStudyDrugRelatedInfusionReactions..............................
4.3.8TreatmentBeyondDiseaseProgression..................................................
4.3.9TreatmentRe-initiationInclusionCriteria:MSI-HCohorts...................
4.4Blinding/Unblinding.........................................................................................
4.5TreatmentCompliance......................................................................................
4.6DestructionandReturnofStudyDrug.............................................................
4.6.1DestructionofStudyDrug.......................................................................
4.6.2ReturnofStudyDrug...............................................................................
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4.7RetainedSamplesforBioavailability/Bioequivalence...................................
5STUDYASSESSMENTSANDPROCEDURES.....................................................
5.1FlowChart/TimeandEventsSchedule.............................................................
5.2StudyMaterials.................................................................................................
5.3SafetyAssessments...........................................................................................
5.3.1ImagingAssessmentfortheStudy............................................................
5.4EfficacyAssessments........................................................................................
5.4.1PrimaryEfficacyAssessment...................................................................
5.4.2SecondaryEfficacyAssessment...............................................................
5.5PharmacokineticandImmunogenicityAssessments........................................
5.5.1PharmacokineticsandImmunogenicityCollectionandProcessing.......
5.6BiomarkerAssessments....................................................................................
5.6.1Serum.......................................................................................................
5.6.2Plasma......................................................................................................
5.6.3Immunophenotyping.................................................................................
5.6.4ExvivoFunctionalAssays.......................................................................
5.6.5PeripheralBloodGeneExpression.........................................................
5.6.6TCellRepertoireAnalysis.......................................................................
5.6.7MicrobiomeAnalysis...............................................................................
5.6.8TumorSamples.........................................................................................
5.7OutcomesResearchAssessments.....................................................................
5.8ResultsofCentralAssessments........................................................................
6ADVERSEEVENTS.................................................................................................
6.1SeriousAdverseEvents....................................................................................
6.1.1SeriousAdverseEventCollectionandReporting....................................
6.2NonseriousAdverseEvents..............................................................................
6.2.1NonseriousAdverseEventCollectionandReporting..............................
6.3LaboratoryTestResultAbnormalities..............................................................
6.4Pregnancy..........................................................................................................
6.5Overdose...........................................................................................................
6.6PotentialDrugInducedLiverInjury(DILI).....................................................
6.7OtherSafetyConsiderations.............................................................................
7 DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES
.................................................................................................................................
 
8STATISTICALCONSIDERATIONS.......................................................................
8.1SampleSizeDetermination...............................................................................
8.2PopulationsforAnalyses..................................................................................
8.3Endpoints..........................................................................................................
8.3.1PrimaryEndpoint(s)................................................................................
8.3.2SecondaryEndpoint(s).............................................................................
8.3.3ExploratoryEndpoint(s)..........................................................................
8.4Analyses............................................................................................................
8.4.1DemographicsandBaselineCharacteristics...........................................
8.4.2EfficacyAnalyses.....................................................................................
8.4.2.1PrimaryEndpointMethods.............................................................
8.4.2.2SecondaryEndpointMethods.........................................................
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8.4.2.3ExploratoryEndpointMethods.......................................................
8.4.3SafetyAnalyses.........................................................................................
8.4.4PharmacokineticAnalyses.......................................................................
8.4.5BiomarkerAnalyses.................................................................................
8.4.6OutcomesResearchAnalyses..................................................................
8.4.7OtherAnalyses.........................................................................................
8.4.7.1ImmunogenicityAnalyses................................................................
8.4.7.2AnalysesofRe-initiationTreatedSubjects.....................................
8.5InterimAnalyses...............................................................................................
9STUDYMANAGEMENT........................................................................................
9.1Compliance.......................................................................................................
9.1.1CompliancewiththeProtocolandProtocolRevisions...........................
9.1.2Monitoring...............................................................................................
9.1.3InvestigationalSiteTraining....................................................................
9.2Records.............................................................................................................
9.2.1RecordsRetention....................................................................................
9.2.2StudyDrugRecords.................................................................................
9.2.3CaseReportForms..................................................................................
9.3ClinicalStudyReportandPublications............................................................
9.4DisseminationofClinicalStudyData...............................................................
10GLOSSARYOFTERMS........................................................................................
11LISTOFABBREVIATIONS..................................................................................
12REFERENCES........................................................................................................
APPENDIX1MANAGEMENTALGORITHMS.......................................................
APPENDIX2ECOGPERFORMANCESTATUS.....................................................
APPENDIX 3 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES(VERSION1.1)WITHBMSMODIFICATIONS........................
 
APPENDIX4MSISTATUSTESTING......................................................................
APPENDIX 5 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODSOFCONTRACEPTION.....................................................................
 
APPENDIX6REVISEDPROTOCOLSUMMARYOFCHANGEHISTORY........
 
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1
INTRODUCTION AND STUDY RATIONALE
1.1
Study Rationale
CA209142 
(CheckMate 
142: 
CHECKpoint 
pathway and 
nivoluMAb 
clinical 
Trial 
Evaluation 142)
is a Phase 2 open-label, multi-centertrial of BMS-936558 (nivolumab) monotherapyand
nivolumab in combination with ipilimumab, BMS-986016,ordaratumumabto estimate the 
response rate in subjects whose colorectal tumors have defects in the DNA mismatch repair system 
(dMMR/MSI-H) or in subjects whose colorectal tumors have proficient MMR 
(pMMR/non-MSI-H). Tumors with the MMR defect arereferred to as having high-level 
microsatellite instability (MSI-H). The central objective of the study will be to determine if 
nivolumab aloneornivolumab in combination therapy demonstratesa clinically meaningful 
objective response rate (ORR) > 30% in distinct patient populations.Well-established tests to 
identify patients with MSI-H colorectal cancer (CRC) include immunohistochemistry (IHC) for 
MMR protein expression, polymerase chain reaction (PCR)-based analysis for the molecular 
signature of microsatellite instability,and next-gen sequencing (NGS) for the corresponding 
genomic defects in the genes coding for MMRor microsatellite instability signature. These tests 
will allow for identification of potential subjects. Patients withMSI-H CRC have a distinctly
recognizable clinicopathological profile and the MSI-H status serves both as a prognostic and 
predictive factor when compared to non-MSI-H CRC patients. Part 
of the clinicopathologic profile 
of MSI-H CRC includes a local and systemic anti-tumoral immune response to evade the control 
of the immune system. This initial control of the MSI-H tumor by immune surveillance gives a 
strong rationale that nivolumabor nivolumab combination therapy, with its mechanism of action 
that abrogates immune tolerance, will have significant clinical activity in advanced MSI-H CRC
or non-MSI-H CRC. 
1.1.1
Colon Cancer Background and Treatment Options
Worldwide, colon cancer (including rectal cancer) is the third most common form of cancer in 
men with 663,000 cases (10% of the total),and second most common in women with 
571,000cases (9.4% of the total) per year.
1This disease predominately occurs in developed 
regions with the highest rates being found in Australia/New Zealand and Western Europe and to a 
lower extent in Africa and South-Central Asia. There is a higher incidence in men vs women with 
a ratio of 1.4:1. Each year,there are about 608,000 deaths from colon cancer,which is 
approximately 8% of all cancer deaths, making colon cancer the fourth mostcommon cause of 
cancer death. In 2013 in the United States (US), an estimated 142,820 new cases will be diagnosed 
with 50,830deaths.
2
Treatment options for patients with metastatic colon or rectal cancer (mCRC) are predominantly 
5-fluorouracil (5-FU) and leucovorin containing regimens in combination with either oxaliplatin 
or irinotecan (FOLFOX or FOLFIRI) with a biologic agent such as bevacizumab. Cetuximab is 
also an option if KRAS status is non-mutated.
3Both regimens are considered to be equivalent,
with a median first-line progression-free survival (PFS) of 8.5 months for FOLFIRI and 8months 
for FOLFOX.
4In second-line for those patients who had first-line therapy with FOLFOX or 
another 5-FU containing 
therapy, 
the median 
PFS for patients 
receiving FOLFIRI is 
approximately 
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4.5 months.
5,6Bevacizumab, ramucirumab,and ziv-afilbercept have indications for second-line 
treatmentin combination with chemotherapy and have demonstrated improvement in median OS 
(mOS); for both biologic agents,the improvement inmOS is less than 2 months:13.5months vs 
12.06monthsfor bevacizumab,
713.3 months vs 11.7 months for ramucirumab,
8and 11.2months
vs 9.8monthfor ziv-aflibercept.
9Cetuximab also has demonstrated an improvement in mOS of 
less than 2months in patients who have previous received chemotherapy, 6.1 months vs 4.6 
months, when compared to best supportive care (BSC).
10Lastly, regorafenib, in patients who have 
been previously treated with fluoropyrimidine-, oxaliplatin-and irinotecan-based chemotherapy, 
an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy, has demonstrated an 
improvement in mOS of less than 2 months, 6.4months vs 5 months,when compared to BSC.
11
Similar results were demonstrated for triflurdine/tipiracil HCl.
12Despite the numerous treatment 
options for mCRC, the benefitof these therapies after first-line therapy is modest,and complete 
radiographical responses are rare, highlighting the need for more effective therapies. 
1.1.2
Microsatellite Instability 
Microsatellite instability (MSI) is the molecular fingerprint of a deficient mismatch repair system
(MMR). The term MSI is widely accepted as a surrogate for both dMMR and MSI-H tumors. 
Approximately 15% of CRCs display MSI-High(MSI-H),owing either to epigenetic silencing of 
MLH1 or a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6 or 
PMS2.
13There are well established methods to detect dMMR/MSI-Hthat are incorporated into 
clinical practice. A clinical and molecular profile of MSI 
tumors has been described, leading to 
the 
concept of an MSI phenotype in CRC. Studies have confirmed that MSI identification can be 
prognostic in that MSI tumors have a better prognosis14than microsatellite stable CRC, but MSI 
status can also be predictive in thatMSI-H cancers do not necessarily have the same response to 
the chemotherapeutic strategies used to treat microsatellite stable tumors. Specifically, Stage II 
MSI tumors might not benefit from 5‑fluorouracil‑based adjuvant chemotherapy regimens.
15,16
In the metastatic setting, however, there areconflicting data regarding MSI status and response to 
chemotherapy17 including association with better,
18 worse,
19 or differential (5-fluorouracil 
compared to capecitabine)
20chemosensitivity, with no randomized trial comparing chemotherapy 
regimens in subjects with MSI-H mCRC or comparing MSI-H and non-high MSI (nMSI-H) 
subjects with mCRC. 
Characterization of the molecular basis of MSI in CRC is underway and initial results show that 
mutations in genes encoding kinases and candidate genes with microsatellite tracts are over‑
represented in MSI tumors.
17Hypermethylation of MLH1can cause BRAFmutations in CRC and 
are more frequent in sporadic MSI-H cases compared to hereditary cases.
21,22The strong local 
immune reaction observed in MSI-H CRC is characterized by peritumoral lymphoid nodules 
(Crohn’s-like reaction) and a dense overall infiltration of the tumor with lymphocytes,
23part of 
which are activated and cytotoxic.
24,25Frameshift mutations encountered in MSI-H CRC might 
lead to 
the generation of tumor-specific antigens.
26In addition, it is known that antigens expressed 
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in a noninflamed environment may induce tolerance rather than eliciting an antitumoral immune 
response27;however, the existence of T cell responses directed against a multiple tumor antigens 
in individuals with MSI-H CRC has been demonstrated in patients.
28,29This observation strongly 
suggests that antigenic structures are generated from coding DNA sequences carrying frameshift 
mutations in sufficient amounts to trigger antigen-specific T cell responses. The cytokine milieu 
encountered at the MSI-H tumor site initially tends to beproinflammatory and favoring T-cell 
response rather than contributing to tolerance induction.
30,31The mechanism by which immune 
tolerance is induced is not completely understood. This initial control of the MSI-H tumor by 
immune surveillance makes it hopeful that nivolumab, with its mechanism of action that abrogates 
immune tolerance, will have significant clinical activity in MSI-H CRC. In study CA209003, a 
Phase 1 trial of subjects with solid tumors, one trial subject with MSI-H metastatic CRC (mCRC) 
had a long-term complete response, suggesting the immune-modulatory approach warrants further 
evaluation.
32
1.1.3
MSI Testing
The National Comprehensive Cancer Network (NCCN)recommends MSI testing for all patients 
with CRC.
33There are several options for testing. The IHC MMR testing consists of staining of 
tumor tissue for loss of expression of the four mismatch repair proteins known to be mutated in 
Lynch syndrome, MLH1, MSH2, MSH6, and PMS2.
34If at least one of these is not normally 
expressed, then the testing indicates the dMMR (MSI)phenotype. PCR amplification of a set of 
mono-and/or di-nucleotide repeats on tumor and normal DNA, followed by comparison of the 
peak patterns by capillary electrophoresis, can also assess for MSI. In 2009, the Evaluation of 
Genomic Applications in Practice and Prevention (EGAPP) Working Group evaluatedIHC and 
PCR testing methods in patients with Lynch Syndrome and found that:
the sensitivity of MSI testing is about 89% for mutations in MLH1 and MSH2, with a lower 
sensitivity of about 77% for mutations in MSH6 (and PMS2), while sensitivity is higher when 
three or more mononucleotide markers are included in the panel; specificity is estimated to be 
90.2%, with an adequate level of evidence;
sensitivity of IHC testing is 83%, regardless of the underlying MMR gene mutation with 
specificity is more variable, and central estimate is 88.8%;
inadequate evidence is available to determine the distribution of mutations in the MMR genes, 
but preliminary estimates are 32% MLH1, 39% MSH2, 14% MSH6, and 14% PMS2.
35
Many 
recommendations for MSI testing include 
recommendations for BRAFtesting forthe 
V600E 
mutation when MLH1expression is absent in the tumor by ICH analysis. The significance of this 
BRAFmutation often indicates that MLH1expression is down-regulated by somatic methylation 
of the promoter region of the gene and not a germline mutation.
36Testing for BRAF may be useful 
for determination of a heritable condition, ie, Lynch Syndrome, but is likely more important as a 
prognostic factor as two recent reports have demonstrated worse survival in MSI-H subjects with 
BRAFmutations, which canoccur in up to 50% of patients with MSI-H tumors.
37,38
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1.1.4
Rationale for CA209142 Study Design
1.1.4.1
Rationale for Nivolumab Monotherapy
Nivolumab monotherapy at 3mg/kg was chosen to be tested in a 2-stage Simon design estimating 
the response rate in MSI-H CRC because of a favorable risk-benefit ratio in multiple other tumor 
types in the large Phase 1 CA209003. The dose and schedule of nivolumab in this study will be 
3mg/kg every two weeks, based upon the analyses of safety, efficacy, and exposure-response data 
from the ongoing Phase 1 study CA209003. Anti-tumor activity was observed at dose levels 
ranging from 1 to 10 mg/kg in melanoma,non-small cell lung cancer (NSCLC), and renal cell 
carcinoma (RCC), as well as at dose levels of 0.1 and 0.3 mg/kg in melanoma. The anti-tumor 
activity of nivolumab in RCC was investigated at dose levels 1 and 10 mg/kg, with the higher 
activity observed at 10 mg/kg.
The observed anti-tumor activity in melanomaand NSCLC was highest at 3 mg/kg, suggesting 
that anti-tumor activity approaches a plateau at dose levels of 3 mg/kg and above. Consistent with 
these observations, the results of the exposure-response analyses for these tumor types show that 
the probability of a tumor response tended to approach a plateau for trough concentrations 
produced by 3 and 10 mg/kg every 2 week dosing.
Nivolumab was adequately tolerated up to 10 mg/kg, the highest dose level tested, and no 
maximum tolerated dose (MTD) was identified. Although the spectrum, frequency, and severity 
of nivolumab-related AEs were generally similar across the dose levels tested, the 10 mg/kg doses 
levelhad numerically higher Grade 3-4 drug-related SAEs and AEs leading to discontinuation. 
Based 
upon 
the 
totality 
of the safety, efficacy, 
and 
exposure-response 
data, 
a 
dose 
of 
3 mg/kg 
every 
2 weeks (Q2W)was selected as the dose anticipated to achieve an appropriate balance of efficacy 
and risk.
1.1.4.2
Rationale for Nivolumab Combined with Ipilimumab
The combination of nivolumab and ipilimumab was chosen as an experimental arm because of 
preclinical and preliminary clinical evidence suggesting synergy between nivolumab and 
ipilimumab. While PD-1 and CTLA-4 are both co-inhibitory molecules, evidence suggests that 
they use distinct mechanisms to limit T cell activation. Preliminary indirect data from peripheral 
T cell assessments suggest that a given T-cell checkpoint inhibitor may modulate host immune 
cell phenotype rendering them more susceptible to alternate checkpoint inhibitors and thereby 
enhancing anti-tumor activity. Specifically, nivolumab increased peripheral CTLA-4+ and 
regulatory T cells in subjects without clinical response in CA209006. In a preclinical melanoma 
model, anti-CTLA-4 therapy increased PD-1+, PD-L1+ and CTLA-4+ tumor infiltrating T cells. 
CTLA-4 knockout mice suffer from a fatal lymphocyte proliferative disorder. CTLA-4 is 
expressed on Tregcells and transiently on activated T cells. CTLA-4 interaction with its ligands 
B7-1 (CD80) and B7-2 (CD86), results in cell cycle arrest, with G1 inhibition particularly evident
in CD4 cells on secondary antigen exposure. In vivo blockade of CTLA-4, utilizing anti-CTLA-4 
mAb, induces regression of established tumors and enhanced antitumor immune responses in 
several immunogenic murine tumor models. Moreover, when anti-CTLA-4 mAb is used in 
conjunction with granulocyte macrophage colony stimulating factor (GM-CSF)-secreting tumor 
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vaccines, poorly immunogenic cancers in mice are rejected. Tumor infiltration with activated 
lymphocytes, associated inflammation, and increased resistance to Treg activity as well as 
microenvironmental changes in tumor vasculature, are the hallmark of the anti-tumor effect of 
ipilimumab. These findings suggest that CTLA-4 blockade, alone or in combination with another 
immunological agent, can induce a potent antitumor response. In addition, in the Phase 2 
ipilimumab monotherapy study CA184004, increases in tumor infiltrating lymphocytes (TILs) and 
interferon-inducible genes were observed following treatment with ipilimumab, and PD-L1 
positive tumor cells co-localize with both TILs and interferon expression in metastatic melanoma. 
The preliminary clinical evidence has demonstrated a higher frequency of patients with substantial 
tumor burden reduction for the combination of nivolumab and ipilimumab. Improved OS
associated with substantial tumor burden reduction has been noted with immunotherapies. For 
instance, improved OShas been noted in metastatic melanoma subjects obtaining a complete 
response to IL-2. If this observation is also applicable to treatment with nivolumab combined with 
ipilimumab then there could also be the potential for large improvements in overall survival 
compared to other targeted therapies or to chemotherapy.
1.1.4.3
Rationale for Nivolumab and Ipilimumab in Treatment-Naive dMMR 
mCRC: Cohort C3
Immune responses to combination therapy with nivolumab and ipilimumab may be more robust in 
patients who are chemotherapy-naive.
39This observation, taken together with the decreased 
benefit from cytotoxic chemotherapy in the dMMR/MSI-H mCRC population,
40suggest that a 
rational approach would be to offer combined immunotherapy to dMMR/MSI-Hpatients earlier 
in the course of their disease.  
Standard of care therapy for mCRC is cytotoxic chemotherapy with response rates >40% in the 
first-line setting, but toxicities reported such Grade 3-4 neutropeniaor diarrheaexceed 40%.
41The 
median time to disease progression is reported as almost 8 months for combination chemotherapy 
without bevacizumab42,43and up to 9.4months with bevacizumab.
42  
Cytotoxic chemotherapy is the standard of care in the first-line treatment of all patients with 
mCRC,
43 including the elderly44 and those with dMMR/MSI-H.
16 However,it hasbeen 
demonstrated that earlier stage dMMR/MSI-H patients get no survival benefit from adjuvant 
cytotoxic chemotherapy. In order to spare early-stage dMMR/MSI-H from treatment-related 
toxicities, expense, and reduced quality of life during chemotherapy, many experts recommend 
against adjuvant 5-FU based chemotherapy for their disease, and these patientsare managed with 
post-resection observation.
16 In the metastatic setting, there is a strong suggestion that 
dMMR/MSI-H patients may have worse prognosis and PFS when treated with cytotoxic 
chemotherapy.
45 Approximately 30% all of mCRC patients will discontinue first-line 
chemotherapy due to toxicity.
42
There is potential for a first-line immunotherapy approach to be particularly beneficial for the 
elderly. Methylation in normalcolon tissue is correlated with aging,
46and sporadic MLH1 
hypermethylation in tumors is much more common in older patients. dMMR/MSI can result from 
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increased frequencies of promoter methylation (the CpG island methylator phenotype, or CIMP). 
CIMP-positive cancers tend to occur in older patients.
47Given ongoing concerns that the elderly 
may be more vulnerable to toxicities of chemotherapy,
48an immuno-oncology approach in the 
first-line would address an unmet need in the elderly mCRC population.Given the clinically 
meaningful and durable responses to combined immunotherapy, research has continued to focus 
on expanding the benefit of PD-1 blockade in mCRC.
Analysis of results from multiple studies across 
tumor types (melanoma, RCC, lung cancer, gastric 
cancer, and hematologic malignancies) hasdemonstrated enhanced antitumor activity and 
response rates for the combination of nivolumab plus ipilimumab when compared to nivolumab 
alone. The efficacy of thiscombination is anticipatedto be equal if not greater 
to 
that 
of nivolumab 
monotherapy, and the safety profile for nivolumab as monotherapy is expected to be comparable 
to 
that for 
the combination with ipilimumab. Hence,it is considered not necessary to have a staged 
enrollment for Cohort C3. To further build on the hypothesis that a combined immunotherapy 
approach may offer prolonged benefit and be well-tolerated in this patient population, Cohort C3
will enroll patients with treatment-naive dMMR/MSI-H mCRC in a 1-stage approach to the 
combination of nivolumab and ipilimumab.
39,49,50
1.1.4.4
LAG-3 and T Cell Exhaustion
Like PD-1, lymphocyte activation gene-3 (LAG-3; CD223) is also a type I transmembrane protein 
that is expressed on the cell surface of activated CD4+ and CD8+ T cells and subsets of NK and 
dendritic cells.
51LAG-3 is closely related to CD4, which is a co-receptor for T helper cell 
activation. Both molecules have 4 extracellularIg-like domains and require binding to 
their ligand, 
major histocompatibility complex (MHC) class II, for their functional activity. In contrast to CD4, 
LAG-3 is only expressed on the cell surface of activated T cells and its cleavage from the cell 
surface terminates LAG-3 signaling. LAG-3 can also be found as a soluble protein,but it does not 
bind to MHC class II,and its function is unknown.
It has been reported that LAG-3 plays an important role in promoting regulatory T cell (Treg) 
activity and in negatively regulating T cell activation and proliferation.
52Both natural and induced 
Treg express increased LAG-3, which is required for their maximal suppressive function.
53,54
Furthermore, ectopic expression of LAG-3 on CD4+ effector T cells reduced their proliferative 
capacity and conferred on them regulatory potential against third-party T cells.
54Recent studies 
have also shown that high LAG-3 expression on exhausted lymphocytic choriomeningitis virus 
(LCMV)-specific CD8+ T cells contributes to their unresponsive state and limits CD8+ T cell 
antitumor responses.
55In fact, LAG-3 maintained tolerance to self and tumor antigens via direct
effects on CD8+ T cells in 2 murine models.
1.1.4.5
Rationale for Combination Nivolumab/Anti-LAG-3 Antibody (BMS-
986016) Therapyin MSI-H mCRC(Cohort C5)
BMS-986016 is a fully human antibody specific for human LAG-3 that was isolated from 
immunized transgenic mice expressing human immunoglobulin genes. It is expressed as an IgG4 
isotype antibody that includes a stabilizing hinge mutation (S228P) for attenuated Fc receptor 
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binding in order to reduce or eliminate the possibility of antibody-or complement-mediated target 
T cell killing. BMS-986016 binds to a defined epitope on LAG-3 with high affinity (Kd, 0.25-0.5 
nM) and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC class II 
(IC50, 0.7 nM). The antibody exhibits potent in vitro functional activity in reversing LAG-3-
mediated inhibition of an antigen-specific murine T-cell hybridoma overexpressing human LAG-
3 (IC50, 1 nM). In addition, BMS-986016 enhances activation of human T cells in superantigen 
stimulation assays when added alone or in combination with nivolumab (anti-PD-1 antibody).
Immune tolerance observed in the setting of tumor development and tumor recurrence, however, 
seems to be mediated by the co-expression of various T cell negative regulatory receptors, not 
solely fromLAG-3. Data from chronic viral infection models,
54,55,56knock-out mice,
57,58,59tumor 
recurrence models,
60and, to a more limited extent, human cancer patients
60,61,62support a model 
wherein T cells that are continuously exposed to an antigen become progressively inactivated 
through a process termed “exhaustion.” Exhausted T cells are characterized by the expression of 
T cell negative regulatory receptors, predominantly CTLA-4, PD-1, and LAG-3, whose action is 
to limit the cell’s ability to proliferate, produce cytokines, and kill target cells and/or to increase 
Treg activity. However, the timing and sequence of expression of these molecules in the 
development and recurrence of tumors have not been fully characterized.
It is hypothesized that CTLA-4 acts as the dominant off-switch for tolerance, but it is the strong 
synergy between the PD-1 and LAG-3 inhibitory pathways that seems to mediate tolerance to both 
self and tumor antigens.
57,58,60Whereas CTLA-4 knockout (KO) mice die prematurely from 
multiorgan inflammation,
63 PD-1 and LAG-3 single knockout mice present minimal 
immunopathologic sequelae.
58 In contrast, dual knock-out mice (LAG3-/-PD1-/-) abrogates 
self-tolerance with resultant autoimmune infiltrates in multiple organs and even lethality.
57,58
These dual knock-out mice also show markedly increased survivalfrom and clearance of multiple 
transplantable tumors.
57
Conversely, extensive co-expression of PD-1 and LAG-3 on tumor-infiltrating CD4+ and CD8+ 
T cells has been shown in distinct transplantable tumors and samples from melanoma, RCC, head 
and neck, NSCLC,and ovarian cancer patients.
60,64,65,66,77,79,80 Blockade of PD-1/PD-L1 
interactions has been successfully used to restore antitumor immunity in preclinical and clinical 
studies. But the simultaneous blockade of PD-1 and LAG-3 pathways on T cells may exert an even 
more robust antitumoral immunity in naive as well as in recurrent tumors due to the possibility of 
reversing LAG-3–mediated T cell exhaustion. In 2 syngeneic mice models, for example, dual anti–
LAG-3/anti–PD-1 antibody therapy is able to cure 
most mice of established tumors that are largely 
resistant to single antibody treatment.
57Furthermore, recurrent tumors from a melanoma mouse 
model with increased Treg cell numbers and increased expression of checkpoint inhibitors PD-1, 
LAG-3, TIGIT, and TIM-3 can be controlled by depletion of Tregs (via FoxP3-DTR) plus the 
administration of anti-PD-L1 antibody. But more importantly, tumor regression of these recurrent 
tumors can also be accomplished with the combination of anti-PD-L1 plus anti-LAG-3 antibodies 
(C9B7W mAb),which also increases T cell activity.
60In a recent analysis, 33% to 47% of head 
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and neck tumors showed a T cell-inflamed phenotype (TCIP) similar to melanoma, based on a 
gene expression signature. Furthermore, various checkpoint molecules were universally co-
expressed in these TCIP tumors,including PD1, CTLA4, LAG3, PDL-2, and IDO, as shown in 
gene expression analysis.
64
Given theaboveliterature supporting synergistic activity of nivolumab and anti–LAG-3 antibody, 
it is hypothesized that this combination could have antitumor effects in solid cancers such as 
mCRC. In a study that examined infiltrating lymphocytes from 108 colorectal tumor samples and 
their peritumoral tissues using immunohistochemistry, the percentage of LAG-3 expressing cells 
was four times higher in tumor samples than in peritumoral tissues.
65
These data argue strongly that dual blockade of the PD-1 and LAG-3 pathways could be a 
promising combinatorial strategy for MSI-H mCRC and support treatment of an MSI-H mCRC 
population with a combination of nivolumab andanti-LAG-3 mAb BMS-986016.
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1.1.4.6
Dose and Scheduling Rationale(Nivolumab and Ipilimumab)
In CA209004, the 3 mg/kg nivolumab and 3 mg/kg ipilimumab cohort exceeded the maximum 
tolerated dose per protocol. In CA209004, while both Cohort 2 (1 mg/kg nivolumab + 3mg/kg 
ipilimumab) and Cohort 2a (3 mg/kg nivolumab + 1 mg/kg ipilimumab) had similar clinical 
activity, a dose of 3 mg/kg of ipilimumab every 3 weeks for a total of four doses and 1mg/kg 
nivolumab every 3 weeks for four doses followed by nivolumab 3mg/kg every 2 weeks until 
progression was chosen. Exposure-response analysis of nivolumab monotherapy across dose 
ranges of 1mg/kg to 10 mg/kg revealedsimilar clinical activity while exposure-response analysis 
of 0.3 mg/kg, 3 mg/kg, and 10 mg/kg of ipilimumab monotherapy have demonstrated increasing 
activity with increase in dose in the Phase 2 study CA184022. Therefore, theoretically,the 
selection of 3 mg/kg of ipilimumab (Cohort 2) may be more clinically impactful than selection of 
3 mg/kg of nivolumab (Cohort 2a). The combination armin this studyhas a similar dose and 
schedule as that in CA209004 for the first 12 weeks, increasing the likelihood of replicating the 
clinical activity seen in the CA209004 study. Based on the clinical activity in CA209004, the 
majority of responses to 
the combination of nivolumab and ipilimumab occur in the first 12 weeks. 
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Given the uncertainty of whether the ipilimumab administered past week 12 contributes to the 
clinical benefit and the fact that the approved schedule for ipilimumab is every 3 weeks for a total 
of four doses in the FDA and EMA approved label dosing section, ipilimumab will administered 
every 3weeks for a total of 4 doses. Nivolumab monotherapy treatment every two weeks until 
progression was studied in CA209003 and has been studied across the nivolumab monotherapy 
Phase 3 registrational trials. Refer to the current nivolumab Investigator Brochure for additional 
information.
Clinical activity of nivolumab and ipilimumab combination was further evaluated in patients with 
stage IIB-IV NSCLC as first-line treatment in CA209012, a large Phase 1, multi-arm safety study 
of nivolumab monotherapy and nivolumab in combination with various systemic anticancer 
therapies. Early combination cohorts of nivolumab 1mg/kg + ipilimumab 3 mg/kg and nivolumab 
3 mg/kg + ipilimumab 1mg/kg, both followed by maintenance nivolumab 3mg/kgQ2W, resulted 
in significant toxicity in the NSCLC population, with 39% of patients discontinuing treatment due 
to a treatment-related adverse events. Thus, additional combination cohorts were initiated using 
lower doses of both nivolumab (1 mg/kg) and ipilimumab (1 mg/kg), or the approved dose of 
nivolumab (3 mg/kg Q2W) with less frequent dosing of ipilimumab (Q6W or Q12W). These new 
regimens were better tolerated, and the safety profile was comparable to what has been observed 
in the nivolumab monotherapy cohort study. Clinical activity was observed in all combination 
cohorts,but numerically higher response rates were observed in the cohorts evaluating the 
approved dose of nivolumab 3 mg/kg, with confirmed response rates 30% for the ipilimumab 1 
mg/kg Q12W and Q6W regimens, cohorts P and Q, respectively.
67Given the similarity in patient 
profiles of advanced NSCLC and CRC, nivolumab 3 mg/kg every 2 weeks and ipilimumab 1 
mg/kg every 6 weeks will be studied in Cohorts C3 and C4 with the expectation that there will not
be changes in the safety profile, as has been demonstrated in NSCLC.
1.1.4.7
Rationale for Treatment Duration and Introducing Re-Initiation in MSI-
H/dMMR Cohorts
Clinicalstudy CA209-142 was originally designed to continue nivolumab monotherapy and 
nivolumab combination treatments until progression in all cohorts. The optimal duration of 
immunotherapy still remains an important question and continues to be investigated. Atthe time 
of Revised Protocol 07, some patients with MSI-H/dMMR mCRC have experienced durable 
clinical benefit and have remained on study treatment for longer than 2 years. Revised Protocol 07 
was developed to identify optimal treatment duration for those patients who achieve maximum 
clinical benefit and to allow re-initiation of study treatment within the first year of treatment 
discontinuation.
Few patients with MSI-H/dMMR mCRC, a distinct and often IO-sensitive subgroup of mCRC, 
seem to experience a unique response pattern, with few late responders and deepening of responses 
with long-term treatment.
68This observation from the CA209-142 study was taken into account 
when defining optimal time for treatment discontinuation for maximum benefit.
Accumulating data suggest that 2 years of PD-1 checkpoint inhibitor treatment may be sufficient 
for long term benefit; therefore this duration was consideredwhen modifying treatment duration 
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for MSI-H/dMMR Cohorts of CA209-142 study. As an example, CA209003, a dose-escalation 
cohort expansion trial evaluating the safety and clinical activity of nivolumab in patients with 
previously treated advanced solid tumors (including 129 subjects with NSCLC), specified a 
maximum treatment duration of 2 years. Among 16 subjects with NSCLC who discontinued 
nivolumab after completing 2 years of treatment, 12 subjects were alive > 5 years and remained 
progression-free without any subsequent therapy. In the CA209003 NSCLC cohort, the OS curve 
begins to plateau after 2 years, with an OS rate of 25% at 2 years and 18% at 3 years.
69These 
survival outcomes are similar to 
Phase 3 studies in previously treated NSCLC, in which nivolumab 
treatment was continued until progression or unacceptable toxicity (2-year OS rates of 23% and 
29%, and 
3 year OS rates 
of 
16% to18% for squamous 
and non-squamous 
NSCLC, respectively).
70   
Similar results have been reported in clinical studies of pembrolizumab, another PD-1 inhibitor. 
Keynote-010 was a randomized phase 3 trial of pembrolizumab (at either 2 mg/kg or 10 mg/kg 
every 3 weeks) versus docetaxel in subjects with previously treated, PD-L1-positive, advanced 
NSCLC which specified a maximum treatment duration of 2 years for pembrolizumab. OS was 
significantly longer with both pembrolizumab 2 mg/kg (HR 0.72, P = 0.00017) and 
pembrolizumab 10 mg/kg (HR 0.60, P < 0.00001) compared to docetaxel, with an OS plateau 
developing beyond 2 years in both pembrolizumab arms. Among 690 patients who received 
pembrolizumab, 47 patients completed 2 years of pembrolizumab andstopped treatment. Most 
were able to maintain their response, including those with stable disease, with only 2 patients (4%) 
having confirmed progression after stopping at 2 years.
71
CA209-142 trial was originally designed to continue nivolumab monotherapy or combination 
treatments until progressionor 
toxicity. 
Recently presented 
data 
from CA209-142 
study in subjects
with MSI-H mCRC tumors 
suggest 
that 
some 
subjectsachieve 
response and 
deepening 
of 
response 
with longer treatment duration. A small number of subjectsachievedresponse as late as second 
year of treatment. Moreover, some subjectswho are still on treatment in earlier cohorts have 
already been on treatment longer than 24 months. Therefore, a strict stopping rule at 2-years was 
not considered ideal for CA209-142.Instead, Revised Protocol 07, incorporates the option to 
discontinue treatment after minimum of 24 months of treatment in subjects who have achieved 
maximum clinical benefit as assessed by the Investigator and described in Section 3.1.4.1. It is not 
yet 
known whether 
subjects with late 
partial 
response would need 
treatment 
longer 
than 
24 months. 
Therefore,to minimizethe potential risk of disease recurrence as a result of premature treatment 
discontinuation, all MSI-H subjects who achieved objective response within second year of 
treatment, will be required to continue to receive study therapy for additional 12 monthsbefore 
considering the optionto discontinuefor maximum clinical benefit (Section 3.1.4.1).  
In addition to treatment discontinuation for maximum clinical benefit, Revised Protocol 07 brings 
the option to re-initiate study treatment for subjects who experience a progression during the first 
year (52 weeks), as long as the eligibility criteria for re-initiation are met (Section4.3.9). MSI-
H/dMMR mCRC has widely shown to be a IO-sensitive subgroup, and some patients may 
potentially benefit from resuming study treatment at time of progression. In advanced NSCLC, 
updated results from KEYNOTE-010 demonstrated that a majority of patients who completed 2 
years of pembrolizumab treatment and subsequently developed confirmed progression benefited 
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from a second course of pembrolizumab (re-initiation).
7225 patients developed progression, and 
14 of these patients started a second course of pembrolizumab. Among patients who underwent 
re-initiation, 6 (43%) had PR and 5 (36%) had SD per BICR per RECIST 1.1. Clinical activity of 
reinitiating study treatment with nivolumab or nivolumab combinations will be evaluatedin 
CA209142to shed light on this important clinical questionin MSI-H/dMMR mCRC.
1.1.4.8
Rationale for Shorter Nivolumab and Ipilimumab Infusion Times
Long infusion times place a burden on patients and treatment centers. Establishing that nivolumab 
and ipilimumab can be safely administered using shorter infusion times of approximately 30 
minutes duration in subjects will diminish the burden provided no change in safety profile. 
Previous clinical studies of nivolumab monotherapy and ipilimumab monotherapy and the 
combination of nivolumab and ipilimumab have used a 60-minute infusion duration for nivolumab 
and 90-minute infusion duration for ipilimumab (1-3mg/kg dosing for both). However, both 
nivolumab and ipilimumab have been administered at up to 10 mg/kg with the same infusion 
duration.
Nivolumab has been administered safely over 60 minutes at doses ranging up to 10 mg/kg 
safely over a long treatment duration. In Study CA209010 (a Phase 2, randomized, double 
blinded, dose-ranging study of nivolumab in subjects with advanced/metastatic clear cell 
RCC),a dose association was observed for infusion site reactions and hypersensitivity 
reactions (1.7% at 0.3 mg/kg, 3.7% at 2 mg/kg and 18.5% at 10 mg/kg). All the events were 
Grade 1 -2 and were manageable. An infusion duration of approximately 30 minutes for 
3mg/kg nivolumab (30% of the dose provided at 10 mg/kg) is not expected to present any 
safety concernscompared to the prior experience at 10 mg/kg nivolumab dose infused over a 
60 minute duration.
Similarly, ipilimumab at 10 mg/kg has been safely administered over 90 minutes. In the 
CA184022 study, where ipilimumab was administered up to a dose of 10 mg/kg, on-study 
drug-related hypersensitivity events (Grade 1-2) were reportedin 1 (1.4%) subject in the 
0.3mg/kg and in 2 (2.8%) subjects in the 10 mg/kg group. There were no drug-related 
hypersensitivity events reported in the 3 mg/kg group. Across 
the 3 treatment groups, no Grade 
3-4 drug-related hypersensitivity events were reported,and there were no reports of infusion 
reactions. Ipilimumab 10 mg/kg monotherapy has alsobeen safely administered as 90-minute 
infusion in large Phase 3 studies in prostate cancer (CA184043) and as adjuvant therapy for 
stage 3 melanoma (CA184029), with infusion reactions occurring in subjects. Administering 
1 mg/kg of ipilimumab representsone-tenth of the 10 mg/kg dose
Overall, infusion reactions including high-grade hypersensitivity reactions have been uncommon 
across nivolumab or ipilimumab clinical studies or 
the combination of nivolumab and ipilimumab. 
Furthermore, a 30-minute break after the first infusion for the combination cohort will ensure the 
appropriate safety monitoring before the start of the second infusion. Overall, a change in safety 
profile is not anticipated with 30-minute infusion of nivolumab, ipilimumab,or combination.
Therefore, shortened infusion times apply to all cohorts receiving nivolumab and ipilimumab.
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1.1.4.9
Rationale for Nivolumab Flat Dosing
The nivolumab dose of 240 mg Q2W was selected based on clinical data and modeling and 
simulation approaches using population PK (PPK) and exposure-response analyses of data from 
studies in multiple tumor types (melanoma, NSCLC, and RCC) where body weight normalized 
dosing (mg/kg) has been used.
Nivolumab PK has been extensively studied in multiple tumor types, including melanoma, 
NSCLC, RCC, 
classical 
Hodgkin lymphoma (cHL), 
squamous 
cell 
carcinoma of the head andneck 
(SCCHN), CRC and urothelial carcinoma and has been safely administered at doses up to 
10mg/kg Q2W. Nivolumab monotherapy was originally approved as a body-weight based dose 
of 3 mg/kg Q2W, and was updated to 240 mg Q2W or 480 mg every 4 weeks (Q4W)in multiple 
indications.
73,74Aflat dose is expected to simplify dosing and administration for re-initiation 
Cohort 2. A flat dose of 240 mgQ3W was equivalent to the 3mg/kg dose at the median body 
weightof approximately 80 kg in patients in the nivolumab program based on modeling and 
simulation. As compared to body weight-corrected dosing regimen, a flat dosing regimen is 
expected to reduce dosing errors.
75Nivolumab 360 mg every 3 weeks (Q3W)is also under 
evaluation in monotherapy and in combination therapy studies. Less frequent 360 mg Q3W and 
480 mg Q4W dosing regimens can reduce the burden to patients of frequent, lengthy IV treatments 
and allow combination of nivolumab with other agents using alternative dosing regimens.
The benefit-risk profiles of nivolumab 240 mg Q2W, 360 mg Q3W,and 480 mg Q4W are 
predicted to be comparable to 3 mg/kg Q2W. This assessment is based on a comprehensive 
characterization of nivolumab PK, safety, efficacy, and exposure-response relationships across 
indications. Population PK (PPK) analyses have shown that the PK of nivolumab is linear with 
proportional exposures over a dose range of 0.1 to 10 mg/kg; no clinically meaningful differences 
in PK across ethnicities and tumor types were observed. Using the PPK model, the exposures 
following administration of several dosing regimens of nivolumab administered as a flat dose were 
simulated, including 240 mg Q2W, 360 mg Q3W,and 480 mg Q4W. The simulated average serum 
concentration at steady state [Cavgss] following administration of nivolumab 360 mg Q3W and 
480 mg Q4W are predicted to be similar to those following administration of nivolumab 240 mg 
Q2W and nivolumab 3 mg/kg Q2W administered to patients over a wide body weight range (34-
180 kg) across tumor types. In addition, nivolumab exposures with 240 mg Q2W, 360 mg Q3W, 
and 480 mg Q4W flat-dose IV regimens across tumor types are maintained well below the 
corresponding exposures observed with the well-tolerated 10 mg/kg IV nivolumab Q2W dose 
regimen.
Extensive exposure-response analyses of multiple PK measures (maximum serum concentration 
at Day 1[Cmax1], average serum concentration at Day 28 [Cavg28], and trough serum 
concentration at Day 28 [Cmin28]) and efficacy and safety endpoints indicated that the efficacy 
of the flat-dose 480 mg IV regimen are similar to that of 3 mg/kg Q2W IV regimen. In exposure-
responseefficacy analyses for OS and ORR conducted in melanoma, RCC, and NSCLC using 
Cavg28 as the exposure measure, probabilities of achievinga response and survival probabilities 
at 1 year and 2 years for IV 480 mg Q4W were similar to that of IV 3 mg/kg Q2W. In exposure-
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responsesafety analyses, it was demonstrated that the exposure margins for safety are 
maintained following nivolumab 480 mg Q4W, and the predicted risks of discontinuations due to 
AEs or death, AE Grade 3+, and immune-mediated AEs (IMAEs) Grade 2+ are similar 
following nivolumab 480 mg Q4W relative to nivolumab 3 mg/kg Q2W across tumor types. 
Based on PK modeling and simulations, administration of nivolumab 480 mg Q4W will be 
started after steady state is achieved with 240 mg Q2W and is predicted to provide Cavgss 
similar to 240 mg Q2W. While 480 mg Q4W is predicted to provide greater (approximately 
20%) maximum steady state concentrations and lower (approximately 10%) steady state trough 
concentrations, these exposures are predicted to be within the exposure ranges observed at doses 
up to 10 mg/kg Q2W used in the nivolumab clinical program, and are not considered to put 
participants at increased risk. Similar to the nivolumab 240 mg Q2W dosing regimen, the 
exposures predicted following administration of nivolumab 480 mg Q4W are on the flat part of 
the exposure-response curves for previously investigated tumors, melanoma,and NSCLC, and 
are not predicted to affect efficacy. Based on these data, nivolumab 480 mg Q4W is expected to 
have similar efficacy and safety profiles to nivolumab 240 mg Q2W.
Based on population pharmacokinetic and exposure-response (efficacy and safety analysis) for 
data from the nivolumab lung program analyses as well as totality of clinical data in nivolumab 
program, the nivolumab 360 mg Q3W regimen is predicted to produce average exposure at steady 
state comparable to 
that 
of the nivolumab 3 mg/kg Q2Wregimen when combined with ipilimumab 
1 mg/kg Q6W. Data from the clinical  sub group efficacy and safety analyses indicated that the 
clinical benefits/risks following nivolumab 360 mg Q3W flat dose administration is expected to 
be similar to that following nivolumab 3 mg/kg Q2W administration, when administered in 
combination with ipilimumab 1 mg/kg Q6W in subjects with unresectable mesothelioma.
76
Moreover, the dosing regimen of nivolumab 360 mg Q3W + ipilimumab 1 mg/kg Q6W was 
demonstrated to be safe and tolerable in 1L NSCLC in Study CA2099LA when combined with 2 
cycles of chemotherapy. Thus, the same regimen without combination with chemotherapy is 
expected to be safe and may be more tolerable in 1L CRC subjects.  
Additional details on nivolumab posologies and risk-benefit can be found in the investigator 
brochure.
1.1.4.10 Rationale for Nivolumab Dose:240 mg Q3W (cStage1/2),480 mg Q4W
(mStage 1/2 and cStage 1/2),and 360 mg Q3W (Cohort 3) During Re-
initiation Treatment 
Nivolumab is currently approved for thetreatment of various tumors, including melanoma, 
NSCLC, SCLC, RCC, cHL, SCCHN, UC, and MSI-H mCRC using a regimen of either nivolumab 
240 mg Q2W or nivolumab 480 mg Q4W. A flat dose is expected to simplify dosing and 
administration for re-initiation Cohort 2.The rationale for a flat dose of 240 mg Q3W is provided 
above in Section 1.1.4.9.
75Subjects inCA209142 originally enrolled to either mStage 1/2 or 
cStage 1/2 whoare going into re-initiation will be treated with nivolumab 480mg every 4 weeks 
(Q4W), which provides a more convenient dosing regimen for subjects. While 480mg Q4W is 
predicted to provide greater (approximately 117%) maximum concentrations and lower 
(approximately 10%) steady state trough concentrations, these exposures are predicted to be lower 
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thanthe exposure ranges observed exposures at doses up to 10 mg/kg Q2W used in the nivolumab 
clinical program, and are not considered to put subjects at increasedrisk. Similar to the nivolumab 
240 mg Q2W dosing regimen, the exposures predicted following administration of nivolumab 480 
mg Q4W, are on the flat part of the exposure-response curves for previously investigated tumors, 
melanoma and NSCLC, and are not predicted to affect efficacy. Based on these data, nivolumab 
480 mg Q4W is expected to have similar efficacy and safety profiles to nivolumab 240 mg Q2W.
The less frequent dosing regimen, nivolumab 360 mg Q3W + ipilimumab 1 mg/kg Q6W, selected 
as the regimen to be used for Cohort 3 subjects re-initiating treatment  is expected to substantially 
reduce the burden on patients and health care providers while offering a favorable benefit/risk 
profile for 1L CRC subjects. Based on population pharmacokinetic and exposure-response 
(efficacy and safety analysis) for data from the nivolumab lung program analyses as well as totality 
of clinical data in nivolumab program, the nivolumab 360 mg Q3W regimen is predicted to 
produce average exposure at steady state comparable to that of the nivolumab 3 mg/kg Q2W 
regimen when combined with ipilimumab 1 mg/kg Q6W.
76
1.1.5
Rationale to Support Dose/Schedule of Nivolumab Combined with BMS-
986016(Cohort C5)
The dose selection and schedule of nivolumab in combination with the BMS-986016 antibody 
have been determined using all available safety (clinical and laboratory) and 
PK/pharmacodynamic data modeling recommendations, and by incorporating toxicity profiles for 
nivolumab (data from the completed StudyCA209003, a Phase 1 nivolumab monotherapy study 
in advanced solid tumors) and BMS-986016 (data from the ongoing Study CA224020).
The 
combination of nivolumab 
and 
BMS-986016 is 
currently being 
evaluated 
in 
Study 
CA224020, 
a Phase 1, dose escalation and cohort expansion study of the safety, tolerability, and efficacy of 
anti-LAG-3 antibody (BMS-986016)administered alone and in combination with anti-PD-1 mAb 
(nivolumab) in advanced solid tumors, and in Study CA224022 in hematologic malignancies.
Table 1.1.5-1:
BMS-986016 Alone or in Combination with Nivolumab in 
StudyCA224020 (Solid Tumors)
BMS-986016 Q2W
Nivolumab Q2W
Number of Subjects
20 mg
NA
5
80 mg
NA
4
240 mg
NA
4
800 mg
NA
10
20 mg
80 mg
7
20 mg
240 mg
9
80 mg
240 mg
129a
160 mg
240 mg
4
240 mg
240 mg
8
Source: Protocol CA224020 Table S.6.4A.2
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a Eight subjects in dose escalation and 121 subjects in dose expansion.
Abbreviation: NA = not applicable.
As of 23-Jan-2017 in StudyCA224020, among all subjects treated with BMS-986016 as 
monotherapy or in combination with nivolumab (N=121), the median duration of therapy was 
8.33weeks (range: 2.0 to 32.7 weeks). Among the subjects treated with BMS-986016 at 160 mg 
and nivolumab at 240 mg (n=4), the median duration of therapy was 9.25 weeks (range: 7.9 to 
12.7weeks).
No DLTs were observed in the BMS-986016 monotherapy cohorts up to the maximum 
administered dose of 800 mg Q2W. A total of 5 DLTs were observed in the combination cohorts: 
1in the BMS-986016 20mg and nivolumab 80mg cohort (Grade3 mucositis); 1 in the 
BMS-986016 20mg and nivolumab 240mg cohort (Grade 4 ventricular fibrillation); 1 in the 
BMS-986016 80mg and nivolumab 240mg cohort (Grade 4 lipase elevation); and 2 in the 
BMS-986016 240mg and nivolumab 240mg cohort (1 event of Grade3 aseptic meningitis and 
1event of Grade5 myocarditis). 
The most common AEs observed among all 157treated subjects and those treated at the 
BMS-986016 160mg and nivolumab 240mg dose level are shown in Table 1.1.5-3. The most 
common SAEs are shown inTable 1.1.5-3. AEs leading to study discontinuation are shown in 
Table 1.1.5-4. On-study deaths through 16-Feb-2017 are shown in Table 1.1.5-5.
As of 20-Feb-2017, an additional 2 subjects have received study treatment with BMS-986016 
160mg and nivolumab 240mg, scheduled Q2W, on Study CA224022 (subjects with hematologic 
malignancies). No subjects have discontinued study treatment due to AEs. There have been no 
treatment-related 
SAEs. All 
of 
the subjects 
are 
still alive and either 
remain 
on 
treatment 
or in safety 
follow-up. For these subjects, Table 1.1.5-2shows the subjects’ treatment exposure, AEs, and 
study outcome. Thus, across both Study CA224020 (solid tumors) and Study CA224022 
(hematologic tumors), 6 subjects have been treated for a minimum of 60 days with the dose level 
of BMS-986016 160 mg and nivolumab 240 mg Q2W.
Table 1.1.5-2:
Safety Results of Subjects Treated with BMS-986016 160mg and 
Nivolumab 240mg Every 2 Weeks on Study CA224022 
(Hematologic Tumors)
Age
Cancer 
Diagnosis
Date of First 
Dose
Number of 
Treatments
Treatment-
related 
Adverse Events
Outcome
59
Hodgkin’s 
Lymphoma
7-Dec-16
4
None
On-treatment
23
Hodgkin’s 
Lymphoma
14-Dec-16
5
None
On-treatment
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Table 1.1.5-3:
Most Common (> 10% ) Adverse Events in Study CA224020
Adverse Event
BMS-986016 160mg and
Nivolumab 240 mg
(N=4)
All BMS-986016 and Nivolumab 
Combination Cohorts 
(N=157)
Any Grade 
n (%)
Grade 3-4 
n (%)
Any Grade
n (%)
Grade 3-4 
n (%)
Fatigue
2 (50.0)
0
34 (21.7)
1 (0.6)
Malignant neoplasm progression
0
0
25 (15.9)
2 (1.3)
Asthenia
0
0
22 (14.0)
1 (0.6)
Nausea
0
0
19 (12.1)
0
Diarrhea
0
0
16 (10.2)
2 (1.3)
Dyspnea
0
0
16 (10.2)
2 (1.3)
Source: Protocol CA224040 Table S.6.1A.2
Table 1.1.5-4:
Most Common Serious Adverse Events (> 10%) in Study CA224020
Serious Adverse Event
BMS-986016 160mg and
Nivolumab 240 mg
(N=4)
All BMS-986016 and Nivolumab 
Combination Cohorts
(N=157)
Any Grade 
n (%)
Grade 3-4 
n (%)
Any Grade
n (%)
Grade 3-4 
n (%)
Malignant neoplasm progression
0
0
25 (15.9)
2 (1.3)
Blindness unilateral
1 (25.0)
1 (25.0)
0
0
Intestinal obstruction
1 (25.0)
1 (25.0)
0
0
Source: Protocol CA224020 Table S.6.3A.2
Table 1.1.5-5:
Adverse Events Leading to Discontinuation in Study CA224020
Adverse Event
BMS-986016 160mg and 
Nivolumab 240 mg
(N=4)
All BMS-986016 and Nivolumab 
Combination Cohorts
(N=157)
Any Grade 
n (%)
Grade 3-4 
n (%)
Any Grade
n (%)
Grade 3-4 
n (%)
Malignant neoplasm progression
0
0
6 (3.8)
1 (0.6)
Meningitis aseptic
0
0
2 (1.3)
2 (1.3)
Lipase increased
0
0
1 (0.6)
1 (0.6)
Mucosal inflammation
0
0
1 (0.6)
1 (0.6)
Myocarditis
0
0
1 (0.6)
0
Pneumonitis
0
0
1 (0.6)
1 (0.6)
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Table 1.1.5-5:
Adverse Events Leading to Discontinuation in Study CA224020
Adverse Event
BMS-986016 160mg and 
Nivolumab 240 mg
(N=4)
All BMS-986016 and Nivolumab 
Combination Cohorts
(N=157)
Any Grade 
n (%)
Grade 3-4 
n (%)
Any Grade
n (%)
Grade 3-4 
n (%)
Troponin I increased
0
0
1 (0.6)
1 (0.6)
Ventricular fibrillation
0
0
1 (0.6)
1 (0.6)
Source: Protocol CA224020 Table S.6.4A.2
Table 1.1.5-6:
On-Study Deaths in Study CA224020
BMS-986016 160mg and 
Nivolumab 240 mg
(N=4)
n (%)
All BMS-986016 and Nivolumab 
Combination Cohorts
(N=157)
n (%)
Deaths
0
32 (20.4)
Disease
0
30 (19.1)
Study treatment toxicity 
(myocarditis)
0
1 (0.6)
Other
0
1 (0.6)
Source: Protocol CA224020 Table S.6.2A
Based on the safety data from Feb-2017 of 157 subjects treated with either monotherapy or in 
combination with nivolumab, BMS-986016 demonstrates a manageable safety profile. Excluding 
disease progression, the most common AEs are constitutional and GI. No DLTs were observed at 
the 160mg dose of BMS-986016 combined with 240 mg of nivolumab. One death was reported 
as due to study treatment-related toxicity (myocarditis); however, this was with the higher 240mg 
dose ofBMS-986016 that will not be utilized in this study. Therefore, BMS-986016 160mg Q2W 
will be administered in combination with nivolumab 240mg Q2W in subjects with recurrent or 
metastatic CRC. 
Additional details are provided in the current version of theBMS-986016 IB.
1.1.6
Rationale for Nivolumab plus Daratumumab Combination Therapy
(Cohort C6)
This study will investigate the combination of daratumumab and nivolumab in patients with 
non-MSI-HCRC.  
The tumor microenvironment plays an important role in determining whether a patient can mount 
an effective immune response to his/her tumor. Tumor cells can induce an immunosuppressive 
microenvironment through multiple mechanisms, resulting in evasion of the anti-tumor immune 
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response. Two such mechanisms include (1) upregulation of PD-L1, which following binding to 
PD-1 on T cells, inhibits activation and expansion of previously activated T cells; and (2) 
recruitment of immunosuppressive cell types such as regulatory T cells (Tregs) and myeloid-
derived suppressor cells (MDSCs). Since individual tumors may use more than one means to 
evade the immune system, more than one method may be needed for optimal tumor regression. 
Nivolumabis a human immunoglobulin G4 (IgG4) monoclonal antibody that blocks the 
interaction between the inhibitory receptor, PD-1, and its ligands PD-L1 and PD-L2, thus allowing 
for sustained activation of T cells. Nivolumab has demonstrated single agent clinical efficacy in 
patients with metastatic melanoma, squamous and non-squamous NSCLC, advanced RCC, head 
and neck cancer, and bladder cancerand has an approved label in these indications. Nivolumab 
has 
also demonstrated 
significant 
response 
rates 
in other 
solid 
tumor malignancies including 
small-
cell lung cancerand hepatocellular carcinoma. The combination of nivolumab with other
immunomodulatorytherapies, such as ipilimumab, has also demonstrated meaningful response 
rates and PFS in multiple solid tumor indications and is approved for the treatment of metastatic 
melanoma in the US. Certain tumor types, however, such as the MSS subtype of CRC, havebeen
shown to have a poor anti-tumor immune response, suggesting that more 
than one method 
to 
target 
the immunosuppressive tumor microenvironment may be necessary to treat this tumor type. The 
potential for additive or synergic 
clinical 
activity when nivolumab is combined 
with 
other 
therapies 
is currently being evaluatedin severaltrials, including CA209142.  
Daratumumab is a human immunoglobulin G1 (IgG1) monoclonal antibody that targets CD38, 
inducing death of CD38-expressing cells through several mechanisms, including 
antibody-dependent cellmediated cytotoxicity (ADCC), complement-dependent cytotoxicity
(CDC), and antibody-dependent cellular phagocytosis (ADCP).
77,78The majority of malignant 
myeloma cells express CD38,and as such, 
treatment 
of patients with MM with daratumumab leads 
to a significant clinical benefit. Daratumumab has shown anti-myeloma activity in 2 clinical 
studies (GEN501 and 
SIRIUS) in patients with 
relapsed and 
refractory 
MM, resulting in significant 
response rates,including stringent complete responses (sCRs) and prolonged clinical responses in 
heavily pretreated patients.
79,80Based on these data, daratumumab was approved by the US Food 
and Drug Administration for patients with MM who have received 3or more prior lines of 
therapy.
81
Daratumumab is an attractive therapeutic antibody in other solid tumor indications given that 
subsets of immunosuppressive cells such as MDSC and Tregs express CS38 and could be targeted 
for depletion by daratumumab.
82,83Consistent with this hypothesis, frequencies of Tregs and 
MDSCs were reduced in MM patients following daratumumab administration. Furthermore, 
daratumumab led to changes in T cell populations includingincreased effector memory CD8+ 
Tcells, increased overall T-cell clonality and increased antiviral and alloreactive T cell 
functionality.
82
Preclinical studies suggest that targeting both CD38 and PD1 pathways may offer improvement in 
anti-tumor efficacy over each single agent alone. In mouse models of lung cancer, molecular 
profiling revealed increases in CD38 mRNA and protein expression in tumors with resistance to 
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PD1/PD-L1 blockade. While tumor growth was detected in mice deficient in PD-L1, 
tumor growth 
was not observed in mice deficient in both PD-L1 and CD38, suggesting that CD38 may be a 
negative regulator of the antitumor immune response.
84Consistent with this hypothesis, treatment 
of mice bearing CD38-positive tumors with a combination of nivolumab and daratumumab mouse 
surrogateantibodies led to a significantly higher number of tumor-free mice compared to single 
agent treatments (BMS unpublisheddata). In tumor biopsies from CRC patients, there is elevated 
expression of CD38 mRNA and an upregulation of a regulatory T cell signature, suggesting an 
immunosuppressive state in CRC.
85
In the current study, the combination ofdaratumumab and nivolumab is hypothesized to deplete 
CD38+ immunosuppressive cells from the tumor microenvironment, thus alleviating the 
immunosuppression so that the nivolumab activated T cells can mount an effective immune 
response to the tumor. This trial will test whether simultaneous blockade of PD-1 with nivolumab 
and the immunoregulatory effects ofdaratumumab will result in enhanced anti-tumor responses in 
patients withCRC or other solid tumors.
1.1.7
Rationale to Support Dose/Schedule of Nivolumab Combined with 
Daratumumab(Cohort C6)
For the nivolumab/daratumumab combination cohort, nivolumab will be administered at 240 mg 
Q2W, an approved nivolumab dosing regimen for NSCLC and RCC indications. Daratumumab 
will be administered at 16 mg/kg QW from Week 1 to 8, Q2W from Week 9 to 24, and Q4W from 
Week 25 and beyond until disease progression as described in the daratumumab label. As 
nivolumab 480 mg Q4W dosing regimen would produce similar exposures to 
that 
of 240 mg Q2W 
dosing regimen based on PPK modeling and simulation, nivolumab will be administered at 480 
mg Q4W starting from Week 25 for the convenience to patients.
Dosing of daratumumab in subjects with multiple myeloma is recommended at 16 mg/kg (weekly 
for 8 weeks, then every 2 weeks for 16 weeks, then every 4 weeks thereafter) administered via IV 
until disease progression or unacceptable toxicity. The dose selection was based on an acceptable 
safety profile, maximal clinical activity, and pharmacokinetics consistent with saturation of the 
target. The data supporting the selection of a 16 mg/kg dose for 
the treatment of multiple myeloma 
are as follows:
Safety: Clinical safety data demonstrated that daratumumab is well-tolerated, with clinically 
manageable side effects, highlighted by the fact that nosubject treated with 16 mg/kg 
daratumumab monotherapy discontinued treatment as a result of a daratumumab related 
adverse event.
For doses above 4 mg/kg, there was no dose dependent toxicity pattern observed.
Clinical efficacy: Clinical response data derived from Study GEN501 and Study MMY2002 
show robust activity among subjects treated at 16 mg/kg with ORRs of 36% and 29%, 
respectively.
The response rates were consistently and significantly higher and deeper at the 16 mg/kg 
dose level as compared to various schedules at the 8 mg/kg dose level.
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Pharmacokinetics: Daratumumab exhibits target-mediated drug disposition. Daratumumab 
binds to CD38 receptors in the body and the complex with daratumumab is rapidly cleared. As 
the dose is increased or after repeatedadministration, CD38 becomes saturated, and the impact 
of target binding clearance is minimized and PK data can indicate target saturation.
Population pharmacokinetic and exposure-response analyses suggested that 16 mg/kg is 
the lowest tested dose at which the majority (approximately 80%) of subjects achieved 
serum concentrations above the model-predicted 99% target saturation threshold and 90% 
of the maximum effect on ORR threshold.
Lowering the dose would likely result in reduced efficacy, whereas increasing the dose 
may not provide further improvement of the benefit-risk profile.
The initial weekly dosing schedule rapidly established efficacious concentrations. The 
every 2 week and every 4 week dosing frequencies were sufficient to produce serum 
concentration levels that maintained target saturation; thus reducing the risk of disease 
progression.
Daratumumab is associated with infusion-related reactions requiring treatment with steroid. In 
GEN501 study, a Phase 1/2 study of daratumumab in relapsed/refractory MM subjects, infusion-
related 
reactions 
were the most 
frequent adverse 
events, 
occurringin 71% of patients. The majority 
of these reactions included Grade 1 and 2, and characterized by rhinitis, cough, headache, pyrexia, 
and dyspnea. Most infusion-related reactions occurred during the first daratumumab infusion,and 
only few patients (<10%) had infusion-related reactions with more than one infusion. The SIRIUS 
(MMY2002) study confirmed the results from GEN501 study that demonstrated single agent 
activity of daratumumab 
with 
a favorable 
toxicity 
profile.
80Among 
106patients who had 
a median 
of 5 prior lines of therapy(95% refractory to lenalidomide and bortezomib) and received 
daratumumab monotherapy at a dose of 16 mg/kg, 43% of the patients experience infusion-related 
reactions, which were predominantly Grade 1 and 2and could be managed with interruption of the 
infusion or extra corticosteroids and antihistamines. Therefore, to mitigate the increased risk of 
infusion-related reactions for nivolumab/daratumumab combination cohort, nivolumab 240 mg 
Q2W administration will start with the third daratumumab infusion,andcorticosteroids will be 
administered before and after treatment. 
Historically, clinical trials with nivolumab have prohibited the use of high dose steroids before and 
during the study due to the potential interference with the immune activation mechanism of 
checkpoint inhibition. Specifically, in the nivolumab registrational trials, patients requiring 
treatment with systemic corticosteroids (greater than 10 mg daily prednisone equivalents) within 
14 days of study drug administration were excluded. However, there have been exceptions to 
eligibility criteria for 
certain 
subjects 
which have not 
appeared 
to 
impact 
the 
efficacy 
of the therapy 
including prophylactic high-dose steroids for contrast dye allergy and non-autoimmune conditions 
such as delayed-type hypersensitivity reaction. Furthermore, high-dose systemic corticosteroids 
and other immunosuppressants are commonly used to 
treat immune-related adverse reactions. This 
concomitant steroid use to manage immune-related AEs does not appear to impair the efficacy of 
nivolumab,and these conclusions have been shared with the regulatory authorities. Pre-treatment 
with steroids has also been allowed in nivolumab trials where corticosteroids are part of standard 
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of care. High doses of dexamethasone have been administered with nivolumab therapy for patients 
with hematological malignancies where both lenalidomide and bortezomib require administration 
with standard doses of dexamethasone. In first-lineNSCLC studies with nivolumaband 
pembrolizumab, steroid premedication is mandated with some chemotherapies,and this has not 
appeared to impact 
overall response rates.
39,86In glioblastomastudies, corticosteroid treatment for 
symptomatic brain lesions is considered standard of care and therefore allowed in these trials. 
Furthermore, the inclusion of steroid treatment in the clinical trials with daratumumab did not 
impact the pharmacodynamic effect of expansion of activated T cells that was observed, 
suggesting that T cell activation and expansion still occurs in the presence of systemic steroid 
treatment. Taken together,the low likelihood that steroid premedication wouldcompromise safety
and the evidence that efficacyis not impacted by steroid premedicationsupport the evaluation of 
the nivolumab in combination with daratumumab given with appropriate steroid premedication.
Based on the well-established safety profiles of daratumumab and nivolumab, it is not anticipated 
that the combination treatment will result in overlapping toxicities.The clinical experience of the 
combination treatment consists of 3 multiple myeloma patients treated in the CA209-039 study 
(Multiple Phase 1 Safety Cohorts of Nivolumab Monotherapy or Nivolumab Combination 
Regimens Across Relapsed/Refractory Hematologic Malignancies), that were treated with 
nivolumab and daratumumab at the doses that will be administered in this study.The current 
duration of treatment in these 
patients ranges from 41-53 
days and 
all 
patients remain 
on study.No 
SAEs have been reported in these 3 patients.Reported AEs include the following: Grade 1 
weakness and Grade 4 neutropenia for nivolumab/daratumumab/pomalidomide cohort and Grade
1 muscle cramps, cough, nasal congestion for nivolumab/daratumumab cohort.All safety data 
from the daratumumab/nivolumab cohort in the current study will be regularly monitored by the 
study physician, the protocol study team, and the BMS and Janssen medical safety teams.
1.1.8
Rationale for Objective Response Rate
Objective response rate (ORR) is the proportion of subjects with tumor size reduction of a 
predefined amount for a minimum time period and is a direct measure of drug antitumor activity.
The significance of ORR is assessed by its magnitude and duration and the percentage of complete 
responses (no detectable evidence of tumor). It is reasonable to test the hypothesis that nivolumab 
alone or in combination with ipilimumab will provide a 
response rate and depth 
of response (tumor 
shrinkage) that may translate to improved OSor provide quality of life benefits for patients with 
metastatic MSI-H CRC. Changes in tumor measurements and tumor responses will be assessed 
using standardized criteria, RECIST 1.1 (Response Evaluation Criteria in Solid Tumors).
87Please 
refer to Appendix 3 for the specifics of the RECIST1.1 criteria to be utilized in this study. In 
addition to investigator assessed response, the protocol contains a plan to use an independent 
radiology review committee (IRRC) to also assess response. 
1.1.9
Rationale for Biomarker Analyses
Nivolumab and Ipilimumab
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The biological basis of nivolumab and ipilimumab in the treatment of oncological disease is to 
modulate the immune system to generate or to restore a durable anti-tumor response leading to 
clearance of tumor. The clinical data generated with the monotherapy and combination therapy 
supports the hypothesis that blockade of PD-1 and CTLA-4 pathways results in rejection of tumor 
by the host immune system.
The precise mechanisms by which nivolumab and ipilimumab exert their anti-tumor activity is 
unclear, however, 
as 
particular 
cell 
types, such 
as 
effector 
T 
cells 
and 
regulatory 
T 
cells,are 
critical 
for the anti-tumor response. Nivolumab and ipilimumab appear to have distinct mechanisms of 
action, based on signaling of the PD-1 and CTLA-4 pathways, and the observations of a rise in 
Absolute Lymphocyte Count elevations in ipilimumab, but not nivolumab, therapy.
Retrospective analysis of advanced melanoma patients treated with ipilimumab showed that 
increased expression of proliferation and polarization markersin CD4+ and CD8+ cells, decreased 
CCR7 and IL-7R on CD4+ T cells, and upregulated Granzyme B in CD8+ T cells may serve as 
pharmacodynamic indicators of the effects of ipilimumab. Increased activation markers ICOS and 
eomesodermin (EOMES) were significantly associated with fewer AEs and less favorable 
outcome, respectively, but baseline elevated expression of EOMES appears to predict favorable 
relapse-free survival in this analysis. 
ICOS potentially could be a useful marker for CD4+ T-cell responses generated after CTLA-4 
blockade. Human leukocyte antigen (HLA-DR) expression could also potentially serve as a T-cell 
marker.
Retrospective gene expression analysis was performed on 46 primary or metastatic melanoma 
tumors, collected in a Phase 2 trial in advanced melanoma subjects.
88Ipilimumab treatment was 
associated with downregulation of a number of melanoma-associated transcripts in the tumors 
within 3 weeks after administering the first dose. Expression of immune-related genes such as 
CD8A, GZMA, LCK, CXCL-9, -10, -11, and CXCR3 in tumors at Week 3 post-treatment was 
associated with the total lymphocyte infiltrate, clinical benefit, and OS. The preliminary results 
suggest that high pre-existing immune activity favors a clinical response to ipilimumab therapy. 
These analyses also provide a list of candidate biomarkers with potential predictive value for 
response to ipilimumab, to be explored in the proposed study. 
Nivolumab and BMS-986016
For PD-L1 and biomarker research testing, tumor tissue (formalin-fixed,paraffin embedded 
archival or recent acquisition) must be received during the screening period. Archival tissue is 
accepted if it is taken <3 months from screening, without any intervening therapies. If PD-L1 
results are available, results will be collected. (Note: Fine Needle Aspiration (FNA) and bone 
metastases samples are not acceptable for submission.).
As LAG-3 is an immune checkpoint expressed by exhausted immune cells, the detection of LAG-
3 in tumor microenvironment prior to the start of treatmentmay yield information on potential 
correlation between LAG-3 expression and clinical benefit. This may enable LAG-3 specific 
precision medicine, based on the biomarker analysis. Furthermore, the characterization of LAG-3, 
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in the context of overall tumor immune phenotyping, would provide insight on the mechanism of 
action in this particular disease setting. 
Detailed immune and tumor phenotyping will be pursued to build clinical data to support the 
clinical findings. The biomarker analysis would include butare not limited to the following: 
1)Examination of tumor-associated immune cells and microenvironment, through proteomics, 
histopathology (in particular LAG-3 expression), NGS, and expression (mRNA) profiling.
2)Genomics (NGS and/or RNA) analysis on tumor, and/or cell-free DNA, for tumor mutation 
burden and tumor genetics analysis 
Nivolumab and Daratumumab
For PD-L1 and biomarker research testing, tumor tissue (formalin-fixed, paraffin embedded 
archival or recent acquisition) must be received during the screening period. (Note: Fine Needle 
Aspiration (FNA) and bone metastases samples are not acceptable for submission.) 
Detailed immune and tumor phenotyping may be pursued to build clinical data to support the 
clinical findings. The biomarker analysis would include but are not limited to the following: 
1)Systemic immune monitoring 
on 
circulating immune 
cells 
and 
secreted 
cytokines, 
chemokines, 
and other related soluble factors.  
2)Examination of tumor-associated immune cells and microenvironment, through proteomics, 
histopathology (eg, CD38, MDSC, TIL), NGS, and expression (mRNA) profiling.
3)Genomics (NGS and/or RNA) analysis on tumor, and/or cell-free DNA, for tumor mutation 
burden analysis 
Summary
Therefore, the major hypotheses that will be addressed by the biomarker plan for CA209142 are: 
Does expression of PD-L1 on tumor cells prior to therapy correlate with clinical efficacy to 
monotherapy or combination therapy?
Does the mutational status of tumor cells (ie,KRAS, Microsatellite instability, BRAF) 
correlate with clinical efficacy to monotherapy or combination therapy?
Can we define distinct pharmacodynamic markers of monotherapy and combination therapy 
in the peripheral compartment?
How does monotherapy or combination therapy alter the activating and negative 
co-stimulatory molecules on immune cells in the periphery and at the tumor site? Are there 
distinct mechanisms of resistance to monotherapy and combination therapy?
Is the intratumoral orperipheral T cell repertoire predictive of response to monotherapy or 
combination therapy?
Does the composition and phenotype of the tumor microenvironment, including microbiota, at 
baseline, or on-treatment, correlate with clinical efficacy?
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1.2
Research Hypothesis 
Treatment with nivolumab monotherapy, nivolumab combined with ipilimumab, nivolumab 
combined with anti-LAG-3 antibody (BMS-986016), or nivolumab combined with daratumumab 
(C6 Cohort)will have clinical activity in subjects with recurrent or metastatic CRC.
1.3
Objectives(s)
1.3.1
Primary Objectives
To evaluate the investigator-assessedORR of nivolumab monotherapy and nivolumab in 
combination witheitheripilimumab, or anti-LAG-3 antibody (BMS-986016)in dMMR/MSI-H 
mCRC; the ORR of nivolumab combined with ipilimumab in subjects with metastatic non-MSI-H 
(pMMR) CRC; and, the ORR of nivolumab combined with daratumumab therapy in subjects with 
metastatic non-MSI-H(pMMR)mCRC.
1.3.2
Secondary Objectives
To evaluate the IRRC-assessed ORR of nivolumab monotherapy and nivolumab in 
combination with either ipilimumab or anti-LAG-3 antibody (BMS-986016) in dMMR/MSI-H 
mCRC; the ORR of nivolumab combined with ipilimumab in subjects with metastatic non-
MSI-H (pMMR) CRC; and, the IRRC ORR of nivolumab combined with daratumumab
therapy in subjects with metastatic non-MSI-H(pMMR)mCRC.
To evaluate the disease control rate (DCR) of nivolumab monotherapy or combined with the 
above agents in subjects with metastatic mCRC.
1.3.3
Exploratory Objectives
To determine 
the 
safety and tolerability [defined 
as 
toxicity 
rates 
(worst CTC 
grade 
per 
subject) 
of adverse events and specific laboratory tests] of nivolumab monotherapy (mStage 1 and 2),
nivolumab in combination with ipilimumab (cStage 1 and 2, and C3Cohort) in subjects with 
metastatic CRC, nivolumab in combination with anti-LAG-3 antibody (BMS-986016) in 
subjects with metastatic dMMR/MSI-H mCRC, or nivolumab in combination with 
daratumumab in subjects with metastatic non-MSI-H (pMMR) mCRC.
To estimate PFS and OS for subjects with metastatic CRC who have received nivolumab 
monotherapy (mStage 1 and 2),nivolumab in combination with ipilimumab (cStage 1 and 2, 
and C3 Cohort, nivolumab in combination with anti-LAG-3 antibody (BMS-986016) in 
subjects with metastatic dMMR/MSI-H mCRC or nivolumab in combination with 
daratumumab in subjects with metastatic non-MSI-H(pMMR)mCRC.
To evaluate the safety and tolerability of nivolumab in combination with ipilimumab in 
subjects with metastatic non-MSI-H CRCin the safety cohort. 
To evaluate investigator-assessed and IRRC-assessed ORR of nivolumab in combination with 
ipilimumab in subjects with metastatic non-MSI-HCRCin the safety cohort.  
To characterize the PK of nivolumab monotherapy, PK of nivolumab,ipilimumab, 
BMS-986016, and daratumumab when combined, and to explore exposure-response 
relationships.
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To characterize the immunogenicity of nivolumab monotherapy, immunogenicity of
nivolumab,ipilimumab, BMS-986016, and daratumumabwhen combined.
To evaluate the pharmacodynamic activity of nivolumab monotherapy, nivolumab in 
combination with ipilimumab, nivolumab in combination with anti-LAG-3 antibody 
(BMS-986016),and nivolumab in combination with daratumumab in subjects with metastatic 
CRC in the peripheral blood and tumor tissue as measured by flow cytometry, 
immunohistochemistry, soluble factor analysis, and gene expression (microarray technology, 
quantitative RT-PCR).
To investigate the association between biomarkers in the peripheral blood and tumor tissue, 
such as PD-L1 expression, with safety and efficacy for subjects with advanced or metastatic 
tumors treated with nivolumab monotherapy,nivolumab in combination with ipilimumab, 
nivolumab in combination with anti-LAG-3 antibody (BMS-986016),and nivolumab in 
combination with daratumumab.
To characterize the discordance rate between repeat MSI testing and prior MSI testing in 
subjects. 
To evaluate health-related quality of life using a validated instrument in the European 
Organisation for Research and Treatment of Care General Cancer Module (QLQ-C30).
To evaluate patient reported general health status as assessed by the five item EQ-5D.
To evaluate clinical activity and safety of nivolumab monotherapy or combination treatment 
after re-initiation. 
1.4
Product Development Background
Information for nivolumab (anti-PD-1 antibody), ipilimumab(YERVOY; anti-CTLA antibody),
and BMS-986016 (anti-LAG-3 antibody) is provided in the sections below; additional details are 
provided in the respective Investigator Brochures.
1.4.1
Nivolumab and Ipilimumab Mechanisms of Action
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response in this setting is thought to rely onimmune surveillance of tumor antigens expressed on 
cancer cells that ultimately results in an adaptive immune response and cancer cell death. The 
immune surveillance functions by limiting the emergence of tumors as they arise and/or causing 
tumor shrinkage. Tumor progression may depend upon acquisition of traits that allow cancer cells 
to evade immune surveillance and an effective immune response. This evasion may occur by 
exploiting any of the checkpoints that control the regulatory immune response, including display 
of antigens and control of co-stimulatory pathways that affect the proliferation of cells involved in 
immunity. Current immunotherapy efforts attempt to break the apparent tolerance of the immune 
system to 
tumor 
cells 
and antigens by 
either introducing 
cancer 
antigens by therapeutic vaccination 
or by modulating regulatory checkpoints of the immune system, either directly by stimulation of 
immune cells by antibodies directed to receptors on T and B cells or indirectly by cytokine 
manipulation. T-cell stimulation is a complex process involving the integration of numerous 
positive, as well as negative, co-stimulatory signals in addition to antigen recognition by the T-
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cell receptor (TCR). Collectively, these signals govern the balance between T-cell activation and 
tolerance to antigens.
Programmed death receptor-1 (PD-1, CD279), a 55 kD type I transmembrane protein, is a member 
of the CD28 family of T-cell co-stimulary receptors that also includes CD28, CTLA-4, ICOS, and 
BTLA.2 PD-1 contains an intracellular membrane proximal immunoreceptor tyrosine inhibitory 
motif (ITIM) and a membrane distal immunoreceptor tyrosine-based switch motif (ITSM). Two 
ligands specific for PD-1 have been identified: PD-L1 (B7-H1/CD274) and PD-L2 (B7-
DC/CD273). PD-L1 and PD-L2 have been shown to down-regulate T-cell activation upon binding 
to PD-1 in both murine and human systems. PD-1 delivers a negative signal by the recruitment of 
SHP-2 to the phosphorylated tyrosine residue in the ITSM in its cytoplasmic region. PD-1 is 
primarily 
expressed 
on 
activated 
T 
cells, 
B 
cells, 
and myeloid 
cells. Further 
evidence for 
a 
negative 
regulatory role of PD-1 comes from studies of PD-1-deficient mice. PD-1-deficient mice develop 
various autoimmune phenotypes, including dilated cardiomyopathy, a lupus-like syndrome with 
arthritis and nephritis, and accelerated diabetes mellitus. The emergence of these autoimmune 
phenotypes is dependent upon the genetic background of the mouse strain and many of these 
phenotypes emerge at different times and show variable penetrance. In addition to the phenotypes 
of null mutations, PD-1 inhibition by antibody-mediated blockade in several murine models has 
been found to play a role in the development of autoimmune diseases such as encephalomyelitis, 
graft-versus-host disease, and type I diabetes. Taken together, these results suggest that PD-1 
blockade has the potential to activate anti-self T-cell responses, but these responses are variable 
and dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not 
accompanied by a universal loss of tolerance to self antigens.
Preclinical animal models of tumors have shown that blockade by PD-1 by monoclonal antibodies 
(mAbs) can enhance the anti-tumor immune response and result in tumor rejection. Antitumor 
activity by PD-1 blockade functions in PD-L1-positive tumors as well as in tumors that are 
negative for the expression of PD-L1. This suggests that host mechanisms (ie, expression of PD-
L1 in antigen-presenting cells) limit the antitumor response. Consequently, both PD-L1 positive 
and negative tumors may be targeted using this approach. In humans, constitutive PD-L1 
expression is normally limited to macrophage-lineage cells, although expression of PD-L1 can be 
induced on other hematologic cells as well, including activated T cells. However, aberrant 
expression of PD-L1 by tumor cells has been reported in a number of human malignancies. PD-
L1 expressed by tumor cells has been shown to enhance apoptosis of activated tumor-specific T 
cells in vitro. Moreover, the expression of PD-L1 may protect the tumor cells from the induction 
of apoptosis by effector T cells. 
Nivolumab (anti-PD-1 mAb) is a fully human monoclonal immunoglobulin (Ig) G4 antibody that 
binds to the programmed death-1 (PD-1) cellsurface membrane receptor, a negative regulatory 
molecule expressed by activated T and B lymphocytes. Blockade of the PD-1 pathway by 
nivolumab was studied using the mixed lymphocyte reaction (MLR). PD-1 blockade resulted in a 
reproducible enhancement of both proliferation and interferon release in the MLR. The effect of 
nivolumab on antigen-specific recall response was investigated using a CMV-restimulation assay 
with human peripheral blood mononuclear cells (PBMCs), and was evaluated by ELISA.
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Nivolumab 3 mg/kg monotherapy is currently approved for the treatment of advanced melanoma 
and lung cancer, metastatic renal carcinoma, and Hodgkin lymphoma, and is being studied in 
several phase 3 and 2 clinical trials in advanced and metastatic solid and hematologic 
malignancies.
Ipilimumab is a fully humanized IgG1 monoclonal antibody binding to the anti-cytotoxic T-cell 
lymphoma-4 antigen (CTLA-4). Ipilimumab is an approved therapy for metastatic melanoma and 
has demonstrated improved overall survival as monotherapy and in combination with 
dacarbazine.
89,90It has been studied in combination with multiple standards of care (SOC) 
therapies including chemotherapy for squamous and non-squamous NSCLC and radiotherapy for 
hormone resistant prostate cancer.
91Ipilimumab iscurrently also approved as adjuvant therapy in 
stage III melanoma.
1.4.2
Summary of Results from the Ipilimumab and Nivolumab Programs
Additional details are also available in the nivolumab and ipilimumab Investigator Brochures (IB).
1.4.2.1
Summary of Safety 
Ipilimumab Monotherapy
In study MDX010-20, the ipilimumab monotherapy arm was administered 3 mg/kg ipilimumab 
every 3 weeks for four doses. In this arm, there were 79% drug related adverse events, with 21% 
being Grade 3/4 and 3/131 (2%) Grade 5. The most frequent adverse events of interest were rash 
(30%), pruritus (33%), diarrhea (33%), colitis (8%), endocrine disorders (9%), AST/ALT 
increased (2%), and hepatitis (1%). Any grade immune related adverse events were 60% and the 
Grade 3/4 immune related adverse events for the same cohort was 13% with the most frequent 
adverse events being diarrhea (5%), colitis (5%), rash (2%), and endocrine disorders (3%).
Comprehensive details on the safety profile of ipilimumab, including results from other clinical 
studies,are available in the ipilimumab product information and Investigator Brochure.
Nivolumab Monotherapy
One study has contributed most 
to 
the clinical experience with nivolumab monotherapy in subjects 
with melanoma and other solid malignancies. CA209003 is an ongoing Phase 1 open label, 
multiple dose escalation study in 306 subjects with select previously treated advanced solid 
tumors, including melanoma, RCC, NSCLC, colorectal cancer, and hormone-refractory prostate 
cancer. Subjects received nivolumab at doses of 0.1, 0.3, 1, 3 or 10 mg/kg intravenously every 
2weeks, up 
to a maximum of 2 years of total therapy. As of 05-Mar-2013, a 
total of 107melanoma 
subjects were treated with nivolumab in the dose range of 0.1-10 mg/kg.
No maximal tolerated dose was identified in CA209003. The incidence, severity and relationship 
of AEs were generally similar across dose levels and tumor types. Nivolumab related AEs of any 
grade occurred in 72.4% of subjects. The most frequent nivolumab related AEs occurring in >5% 
of subjects included: fatigue (25.7%), rash (13.5%), diarrhea (11.8%), pruritus (10.2%), nausea 
(7.9%), decreased appetite (7.9%), hemoglobin decreased (5.9%) and pyrexia (5.3%).
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The majority of events were low grade, with grade 3-4 drug related AEs observed in14.8% of 
subjects. The most common Grade 3-4 drug-related AEs occurring in > 1% of subjects were: 
fatigue (1.6%), lymphopenia (1.3%), abdominal pain (1%), diarrhea (1%), hypophosphatemia 
(1%) and pneumonitis (1%). At least one SAE was reported for 150 (49.3%) of the 304 subjects 
at all dose levels. Grade 3-4 SAEs were reported for 23 subjects (7.6%). Drug-related SAEs 
occurred in 11.5% of subjects. Grade 3-4 drug-related SAEs reported in at least 2 subjects 
included: diarrhea (3 subjects, 1.0%), pneumonitis (3 subjects, 1.0%), pneumonia (2 subjects, 
0.7%) and lipase increased (2 subjects, 0.7%). Additional select treatment-related AEs have 
occurred with low frequency (< 5%) but are considered clinically meaningful, as they require 
greater 
vigilance for 
early recognition and 
prompt intervention. 
These AEs include: ALT increased 
(4.3%), AST increased (3.6%), pneumonitis (3.3%), hypothyroidism (3.0%), hyperthyroidism 
(1.3%), renal failure (1.0%), adrenal insufficiency (0.7%) and colitis (0.7%). Grade 3-4 eventsof 
pneumonitis were reported in 3 subjects (1.0%) as described above (1 event was Grade 4). Grade 
3 events of colitis, ALT increased, and AST increased were reported in 2subjects (0.7%) each. 
Grade 3 events of adrenal insufficiency, hyperthyroidism, and hypothyroidism were reported in 1 
subject (0.3%) each. Treatment-related AEs leading to discontinuation were reported in 18 (5.9%) 
of the 304 treated subjects on CA209003. The only events reported in more than 1 subject were 
pneumonitis (4 subjects; 1.3%) and hepatitis (2subjects; 0.7%). There were 3 (1%) drug related 
deaths; each occurred after development of pneumonitis.
Preliminary new non-clinical safety findings of adverse pregnancy outcomes and infant losses in 
the absence of overt maternal toxicity have been reported. The findings of increased late stage 
pregnancy loss and early infant deaths/euthanasia in nivolumab exposed pregnant monkeys 
suggest a potential risk to human pregnancy if there is continued treatment with nivolumab during 
pregnancy.
Additional details on the safety profile of nivolumab, including results from other clinical studies, 
are also available in the Investigator Brochure.
Nivolumab Combined with Ipilimumab
In the Phase 1 study CA209004, ascending doses of nivolumab have been studied concomitantly 
with ascending doses of ipilimumab in subjects with unresectable or metastatic melanoma. In each 
arm in this multi-arm study, ipilimumab was administered once every 3 weeks for 4 doses with 
nivolumab administered once every 3 weeks for 8 doses. Starting at week 24, ipilimumab and 
nivolumab were administered once every 12 weeks for 8 doses. The three initial dose-escalation 
cohorts consisted of Cohort 1 (nivolumab 0.3 mg/kg plus ipilimumab 3 mg/kg; n= 14), Cohort 2 
(nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; n = 17) and Cohort 3 (nivolumab 3mg/kg plus 
ipilimumab 3 mg/kg; n = 6). Later, the study was amended to include Cohort 2a which evaluated 
nivolumab 3 mg/kg plus ipilimumab 1 mg/kg (n = 16).
The following 
DLTs 
were 
observed in 
Cohort 
1 
-Grade 
3 
elevated 
AST/ALT 
(1 subject); in 
Cohort 
2 -Grade 3 uveitis (1 subject) and Grade 3 elevated AST/ALT (1 subject) and in Cohort 3 -Grade 
4 elevated lipase (2 subjects) and Grade 3 elevated lipase (1 subject). Based on these data, Cohort 
2 was identified as the maximum tolerated dose (MTD) and Cohort 3 exceeded the MTD.
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As of 15-Feb-2013, a total of 53 melanoma subjects were treated with nivolumab combined with 
ipilimumab in CA209004 across cohorts 1, 2, 2a, and 3, including subjects who receivedhigher 
cumulative doses of the combination components than planned in the current study. At least one 
AE regardless of causality has been reported in 98% of subjects treated. The most common 
(reported at > 10% incidence) treatment-related AEs (any Grade %; Grade 3-4 %: 93; 53) are rash 
(55; 4), pruritus (47; 0), vitiligo (11; 0), fatigue (38; 0), pyrexia (21, 0), diarrhea (34; 6), nausea 
(21, 0), vomiting (11, 2), ALT increased (21; 11), AST increased (21; 13), lipase increased (19; 
13), amylase increased (15, 6), headache (11, 0), and cough (13, 0).
The majority of AEs leading to discontinuation (regardless of causality) were Grade 3 or 4 
(reported in 11 of 53 subjects, 21%). Grade 3 events included lipase increased, ALT increased, 
AST increased, lipase increased, troponin I increased, colitis, diverticular perforation, pancreatitis, 
tachycardia, renal failure acute, choroiditis, autoimmune disorder, and pneumonitis. One subject 
each discontinued due to Grade 4 events of blood creatinine increased and AST increased. No 
drug-related deaths were reported.
Currently, the combination therapy of 3 mg/kg ipilimumab plus 1 mg/kg nivolumab is approved 
for the treatment of patients with BRAF V600 wild-type and BRAF V600 mutation-positive 
unresectable or metastatic melanoma. 
1.4.2.2
Summary of Clinical Activity
There has been no clinical trial so far quantitating the clinical benefit of nivolumab or nivolumab 
plus ipilimumab in MSI-H CRC. One subject in clinical trial CA209001, a 67-year-old male with 
MSI-High CRC metastatic to intra-abdominal lymph nodes received five doses of nivolumab at 
3mg/kg and experienced a complete response by radiographical criteria persisting beyond 
21months. In clinical trial CA209003, 19 out of 306 subjects had a baseline diagnosis of colon or 
rectal cancer. These subjects were treated with 10 mg/kg nivolumab monotherapy and the safety 
experience was consistent with other solid tumor types in this study. No responses were noted in 
these subjects, however, the MSI status of these subjects were never confirmed.
The following summary notes the ability of nivolumab and nivolumab plus ipilimumab to induce 
responses at estimated rates that equal or surpass those of active controls in a spectrum of solid 
tumors. 
Nivolumab Monotherapy
In CA209003, the clinical activity of nivolumab was demonstrated in a variety of tumor types, 
including melanoma, RCC, and NSCLC. Clinical activity was noted across a range of doses 
(0.1mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg, and 10 mg/kg). In CA209003, as of the clinical cut-off 
date of 18-Mar-2013, a total of 304 subjects with melanoma, RCC, and NSCLC have been 
evaluated for clinical activity. A response of either CR or PR, as determined by investigator 
assessed tumor evaluations based on RECIST 1.1, has been reported at all dose levels. No 
responses (CR or PR) have been reported in subjects with colorectal carcinoma (MSI status was 
not determined in these subjects) or castrate-resistant prostate cancer. 
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In NSCLC, the most active doses were 3 and 10 mg/kg. An ORR of 19% to 26% was reported 
with a 24-week progression-free survival rate (PFSR) of 25% to 45%. Only a single response 
(1/33) was reported at 1 mg/kg. Durable responses were observed in both squamous and 
non-squamous subtypes. Historically, ORR of 5% to 10% and median PFS (mPFS) of 2 to 
3months has been reported with docetaxel treatment in previously-treated NSCLC subjects.
A complete response (CR) or partial response (PR) was reported in 33% (95%CI: 22%-41%) of 
the 107 response-evaluable subjects with melanoma treated with nivolumab monotherapy Q2W at 
doses ranging from 0.1 to 10 mg/kg in MDX1106-03. The responses were durable with a PFSR at 
24 weeks of 44%.
Of the 34 response evaluable RCC subjects in MDX1106-03, responses were reported in both the 
1 mg/kg (5 of 18 subjects, 27.8%) and 10 mg/kg (5 of 16 subjects, 31.3%) treatment groups. 
Estimated PFSR at 24 weeks was 50% in the 1 mg/kg and 67% in the 10 mg/kg nivolumab 
treatment groups.
Nivolumab Combined with Ipilimumab
As noted above, nivolumab monotherapy has not demonstrated responses in cases of CRC where 
MSI status has not been determined. Given the 4% prevalence of MSI-H in the population with 
metastatic disease, it is likely that the near entirety of these subjectswould be non MSI-H. Thus, 
nivolumab monotherapy will not be assessed further in the non-MSI population in this trial. In 
other solid tumors, the combination of nivolumab and ipilimumab has shown response rates and 
depth of response exceeding the rates seen with monotherapy with either agent. This trial will first 
assess the safety of this combination in non MSI-H subjects before proceeding with an assessment 
of efficacy and safety in MSI-H subjects. Assessing activity in non-MSI-H disease in the initial 
safety cohort is beyond the scope of this non-comparative trial, although any anti-tumor activity 
in the dose escalation safety arm will be described. Details of the activity of the combination in 
other solid tumors follow.
As of the 15-Feb-2013 clinical cut-off in CA209004, of the 52 subjects evaluable for response, 21 
subjects (40%) had an objective response by modified World Health Organization (mWHO) 
criteria. In an additional 2 subjects (4%) there was an unconfirmed objective response. In Cohort 
1 (0.1 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 14 evaluable subjects had an objective 
response by mWHO (21%); 1 CR and 2 PRs with an additional PR by immune-related mWHO 
criteria (irPR). 55 In Cohort 2 (1 mg/kg nivolumab + 3 mg/kg ipilimumab), 9 out of 17 evaluable 
subjects had an objective response by mWHO (53%; 3 CRs (18%), 6 PRs (35%) with two 
additional subjects experiencing immune-related SD (irSD). In Cohort 2a (3 mg/kg nivolumab + 
1 mg/kg ipilimumab), 6 out of 15 response evaluable subjects had an objective response rate by 
mWHO (40%; 1 CR (7%), 5 PRs (33%) with 2 additional uPRs (13%) and 2 irSDs and 1 irPR). In 
Cohort 3 (3 mg/kg nivolumab + 3 mg/kg ipilimumab), 3 out of 6 evaluable subjects had an 
objective response by mWHO (50%; 3 PRs (50%) with 1 additional irPR and 1 irSD. Preliminary 
analysis revealed 16 of the 52 evaluable subjects (31%) had > 80% reduction in the size of target 
tumor lesions by the week 12 evaluation. This is compared to < 2% for 3 mg/kg ipilimumab 
monotherapy based on CA184020(N=540) and < 3% for nivolumab monotherapy based on 
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CA209003 (N=94, 0.1-10 mg/kg). The concurrent administration of nivolumab and ipilimumab 
was safe and resulted in rapid and deep tumor regressions. The combination of nivolumab with 
ipilimumab is currently also being investigated in NSCLC, metastatic clear cell renal cell 
carcinoma, and in advanced melanoma.
1.4.3
Nivolumab Combined with BMS-986016(Cohort C5)
1.4.3.1
Nonclinical Pharmacology Studies utilizing Murine Anti-PD-1 and Anti-
LAG-3 Antibodies
The importance of LAG-3 as an immunotherapy target was validated in murine in vivo models 
using 2 surrogate antibodies specific for mouse LAG-3. These studies evaluated tumor growth 
inhibition in syngeneic tumor models (Sa1N fibrosarcoma and MC38 colon adenocarcinoma) and
monitored acceleration of autoimmunity in the non-obese diabetic (NOD) model. Anti-LAG-3 
antibody administration resulted in both overall tumor growth inhibition and an increase in the 
number of tumor-free (TF) mice in those treatment groups (Figure 1.4.3.1-1).
Anti-LAG-3 antibody administered in combination with anti-PD-1 antibody provided enhanced 
antitumor activity above the activity of either agent alone. For example, in multiple Sa1N tumor 
models, anti-LAG-3 antibody resulted in 20%-30% TF mice compared to control and anti-PD-1 
antibody-treated mice (0%-10% TF mice), while the combination of anti-LAG-3 and anti-PD-1 
antibodies resulted in 60%-90% TF mice. In the MC38 model, anti-LAG-3 antibody showed 
modest tumor growth inhibition alone but when administered in combination with anti-PD-1 
antibody, resulted in 
enhanced 
antitumor 
activity above 
that 
observed for 
anti-PD-1 
antibody alone 
(80% vs. 40% TF mice, respectively).
Figure 1.4.3.1-1:
Antitumor Activity of Anti-LAG-3 and Anti-PD-1 Antibodies in 
Murine Models
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1.4.3.2
Clinical PharmacologyBMS-986016
The current Phase 1 clinical program is evaluating BMS-986016 in advanced solid tumors (special 
focus in NSCLC, RCC, and malignant melanoma) in Study CA224-020 and relapsed refractory 
hematological malignancies (Hodgkin and non-Hodgkin lymphomas) in Study CA224-022. As of 
29-Jun-2016, 
89 
subjects 
have beentreated 
with BMS-986016 in 
these 
2ongoing studies 
assessing 
PK, clinical activity, and safety. An interim determination of BMS-986016 multiple dose PK was 
carried out using all available serum concentrations data from Studies CA224 020 and CA224 022. 
In general, the Cmax and area under the concentration versus time curve over the dosing interval 
(AUC[TAU]) values over the first dosing interval increased approximately equal to the increment 
in theBMS 986016 dose. The PK of BMS-986016 and nivolumab was notalteredwhen given in 
combination. BMS-986016 concentration time data were reasonably described by population PK 
model with linear, 2compartment, zero-order IV infusion model with first order elimination. The 
model estimated mean T-HALF was 19 days, and the typical CLT was 13.7 mL/h. The population 
PK model will be used to understand the source of variability in BMS-986016 PK and effect of 
intrinsic and extrinsic factors.
Currently available data suggest that BMS-986016 monotherapy exhibits a low level of
immunogenicity, with 6 out of 42 subjects having at least 1 post-baseline positive anti-drug 
antibody (ADA) samples. 
There 
are limited 
data 
available in 
combination cohort 
to 
make inference 
on immunogenicity rate.
1.4.3.3
Clinical Safety Combination Therapy(Nivolumab plus BMS-986016)
Based on preliminary data as of 20-Feb-2017, treatment with BMS 986016 in combination with 
nivolumab has been administered to 29 subjects in study CA224-020 at these dose levels: 
20 mg BMS-986016 plus 80 mg nivolumab: 7 subjects 
20mg BMS-986016 plus 240 mg nivolumab:  9 subjects
80 mg BMS-986016 plus 240 mg nivolumab:  129subjects 
160 mg BMS-986016 plus 240 mg nivolumab: 6subjects
240 mg BMS-986016 plus 240 mg nivolumab:  8subjects
No MTD 
reached at the tested doses up to 160mg BMS-986016 and 240 mg nivolumab (flat dose, 
Q2W). Evaluation of 240 mg BMS-986016 and 240 mg nivolumab combination dose is ongoing. 
There was no relationship between the incidence, severity, or causality of AEs and combination 
therapy. Most AEs were oflow grade (Grade 1 to 2) with 7drug-related SAEs across all 
combination cohorts, as follows: Grade 3-4malignant neoplasm progression (n = 1), Grade 3-4
meningitis aseptic (n = 2), Grade 3-4lipase increase (n = 1), Grade 3-4mucosal inflammation(n 
= 1), Grade 3-4pneumonia (n =1), Grade 3-4Troponin I increase (n = 1), and Grade 4 ventricular 
fibrillation(n = 1). AEs were generally self-limited or reversible with appropriate therapy, except 
for the 
Grade4 
myocarditis event 
which 
progressed to 
Grade5 
after 
the 
clinicalcut-off 
date. 
Grade 
2 infusion-related reactions were reported in 2 subjects during infusion of nivolumab and were 
manageable following protocol guidelines.Fifteen deaths occurred in subjects treated with 
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combination therapy. All deathswere due to disease progression and were considered not related 
to study drug, except for the drug-related myocarditis death which occurred after the clinical cut-
off date.
1.4.4
Daratumumab 
1.4.4.1
Mechanism of Action
Daratumumab is a targeted immunotherapy that binds to tumor cells that overexpress CD38, a 
transmembrane glycoprotein, in multiple myeloma plasma cells. Multiple mechanisms of action 
(MoA) have been observed for daratumumab, including complement-dependent cytotoxicity 
(CDC), antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis by Fc gamma 
receptor mediated crosslinking of tumor-bound monoclonal antibodies, and antibody-dependent 
cellular phagocytosis (ADCP).  
Translational biomarker studies of samples from patients treated in daratumumab Phase 1 and 
Phase 2 studies (Studies GEN501 and MMY2002, respectively) have revealed previously 
unknown immunomodulatory effects of daratumumab.
87Detailed analysis by flow cytometry of 
changes in circulating immune cells demonstrated that daratumumab was able to induce large 
increases in CD8+ T numbers. Next generation TCR sequencing was utilized to evaluate changes 
in T cell clonality. Interestingly, in patients who responded to daratumumab, both the maximal 
individual increase in a T cell clone, as well as the sum of expanded T cell clones, were 
significantly increased suggesting that this T cell expansion may have a role in eliminating the 
myeloma cells. In order to assess the potential mechanism by which daratumumab could lead to 
these increases in T cell clones, additional analysis revealed that there was a rapid and sustained 
elimination of highly immunosuppressive subsets of CD38+Tregs, CD38+MDSCs, and CD38+  
Bregs in patients treated with daratumumab. Interestingly, the CD38+Tregs identified is a novel 
population of Tregs that are more immunosuppressive than CD38-Tregs. Inaddition,ithasalso
beenshownthatdaratumumabcanmodulatetheenzymaticactivityofCD38andpotentiallylead
toareductioninimmunosuppressiveadenosinelevelsinthetumormicroenvironment.
92
Some of daratumumab’s most differentiating attributes are the depth of response achieved in 
responders and the drug’s multifaceted MoA.Based upon these new findings, it is hypothesized 
that daratumumab’s deep and durable responses in patients with multiple myeloma are induced, in 
part, by the immunomodulatory activity that removes immune suppressive functions of CD38+ 
MDSC, CD38+ TReg, and CD38+ BReg cells and increases Tcell clonality. A figure 
summarizing daratumumab’s novel, converging MoAs is presented in Figure 1.4.4.1-1.
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Figure 1.4.4.1-1:
Daratumumab Mechanism of Action 
ADCC= antibody dependent cellular cytotoxicity ADCP=antibody dependent cellular phagocytosis;
CDC=complement-dependent cytotoxicity.
Note: Previously reported to kill tumor cells by immune-mediated mechanisms, such as ADCC, ADCP, and CDC, as 
well as by programmed cell death via cross linking of the antibody on the cell surface, it is now known that 
daratumumab also induces immunomodulatory effects via several different pathways that contribute to killing of 
CD38+ immune cells that modulate Tcell activity, namely MDSC, TReg, and BReg.  This is a novel mechanism 
previously unreported that is hypothesized to drive development of multiple opportunities for daratumumab beyond 
CD38+ myeloma and other heme malignancies
1.4.4.2
Summary of Daratumumab Clinical Pharmacology
Daratumumab is a first-in-class immunoglobulin G1 kappa (IgG1κ) human monoclonal antibody 
(mAb) that specifically binds to the CD38 protein expressed on the surface of multiple myeloma 
tumor cells and other cell types at various levels. In vitro, daratumumab can induce tumor cell lysis 
through complement dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and 
antibody-dependent cellular phagocytosis in malignancies expressing CD38. 
The population pharmacokinetic (PK) analysis included patients with multiple myeloma who 
received daratumumab. Over the dose range from 1 to 24 mg/kg, AUC increases more than dose 
proportionally. Clearance decreases with increasing dose and repeated dosing, indicating 
target-mediated pharmacokinetics. Following the recommended dose and schedule, the Cmax at 
the end of weekly dosing is 2.9-fold higher than following the first infusion. Daratumumab steady 
state is achieved approximately 5 months into the every 4-week dosing period,and the Cmax at 
steady-state to Cmax after the first dose is 1.6. The mean (SD) linear clearance and mean (SD) 
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central volumeof distribution are estimated to be 171.4 (95.3) mL/day and 4.7 (1.3) L, 
respectively. The mean (SD) estimated terminal half-life associated with linear clearance is 
approximately 18 (9) days. Population PK analyses indicated that the central volume of 
distribution and clearance of daratumumab increase with increasing body weight, supporting the 
body weight-based dosing regimen. Population PK analyses also show that age (31-84 years), 
gender, mild to severe renal impairment (15 to 89 mL/min),and mild hepatic impairment do not 
have clinically important effects on the pharmacokinetics of daratumumab. 
Exposure-response analyses for efficacy and safety were conducted using data from trials GEN501 
and MMY2002. The exposure-efficacy analysis shows that ORR increases with increasing 
daratumumab concentration, with a plateau achieved at daratumumab maximal pre-infusion 
concentrations (Cpre-infusion, max) 270 µg/mL. Furthermore, the median PFS appears shorter 
in patients with daratumumab Cpre-infusion,max <270µg/mL (1.9 month) and longer (6.6 
months) in those with daratumumab concentrations >270µg/mL. However, this analysis was 
confounded by baseline risk factors such as disease severity. There was no exposure-safety 
relationship for infusion related reactions(IRR), thrombocytopenia, anemia, neutropenia and 
lymphopenia within the exposure range from 0.1 to 24mg/kg studied in trials MMY2002 and 
GEN501.
1.4.4.3
Summary of Daratumumab Clinical Activity
Based on the preclinical activity of daratumumab, a Phase 1/2 study was initiated in MM patients 
with relapsed/refractory disease (GEN501 study).
79In the first-in-human dose-escalation part of 
the study the MTDwasnot reached with dose levels up to 24mg/kg. In the Phase 2 part of the 
study, patients with a median of 4 prior lines of therapy (majority refractory to lenalidomide and 
bortezomib) were treated with daratumumab at a dose of 8 mg/kg or 16mg/kg. The ORR(at least 
PR) was 36% in the 16 mg/kg cohort and 10% in the 8 mg/kg group. Remarkably, in this 
extensively pretreated group of patients, 2 out of 42 patients treated with 16 mg/kg daratumumab 
achieved a first complete response. The median PFS in the 8 mg/kg and 16 mg/kg groups were 2.4 
and 5.6 months, respectively. The 12-month survival was 77% for both groups. The most frequent 
adverse events were infusion-related reactions, which occurred in 71% of patients. The majority 
of these reactions included Grade 1 and 2 and were characterized by rhinitis, cough, headache, 
pyrexia, and dyspnea. Most infusion-related reactions occurred during the first daratumumab 
infusion,and only few patients (<10%) had infusion-related reactions with more than one infusion. 
TheSIRIUS (MMY2002) study confirmed the results from GEN501 study that demonstrated 
single agent activity of daratumumab with a favorable toxicity profile.
80One hundred six patients, 
with a median of 5 prior lines of therapy (95% refractory to lenalidomide and bortezomib), 
received daratumumab monotherapy at a dose of 16 mg/kg. At least a PR was achieved in 29% of 
patients with stringent CR in 3%. Themedian duration of response was 7.4months. The median 
PFSwas 3.7 months and 1-year OS was 65%. Notably, subgroup analysis showed 
that in the group 
of patients who were refractory to lenalidomide, pomalidomide, bortezomib and carfilzomib, PR 
or better was achieved in 21% of these patients. Infusion-related reactions were observed in 43% 
of the patients and were predominantly Grade 1 and 2 and could be managed with interruption of 
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the infusion or extra corticosteroids and antihistamines. In conclusion, results from these studies 
show that daratumumab is well tolerated and that in the 16 mg/kg cohort at least a partial response 
can be achieved in 29-36% of the patients.
93,94,95Virtually all patients with PR or CR, achieved 
50% reduction in tumor load within 3 months after start of therapy. 
Based on preclinical evidence showing potential benefit of combining daratumumab with 
lenalidomide,
96,97,98 another Phase 1/2 study is currently evaluating the combination of 
daratumumab plus lenalidomide and dexamethasone in relapsed/refractory MM (GEN503; 
NCT01615029). Preliminary safety data show a manageable toxicity profile and high efficacy of 
this three-drug regimen.
99,100
Daratumumab has also been shown to be safe, tolerable and efficacious when combined with other 
immunomodulatory agents in two separate Phase 3 trials combining daratumumab with 1) 
lenalidomide and dexamethasone (POLLUX) and 2)pomalidomide and dexamethasone 
(CASTOR). In the POLLUX trial, lenalidomide-dexamethasone was combined with or without 
daratumumab in patients with relapsed/refractory myeloma with 1-3 previous lines of therapy 
(patients with lenalidomide-refractory disease were excluded).
101In this study the daratumumab 
treated patients had a significantly higher CR rate and an unprecedented improvement in the PFS 
(HR: 0.37). There was no additional toxicity when daratumumab was added to 
lenalidomide-dexamethasone, except for infusion-related reactions, which occurred in 
approximately half of the patients mostly during the first infusion. Another Phase 3 trial compared 
bortezomib-dexamethasone withor without daratumumab.
102Also in this study there was a 
significant improvement in CR rate, leading to a significant improvement of the PFS (HR: 0.39). 
Also,in the CASTOR study,daratumumab didnot add toxicity to bortezomib-dexamethasone, 
except for infusion-related reactions occurring in approximately half of the patients, mostly during 
the first infusion of daratumumab.
1.5
Overall Risk/Benefit Assessment
Despite several therapies available for the treatment of mCRC, the incremental benefit of these 
treatments after treatment with a first-line regimen is small, as discussed in Section 1.1.1, and 
represents an area of unmet medical need. Furthermore, patients with MSI-H CRC do not appear 
to consistently have the same benefit from fluorouracil, the backbone of combination regimens for 
mCRC, as patients with non-MSI-H. Reliable testing methods exist to identify these subjects with 
MSI-H tumors who may not reliably respond to fluorouracil. Non-fluorouracil based treatment 
options include single agent cetuximab and regorafenib,both of which have demonstrated a 
survival advantage in the later line settings compared to BSC,but these benefits are less than 2 
months and do not provide long term responses. 
Patients with MSI-H CRC have distinct molecular and clinicopathologic phenotypes, including 
immune-related findings germane to the mechanism of action of nivolumab. Nivolumab 
monotherapy has demonstrated clinical activity across several tumor types, including advanced 
melanoma, NSCLC, and RCC. Nivolumab has demonstrated a manageable safety profile in 
patients > 1500 patients across all clinical trials. The most common AEs included fatigue, rash, 
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pruritus,diarrhea, and nausea. The AE profile for nivolumab monotherapy does not appear to be 
dose dependent and appears to be similar across a range of solid tumors studied.
Ipilimumab 3 mg/kg is approved for use in the US (advanced melanoma) and in the EU 
(forpreviously treated advanced melanoma) based on OS benefit in randomized trials. 
Furthermore, clinical activity with ipilimumab has been observed in patients with NSCLC,SCLC, 
and prostate carcinoma. The efficacy of ipilimumab in these tumor types is being investigated in 
ongoing Phase 3 trials. The currently approved dose for ipilimumab in melanoma patients is 3 
mg/kg every 3weeks for up to 4doses. Ipilimumab has demonstrated a manageable safety profile 
and treatment guidelines for immune-related adverse events are established based on 
>10,000patients treated in clinical trials.
The combination of nivolumab and ipilimumab has the potential for increased benefit compared 
to both ipilimumab monotherapy and nivolumab monotherapy. In Study CA209004, 53% of the 
subjects with advanced melanoma treated at the dose level of nivolumab 1 mg/kg combined with 
ipilimumab 3 mg/kg had an objective response, the majority of which had deep tumor reduction 
of 80% or more. This deep response compares favorably to results with 3 mg/kg ipilimumab 
monotherapy or nivolumab monotherapy and is the basis for an 
ongoing randomized Phase 3 study 
in advanced melanoma (CA209067). Studies investigating the efficacy and safety of nivolumab in 
combination with ipilimumab are ongoing in NSCLC and RCC.
The combination of nivolumab and ipilimumab has the potential for increased frequencies of 
adverse events compared to ipilimumab monotherapy or nivolumab monotherapy. The most 
common (reported at > 10% incidence) treatment-related AEs are fatigue, rash, pruritus, diarrhea, 
lipase increased, pyrexia, ALT increase, AST increased, amylase increased,and vitiligo. 
This class 
of AEs are expected for the combination of nivolumab and ipilimumab based on the known AE 
profile of each drug alone. In addition, many of the Grade 3-4 adverse events were laboratory in 
nature (ie,liver function tests [LFTs], lipase, amylase), were without clinical sequelae,and have 
been manageable and reversible following intervention dose delays or with systemic steroid 
treatment. However, these AEs have the potential to be fatal if not detected early and managed per 
the established algorithm,and fatal AEs have been reported for both ipilimumab and nivolumab 
monotherapy. 
As of June 
2013, 
one 
subject died because 
of 
a 
study 
treatment-related 
adverse 
event 
(toxicepidermal necrolysis, TEN) in the nivolumab + ipilimumab development program. Fatal 
TEN has previously been reported for ipilimumab monotherapy.
Evaluating both nivolumab monotherapy and the combination of nivolumab and ipilimumab in 
subjects with advanced or metastatic MSI-H CRC, who may not derive the same benefit from 
fluorouracil based regimens, will potentially generate efficacy signals as a basis for a further 
clinical development in this distinct tumor type.
Across multiple tumors, 3 mg/kg nivolumab monotherapy has demonstrated a 
tolerable AE profile 
in hundreds of subjects,and thatprofileappears to 
be independent of tumor type. The combination 
of 1 mg/kg nivolumab + 3 mg/kg ipilimumab has demonstrated an acceptable AE profile in 
melanoma and is currently in Phase 3. The same regimen is currently being studied in RCC and 
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NSCLC. The following safety measures have been employed to ensure safety of the subjects in 
this current study:
Two-stage design used which will stop an individual arm for lack of sufficient activity
For the combination arm, an initial dose escalating safety evaluation phase will be performed 
to determine theoptimal dose for advanced CRC.
Intense toxicity monitoring will help to ensure the subjects’ safety in Study CA209142, 
including frequent safety conference calls with investigators and representatives of the 
sponsor.
A BMS safety management team(SMT) routinely reviews safety signals across the entire 
nivolumab program, including all ongoing combinations with ipilimumab.
MSI-H Cohort C3(No prior Treatment in Metastatic Setting, Nivolumab + Ipilimumab):
Given the preliminary efficacy and tolerability of nivolumab + ipilimumabin a biomarker-selected 
population of dMMR/MSI-H mCRC patients, and the known toxicity of first-line chemotherapy 
for mCRC, the potential benefit of a first-line approach in dMMR/MSI-H mCRC appears to 
outweigh the potential risk.  
MSI-H Cohort C5 (Nivolumab + BMS-986016):
The combination of nivolumab plus BMS-986016has the potential for increased benefit 
compared to monotherapy targeting the PD-1 pathway, ie, nivolumab monotherapy. In the 
nonclinical GLP toxicology study, lymphoplasmacytic infiltration in the choroid plexus (and 
spinal cord) was reported at the highest doses of anti-PD-1 antibody (3/6 animals) and the 
anti-LAG-3 + anti-PD-1 antibody combination (5/6). Importantly, these findings were notreported 
with anti-LAG-3 antibody aloneateither 30 mg/kg or 100 mg/kg (highest dose).
These are nonspecific histopathology changes, without clinical manifestations in all but one of the 
animals treated with combination therapy, which have been observed in other studies with 
antibodies and small molecules in monkeys. However, an exaggerated immunostimulatory 
pharmacologic effect of the combination of BMS-986016 plus nivolumab cannot be disregarded. 
Also, given the short study period (6 weeks) and the long half-lives of BMS-986016 and 
nivolumab, a potential long-term effect has not been ruled out. Potential lymphoplasmacytic 
inflammation of the choroid plexus could manifest in human subjects as aseptic meningitis or 
encephalitis.
As of 29-Jun-2016, the observed drug-related AEs with potential for neurotoxic etiology have 
occurred in 10 subjects (10%) treated across all monotherapy and combination dose cohorts (up to 
and including the 80 mg BMS-986016/240 mg nivolumab cohort) in both the hematological 
malignancy and solid tumor early phase studies. Related AEs included headache (n=4), dysgeusia 
(n=3), peripheral neuropathy 
(n=2), blurred 
vision (n=1), 
and 
ataxia 
(n=1). The 
severity in all cases 
was Grade 1 except for a single Grade 2 headache and a single Grade 2 peripheral neuropathy. The 
Grade 1 ataxia resolved within 48 hours. None of the events have been associated with any 
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documented neurologic pathologic finding, nor did any of these events directly contribute 
to a dose 
interruption. Nonetheless, in this clinical study, monitoring measures include: 
1)Exclusion of subjects with active neurological disease, confirmed history of encephalitis, 
meningitis, or uncontrolled seizures in the year prior to informed consent 
2)Investigators and sitepersonnel are trained on the use of treatment guidelines for neurological 
toxicity and immune-related AE management algorithms upon site initiation
3)Clinical monitoring of subjects for signs and symptoms of neurologic toxicities
4)The following protocol defined actions are triggered upon a Grade 2 neurological AE: 
a)Holding therapy 
b)Follow the neurological AE management algorithm
c)Complete neurological examination performed by a neurologist
Treatment with BMS-986016 may be associated with a risk ofaseptic meningitis or encephalitis. 
Increased safety precautions have been instituted in this study to mitigate this risk.
Therapy with BMS-986016 and nivolumab is investigational,and it is possible that a higher 
incidence of immune-relatedadverse events (irAEs) may occur with the combination of 
2antibodies targeting T cells. As of 29-Jun-2016, drug-related SAEs were reported in 4 of the 
28subjects treated with BMS-986016 in combination with nivolumab in Part B. These included
Grade 3 mucosal inflammation (1 subject), Grade 3 dyspnea (1 subject), Grade 4 ventricular 
fibrillation (1 subject), and Grade 4 myocarditis (1 subject). Regarding non-serious AEs, treatment 
with BMS-986016 monotherapy, and in combination with nivolumab, in both early phase studies, 
low-grade,drug-related AEs consistent with immune-mediated AEs have been experienced. These 
events are indirectevidence of the ability of BMS-986016 to activate T-cells.
Low-grade,likely immune-related AEs experienced include 2 subjects experiencing Grade 2 
hypothyroidism, 2 subjects experiencing Grade 1 alterations in TSH levels, 1 subject with Grade1 
thyroiditis, 1 subject with Grade 1 vitiligo (20 mg monotherapy), and 1 subject with Grade 2 
pneumonitis (800 mg monotherapy).
As of 29-Jun-2016, drug-related SAEs were reported in 4 of the 28 subjects treated with 
BMS-986016 in combination with nivolumab in Part B of Study CA224-020. Two of these events 
were cardiovascular events: Grade 4 ventricular fibrillation and Grade 4 myocarditis. Additional 
safety measures for 
cardiovascular 
risks implemented 
for subjects 
receiving 
combination 
treatment 
with Cohort C5have been added to the protocol: 
1)Exclusion of subjects with history of myocarditis, regardless of etiology.
2)Exclusion Criteria under significant cardiac events: history of 2 
or more myocardial infarctions 
(MIs) OR 2 or more coronary revascularization procedures.
3)Screening left ventricular ejection fraction (LVEF) assessment (if not performed in the last 
6months) with documented LVEF 50% by either transthoracic echocardiogram or multiple 
gated acquisition scan (transthoracic echocardiogram being the preferred test) for subjects.
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4)Increased 
emphasis in 
clinical monitoring 
of 
subjects 
for signs and symptoms 
of 
cardiovascular 
toxicities during training meetings and safety teleconferences.
5)Addition of pre-dose ECG testing.
6)Addition of troponin laboratory testing
non-MSI-H Cohort C6 (Nivolumab + Daratumumab):
Daratumumab induces antimyeloma effects via multiplemechanisms of action. An additional 
mechanism of action has been proposed in which treatment with daratumumab eliminates a 
population of highly immunosuppressive CD38+ Tregs, T-cell MDSCs, and Bregs and thus 
stimulates T-cell effector functions.
82 This immunomodulatory effects of daratumumab, 
specifically its ability to promote T-cell expansion and activation, are expected to potentiate the 
effect of anti-PD-1 antibody. The combination of nivolumab plus daratumumab is expected to 
potentiate the effect of nivolumab by sensitizing the bone marrow T cells to PD-1 blockade, which 
would translate in augmented clinical benefit. 
Daratumumab is approved asmonotherapy for third-line treatment of MM patients who failed 
prior therapies.
79,80Recent reported results demonstrated safety and efficacy when combined with 
other immunomodulatory therapies in second-line MM, including lenalidomide and 
dexamethasone.
97Daratumumab’s primaryadverse events includes infusion reactions, which are 
reported to be uncommon with nivolumab (refer to nivolumab IB). However, infusion-related 
reactions to daratumumab occur in close to 50% of the patients, largely with the first infusion. 
According to the currently approved United States Prescribing Information (USPI),
103
daratumumab infusions should be interrupted for infusion reactions of any severity, and drug 
should be permanently discontinued in case of life-threatening infusion reactions. Pre-infusion and 
post-infusion medication should be administered to all patients, per the currently approved 
USPI.
103Severe infusion-related reactions have been reported in less than 1% of subjects in 
clinical trials with nivolumab, with overall rates of infusion-related reactions of any grade ranging 
from 1% to 6%. The risk of infusion reactions is greater with the first and second infusions with 
daratumumab and decreases for subsequent doses. Therefore, to minimize the likelihood of 
infusion-related reactions to the nivolumab and daratumumab combinations, the first nivolumab 
dose is administered at Week 3 (ie, after the first two doses of daratumumab at Weeks 1 and 2). 
Further, on each dosing day when nivolumab is administered with daratumumab, the required pre-
infusion medication for daratumumab is administered first, followed by the nivolumabinfusion, 
and then by the daratumumab infusion.
Other AEs of any grade reported in a high frequency (>25%) of daratumumab-treated subjects 
include low-grade fatigue and nausea,which have been associated with nivolumab treatment.  
Only one severe AEs (Grade 3/4) of pneumonia has been reported with daratumumab (>5% 
frequency). Pneumonia is considered uncommon with nivolumab asreported in the USPI; 
however,severe cases have been reported. The hematological AEs that have been reported 
following treatment with daratumumab (anemia, thrombocytopenia, neutropenia, lymphopenia), 
which are common in subjects with hematological malignancies, are not expected to be observed 
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nivolumab
in 
subjects 
with 
solid 
tumors. In 
contrast 
to 
nivolumab, 
there 
have been no 
cases 
of immune-related 
AEs, including pneumonitis, reported in the label for daratumumab. When comparing the toxicity 
profile of daratumumab and nivolumab in hematologic malignancies, there is little overlap of AE 
profiles. Based on the above assessment, the potential benefit of combining nivolumab and 
daratumumab appears to outweigh the potential risk. The overall risk/benefit assessment supports 
the evaluation of these combinations in this setting.
It is possible that unforeseen or unanticipated AEs may occur. In order to minimize the overall 
risks to participating subjects, the protocol has inclusion-exclusion criteria appropriate to the 
populationand specific follow-up safety assessments. Routine safety monitoring for all the AEs 
described above will be implemented in the protocol to ensure that we are monitoring the potential 
for overlapping toxicities.Toxicity monitoring will help to ensure the subjects’ safety and will 
include frequent safety conference calls with investigators and routine reviews by a BMS SMT.
Adverse events and SAEs will continue to be reviewed expeditiously by the Medical Monitor, 
investigators,and the Pharmacovigilance group to monitor safety.
Treatment Duration and Re-Initiation Option in MSI-H/dMMR mCRC Cohorts
As detailed in Section1.1.4.7, accumulating data suggest that 24 months of PD-1 checkpoint 
inhibitor treatment may be sufficient for long term benefit; therefore this duration was considered 
when modifying treatment duration for MSI-H/dMMR Cohorts of CA209-142 study. Given the 
fact that some subjects have been on treatment longer and MSI-H/dMMR might have a unique 
response 
pattern, 
a 
strict 
stopping 
rule 
at 
2-years 
was not 
considered ideal for 
CA209-142. 
Subjects 
who achieved objective response within the second year of treatmentwill be required to continue 
to receive study therapy for additional 12 months beforethe option to discontinue treatmentfor 
maximum clinical benefit is allowed. (Section3.1.4.1). These measures maintain a favorable 
overall risk-benefit assessment for Study CA209142 andjustify the conduct of the trial and the 
incorporation of Revised Protocol 07.
2
ETHICAL CONSIDERATIONS
2.1
Good Clinical Practice
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50).
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) approval/favorable opinion prior to initiation of the study.
All potential serious breaches must be reported to BMS immediately. A serious breach is a breach 
of the conditions and principles of GCP in connection withthe study or the protocol, which is 
likely to affect, to a significant degree, the safety or physical or mental integrity of the subjects of 
the study or the scientific value of the study.
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Personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.
This 
study will not 
use 
the 
services 
of study 
personnel 
where 
sanctions have been invoked 
or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure, debarment). 
2.2
Institutional Review Board/Independent Ethics Committee 
Before study initiation, the investigator must have written and dated approval/favorable opinion 
from the IRB/IEC for the protocol, consent form, subject recruitment materials 
(eg,advertisements), and 
any 
other 
written information 
to 
be provided 
to 
subjects. 
The investigator 
or BMS should also provide the IRB/IEC with a copy of the Investigator Brochure or product 
labeling information to be provided to subjects and any updates. 
The investigator or BMS should provide the IRB/IEC with reports, updates and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to regulatory 
requirements or institution procedures.
2.3
Informed Consent
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate. 
In situations where consent cannot be given to subjects, 
their legally acceptablerepresentatives are 
clearly and fully informed about the purpose, potential risks, and other critical issues regarding 
clinical studies in which the subject volunteers to participate. 
BMS will provide the investigator with an appropriate (ie, Global or Local) sample informed 
consent form which will include all elements required by ICH, GCP and applicable regulatory 
requirements. The sample informed consent form will adhere to the ethical principles that have 
their origin in the Declaration of Helsinki.
Investigators must:
1)Provide a copy of the consent form and written information about the study in the language in 
which the subject is most proficient prior to clinical study participation. The language must be 
non-technical and easily understood. 
2)Allow time necessary for subject or subject'
s legally acceptable representative to inquire about 
the details of the study.
3)Obtain an informed consent signed and personally dated by the subject or the subject'
s legally 
acceptable representative and by the person whoconducted the informed consent discussion. 
4)Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisionsare completed for new information.
5)If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the subject.
6)Revise the informed consent whenever important new information becomes available that is 
relevant to the subject'
s consent. The investigator, or a person designated by the investigator, 
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should fully inform the subject or the subject'
s legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
subject'
s willingness to continue participation in the study. This communication should be 
documented. 
The 
confidentiality of records that 
could identify subjects must 
be protected, 
respecting 
the 
privacy 
and confidentiality rules applicable to 
regulatory requirements, the subjects'
 signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization.
The consent form must also include a statement that BMS and regulatory authorities have direct 
access to subject records. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society.
3
INVESTIGATIONAL PLAN
3.1
Study Design and Duration
CA209142 is a Phase 2 open-label, multi-center, trial of nivolumab monotherapy (Arm N)or in 
combination therapy(Cohort N + I) to estimate the response rate in MSI-H CRCand non-MSI-H 
CRC. CA209142 completed a safety cohort of subjects with non-MSI-H CRC to assess the safety 
and tolerability of nivolumab in combination with ipilimumab in subjects with non-MSI-H CRC 
in preparation for an analogous 2-stage assessment of theresponse rate for the combination in 
MSI-H CRC. 
As described inFigure 3.1-1,subjects withrecurrent or metastatic CRC receivednivolumab or 
nivolumab with ipilimumab,depending on the response rate in the monotherapy MSI-H cohort 
andthetolerability of the nivolumab combined with ipilimumab combination in the non-MSI 
safety cohort.
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Figure 3.1-1:
Study Design Schematic(Arm N and Arm N +I) and Non-MSI-H 
Safety Cohort
mStage = 
monotherapy Stage; cStage 
= combination Stage; Arm N 
= Nivolumab monotherapy; Arm N+I=nivolumab 
in combination with ipilimumab; nMSI-H N+I = non-MSI-H nivolumab in combination with ipilimumab
For the monotherapy mStage 1, if 7 or more subjects with microsatellite metastatic CRC (MSI-H 
mCRC) have a confirmed PR or CR, mStage 2 will open to enroll an additional 29 subjects. A 
confirmed PR or CR is defined as a subsequent confirmatory scan performed 4 weeks after the 
first scan. If there are more than 2 but less than 7 responses in the first 19 subjects, accrual to the 
mStage1 arm will be stopped, and the combination cStage1 arm will be opened for accrual.
CA209142 will also contain a safety cohort 
of subjects with non-MSI-H mCRC to assess the safety 
and tolerability of nivolumab in combination with ipilimumab in subjects with non-MSI-H mCRC 
and provide the starting dose for cStage 1. 
If 7 or more subjects in cStage 1 with MSI-H mCRC have a confirmed PR or CR, cStage 2 will 
open to enroll an additional 29 subjects. If 6 or fewer of the first 19 subjects with MSI-H mCRC 
have a confirmed PR or CR, cStage 1 will close, and the trial will end. Additionally, if 2 or fewer 
of the first 19 subjects in mStage 1 have a confirmed CR or PR, the trial will close. The 
determination of response rate will be based on investigator-assessed tumor response per RECIST 
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1.1 criteria. Subjects in mStage 1 or cStage 1 who remain on treatment shouldcomplete a 24-week 
follow up for an assessment of ORR.
For the monotherapy mStage 1/2 and 
the combination 
therapy cStage 1/2, 
the 
option to discontinue 
treatment at maximum clinical benefit as assessed by the Investigator and defined in Section 
3.1.4.1has been incorporated. Re-initiation of treatment upon progression after discontinuation at 
maximum clinical benefit is an option for eligible MSI-H subjects as described in Section 3.1.4.8.
The CA209142 study also includesan additionalC3cohort as described below in Figure 3.1-2.
The C3cohort will enroll 30MSI-H subjects who have not had prior therapy for their metastatic 
disease. For Cohort C3, the option to discontinue treatment at maximum clinical benefit as 
assessed by the Investigator and defined in Sections 3.1.4.1has been incorporated. Re-initiation 
of treatment upon progression after discontinuation at maximum clinical benefit is an option for 
eligible MSI-H subjects as described in Section 3.1.4.8.
Figure 3.1-2:
Study Schematic for Cohort 3
The CA209142 study includesan additional C4 cohort as described below inFigure 3.1-3. All 
information pertaining to the C4 cohort was added via a site-specific Amendment 06. This cohort 
is only open at 2 sites. This cohort will enroll 30 previously-treated non-MSI-H subjects with 
metastatic CRC. 
Figure 3.1-3:
Study Schematic for Cohort 4
The CA209142 study includes a C5 cohort as described below inFigure 3.1-4. The C5 cohort will 
enroll 40 previously-treated MSI-Hsubjectswho have not had prior anti-PD-1 therapy for their 
metastatic CRC disease. For Cohort C5, the option to discontinue treatment at maximum clinical 
benefit as assessed by the Investigator and defined in Sections 3.1.4.1has been incorporated. Re-
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initiation of treatment upon progression after discontinuation at maximum clinical benefit is an 
option for eligible MSI-H subjects as described in Section 3.1.4.8.
Figure 3.1-4:
Study Schematic for Cohort 5 (C5)
The CA209142 study includesa C6 cohort as described below inFigure 3.1-5. The C6 cohort will 
enroll 40 previously-treated non-MSI-H subjectswith metastatic CRC. 
Figure 3.1-5:
Study Schematic for Cohort 6 (C6)
All subjects will undergo screening evaluations to determine eligibility within 28 days prior to the 
start of therapy. A baseline tumor imaging assessment will be performed prior to the start of 
therapy. Tumor tissue must be provided for biomarker analysis. Central lab must provide IVRS 
with confirmation of receipt of evaluable tumor tissue prior to study treatment. Subjects whose 
repeat testing does not confirm MSI-H status will be replaced but will be allowed to continue on 
study therapy. Subjects on C3will be accepted with a valid local MSI result. 
Treatment beyond initial investigator-assessed progression is permitted if the subject has an 
investigator-assessed clinical benefit and is tolerating study drug, see Section 4.3.8.The 
investigator-assessed tumor response based on RECIST 1.1 criteria will be used to guide the stage 
1 decision and for the primary analysis of the ORR. In addition,an independent radiology review 
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committee (IRRC) will perform central review of the imaging per RECIST 1.1 criteria upon study 
completion. Details will be included in the IRRC charter. 
3.1.1
Mismatch Repair/Microsatellite Instability Testing
MSI-H (Microsatellite Instability High) is most frequently determined by PCR. MSI-H in tumors 
refers to changes in twoor more of the five National Cancer Institute-recommended panels of 
microsatellite markers in tumor tissue. The original (1997) Bethesda guidelines proposed a panel 
of five microsatellite markers for the uniform analysis of MSI in HNPCC. This panel, which is 
referred to as the Bethesda panel, included two mononucleotide (BAT-25 and BAT-26) and three 
dinucleotide (D5S346, D2S123, and D17S250) repeats.
104Individual testing sites may utilize a 
slightly different panel of markers incorporating alternative mononucleotide and/or dinucleotide 
markers. Regardless of the panel of markers, samples with instability in 30%or more of these 
markers are defined as MSI-H, whereas those with <30%unstable markersare designated as MSI-
Low (MSI-L). Samples with no detectable alterations are MSS.
Mismatch repair deficiency (dMMR) determined by immunohistochemistry (IHC) refers to the 
loss of expression of one or more of the mismatch repair proteins (MLH1, MSH2, MSH6 or 
PMS2). Loss of expression is restricted to tumor cells, with preserved expression in immune 
infiltrate, and normal adjacent tissue. Loss of MLH1 expressionis usuallyaccompanied by loss of 
PMS2, and loss of MSH2 is usually accompanied by the loss of MSH6 expression.
dMMR/MSI-H can also be diagnosed by next-gen sequencing (NGS) through pathogenic 
mutations in the MMR genes or MSI.
Sites should query a subject’s medical history for prior MSI testing detected by an accredited 
laboratory per local regulations to select subjects for the MSI-H or non-MSI-H cohorts. MSI-H or 
non-MSI-H status in potential subjects will be determinedprior to screening as part of standard 
diagnostic testing by investigators. Please refer to Appendix 4 regarding MSI testing panel 
descriptions and classification of MSI statusto ensure historic MSI status determination is aligned 
with the protocol prior to enrollment. 
For both themStage1/2 and cStage1/2MSI-H and thedose findingnon-MSI-H cohorts, a PCR 
test will be utilized for repeat testing. For all cohorts, additional tumor samples must be sent to 
BMS for future confirmatory studies of the in vitrodiagnostic. A lab manual separate from the 
protocol will provide detailed information regarding MSI testing and sample requirements.
3.1.2
Non-MSI-H Subjects (Independent Safety Sub-Trial)
An independent safety sub-trial in non-MSI H subjects will inform the safe and tolerable dose level 
for cStage 1 in subjects with MSI-H mCRC. The combination of nivolumab and ipilimumab is 
already being evaluated in Phase 3 in advanced melanoma and has more recently been tested in 
NSCLC and RCC. This regimen is expected to also be tolerable in mCRC, but given the potential 
for gastrointestinal toxicities with ipilimumab and nivolumab (eg,colitis),a dose escalating safety 
phase will assess the safety and tolerability of nivolumab in combination with ipilimumab and 
evaluate different doses of each agent. Enrollment in the non-MSI-H N+I SafetySub Trial will 
occur in parallel to mStage 1. 
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3.1.2.1
Dose Escalating Safety Evaluation for Nivolumab in Combination with 
Ipilimumab in non-MSI-H Subjects 
Table 3.1.2.1-1contains the dose levels for the non-MSI-H dose escalation safety cohort. 
Table 3.1.2.1-1:
Dose Cohort for Safety non-MSI-H N+I
Dose Cohort Level
Nivolumab (mg/kg)
Ipilimumab (mg/kg)
-1
0.3
1
1
1
1
2a
1
3
2b
3
1
The first dose cohort will be Dose Level 1, 1 mg/kg each of nivolumab and ipilimumab. If this 
combination is deemed tolerable, then subjects will be randomized (1:1) to one of two dose levels:
Dose Level 2a (N1+I3): 1 mg/kg nivolumab + 3mg/kg ipilimumab, or 
Dose Level 2b (N3 + I1): 3 mg/kg nivolumab + 1 mg/kg ipilimumab 
The tolerable dose of the combination willbe brought into an analogous 2-stage design if 
nivolumab monotherapy 
(mStage 
1) does 
not 
have 
7 
or more 
responders 
out 
of 
the first 
19subjects.
IfLevel 1 is not tolerable, then Level -1 will be initiated. There will be no dose escalation beyond 
Levels 2a and 2b. Once the decision on the dose level for further investigation has been confirmed, 
that dosing level will be used in cStage 1 in subjects with MSI-H (Section 3.1.4.3).
Subjects need to be followed up for at least 6 weeks after start of study treatment before 
determination of the tolerability of a dose level. However, tolerability beyond 6 weeks may also 
be taken into consideration. 
The criteria for tolerability for Dose Level 1 (and -1 if necessary) (Table 3.1.2.1-2) are based on 
drug-related adverse events leading to permanent discontinuation (listed in Section 4.3.6) and 
include:
If none of the first 3 subjects in the dose level permanently discontinue treatment due to study 
drug-related adverse events within the first 6 weeks, then this dose cohort will be deemed as 
tolerable. 
If one or two of the first 3 subjects in the dose level permanently discontinue treatment within 
the first 6 weeks due to study drugrelated adverse events, this cohort will be expanded to 6 
subjects.
If one of 6 subjects in the dose level permanently discontinues treatment due to study drug 
related adverse events within the first 6 weeks, then the dose level will be deemed as tolerable. 
If two 
of 
6 
subjects in 
the 
dose level 
permanently discontinue 
treatment 
within 
the first 
6weeks 
due to study treatment related adverse events, this dose level may be expanded to 9subjects. 
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If an expansion is not possible because of the severity of the adverse events leading to 
permanent discontinuation, then this dose cohort will be deemed not tolerable. 
If no more than twoof 9 subjects in the dose level permanently discontinue treatment due to 
study treatment related adverse events within the first 6 weeks, then the dose level will be 
deemed as tolerable.
If at least 
three of the first 9 subjects in Dose Level 1 permanently discontinue treatment within 
the first 6 weeks due to study treatment related adverse events, a Dose Level -1 Cohort may 
proceed.
For the decision to enroll a Dose Level -1, the clinical severity of the adverse events leading to 
permanent discontinuation in Dose Cohort 1 will be taken into consideration.
Table 3.1.2.1-2:
Dose Level Decisions (Dose Level 1 and Dose Level -1) for Arm non-
MSI-H N+I
Number of subjects treated and 
followed up for at least 6 weeks 
after start of study treatment
Number of subjects with 
permanent discontinuation due to 
treatment related adverse events
Next Step
3
0
Dose tolerable
3
1-2
Expand to 6 subjects
6
1
Dose tolerable
6
2
Expand to 9 subjects
9
2
Dose tolerable
9
3
Dose not tolerablea
a discussion with investigators to review risk/benefit taking into account reversibility of AEs and depth of response
Table 3.1.2.1-3contains the dosing schedule for Arm N+I weeks 1-12.
Table 3.1.2.1-3:
Dosing Schedule for Arm nMSI-H N+I (Week 1-12) -Nivolumab + 
Ipilimumab Combination
Every 3 Week Dosing
Study Part
Day 1
Dose 1/Week 1
Day 1
Dose 2/Week 4
Day 1
Dose 3/Week 7
Day 1
Dose 4/Week 10
Dose Escalation 
Phase Dose Level 
-1
0.3 mg/kg 
Nivolumab 1 mg/kg 
Ipilimumab
0.3 mg/kg 
Nivolumab 1 mg/kg 
Ipilimumab
0.3 mg/kg
Nivolumab 1 mg/kg 
Ipilimumab
0.3 mg/kg 
Nivolumab 1 mg/kg 
Ipilimumab
Dose Escalation 
Phase Dose Level 
1
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
1 mg/kg Nivolumab 
1 mg/kg Ipilimumab
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Table 3.1.2.1-3:
Dosing Schedule for Arm nMSI-H N+I (Week 1-12) -Nivolumab + 
Ipilimumab Combination
Every 3 Week Dosing
Study Part
Day 1
Dose 1/Week 1
Day 1
Dose 2/Week 4
Day 1
Dose 3/Week 7
Day 1
Dose 4/Week 10
Dose Escalation 
Phase Dose Level 
2a
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
1 mg/kg Nivolumab 
3 mg/kg Ipilimumab
Dose Escalation 
Phase Dose Level 
2b
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
3 mg/kg Nivolumab 
1 mg/kg Ipilimumab
Table 3.1.2.1-4contains the dosing schedule for Arm N+I weeks 13 and following.
Table 3.1.2.1-4:
Dosing Schedule for Arm nMSI-H N+I (Week 13 and following) 
Nivolumab + Ipilimumab Combination Escalation Cohort
Every 2 Week Dosing
Day 1
Week 13
Day 1
Week 15
Day 1, Week 17, 19, 21 
and every other week thereafter
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
3 mg/kg Nivolumab 
Approximately 10 subjects with recurrent or metastatic nMSI-H CRC will be randomized (1:1) to 
Dose Level 2a (N1+I3) and Dose Level 2b (N3+ I1). Tolerability and safety of a treatment arm 
will be determined after all subjects per arm have completed four doses 
of the combination or have 
discontinued dosing prior to completing four doses. However, tolerability beyond four doses of 
the combination during the nivolumab monotherapy time period may also be taken into 
consideration. All subjects will continue to be followed for safety, progression, and overall 
survival after discontinuation of study medication. The tolerability criteria used to advance the 
dose level to the MSI-H cStage 1 will based on drug-related adverse events leading to permanent 
discontinuation (listed in Section 4.3.6) and include the following:
If no more 
than one-third of the subjects in either Dose Level 2a or 2b permanently discontinue 
study medication prior to completing four doses due to treatment-related adverse events then 
this dose cohort will be deemed as tolerable. 
If more than one-third of subjects in either Dose Level 2a or 2b permanently discontinue study 
medication prior to completing four doses due to treatment-related adverse events, then the 
safety and tolerability of that treatment arm will be reviewed prior to randomizing any 
additional subjects. A decision will be made by the sponsor whether to continue enrollment or 
advance either treatment arm into the MSI-H Cohort, ie, cStage 1.
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If both Dose Level 2a and 2b are deemed tolerable, the sponsor will review the adverse events and 
efficacy results to determine which dose level will advance to cStage 1. If both Dose Level 2a and 
2b are not deemed tolerable, Dose Level 1 will be advanced to cStage 1. 
Subjects enrolled in the non-MSI high safety cohort who discontinue from treatment prior to 
6weeks 
of exposure 
to 
study drug due to reasons not 
related 
to 
study 
drug toxicity will be replaced, 
if necessary. 
3.1.2.2
Evaluation of Risk/Benefit for Doses that Do Not Meet Tolerable Criteria
In the event of 3 of the first 9 subjects requiring permanent discontinuation in Dose Level -1, a 
discussion with investigators may be held to review the risk/benefit of this regimen. The rationale 
for this evaluation is that the most frequent severe drug-related AEs for the combination in 
melanoma have been asymptomatic, reversible laboratory events (ie, LFTs and lipase),and there 
is preliminary evidence of deep and durable responses in the N+I arm in advanced melanoma 
(CA209004). Therefore, a discussion of the risk/benefit of the regimen will be triggered if the 
following criteria are met:
A majority of subjects 
who 
discontinue due to 
treatment-related 
AEs 
have 
deep 
tumor response 
(ie, > 80% reduction)
All treatment-related AEs leading to discontinuation are non-fatal, reversible and without 
severe sequela (ie, GI perforation)
A majority of the treatment related AEs are laboratory in nature, asymptomatic, and 
monitorable via routine blood draws
If a decision is made to 
continue with a regimen because 
of a favorable 
risk/benefit 
profile 
(ie,non-
fatal AEs in subjects with near CRs that are durable) and despite meeting the ‘not 
tolerable’ criteria 
above, then IRBs must be notified, ICFs must be updated, and discussion of the risk/benefit must 
be documented with all future subjects who enroll on this regimen.
3.1.3
Screening
Begins by establishing the subject’s initial eligibility and signing of the informed consent form 
(ICF).
Subject is enrolled using the Interactive Voice Response System (IVRS) must be provided for 
biomarker analyses. 
Tumor tissue obtained in the metastatic setting or from an unresectable site of disease 
Sufficient tumor tissue (as determined by local pathologist) obtained before start of study 
treatment in the metastatic setting or from an unresectable site (block or minimum of 
30slides, obtained from core biopsy, punch biopsy, excisional biopsy or surgical 
specimen) will be submitted to the central laboratory. 
The central lab must provide IVRS with confirmation of receipt of evaluable tumor tissue 
prior to initiating study treatment. 
For subjects 
where 
a biopsy is not 
feasible, 
archival tumor 
material must 
be made available. 
Subjects should have not received systemic therapy subsequent to archived biopsy. 
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An additional source of tumor tissue must be available if the tissue obtained adhering to 
the above guidelines cannot be tested due to poor quality or quantity. Accordingly, all 
subjects must also have archive tumor tissue obtained prior to the last systemic therapy 
received in the metastatic setting or from an unresectable site of disease. 
For all cohorts, medical record documentation of MSI testing results will be available prior to 
screening. Detailed instructions of the obtaining, processing, labeling, handling, storage,and 
shipment of these specimens will be provided in a separate Laboratory Manual at the time of 
study initiation. 
Determine KRAS and BRAF Mutation status. This test is expected to be already performed 
for this population.
Baseline disease or tumor imaging assessments should be performed within 28 days of 
Treatment Day 1 (according toTable 5.1-1)
Subject is assessed for study eligibility within the required timeframe found inTable 5.1-1.
The screening phase either ends with confirmation of full eligibility and treatment assignment 
for the subject, or with the confirmation that the subject is a screen failure.
See subsections in Section 3.3.1for cohort-specific screening requirements. 
3.1.4
Treatment
3.1.4.1
Study Treatment Duration (MSI-H Cohorts Only) 
In MSI-H Cohorts only [mStage 1/2,cStage 1/2, C3 (1L), C5 (BMS-986016 /anti-LAG3] study 
treatment will be given until one of the following conditions ismet, whichever occurs first:
1)Disease 
progression, 
except for 
subjectseligible for 
treatment 
beyond 
progression 
(See 
Section 
4.3.8)
2)Unacceptable toxicity
3)Withdrawal of consent
4)Maximum clinical benefit(optional)-Subjects who attainallof the following criteriawill 
have the option to discontinue treatment:
a)Maximum clinical benefit per Investigator 
b)Minimum 12 months of treatment (in the absence of unacceptable toxicity) after date of 
first response (PR or CR) if the patient achieved response
c)Minimum 24 months between first dose of study treatment and discontinuation for 
maximum clinical benefit 
d)No progression since week 12 of study treatment. 
Restaging imaging must be evaluated before decision to discontinueat maximum clinical 
benefit.If the subject’s BOR is SD, it is encouraged to ensure approximately 24 months of 
treatment before 
the decision to discontinue at maximum clinical benefit in order 
to capture 
any late responses.  
Please see Section3.1.4.8andFigure 3.1.4.8-1:for treatment options upon progression for 
subjectswho discontinue at maximum clinical benefit per above description. All criteria
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listed abovemust have been met and the subjectmust have continued required safety and 
efficacy follow up procedures to be eligible for re-initiation consideration. 
Re-initiation of treatment is an option for eligible MSI-H subjects who progress within 1 
year (52 weeks) of discontinuation for maximum clinical benefit. Subjects who 
discontinuation for maximum 
clinical benefit 
and 
progress after 
52 
weeks 
of follow-up will 
not have the option to re-initiate treatment.
5)The end of study
3.1.4.2
MSI-H Nivolumab Monotherapy (Arm N): mStage 1 and 2
Administration of nivolumab should begin within 3 days of treatment assignment. 
Women of child bearing potential (WOCBP) must have a negative pregnancy test to be done 
within 24 hours prior to first dose, and then every 4 weeks (1 week) regardless of dosing 
schedule.
On trial laboratory and vital sign assessments (after D1W1) should be drawn within 72 hours 
prior to dosing according to the schedule inTable 5.1-2. Specific laboratories will be 
performed more frequently during the first dose administration (according toTable 5.1-2). 
Adverse event assessments should be documented at each clinic visit.
Biomarker, PK,and immunogenicity samples will be obtainedaccording to the schedules in Table 
5.5.1-2andTable 5.6.8-1.
Study drug dosing may be delayed for toxicity up to 6 weeks from the last dose. See 
Section4.3.3.
Patient-reported 
outcome(s) (PRO) instruments (EORTC QLQ-C30 & EQ-5D Questionnaires) 
will be completed for subjects,except for those enrolled in the non-MSI-H Safety Cohort,
following drug vial assignment but before first dose and every 6 weeks thereafter perTable 
5.1-2.
Nivolumab is administered as an IV infusion at a dose of 480 mg Q4W (replacing the dose of 
3 mg/kg every 2 weeks)until discontinuation of study therapyand for reasons described in 
Section 3.1.4.1, Study Treatment Discontinuation.in subjects receiving nivolumab beyond 
progression, discontinuation due to toxicity, withdrawal of consent, or the study ends.
This phase ends when the subjectis discontinued from study therapyfor reasons specified in 
Section3.5and Section4.3.6. Subjects who discontinue treatment at Maximum Clinical 
Benefit as specified in Section 3.1.4.1may re-initiate 
treatment (see Sections 3.1.4.8and 4.3.1) 
if all eligibility criteria are met(Section4.3.9). All subjects will proceed to follow-up as 
described in Section 3.1.9and in Table 5.1-7regardless of the reason for discontinuation from 
the originaltreatmentphase of the study. Study scheduleofassessmentsfor re-initiation 
screening, re-initiation treatment,and follow-up after re-initiation are presented in Section 5.1.
3.1.4.3
MSI-H Nivolumab + Ipilimumab(Arm N+I): cStage 1 and 2
Administration of nivolumab in combination with ipilimumab should begin within 3 days from 
treatment assignment
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Women of child bearing potential (WOCBP) must have a negative pregnancy test within 24 
hours prior to first dose, andthen every 4 weeks (1 week) regardless of dosing schedule.
Adverse event assessments will be documented at each visit throughout the study.
On trial laboratory and vital sign assessments (after D1W1) should be drawn within 72 hours 
prior to dosing according to the schedule inTable 5.1-3. Specific laboratories will be 
performed more frequently during the treatment administration (according toTable 5.1-3).
Biomarker, PK and immunogenicity samples will be obtainedaccording to the schedules inTable 
5.5.1-1andTable 5.6.8-2.
Study drug dosing may be delayed for toxicity up to 6 weeks from the last dose. See 
Section4.3.3.
Patient-reported 
outcome(s) (PRO) instruments (EORTC QLQ-C30 & EQ-5D Questionnaires) 
will be completed forall subjects,except for those enrolled in the non-MSI-H Safety Cohort,
following drug vial assignment but before firstdose, and every 6 weeks thereafter perTable 
5.1-3.
For Weeks 1-12, the non-MSI-H safety cohortwill provide the dosing level for the every three 
week dosing of nivolumab in combination with ipilimumab:
For Weeks 13 and following (beyond Dose4 of nivolumab in combination with ipilimumab), 
nivolumab is administered as an IV infusion at a dose of 480 mg Q4W (replacing the dose of 
3 mg/kg every 2 weeks). 
Administration of nivolumab in combination with ipilimumab (Dose 1 through Dose 4 of 
combination) or nivolumab alone (beyond Dose 4/Week 12 of combination) continues until 
discontinuation of study therapyfor reasons described in Section 3.1.4.1, “Study Treatment 
Duration”.
This phase ends when the subjectis discontinued from study therapyfor reasons specified in 
Section3.5and Section4.3.6. Subjects who discontinue treatment at Maximum Clinical 
Benefit as specified in Section 3.1.4.1may re-initiate 
treatment (see Sections 3.1.4.8and 4.3.1) 
if all eligibility criteria are met (Section4.3.9.). All subjects will proceed to follow-up as 
described in Section 3.1.9and in Table 5.1-7regardless of the reason for discontinuation from 
the original treatment phase of the study. Study schedule of assessments for re-initiation 
screening, re-initiation treatment, and follow-up after re-initiation are presented in Section 5.1.
3.1.4.4
Non-MSI-H Safety Cohort (Nivolumab + Ipilimumab)
Administration of nivolumab in combination with ipilimumab should begin within 3 days of 
treatment assignment. 
Women of child bearing potential (WOCBP) must have a negative pregnancy test within 24 
hours prior to first dose, and then every 4 weeks (1 week) regardless of dosing schedule.
Dose Escalation Phase: 
Dose Level -1, Nivolumab 0.3 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for 
4 doses, then nivolumab 3 mg/kg IVQ2W
Dose Level 1, Nivolumab 1 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W for 
4doses, then nivolumab 3 mg/kg IV Q2W. 
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Dose Level 2: Randomization (1:1) to the following arms
Dose Level 2a:Nivolumab 1 mg/kg IV combined with ipilimumab 3 mg/kg IV Q3W
for 4 doses, then nivolumab 3 mg/kg IV Q2W.
Dose Level 2b:Nivolumab 3 mg/kg IV combined with ipilimumab 1 mg/kg IV Q3W 
for 4 doses, then nivolumab 3 mg/kg IV Q2W.
Staged Enrollment Phase: Dose Level determined in Dose Escalation Phase. SeeTable 3.1.2.1-1, 
Table 3.1.2.1-2,Table 3.1.2.1-3, andTable 3.1.2.1-4.
Adverse event assessments will be documented at each visit throughout the study.
On-study laboratory assessments (after D1W1) should be drawn within 72 hours prior to 
dosing according to the schedule inTable 5.1-3.
Biomarker, PK,and immunogenicity samples will be obtainedaccording to the schedules in Table 
5.5.1-1andTable 5.6.8-2.
Study drug dosing may be delayed for 
toxicity for up 
to 6 weeks from the last dose. 
See Section 
4.3.3.
For Weeks 13 and following (beyond Dose 4 of nivolumab in combination with ipilimumab), 
nivolumab is administered as an IV infusion at a dose of 3 mg/kg every 2 weeks. 
Administration of nivolumab in combination with ipilimumab (Dose 1 through Dose 4 of 
combination) or nivolumab alone (beyond Dose 4/Week 12 of combination) continues until 
disease progression or until discontinuation of study therapy in subjects receiving study 
therapy beyond progression, discontinuation due to toxicity, withdrawal of consent, or the 
study ends.
This phase ends when the subject is discontinued from study therapy. Please refer to 
Section3.5and Section4.3.6for reasons for discontinuation.
3.1.4.5
MSI-H C3Cohort (No Prior Treatment in Metastatic Setting, Nivolumab + 
Ipilimumab)
Administration of nivolumab in combination with ipilimumab should begin within 3 days of 
treatment assignment. 
Women of child bearing potential (WOCBP) must have a negative pregnancy test within 24 
hours prior to first dose, and then every 4 weeks (1 week) regardless of dosing schedule.
Adverse event assessments will be documented at each visit throughout the study.
On-study laboratory assessments (after D1W1) should be drawn within 72 hours prior to 
dosing according to the schedule inTable 5.1-4. 
Biomarker, PK and immunogenicity samples will be obtainedaccording to the schedules in
Table 5.5.1-3andTable 5.6.8-3.
Study drug dosing may be delayed for 
toxicity for up 
to 6 weeks from the last dose. 
See Section 
4.3.3.
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Administration of study drug continues until discontinuation of study therapy for reasons 
described in Section 3.1.4.1, “Study Treatment Duration”.
Patient-reported 
outcome(s) (PRO) instruments (EORTC QLQ-C30 & EQ-5D Questionnaires) 
will be completed following drug vial assignment but before first dose, and every 6 weeks 
thereafter perSection 5.7.
This phase ends when the subjectis discontinued from study therapyfor reasons specified in 
Section3.5and Section4.3.6. Subjects who discontinue treatment at Maximum Clinical 
Benefit as specified in Section 3.1.4.1may re-initiate 
treatment (see Sections 3.1.4.8and4.3.1) 
if all eligibility criteria are met (Section 4.3.9.). All subjects will proceed to follow-up as 
described in Section 3.1.9and in Table 5.1-7regardless of the reason for discontinuation from 
the original treatment phase of the study. Study schedule of assessments for re-initiation 
screening, re-initiation treatment, and follow-up after re-initiation are presented in Section 5.1.
3.1.4.6
MSI-H C5 Cohort (2L inMetastatic Setting, Nivolumab + BMS-986016)
Administration of nivolumab in combination with BMS-986016 should begin within 3 days of 
treatment assignment. 
Women of child bearing potential (WOCBP) must have a negative pregnancy test within 24 
hours prior to first dose, and then every 4 weeks (1 week) regardless of dosing schedule.
Adverse event assessments will be documented at each visit throughout the study.
Neurological exams by a neurologistshould be performedin subjects who experience a study 
drug related Grade 2 neurological AE.
On-study laboratory assessments, including cardiac troponin levels,(after D1W1) should be 
drawn within 72 hours prior to dosing according to the schedule in Table 5.1-5. 
12-lead ECG to be performed within 72 hours prior to dosing
Biomarker, PK,and immunogenicity samples will be obtainedaccording to the schedules in 
Table 5.5.1-4and Table 5.6.8-3.
Study drug dosing may be delayed for 
toxicity for up 
to 6 weeks from the last dose. 
See Section 
4.3.3.
Administration of study drug continues until discontinuation of study therapy for reasons 
described in Section 3.1.4.1, “Study Treatment Duration”..
Patient-reported 
outcome(s) (PRO) instruments (EORTC QLQ-C30 & EQ-5D Questionnaires) 
will be completed following drug vial assignment but before first dose, and every 6 weeks 
thereafter perTable 5.1-5.
This phase ends when the subjectis discontinued from study therapyfor reasons specified in 
Section3.5and Section4.3.6. Subjects who discontinue treatment at Maximum Clinical 
Benefit as specified in Section 3.1.4.1may re-initiate 
treatment (see Sections 3.1.4.8and 4.3.1) 
if all eligibility criteria are met (Section 4.3.9.). All subjects will proceed to follow-up as 
described in Section 3.1.9and in Table 5.1-7regardless of the reason for discontinuation from 
the original treatment phase of the study. Study schedule of assessments for re-initiation 
screening, re-initiation treatment, and follow-up after re-initiation are presented in Section 5.1.
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3.1.4.7
non-MSI-H C6 Cohort (Nivolumab + Daratumumab)
Administration of study drugshould begin within 3 days of treatment assignment. 
Women of child bearing potential (WOCBP) must have a negative pregnancy test within 
24hours prior to first dose, and then every 4 weeks (1 week) regardless of dosing schedule.
Adverse event assessments will be documented at each visit throughout the study.
On-study laboratory assessments (after D1W1) should be drawn within 72 hours prior to 
dosing according to the schedule inTable 5.1-6. 
Herpes Zoster virus antiviral prophylaxis should be initiatedwithin 1 week after starting 
daratumumaband continue during the Treatment Phase per institutional guidelines, and for 
3months following treatment discontinuation.
Biomarker, PK,and immunogenicity samples will be obtainedaccording to the schedules in 
Table 5.5.1-5and Table 5.6.8-3.
Study drug dosing may be delayed for 
toxicity for up 
to 6 weeks from the last dose. 
See Section 
4.3.3.
Administration of study drug continues until disease progression or until discontinuation of 
study therapy in subjects receiving study therapybeyond progression, discontinuation due to 
toxicity, withdrawal of consent, or the study ends.
Patient-reported 
outcome(s) (PRO) instruments (EORTC QLQ-C30 & EQ-5D Questionnaires) 
will be completed following drug vial assignment but before first dose, and every 6 weeks
through Week 24 and then at each dose, starting with Week 25 according to Table 5.1-6.
This phase ends when the subject is discontinued from study therapy. Please refer to 
Section3.5andSection 4.3.6for reasons for discontinuation.
3.1.4.8
Treatment Options Upon Progression after Treatment Discontinuation 
At Maximum Clinical Benefit
Subjectswho have discontinued study treatment after achievingmaximum clinical benefit as 
specifiedin Section 3.1.4.1must continue imaging every 12 weeks,and the investigator must 
ensure close monitoring of symptoms and complete safety follow up as indicated for AEs. 
If progression occurs 52 weeks afterlast dose of study treatment,subjects have the 
optionto re-initiate treatment with nivolumabmonotherapy, or the combination of nivolumab 
with ipilimumab or with BMS-986016 (anti-LAG3) based on the initial cohort assignment,
following new baseline assessments for eligibility. 
The inclusion/exclusion criteria for re-initiation are described in Section4.3.9. Re-initiation 
treatment 
schedules 
are 
described in 
Section4.3.1and 
Table 
4.3.1-1. 
Time and 
events schedule 
of study assessmentsduring  re-initiationscreening, during re-initiation treatment and during 
follow-upafter re-initiation are included in Section 5.1
Treatment duration after re-initiation,inclusive of treatment beyond progression,will befora 
maximum of 24 months.
If progressionoccurs >52 weeksafter last dose of study treatment, continue survival 
follow-up per Table 5.1-7. 
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Re-initiation of treatment is not permittedafter 52 weeks of discontinuation at maximum 
clinical benefit.
Subjects who discontinue re-initiated treatment for PD are eligible for treatment beyond 
progression (SeeSection 4.3.8).
Treatment options for subjects in MSI-H cohorts who discontinue treatment at maximum clinical 
benefit are presentedbelow:
Figure 3.1.4.8-1:
Treatment Options at Progression for MSI-H subjects who 
Discontinue Treatment at Maximum Clinical Benefit
3.1.5
Review of Safety
The subjects’ safety will be monitored on an ongoing basis as described fully in Section 6.
Decisions for the safety evaluation phase of Arm N+I and for continuing from Stage1 to Stage2 
in both 
treatment arms will be made in conjunctionwith the investigators. In addition, a BMS SMT
routinely reviews safety signals across the entire nivolumab program including combination 
studies with ipilimumab.
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3.1.6
Treatment beyond progression
Treatment beyond investigator-assessed RECIST 1.1-defined progression will be permitted if the 
subject experiences investigator-assessed clinical benefit and the subject is tolerating the study 
treatment. All decisions to continue treatment beyond initial progression must be discussed with 
the BMS Medical Monitor.Subjects who re-initiate treatment are eligible for treatment beyond 
progression. See Section 4.3.8for additional details.
3.1.7
Intrasubject Dose Reductions
Intrasubject dose reduction is not permitted for any reason. Dose delays for the management of 
study treatment-related adverse events are described in Section 4.3.3.
3.1.8
Mandatory Availability of Tumor Material
Tumor tissue must be submitted to the Central Laboratory prior to treatment for retrospective 
biomarker analyses.Submission of tumor tissue prior to start of re-initiation is optional, but 
strongly encouraged. 
3.1.9
Follow up
3.1.9.1
Follow -up for all Cohorts After Initial Study Treatment
Follow-up 
begins 
when 
the 
decision to 
discontinue a subject from study 
therapy is made (no further 
treatment with study therapy).
Subjects whostarted a systemic cancer treatment 
outside of this study will not continue with tumor 
imaging assessments.
Subjects who discontinue treatment for reasons other than tumor progression will continue to have 
tumor imaging assessments beginning 6 weeks (1week) after first dose and continuing every 6 
weeks (1 week) for the first 24 weeks from first dose, and every 12weeks (1week) thereafter 
until disease progression (investigator-assessed RECIST 1.1-defined progression). 
In order to help reduce unnecessary participant burden and help optimize participant safety by 
reducing the possible radiation exposure risk of a secondary malignancy, investigators should 
reduce scan frequency for participants having disease control 3 years after the first doseper Table 
5.1-14b.The participant’s tumor assessment schedule should be modified to every 24 weeks,
unless clinically indicated,to continue tumor assessments every 12 weeks.
Subjects will be followed for drug-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.
After completion of the first two follow-up visits, subjects enrolled in the MSI-H cohort 
(Cohorts N and N+I) and Cohorts C3, C4, C5, and C6 willcontinue to survival follow-upper 
Table 5.1-7.Please see Section 3.1.10for end of the study definitionand duration of follow-
up for survival.
Refer to Table 5.1-7for additional follow-up assessments. 
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3.1.9.2
Follow-up for Re-initiated Subjects in MSI-H Cohorts 
Follow-up for re-initiated subjects begins when the decision to discontinue a subject from re-
initiated study therapy is made (no further treatment with study therapy).Refer to Table 5.1-13for 
the schedule of assessments after the discontinuation of re-initiated treatment. 
3.1.10
End of StudyDefinition
The start of the trial is defined as FPFV.The study will conclude whena minimum of 5 yearsof 
follow-up fromfirst treatmentfor the last participant is reached or survival follow-up is concluded
for all subjects, whichever occurs first.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.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has been 
performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or investigator may include, but are 
not limited to:
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local Health Authorities, the Sponsor’s procedures, or GCP guidelines
Inadequate recruitment of participants by the investigator
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
3.2
Post Study Access to Therapy
At the conclusion of the study, subjects who continue to demonstrate clinical benefit will be 
eligible to receive study drug. Study drug 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 study drug if 
any of the following occur: a) 
the marketing application is rejected by responsible health authority; 
b) the study is terminated due to safety concerns; c) the subject can obtain medication from a 
government sponsored or private health program; or d) therapeutic alternatives become available 
in the local market.
3.3
Study Population
For entry into the study, the following criteria must be met.
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3.3.1
Inclusion Criteria
1)Signed Written Informed Consent
a)Subjects 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 subject care.
b)Subjects must be willing and able to comply with scheduled visits, treatment schedule,
laboratory tests, tumor biopsies, and other requirements of the study.
2)Target Population
a)Histologically confirmed CRC
b)Metastatic or recurrent CRC
c)Microsatellite instability expression detected by an accredited laboratory per local
regulations, see Section 3.1.1and Appendix 4
i) Subjects with MSI-Htumors will enroll in the MSI-H Cohort(Cohort N and Cohort N
+I) (mStage and cStage groups),the C3Cohort, and the C5 Cohort.
ii)Subjects with phenotypes that are non-MSI-H will enroll in the non-MSI-H Safety
Cohortand the C6 Cohort.
d)Prior treatment:
i) For subjects with recurrent or metastatic CRCin the MSI-H Cohorts:
(1)Progression during, after, or have been intolerant to 1 line treatment(s) for their
metastatic disease, which must include at least
(i)A fluoropyrimidine, and
(ii)Oxaliplatin or irinotecan,
1.Subjects who received oxaliplatin in an adjuvant setting should have
progressed during or within 6 months of completion of adjuvant
therapy in order for oxaliplatin to count as a prior therapy needed for
entry.
OR 
(2)Subject actively refuses chemotherapyfor the treatment of metastatic (Stage IV) or
locally advanced disease considered as standard treatment for this disease stage,
despite being informed by the investigator about the treatment options. The
subject’s refusal must be thoroughly documented. The investigator will discuss
each individual subject refusing chemotherapy with the sponsor’s medical monitor
to confirm eligibility.
ii)For subjects with non-MSI-H CRC for the non-MSI-H Safety Cohort:
(1)Progression during, after, or been intolerant following the last administration of
approved standard therapies, which must include at minimum a fluoropyrimidine
and oxaliplatinoririnotecan, as well as at least one of the following agents, if
approvedin standard national guidelines, 
bevacizumab, 
cetuximab 
or panitumumab
(if KRAS wild type), and regorafenib.
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OR
(2)Subject actively refuses chemotherapy(including drugs or biologics)for the 
treatment of metastatic (Stage IV) or locally advanced disease considered as 
standard treatment for this disease stage, despite being informed by the investigator 
about the treatment options. The subject’s refusal must be thoroughly documented. 
The investigator will discuss each individual subject refusing chemotherapy with 
the sponsor’s medical monitor to confirm eligibility.
iii)For subjects with metastatic or recurrent CRC in the MSI-H C3 Cohort, subjects must 
have not had treatment for their metastatic disease.
iv)For subjects with metastatic or recurrent CRC in the C6Cohort:Progression during, 
after, or been intolerant following the last administration of approved standard 
therapies, which must include at minimum a fluoropyrimidine, and oxaliplatin or 
irinotecan
e)Subjects must have measurable disease per RECIST 1.1. Subjects with lesions in a 
previously irradiated field as the sole site of measurable disease will be permitted to enroll 
provided the lesion(s) have demonstrated clear progression and can be measured 
accurately.
f) Subject willing to comply to provide tumor tissue (archival or fresh biopsy specimen), 
including possible pre-treatment biopsy, for PD-L1 expression analysis and other 
biomarker correlative studies(See Section 3.1.3for additional detailsregarding the 
requirements for tumor tissue). 
g)ECOG Performance Status of 0-1. See Appendix 2 for ECOG Performance Status scale. 
h)Prior palliative radiotherapy must have been completed at least 2 weeks prior to study drug 
administration.
i) Screening laboratory values must meet 
the following criteria and should be obtained within 
14 days prior to first dose:
i) WBC 2000/μL
ii)Neutrophils 1500/μL
iii)Platelets 100 x10
3/μL
iv)Hemoglobin > 9.0 g/dL 
v)Serum creatinine 1.5 x ULN or creatinine clearance (CrCl) 40 mL/min (using the 
Cockcroft-Gault formula):
Female CrCl = (140 -age in years) x weight in kg x 0.85
72 x serum creatinine in mg/dL
Male CrCl = (140 -age in years) x weight in kg x 1.00
72 x serum creatinine in mg/dL
vi)AST/ALT 3x ULN 
(1)For subjects in Cohort 6: AST/ALT 2.5 x ULN
vii)Total Bilirubin 1.5 x ULN (except subjects with Gilbert Syndrome, who can have 
total bilirubin <3.0 mg/dL). 
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viii) Cardiac Troponin T (cTnT) 
or I 
(cTnI) ≤ 2 × institutional ULN. Subjects with cTnT 
or cTnI levels between > 1 
to 
2 × ULN will be permitted if repeat levels within 24hours 
are 1 ULN (Cohort C5 only)
(1)If cTnT or cTnI levels are >1 ULN at 24 hours, the subject may undergo a cardiac 
evaluation and be considered for treatment, following a discussion with the BMS 
Medical Monitor or designee.
j) Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the 
study as a pre-treatment failure (ie, subject has not been treated / has not been treated). If 
re-enrolled, the subject must be re-consented.
k)LVEF assessment with documented LVEF 50% by either TTE 
or MUGA (TTE preferred 
test) within 6 months from first study drug administration (Cohort C5 only)
3)Age and Reproductive Status
a)Men and women, ages 18 years of age
b)Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24hours 
prior to the start of study drug.
c)Women must not be breastfeeding
d)WOCBP must agree to follow instructions for method(s) of contraception from the time of 
enrollment for the duration of treatment with study drug(s) plustime required for the 
investigational drug to undergo approximately five half-lives plus 30 days (duration of 
ovulatory cycle) for a total of5 monthspost treatment completion.
e)Men who are sexually active with WOCBP must agree to follow instructions for method(s) 
of contraception for the duration of treatment with study drug(s) plus time required for the 
investigational drug to undergo approximately five half-livesplus 90days (duration of 
sperm turnover) for a total of 7 months post-treatment completion.
f) Azoospermic males and WOCBP who are continuously not heterosexually activeare 
exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy 
testing as described in these sections.
g)During the study and for 3 months after receiving the last dose of daratumumab, a woman 
must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on 
the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the 
use of highly effective methods of contraception. Highly effective methods of contraception have 
a failure rate of < 1% per year when used consistently and correctly.
At a minimum, subjects must agree to use one highly effective method of contraception See 
Appendix 5 for recommendedmethods ofcontraception.
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3.3.2
Exclusion Criteria
1)Target Disease Exceptions
a)Active brain metastases or leptomeningeal metastases. Subjects 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 (>10mg/day 
prednisone equivalents) for at least 2 weeks prior to study drug administration.
2)Medical History and Concurrent Diseases
a)Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may 
increase the risk associated with study participation or study drug administration, impair 
the ability of the subject to receive protocol therapy, or interfere with the interpretation of 
study results.
b)Prior malignancy active within the previous 3 years except for locally curable cancers that 
have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder 
cancer, or carcinoma in situ of the prostate, cervix, or breast.
c)Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type 
I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring 
hormone replacement, psoriasis not requiring systemic treatment, or conditions not 
expected to recur inthe absence of an external trigger are permitted to enroll.
d)Subjects with a condition requiring systemic treatment with either corticosteroids (>10mg 
daily prednisone equivalents) or other immunosuppressive medications within 14 days of 
study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 
mg daily prednisone equivalents are permitted in the absence of active autoimmune 
disease.
e)Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any 
other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint 
pathways, including prior therapy with anti-tumor vaccines or other immuno-stimulatory 
antitumor agents.Prior treatment with daratumumab or other anti-CD-38 therapies.
f) All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must 
have resolved to Grade 1 (NCI CTCAE version 4) or baseline before administration of 
study drug. Subjects with toxicities attributed to prior anti-cancer therapy which are not 
expected to resolve and result in long lasting sequelae, such as neuropathy after platinum 
based therapy, are permitted to enroll.
g)Treatment with any chemotherapy, curative intent radiation therapy, biologics for cancer, 
or investigational therapy within 
28 
days 
of first 
administration 
of 
study 
treatment 
(subjects 
with prior cytotoxic or investigational products < 4 weeks prior to treatment might be 
eligible after discussion between investigator and sponsor, if toxicities from the prior 
treatment have been resolved to Grade 1 (NCI CTCAE version 4).Prior focal palliative 
radiotherapy must have been completed at least 2 weeks before study drug administration.
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h)Active neurological disease or confirmed history of encephalitis, meningitis, or 
uncontrolled seizures in the year prior to informed consent for Cohort C5 only
i) Uncontrolled or significant cardiovascular disease including, but not limited to, any of the 
following (Cohort C5 only):
i) Myocardial infarction (MI) or stroke/transient ischemic attack (TIA) within the 
6months prior to consent
ii)Uncontrolled angina within the 3 months prior to consent
iii)Any history of clinically significant arrhythmias (such as ventricular tachycardia, 
ventricular fibrillation, or torsades de pointes)
iv)QTc prolongation > 480 msec
v)History of other clinically significant cardiovascular disease (ie, cardiomyopathy, 
congestive heart failure with New York Heart Association [NYHA] functional 
classification III-IV, pericarditis, significant pericardial effusion, significant coronary 
stent occlusion, deep venous thrombosis, etc )
vi)Cardiovascular disease-related requirement for daily supplemental oxygen 
vii)History of two or more MIs OR two or more coronary revascularization procedures
viii) Subjects with history of myocarditis, regardless of etiology
j) For Cohort C6only
i) Known history of stage 3 or 4 chronic obstructive pulmonary disease (COPD). 
ii)Known moderate or severe persistent asthma within the past 2 years, or uncontrolled 
asthma of any classification. Note that subjects who currently have controlled 
intermittent asthma or controlled mild persistent asthma are allowed to participate in 
the study.
iii)Screening 12-lead ECG showing a baseline QT interval as corrected (QTc) >480msec
iv)Vaccination with live attenuated vaccines within 4 weeks of first study agent 
administration 
3)Physical and Laboratory Test Findings
a)Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus 
(ribonucleic acid or HCV antibody) indicating acute or chronic infection
b)Known history of testing positive for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS).
4)Allergies and Adverse Drug Reaction
a)History of allergy to study drug components.
b)History of severe hypersensitivity reaction to any monoclonal antibody.
5)Sex and Reproductive Status
a)WOCBP whoare pregnant,breastfeeding
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b)Women with a positive pregnancy test at enrollment or prior to administration of study 
medication
6)Other Exclusion Criteria
a)Prisoners or subjects who are involuntarily incarcerated
b)Subjects 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 
subjects and that the results of the study can beused. It is imperative that subjects fully meet all 
eligibility criteria.
3.3.3
Women of Childbearing Potential
A woman of childbearing potential (WOCBP) is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause 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, 
women under the age of 55 years must have a serum follicle stimulating hormone, (FSH) level > 
40mIU/mL to confirm menopause.*
*Women treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their judgment 
in checking serum FSH levels. If the serum FSH level is > 40 mIU/ml at any time during the 
washout period, the woman can be considered postmenopausal:
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermal products
8 week minimum for oral products
Other parenteral products may require washout periods as long as 6 months.
3.4
Concomitant Treatments
3.4.1
Prohibited and/or Restricted Treatments
The following medications are prohibited during the study:
Immunosuppressive agents (except to treat a drug-related adverse event)
Systemic corticosteroids > 10 mg daily prednisone equivalent (except as stated in Section3.4.3
or to treat a drug-related adverse event). 
Live/attenuated vaccines (eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles, 
mumps, rubella [MMR]) 
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Any concurrent antineoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
radiation therapy except for palliative radiation therapy described in Section 3.4.3or standard 
or investigational agents for treatment of cancer).
Coronavirus disease 2019 (COVID-19)vaccines that are NOT live are permitted during the 
study and after the last dose of investigation product.Non-live COVID-19 vaccination is 
considered a simple concomitantmedication within the study. However, the efficacy and 
safety of non-live
vaccines (including non-live COVID-19 vaccines) in participants receiving
study drugis unknown.
The following are NOT live vaccines: inactivated vaccines (eg, heat-killed and formalin-
killed vaccines), subunit vaccines (eg, influenza and pneumococcal vaccines), toxoid 
vaccines, nucleic acid vaccines that do not encode potentially infectious virus (eg, 
Pfizer/BioNTech and Moderna COVID-19 vaccines) and replication-incompetent 
recombinant vector vaccines (eg, AstraZeneca/University of Oxford COVID-19 vaccine).
Please contact the Clinical Trial Physician/Medical Monitor with any questions related to 
COVID-19 vaccines.
Supportive care for disease-related symptoms may be offered to all subjects on the trial.
3.4.2
Other Restrictions and Precautions
3.4.2.1
Surgical Resection Following Initial Response
Investigators may choose to resect solitary lesions in subjects with residual disease and render the 
subject free of macroscopic disease. Subjects enrolled in this study may have lesions surgically 
resected only following consultation with the Medical Monitor and following the Week 24 tumor 
imaging assessments. If additional tumor shrinkage is noted compared to the tumor imaging 
assessments at Week18, it is highly encouraged 
that surgical resection be delayed until subsequent 
scans fail to demonstrate further shrinkage. Subjects with a confirmed PR who go on to have 
surgical resection of remaining disease will be considereda PR. Subjects with SD who go on to 
have surgical resection of remaining disease will be considered a SD. Subjects may continue 
treatment after surgery. Tumor tissue of any resected solitary lesion should be submitted to BMS 
(see Section 5.6.8). Detailed instructions of the obtaining, processing, labeling, handling, storage,
and shipment of these specimens will be provided in a separateProcedure Manual at the time of 
study initiation.
3.4.2.2
Blood Typing (C6 Cohort Only)
Blood Type, Rh, and IAT(Indirect Antiglobulin Test)should be done before the first dose of 
daratumumab. Subject RBC phenotyping (standard 
or extended) is an alternative option to 
the IAT 
test, if locally required. Either method must be completed prior to first daratumumab infusion.
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to identify 
a patient’s antibodies to minor antigens so that suitable donor blood can be given for transfusion. 
Daratumumab does not interfere with ABO/RhD typing. CD38 is expressed at very low levels on 
erythrocytes. Daratumumab binds to the CD38 on erythrocytes, which results in a positive IAT 
(Indirect Coombs Test). This positive result masks the detection of antibodies to minor antigens 
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and may prevent or delay blood banks from issuingdonor blood for transfusion. This effect occurs 
during daratumumab treatment and for up to 6 months after treatmentends. Subjects will receive 
a patient identification wallet card for the study that includes the blood profile (ABO, Rh, and IAT 
or phenotyping) determined before the first infusion of daratumumab along with information on 
the IAT interference for healthcare providers/blood banks. Subjects are to carry this card 
throughout the treatment period and for at least 6 months after treatment ends. Blood banks can 
eliminate the daratumumab interference with IAT by treating reagent RBCs with dithiothreitol 
(DTT).
105
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include:
1)Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units
2)Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs
Uncrossmatched, 
ABO/RhD compatible 
RBC 
units 
should 
be 
administered if 
transfusion is needed 
emergently as per local blood bank practice.
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies.
3.4.2.3
Herpes Zoster VirusAntiviral Prophylaxis (C6 Cohort Only)
Prophylaxis for Herpes Zoster Virus reactivation is recommended for patients receiving 
daratumumab in this study. In the randomized controlled combination therapy studiesof patients 
with multiple myeloma with daratumumab, herpes zoster was reported in 2%-5% of subjects.
103
Oral Prophylaxis for herpes zoster reactivation is recommended during the Treatment Phase. 
Initiate antiviral prophylaxis within 1 week after starting daratumumab. Continue antiviral 
prophylaxis during the Treatment Phase as per institutional guidelines and for 3 months following 
treatment discontinuation. 
3.4.3
Permitted Therapy 
Subjects are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses including 
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.
The potential for overlapping toxicities with radiotherapy and nivolumab alone or in combination 
with either ipilimumab, BMS-986016, or daratumumabcurrently is not known. Therefore, 
palliative radiotherapy is not recommended while receiving study drugs. If palliative radiotherapy 
is required, then study drugsshould be withheld for at least 1 week before, during,and 1 week 
after radiation. Subjects should be closely monitored for any potential toxicity during and after 
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receiving radiotherapy, and AEs considered related to radiotherapy should resolve to Grade1 
prior to resuming study drugs. Only non-target lesions included in the planned radiation field or 
CNS lesions may receive palliative radiotherapy. Details of palliative radiotherapy should be 
documented in the source records and electronic case report form (eCRF). Details in the source 
records should include: dates of treatment, anatomical site, dose administered and fractionation 
schedule, and adverse events. Subjects receiving limited field palliative radiation therapy will be 
considered to have unequivocal progression of disease in the non-target lesion. Symptoms 
requiring palliative radiotherapy 
should 
be 
evaluated 
for 
objective 
evidence 
of 
disease 
progression. 
Administration of additional study drugsto subjects who received limited field palliative radiation 
should follow guidelines specified in Section 4.3.8Treatment beyond Disease Progression.
3.5
Discontinuation of Subjects from Treatment
Subjects MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons:
Subject’s request to stop study treatment
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 subject
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
Any drug-related adverse event requiring discontinuation according to the management 
algorithms in the Appendix of the nivolumab IB. 
Additional protocol specified reasons for discontinuation (see Sections3.1.4.1and 4.3.6)
In the case of pregnancy, the investigator must immediately notify the BMS Medical 
Monitor/designee of this event. In most cases, the study drug will be permanently discontinued in 
an appropriate manner. If the investigator determines a possible favorable benefit/risk ratio that 
warrants continuation of study drug, a discussion between theinvestigator and the BMS Medical 
Monitor/designee must occur.
All subjects who discontinue investigational product should comply with protocol specified 
follow-up procedures as outlined in Section 5. The only exception to this requirement is when a 
subject 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 subject’s completion of the study, the reason for the 
discontinuation must be documented in the subject’s medical records and entered on the 
appropriate case report form (CRF) page.
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3.6
Post Treatment Study Follow up
In this study, objective response rate is the primaryendpoint of the study. Tumor responses 
initiated by immunotherapy with nivolumab or nivolumab combined with ipilimumab, BMS-
986016, and daratumumabmay evolve after treatment discontinuation. Therefore, post treatment 
study follow-up is of critical importance and is essential to preserving subject safety and the 
integrity of the study. Subjects 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 5until 
death or the conclusion of the study.
3.6.1
Withdrawal of Consent
Subjects 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 
subject specifically withdraws consent for any further contact with him/her or persons previously 
authorized by subject to provide this information. Subjects should notify the investigator of the 
decision to withdraw consent from future follow-up in writing, whenever possible. The 
withdrawal of consent should be explained in detail in the medical records by the investigator, as 
to whether the withdrawal is from further treatment with study drug only or also from study 
procedures and/or post 
treatment study follow-up, and entered on 
the appropriate CRF page. In the 
event that vital status (whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in accordance 
with local law.
3.6.2
Lost to Follow-Up
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit:
All reasonable efforts must be made to locate participants to determine and report their 
ongoing status. This includes follow-up with persons authorized by the participant.
Lost to follow-up is defined by the inability to reach the participant after a minimum of 3
documented phone calls, faxes, or emails,as well as lack of response by participant to 1
registered mail letter. All attempts should be documented in the participant’s medical 
records.
If it is determined that the participant has died, the site will use permissible local methods 
to obtain date and cause of death.
If the 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 obtainingthe
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, inorder to obtain updated contact information.
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nivolumab
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.
4
TREATMENTS
Study drugs include both Non-investigational (NIMP) and Investigational Medicinal Products 
(IMP) and can consist of the following:
All products, active or placebo, being tested or used as a comparator in a clinical trial. 
Study required premedication, and 
Other drugs administered as part of the study that are critical to claims of efficacy 
(eg,background therapy, rescue medications)
Diagnostic agents: (such as glucose for glucose challenge) given as part of the protocol 
requirements must also be included in the dosing data collection
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4.1
Study Treatments
Table 4.1-1:
Product Description: Treatment Period
Product Description / 
Class and Dosage Form
Potency/Route of 
Administration
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 or Various 
packaging 
configurations
Refer to the label on container and/or pharmacy manual
Ipilimumab
(BMS-734016) Solution 
for Injection
200 mg
(5 mg/mL)
IP
Open label
Vial or Various 
packaging 
configurations
Refer to the label on container and/or pharmacy manual
Anti-LAG-3
(BMS-986016-01b)
Solution for Injection
100 mg
(10 mg/mL) or 
80mg 
IP
Open label
Vial or Various 
packaging 
configurations
Refer to the label on container and/or pharmacy manual
Daratumumab
Solution for Injection 
100 mg 
(20 mg/mL)
and/or 400 mg (20 
mg/mL)
IP
Open label 
Vial or Various 
packaging 
configurations
Refer to label on container or package insert/summary 
of
product characteristics
a Nivolumab is labeled as BMS-936558-01 Solution for Injection
b Designated as BMS-986016 in the protocol
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4.1.1
Investigational Product
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.
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 subjects. The investigational product must be dispensedonly from official study sites by 
authorized personnel according to local regulations. 
In this protocol, investigational products are: nivolumab and ipilimumab.
The investigational products arenivolumab combined withBMS-986016 for Cohort C5.
The investigational products are nivolumab combined with daratumumab for Cohort C6. 
4.1.2
Non-investigational Product
Other medications used 
as 
support 
or escape 
medication for 
preventative, 
diagnostic, 
or 
therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as non-
investigational products. 
In this protocol, non-investigational product(s) is/are: Not applicable for this study. 
4.1.3
Handling and Dispensing
The product storage manager should ensure that the study drug isstored in accordance with the 
environmental conditions (temperature, light, and humidity) as determined by BMS. If concerns 
regarding the quality or appearance of the study drug arise, the study drug should not be dispensed 
and contact BMS immediately.
Investigational product documentation must be maintained that includes all processes required to 
ensure drug is accurately administered. This includes documentation of drug storage, 
administration and, as applicable, storage temperatures, reconstitution, anduse of required 
processes (eg, required diluents, administration sets).
For non-investigational product, if marketed product is utilized, it should be stored in accordance 
with the package insert, summary of product characteristics (SmPC), or similar.
Please refer to the current version of the Investigator Brochure and/or Pharmacy Manualfor 
complete storage, handling, dispensing, and infusion information for nivolumab,ipilimumab,
BMS-986016, and daratumumab.
4.1.3.1
Nivolumab
Please refer to the current versionof the Investigator Brochure and/orPharmacy Manualfor 
complete storage, handling, dispensing, and infusion information for nivolumab.
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Nivolumab is to be administered as an approximately 30-minute IV infusion. Atthe end of the 
infusion, flush the line with a sufficient quantity of normal saline.
4.1.3.2
Ipilimumab
Please refer to the current version of the Investigator Brochure and/or Pharmacy Manualfor 
complete storage, handling, dispensing, and infusion information for ipilimumab.
Ipilimumab is to be administered as an approximately 30-minute IV infusion. At the end of the 
infusion, flush the line with a sufficient quantity of normal saline or dextrose.
4.1.3.3
Nivolumab and Ipilimumab Combination
When both nivolumab and ipilimumab are to be administered on the same day, separate infusion 
bags and filters must be used for each infusion. Nivolumab is to be administered first. The 
nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the ipilimumab infusion.The second infusion will always be ipilimumab and will 
start no sooner than 30 minutes after completion of the nivolumab infusion.
4.1.3.4
Nivolumab and BMS-986016 Combination
In Cohort C5, where both nivolumab and BMS-986016 are administered, nivolumab will be 
administered first, as an approximately 30-minute IV infusion. At the end of the infusion, flush the 
line with a sufficient quantity of normal saline or 5% dextrose solution. When both study drugs 
(nivolumab and BMS-986016) are to be administered on the same day, separate infusion bags and 
filters must be used for each infusion. Nivolumab is to be administered first. The nivolumab 
infusion must be promptly followed by a saline flush to clear the line of nivolumab before starting 
the BMS-986016 infusion. The second infusion will be BMS-986016 and will start after the 
infusion line has been flushed, filters changed,and patient has been observed to ensure no infusion 
reaction has occurred. BMS-986016 infusion will start within 60 minutes after completion of the 
nivolumab infusion. Further details regarding preparation and administration will be provided 
separately in the pharmacy manual.
4.1.3.5
Nivolumab and Daratumumab Combination
In Cohort C6, daratumumab injection for IV infusion is considered IMP for this study. 
Daratumumab is an immunoglobulin G1 kappa human monoclonal antibody against CD38 
antigen, produced in a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant 
DNA technology. The molecular weight of daratumumab is approximately 148 kDa. 
Daratumumab is supplied as a colorless to pale yellow preservative-free solution for intravenous 
infusion in single-dose vials. Starting on Week 3, when both nivolumab and daratumumab are 
administered, nivolumab should be administered first followed bydaratumumab by at least
30minutes aftercompletion of nivolumabinfusion.
Pre-infusion medications should be administered before starting daratumumabinfusions.On days 
when nivolumab and daratumumab are being administered, daratumumab pre-infusion 
medications can be administered prior to the nivolumab infusion. The post-infusion medications 
should be administered after daratumumab infusions.
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Therefore, the sequence of administration on days when nivolumab and daratumumab are 
administered should be as follows:
Daratumumab pre-medications
Nivolumab
Daratumumab
Daratumumab post-infusion medications. 
Daratumumab Preparation
Please refer to the current version of the Investigator Brochure and/or Pharmacy Manual for 
complete preparation information for daratumumab.
Daratumumab Administration
Because of this high risk of infusion-related reactions daratumumab infusions will be administered 
per the Investigator’s Brochureby a healthcare professional, with immediate access to emergency 
equipment and appropriate medical support to manage infusion reactions if they occur, and all 
subjects will receive pre-infusion and post-infusion medication perthe descriptions in Section 
4.1.4.  
Before administration the drug product should be stored and prepared as per the instructions in 
pharmacy manual. Daratumumab (dose) will be administered as an IV infusion. Each subject’s 
dose will be calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest 
kilogram. The dose of daratumumab to be administered to a subject will be calculated by 
multiplying the subject’s weight (kg) by 16 mg/kg. The dose of daratumumab will remain constant 
throughout the study, unless the subject’s weight changes more than 10% from Cycle 1 Day 1. All 
infusions will be planned as outpatient visits. Subjects will receive pre-infusion medications and 
post-infusion medications as detailed inSection 4.1.4. 
The infusion start and stop 
time will be recorded in the CRF. If the infusion is stopped mid-session 
for any reason, the stop/start time must be recorded together with an explanation.
The dilution volumes, initial infusion rates, and increment for the first, second, and subsequent 
doses are provided in Table 4.1.3.5-1. The first infusion, with a volume of 1,000 mL, takes 
approximately 8 hours; the second and subsequent infusions, with volumes of 500 mL, takes
approximately 4 hours.The maximum infusion rate for all infusions is 200 mL/hour. The sponsor 
may modify the infusion rates or the pre-infusion medications prospectively based upon the 
information collected to date from this and other studies. Additional details for administration 
times and rates, as well as pre-infusion medications, will be provided in the pharmacy manual.
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Table 4.1.3.5-1:
Daratumumab Infusion Rates
Dilution Volume
Initial Infusion 
Rate (first hour)
Increments of 
Infusion Rate
Maximum Infusion 
Rate
First infusion
1000mL
50mL/hour
50mL/hour
every hour
200mL/hour
Second infusiona
500mL
50mL/hour
50mL/hour
every hour
200mL/hour
Subsequent 
infusionsb
500mL
100mL/hour
50mL/hour
every hour
200mL/hour
a Modified rates should only beused if the first infusion of daratumumab was well tolerated as defined by an absence 
of > Grade 1 infusion-related reactions during the first 3 hours.
b Modified rates should only be used if the first 2 infusions of daratumumab were well tolerated as defined by an 
absence of > Grade 1 infusion-related reactions during a final infusion rate of 100 mL/hr.
4.1.4
Guidelines for Prevention and Management of Infusion Reactions 
(Daratumumab and Nivolumab + Daratumumab Combination)
4.1.4.1
Pre-infusion Medicationfor Daratumumab
Pre-infusion medication to be administered to all subjects approximately 1 hour prior to every 
daratumumab infusion:
IV corticosteroid. Methylprednisolone 100 mg, or equivalent dose administered intravenously.
Following the second infusion, the dose of methylprednisolonemay be reduced (oral or IV 
methylprednisolone 60 mg) PLUS
Oral antipyretics (acetaminophen 650 to 1000 mg), PLUS
Oral or IV antihistamine (diphenhydramine 25 to 50 mg or Leukotriene Inhibitor (optional) on 
Cycle 1 Day 1: montelukast 10 mg PO, or equivalent). Avoid IV use of promethazine
4.1.4.2
Post-Infusion Medicationfor Daratumumab
Post-infusion medication to be administered to allsubjects to reduce the risk of delayed infusion 
reactions:
Oral corticosteroid (20 mg methylprednisolone or equivalent dose of a corticosteroid in 
accordance with local standards) on the first and second day after all infusions
At the investigator discretion, for subjects with a history of obstructive pulmonary disorder, 
short and long-acting bronchodilators and inhaled corticosteroids can be administered. 
Following the first 4 infusions, if subjects experience no major infusion reactions, these 
additionalinhaled post-infusion medications may be discontinued.
Subjects should be carefully monitored for infusion reactions during daratumumab administration. 
If an acute infusion reaction is noted, subjects should be managed according to the Investigator’s 
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Brochure. All subjects should have blood pressure monitored before and after all infusions. For 
the first two infusions, blood pressure should also be monitored during the infusion. 
There will be no dose escalations or reductions of daratumumab allowed. Doses of daratumumab 
may be interrupted, delayed, or discontinued depending on how well the subject tolerates the 
treatment.
For subjects with a higher risk of respiratory complications (eg,subjects with mild asthma or 
subjects with COPD who have an FEV1 <80%at screening or developed FEV1 <80% during the 
study without any medical history),the following post-infusion medications should be considered:
Antihistamine (diphenhydramine or equivalent) 
Leukotriene inhibitor (montelukast or equivalent)
Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol 
Control medications for lung disease (eg, inhaled corticosteroids long-acting 2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salmeterol inhaled corticosteroids for subjects with COPD)
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2nights after an 
infusion. If subjects are hospitalized, 
then their spirometry test (FEV1) should be performed before 
discharge. If these subjects are not hospitalized, then a follow-up telephone call should be made to 
monitor their condition within 48 hours after all infusions. If no infusion-related reaction has 
occurred, the follow-up telephone call 48 hours after the infusion is not required. If the subject has 
not experienced a significant medical event but is hospitalized overnight 
only for observation, then 
the hospitalization should not be reported as a serious adverse event. Investigators may prescribe 
bronchodilators, H1-antihistamines, and corticosteroids that are deemed necessary to provide 
adequate supportive care in the event a bronchospasm occurs after subjects are released from the 
hospital/clinic. If an at-risk subject experiences no major infusion-related reactions, then these 
post-infusion medications may be waived after 4 doses at the investigator’s discretion. 
4.2
Method of Assigning Subject Identification
The subject number will be assigned through an interactive voice response system (IVRS) once 
the subject has signed the informed consent form and is registered. Every subject that signs the 
informed consent form must be assigned a subject number in IVRS. Specific instructions for using 
IVRS will be provided to the investigational site in a separate document.
The investigator or designee will register the subject 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
Gender at birth
Pre-treatment status (For C3 Cohort. Subjects must have not received prior 
therapy for mCRC)
MSI Status 
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Once enrolled in IVRS, enrolled subjects that have met all eligibility criteria will be ready for 
treatment assignment and drug vial assignment through the IVRS. 
For CohortsC3,C5, and C6,tissue submitted for subjects will be assessed for quality with anH&E 
stain, and only those subjects who have met tissue quality thresholds can be assigned study drug. 
The following information is required for drug vial assignment:
Subject number
Date of birth
MSI status
Subjects meeting all eligibility criteria willbe assigned tothe appropriate cohort through the 
IVRS
Specific instructions (including anenrollmentworksheet) for central enrollmentand treatment 
assignment procedure will be provided to the site
Re-initiation
Subjectstreatedin cohorts mStage 1/2 (C1;Arm N),cStage 1/2 (C2;Arm N +I), C3 or C5 will be 
eligible for re-initiation within the IVRS if Revised Protocol 07 has been approved at their siteand 
if all criteria for re-initiation have been met. Subjects’ original cohort assignment will determine 
their re-initiation treatment regime as specified in Section 4.3.1and their treatment assignment 
will be as inTable 4.3.1-1;note that subjects initially treated in cStage or mStage cohorts or 
Cohort3 will have a different dosing schedule thanduring the initial phase of treatment.  
The following information is required for drug vial assignment for Re-initiation:
Subject number
Date of birth
Previously Assignment into C1,C2, C3 or C5
Subjects meeting all eligibility criteria will be reinitiated through the IVRS.
4.3
Selection and Timing of Dose for Each Subject
The dosing regimen and schedule for Arm N and Arm N+I are detailed in Table 4.3-1(Arm N), 
Table 4.3-2(Arm N+I, Week1-12),Table 4.3-3(Arm N+I, Week 13 and following). Table 4.3-4
describes the dosing regimen for the C3 Cohort.Table 4.3-5describes the dosing regimen for the 
C5 Cohort. Table 4.3-6describes the dosing regimen for the C6 Cohort. 
Table 4.3-1:
Dosing Schedule for Arm N -Nivolumab Monotherapy
Every 4-Week Dosing
480 mg Nivolumab 
Note:See for Section 3.1.4.1for treatment duration
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Table 4.3-2:
Dosing Schedule for cStage 1/2 Arm N+I (Week 1-12) -Nivolumab 
+ Ipilimumab Combination
Every 3 Week Dosing
Study Part
Day 1
Dose 1/Week 1
Day 1
Dose 2/Week 4
Day 1
Dose 3/Week 7
Day 1
Dose 4/Week 10
Dose Escalation Phase 
Dose Level -1
0.3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
0.3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
0.3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
0.3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
Dose Escalation Phase 
Dose Level 1
1 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
1 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
1 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
1 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
Dose Escalation Phase 
Dose Level 2a
1 mg/kg 
Nivolumab
3 mg/kg 
Ipilimumab
1 mg/kg 
Nivolumab
3 mg/kg 
Ipilimumab
1 mg/kg 
Nivolumab
3 mg/kg 
Ipilimumab
1 mg/kg 
Nivolumab
3 mg/kg 
Ipilimumab
Dose Escalation Phase 
Dose Level 2b
3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
3 mg/kg 
Nivolumab
1 mg/kg 
Ipilimumab
Efficacy (cStage)a
(3mg/kgNivolumab+ 1 mg/kg Ipilimumab)Q3W x4
a The staged phase uses maximum tolerable dose identified in escalation phase.
Table 4.3-3:
Dosing Schedule for cStage 1/2 Arm N+I (Week 13 and following) -
Nivolumab + Ipilimumab Combination
Every 4 Week Dosing
480 mg Nivolumab 
Note:See for Section 3.1.4.1for treatment duration
Table 4.3-4:
Dosing Schedule for C3 Cohort: Nivolumab + Ipilimumab 
Combination
Every 2 or 6 Week Dosing
Day 1
Week 1
Day 1, Week 3, 5, 7, 9 
and every other week thereafter
Day 1 Week 7, 13, 19 and every 6 
weeks thereafter*
3 mg/kg Nivolumab 
3 mg/kg nivolumab over 
30minutes 
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Table 4.3-4:
Dosing Schedule for C3 Cohort: Nivolumab + Ipilimumab 
Combination
Every 2 or 6 Week Dosing
Day 1
Week 1
Day 1, Week 3, 5, 7, 9 
and every other week thereafter
Day 1 Week 7, 13, 19 and every 6 
weeks thereafter*
1 mg/kg Ipilimumab
1 mg/kg ipilimumabover 
30minutes
Note:See for Section 3.1.4.1for treatment duration
Nivolumab and Ipilimumab combination:
When both nivolumab and ipilimumab are to be administered on the same day, separate infusion 
bags and filters must be used for each infusion. Nivolumab is to be administered first. The 
nivolumab infusion must be promptly followed by a saline flush to clear the line of nivolumab 
before starting the ipilimumab infusion.The second infusion will always be ipilimumaband will 
start no sooner than 30 minutes after completion of the nivolumab infusion. 
Dosing calculation based on weight:
The dosing calculations should be based on the body weight.If the subject’s weight on the day of 
dosing differs by > 10% from the weight used to calculate the dose, the dose must be recalculated. 
The weight used to calculate the dose should always be the most recently recorded weight. All 
doses should be rounded to the nearest milligram. There will be no dose modifications allowed. 
Body weight is determined as detailed in the Flow Chart/Time and Events Schedule of this 
protocol.
Dosing modifications:
There will be no dose modifications allowed for the management of toxicities of individual 
subjects.
For Q2W nivolumab dosing cycles, subjects may be dosed no less than 12 days between doses. 
For Q3W nivolumab dosing cycles, subjects may be dosed no less than 19 days between doses. 
For Q4W nivolumab dosing cycles, participants may be dosed no less than 25 days from the 
previous dose. For Q6W ipilimumab dosingcycles, participants may be dosed no less than 5 weeks 
from the previous dose. If dosing is delayed, both nivolumab and ipilimumab must be delayed 
together. If dosing is resumed after a delay, both nivolumab and ipilimumab must be resumed on 
the same day.
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Table 4.3-5:
Dosing Schedule for C5 Cohort: Nivolumab + BMS-986016 
Combination
Day 1 Week 1
Day 1, Week 3, 5, 7, 9
and every other week thereafter*
240mg nivolumab flat dose
240 mg nivolumab flat doseIV over 30 minutes
160mg BMS-986016
160mg BMS986016IV over 60 minutes
Note:See for Section 3.1.4.1for treatment duration
Table 4.3-6:
Dosing Schedule for C6Cohort: Nivolumab + Daratumumab 
Combination
Drug
Dose
Frequency of 
administration
Route of 
administration
Duration
Nivolumab
240 mg 
flat dose
every 2 weeks 
starting on 
Week3
30 minute Intravenous 
(IV) infusion
Until progression, 
toxicity, or 
discontinuation 
from study
Nivolumab
480mg 
flat dose
every 4 weeks 
starting on 
Week 25
30 minute Intravenous 
(IV) infusion
Until progression, 
toxicity, or 
discontinuation 
from study
Daratumumab
16 mg/kg
Every week 
(Weeks 1-8)
Every 2 weeks 
(Weeks 9-24)
Every 4 weeks 
(Starting on 
Week 25 and 
thereafter)
(IV) infusion
Please refer to the 
daratumumab 
investigators brochure
or pharmacy manual
forinfusion details.
Until progression, 
toxicity, or 
discontinuation 
from study
4.3.1
Re-initiation Dose Schedules
Subjects in the cohortslisted in Table 4.3.1-1who met eligibility criteria for re-initiation of 
treatment (Section3.1.4.8) will receive treatment as presented below: 
Table 4.3.1-1:
Treatment Schedules for Re-Initiation
Cohort
Treatment upon Re-initiation
mStage 1/2
Nivolumab 480 mg Q4W
cStage 1/2
Nivo 240mg+ Ipi 1mg/kg Q3W for 4 doses, followed by 
Nivolumab 480 mg (Q4W)
C3 (1L)
Nivo 360mg Q3W + Ipi 1mg/kg Q6W
C5 (BMS-986016 /anti-LAG3)
Nivo 240mg Q2W + BMS-986016 (LAG3) 160mg Q2W 
Note: “Re-initiation”relates to maximum clinical benefit participants.
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Treatment duration after re-initiation, inclusive of treatment beyond progression will be a 
maximum of 24 months.
4.3.2
Antiemetic Premedications
Antiemetic medications should not be routinely administered prior to dosing of drugs. See Section 
4.3.7for subsequent premedication recommendations following a study drug-related infusion 
reaction.
4.3.3
Dose Delay Criteria
Dose delay criteria apply for all drug-related adverse events (regardless of whether or not 
the event 
is attributed to nivolumab, ipilimumab, BMS-986016,daratumumab, or combinations). All study 
drugs must be delayed until treatment can resume (see Section 4.3.5). Treatment delays up to 6 
weeks from the last dose are allowable.Study therapy should also be delayed in cases of confirmed 
or suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)infection, regardless 
of the severity.
Nivolumab and ipilimumab administration should be delayed for the following:
Any Grade 2 non-skin, drug-related adverse event, with the following exceptions:
Grade 2 drug-related fatigue or laboratory abnormalities do not require a treatment delay
Any Grade 3 skin, drug-related adverse event
Any Grade 3 drug-related laboratory abnormality, with the following exceptions for 
asymptomatic amylase or lipase, AST, ALT, or total bilirubin:
Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis do not require a dose delay.
If a subject has a baseline AST, ALT, or total bilirubin that is within normal limits, delay 
dosing for drug-related Grade 2 toxicity
If a subject has baseline AST, ALT, or total bilirubin within the Grade 1 toxicity range, 
delay dosing for drug-related Grade 3 toxicity
Nivolumab and BMS-986016 (C5 Cohorttreatment) administration should be delayed for the 
following:
Select drug-related AEs and drug-related laboratory abnormalities:
Grade 3 skin
Grade 1 pneumonitis
Single grade increase shift in abnormality in AST, ALT, and total bilirubin
Grade 2 creatinine
Grade 2 diarrhea or colitis
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nivolumab
Grade 2 neurological AE
Grade 4 amylase and/or lipase abnormalities regardless of symptoms or clinical
manifestations
1x ULN troponin, hold dose and repeat troponin after 24 hours.All troponin elevations 
require a dose delay to allow for prompt cardiac evaluation. Following this evaluation, 
determination of further treatment will be based on the discretion of the PI.
Any AE, laboratory 
abnormality, 
or concurrent illness 
that, 
in the judgment 
of 
the 
 
Investigator, 
warrants delaying the dose of study drug
Grade 2 Myocarditis
Nivolumaband daratumumab (C6 Cohort treatment) administration should be delayed for the 
following:
Grade 4 hematologic toxicity, except for Grade 4 lymphopenia
Grade 3 or higher thrombocytopeniawithbleeding
Febrile neutropenia
Neutropenia with infection, of any grade
Grade 3 or higher non-hematologic toxicities with the following exceptions: 
Grade 3 nausea that responds to antiemetic treatment within 7 days
Grade 3 vomiting that responds to antiemetic treatment within 7 days
Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days
Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab
In Weeks 1 to 8, daratumumab doses that fall outside of the pre-specified window of -1 to +3 days 
must be skipped.
In Weeks 9 to 24, daratumumab dosing may be delayed for up to 1 week. If unable to administer 
within 1 week, then the dose should be skipped,and resumption of the daratumumab continues per 
the protocol defined schedule.
From Week 
25 
and beyond, 
the first 
dose (Week 
25) can be delayed 21 
days. 
Doses that 
falloutside 
the allowed window should be skipped.
During periods when daratumumab doses are skipped, daratumumab PK andimmunogenicity 
samples should not be drawn. 
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Table 4.3.3-1:
Daratumumab Dose Delay Guidance
Week
Frequency
Dose Held
Dosing Re-start
1-8
Weekly (q1wk)
>3 days
next planned weekly dosing date
9-24
Biweekly (q2wks)
>7 days
next planned biweekly dosing date
25+
Every 4 weeks (q4wks)
>21days
next planned every 4 weeks dosing date
Subjects experiencing a Grade 4infusion reaction or their third Grade 3 infusion reaction related 
to daratumumab must permanently discontinue daratumumab.See Section 4.3.7for additional 
details on the treatment of infusion reactions. 
Any adverse event deemed to be related to daratumumab that requires a dose hold of more than 
3consecutive planned doses will result in permanent discontinuation of daratumumab. If a dose 
delay occurs, then pharmacokinetic and pharmacodynamic assessments should be performed on 
the actual day of study drug administration, not on the original scheduled administration day
Subjects whose dose are missing 3 consecutive planned doses of daratumumab for reasons other 
than toxicity should be withdrawn from study drug, unless, upon consultation with the sponsor and 
the review of safety and efficacy, continuation is agreed upon. Subjects who are withdrawn from 
daratumumab may continue to receive nivolumab.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of study medication.
Because of the potential for immunotherapy-related AEs requiring early recognition and prompt 
intervention, management algorithms have been developed for suspected pulmonary toxicity, GI 
toxicity, hepatotoxicity, endocrinopathy, skin toxicity, neurological toxicity,and nephrotoxicity.
In order to standardize the management of adverse eventsfor all subjects, treatment management 
algorithms recommended for utilization in this study are included in Appendix 1.Adverse event 
treatment management algorithms included in the nivolumab IB or ipilimumab IB might be 
considered for individual cases.
4.3.3.1
Management Algorithms for Immuno-Oncology Agents
Immuno-oncology (I-O) agents are associated with adverse events that can differ in severity and 
duration than adverse events caused by other therapeutic classes. Nivolumab, ipilimumab, BMS-
986016, and daratumumabare considered immuno-oncology agents in this protocol. Early 
recognition and management of adverse events associated with immuno-oncology agents may 
mitigate severe toxicity. Management algorithms have been developed to assist investigators in
assessing and managing the following groups of adverse events:
Gastrointestinal
Renal
Pulmonary
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Hepatic
Endocrinopathies
Skin
Neurological
Myocarditis
While the ipilimumab investigator brochure contains safety management algorithms for similar 
adverse events, the recommendations are to follow the nivolumab algorithms for 
immuno-oncology agents (I-O) in order to standardize the safety management. Therefore, the 
algorithms recommended for utilization in this protocol are included in Appendix1.
For subjects expected 
to 
require more 
than 4 weeks of corticosteroids 
or 
other immunosuppressants 
to manage an adverse event, consider recommendations provided in Appendix 1.
4.3.4
Dose Modifications
There will be no dose reductions for nivolumab, ipilimumab, BMS-986016 ordaratumumab.
4.3.5
Criteria to Resume Treatment
Subjects may resume treatment with study drug when the drug-related AE(s) resolve to Grade1 
or baseline value, with the following exceptions:
Subjects may resume treatment in the presence of Grade 2 fatigue 
Subjects who have not experienced a Grade 3 drug-related skin AE may resume treatment in 
the presence of Grade 2 skin toxicity 
Subjects with baseline Grade 1 AST/ALT or 
total bilirubin who require dose delays for reasons 
other than a 2-grade shift in AST/ALT or total bilirubin may resume treatment in the presence 
of Grade 2 AST/ALT OR total bilirubin. Subjects with combined Grade 2 AST/ALT AND
total bilirubin values meeting discontinuation parameters 
(Section 
4.3.6) should have 
treatment 
permanently discontinued
Drug-related pulmonary toxicity, diarrhea, or colitis, must have resolved to baseline before 
treatment is resumed
Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment
Subjects in the C5 Cohort may resume treatment with BMS-986016 when troponin levels 
return to normal
In the case of prior SARS-CoV-2 infection,symptoms shouldhave resolved in order to resume 
study treatment andthere should be no sequelae that would place the participant at a higher risk of 
receiving study intervention.
If the criteria to resume treatment are met, 
the subject should restart 
treatment at 
the next scheduled 
timepoint per protocol. However, if the treatment is delayed past the scheduled timepoint per 
protocol, the scheduled study treatment administration will be delayed, but not skipped, until 
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dosing resumes. In particular, this is to ensure that subjects in Arm N+I will receive 4 
administrations of combined nivolumab and ipilimumab treatment if toxicity allows.
If dose delay is necessary for subjects in Arm N+I during Week 1-12and for subjects in Cohort 
C3, both nivolumab and ipilimumab must be delayed until treatment can resume. However, if a 
nivolumab-related infusion reaction prevents subsequent infusion of ipilimumab on the same day, 
the dose of ipilimumab should be replaced as soon as possible. In such instances, at least 19 days 
mustelapse between the replacement dose of ipilimumab and the administration of the next dose 
of nivolumab combined with ipilimumab.
If treatment is delayed > 6 weeks from the last dose, the subject must be permanently discontinued 
from study therapy, exceptas specified in Section 4.3.6.
Subjects may resume treatment with daratumumab in Cohort 6, upon recovery from toxicity to 
Grade 2 or baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm 
must be fully recovered.If the daratumumab administration does not commence within the 
pre-specified window of the scheduled administration date, then the dose will be considered a 
missed dose. Administration may resume at the next planned dosing date.
4.3.6
Discontinuation Criteria
Treatment with nivolumab,ipilimumab, and/or BMS-986016should be permanently discontinued 
for the following:
Any Grade 2 drug-related uveitis or eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment 
Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions for drug-related laboratory abnormalities, endocrinopathies, uveitis, pneumonitis, 
bronchospasm, diarrhea, colitis, neurologic toxicity, hypersensitivity reactions, and infusion 
reactions:
Grade 3 drug-related uveitis, pneumonitis, bronchospasm, diarrhea, colitis, neurologic 
toxicity, myocarditis, hypersensitivity reaction, or infusion reaction of any duration 
requires discontinuation
For Grade 3 endocrinopathy adverse events such as adrenalinsufficiency, ACTH 
deficiency, hyper-or hypothyroidosis, or glucose intolerance, which resolve or are 
adequately controlled with physiologic hormone replacement (steroids, thyroid hormones) 
or glucose controlling agents, respectively, do not require treatment discontinuation
Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation
Any drug-related liver function test (LFT) abnormality that meets 
the following criteria 
require discontinuation: 
o AST or ALT > 8 x ULN
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o Total bilirubin > 5 x ULN
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN
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
Grade 4 amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis. 
Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72hours 
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 dosing interruption lasting > 6 weeks from the last dose with the following exceptions:
Dosing interruptions to allow for prolonged steroid tapers to manage drug-related adverse 
events are allowed. Prior to re-initiating treatment in a subject with a dosing interruption 
lasting 
> 
6 
weeks from 
the last 
dose, 
the 
BMS medical monitor/designeemust 
be consulted. 
Tumor imaging assessments should continue as per protocol even if dosing is interrupted. 
Dosing interruptions > 6 weeks from the last dose that occur for non-drug-related reasons 
may be allowed if approved by the BMS medical monitor/designee. Prior to re-initiating 
treatment in a subject with a dosing interruption lasting > 6 weeks from the last dose, the 
monitor/designeemust be consulted. Tumor imaging assessments should continue as per 
protocol even if dosing is interrupted.
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the subjectwith continued nivolumab, 
ipilimumab, and/or BMS-986016dosing.
Daratumumabtreatment should be permanently discontinued for the following reasons:
Grade 4infusion reactionsrelated to daratumumab.
For Grade 3 infusion reactions related to daratumumab: Once reaction symptoms resolve, 
consider restarting the infusion at no more than half the rate at which the reaction occurred. If 
the patient does not experience additional symptoms, resume infusion rate escalation at 
increments 
and intervals as 
outlined in 
Table 
4.1.3.5-1. 
Repeat 
the 
procedure 
above in the event 
of recurrence of Grade 3 symptoms. Permanently discontinue daratumumab upon the third 
occurrence of a Grade 3 or greater infusion reaction.
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Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, 
presents 
a 
substantial clinical 
risk 
to 
the 
subject, 
regardless 
of 
cohort,with continued 
study drugdosing should discontinue the study drugs. 
The consideration to re-initiate study therapy in selected cases at any time point after 
discontinuation could be made on a case-by-case basis after considering the overall benefit/risk 
profile and in consultation between the Investigator and the study Sponsor. The selected subjects 
will need 
to 
meet 
eligibility criteria. 
The 
original 
dose and 
schedule 
and 
protocol 
rules 
would apply 
accordingly (Section4.3.6).
The assessment for discontinuation of study drug should be made separately considering each 
study drugcomponent in the nivolumab and ipilimumab, and nivolumab and daratumumab 
(Cohort C6) combinations. If discontinuation criteria are attributed with only one drug used in this 
trial, once the subject meets criteria to resume therapy, the subject may continue dosing with 
nivolumab if nivolumab was not attributed to criteria for discontinuation. 
In the nivolumab and BMS-986016 combination (Cohort C5), if discontinuation criteria are met, 
both drugs (nivolumab and BMS-986016) will be discontinued regardless of the assessment of 
attribution to a particular study drug.
If a subject meets criteria for discontinuation and the investigator is unable to determine whether 
the event is related to both or one study drug, the subject should discontinue all study drugs and 
be taken off the treatment phase of the study.
4.3.7
Treatment of Study DrugRelated Infusion Reactions
Since nivolumab,ipilimumab, and BMS-986016containonly human immunoglobulin protein 
sequences, it is unlikely to be immunogenic and induce infusion or hypersensitivity reactions. 
However, if such a reaction were to occur, it might manifest with fever, chills, rigors, headache, 
rash, pruritus, arthralgias, hypo-or hypertension, bronchospasm, or other symptoms. All Grade 3 
or 4 infusion reactions should be reported within 24 hours to the BMS Medical Monitor and 
reported as an SAE if criteria are met. Infusion reactions should be graded according to NCI 
CTCAE (version4.0) guidelines.
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines as appropriate:
For Grade 1 symptoms: (Mild reaction; infusion interruption not indicated; intervention not 
indicated)
Remain at bedside and monitor subject until recovery from symptoms. The following prophylactic 
premedications are recommended for future infusions: diphenhydramine 50mg (orequivalent) 
and/or paracetamol 325 to 1000 mg (acetaminophen) at least 30minutes before additional 
nivolumab administrations.
For 
Grade 2 
symptoms: 
(Moderate reaction 
requires therapy 
or infusion interruption but 
responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
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narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 24 
hours).
Stop the study druginfusion, begin an IV infusion of normal saline, and treat the subject with 
diphenhydramine 50 mg IV (or equivalent) and/or paracetamol 325 to 1000mg (acetaminophen); 
remain at bedside and monitor subject until resolution of symptoms. Corticosteroid 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 subject closely. If symptoms recurthen no further study drugwill be administered 
at 
that visit. Administer diphenhydramine 50 mg IV, and remain at bedside and monitor 
the subject 
until resolution of symptoms. The amount 
of study drug infused must be recorded 
on 
the electronic 
case reportform (eCRF). The following prophylactic premedications are recommended for future 
infusions: diphenhydramine 50 mg (orequivalent) and/or paracetamol 325 to 1000mg 
(acetaminophen) should be administered at least 30 minutes before additional study drug
administrations. If necessary, corticosteroids (recommended dose: up to 25mg of IV 
hydrocortisone or equivalent) may be used.
For Grade 3 or Grade 4 symptoms:(Severe reaction, Grade 3: prolonged [ie, not rapidly 
responsive to symptomatic medication and/or brief interruption of infusion]; recurrence of 
symptoms following initial improvement; hospitalization indicated for other clinical sequelae [eg, 
renal impairment, pulmonary infiltrates]). Grade 4: 
(life-threatening; pressor 
or ventilatory support 
indicated). 
Immediately discontinue infusion of study drug. Begin an IV infusion of normal saline, and treat 
the subject as follows. Recommend bronchodilators, epinephrine 0.2 to 1mg of a 1:1,000 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. Subject should be monitored until the investigator is comfortable that the 
symptoms 
will not 
recur. 
Study 
drugwill be permanently discontinued. 
Investigators 
should follow 
their institutional guidelines for the treatment of anaphylaxis. Remain at bedside and monitor 
subject until recovery from symptoms. In the case of late-occurring hypersensitivity symptoms 
(eg, appearance of a localized or generalized pruritus within 1 week after treatment), symptomatic 
treatment may be given (eg,oral antihistamine, or corticosteroids).
Management of daratumumab infusion-related reactions
Subjects should be carefully observed during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of any infusion reactions, and resources necessary 
for resuscitation must be available. Attention to staffing should be considered when multiple 
subjects will be dosed at the same time. 
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion and 
manage symptoms. Management of infusion reactions may further require reduction in the rate of 
infusion, or treatment discontinuation of daratumumab.
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Grade1-2 (mild to moderate):Once reaction symptoms resolve, resume the infusion at no more 
than half the rate at which the reaction occurred. If the patient does not experience any further 
reaction symptoms, infusion rate escalation may resume at increments and intervals as appropriate 
as outlined in Table 4.1.3.5-1.
Grade 3 (severe):Once reaction symptoms resolve, consider restarting the infusion at no more 
than half the rate at which the reaction occurred. If the subject does not experience additional 
symptoms, resume infusion rate escalation at increments and intervals as outlined in Table 4.1.3.5-
1. Repeat the procedure above in the event of recurrence of Grade 3 symptoms. Permanently 
discontinue daratumumab upon the third occurrence of a Grade 3 or greater infusion-related 
reaction.
Grade 4 (life threatening):Permanently discontinue daratumumab treatment.
4.3.8
Treatment Beyond Disease Progression
Accumulating evidence indicates a minority of subjects treated with immunotherapy may derive 
clinical benefit despite initial evidence of PD.
106The assessment of clinical benefit should take 
into account whether the subject is clinically deteriorating and unlikely to receive further benefit 
from continued treatment. 
Subjects will be permitted to continue treatment for up to 24 monthsbeyond initial RECIST 1.1 
defined PDassessed by the investigator.
Subjects who progress following re-initiationof treatment have the option to be treated beyond 
progression for a cumulative maximum of 24 monthsfrom re-initiation dose.
All decisions to continue treatment beyond initial progression must be discussed with the BMS 
Medical Monitor and documented in the study records.
All subjects treated beyond progression must meet the criteria below:
1)Investigator-assessed clinical benefit, and do not have rapid disease progression
2)Tolerance of study drug
3)Stable performance status
4)Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression(eg, CNS metastases)
5)Subject provides written informed consent prior to receiving any additional nivolumab 
treatment, or nivolumab in combination with ipilimumab treatment, using an ICF describing 
any reasonably foreseeable risks or discomforts, or other alternative treatment options.
Treatment beyond progression may be administered during or after localized interventions 
(surgery/radiation therapy).
For subjects with timepoint response of progression being treated beyond progression, scans 
should be repeated every 12 weeksor earlier,as clinically indicated,to assessfurther disease 
progression.
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Subjects will be re-consented with an ICF describing any reasonably foreseeable risks or 
discomforts.For subjects who have re-initiated treatment per Revised Protocol 07, treatment 
beyond progression will be according to the dose schedule during the re-initiation period. 
Subjects should discontinue study therapy upon further evidence of further progression, defined 
as an additional 10% or greater increase with a minimum 5 mm absolute increase in tumor burden 
volume from time of initial progression (including all target lesions and new measurable lesions).
Study treatment should be discontinued permanently upon documentation of further progression.
New lesions are considered measurable at the time of initial progression if the longest diameter is 
at least 10 mm (except for pathological lymph nodes, which must have a short axis of at least 
15mm). Any new lesion considered non-measurable at 
the time of initial progression may become 
measurable and therefore included in the tumor burden measurement if the longest diameter 
increases to at least 10 mm (except for pathological lymph nodes, which must have an increase in 
short axis to at least 15 mm).  In situations where the relative increase in total tumor burden by 
10% is solely due to inclusion of new lesions which become measurable, these new lesions must 
demonstrate an absolute increase of at least 5 mm.
For statistical analyses thatinclude the investigator-assessed progression date, subjects who 
continue treatment beyond initial investigator-assessed, RECIST 1.1-defined progression will be 
considered to have investigator-assessed progressive disease at the time of the initial progression 
event.
4.3.9
Treatment Re-initiationInclusion Criteria: MSI-H Cohorts
Subjects in MSI-H cohorts who discontinuestudy treatment at Maximal Clinical Benefit,(Section 
3.1.4.1)are permitted to re-initiate treatment(see Section 3.1.4.8andTable 4.3.1-1),if disease 
progression defined by RECIST criteria occurs within 1 year (52 weeks) andthe following 
criteria are met:
1)Investigator assessed clinical benefit and no rapid disease progression
2)Tolerance of study drug
3)Stable performance status
4)Adequate blood, liver, kidney and cardiac function per Inclusion criteria 2i (Section 3.3.1)
5)Adequate re-initiation screening requirements per Table 5.1-8
6)Treatment Re-initiation will not delay an imminent intervention to prevent serious 
complications of disease progression (eg. CNS metastases)
7)Subjects have signed and dated an IRB/IEC approved written informed consent form for 
re-initiation in accordance with regulatory and institutional guidelines.
4.4
Blinding/Unblinding
Not applicable.
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4.5
Treatment Compliance
Treatment compliance will be monitored by drug accountability as well as the subject’s medical 
record and eCRF.
4.6
Destruction and Return of Study Drug
4.6.1
Destruction of Study Drug
For 
this 
study, 
study 
drugs 
(those supplied by BMS or 
sourced 
by the investigator) 
such 
as 
partially 
used study drug containersandvials and syringes may be destroyed on site. 
Any unused study drugs can only be destroyed after being inspected and reconciled by the 
responsible BMS Study Monitor unless study drug containers must be immediately destroyed as 
required for safety, or to meet local regulations (eg, cytotoxics or biologics). 
On-site destruction is allowed provided the following minimal standards are met:
On-site disposal practices must not expose humans to risks from the drug.
On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances.
Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copyprovided to BMS upon request.
Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, ie, incinerator, licensed sanitary landfill, or licensed waste disposal vendor 
must be documented.
Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period.
If conditions for destruction cannot be met the responsible BMS Study Monitor will make 
arrangements for return of study drug.
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept.
4.6.2
Return of Study Drug
If study drug will not be destroyed upon completion or termination of the study, all unused and/or 
partially used study drug that was supplied by BMS must be returned to BMS. The return of study 
drug will be arranged by the responsible BMS Study Monitor. 
It is the investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, local, 
and institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
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4.7
Retained Samples for Bioavailability / Bioequivalence
Not applicable for this study.
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5
STUDY ASSESSMENTS AND PROCEDURES
5.1
Flow Chart/Time and Events Schedule 
Table 5.1-1:
Screening Procedural Outline (CA209142)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Original IC in screening for protocol participation;
Study allows for re-enrollment of a subject that has discontinued the study as a pre-treatment 
failure. If re-enrolled, the subject must be re-consented and assigned a new subject number 
from IVRS.
Inclusion/Exclusion Criteria
X
All inclusion/exclusion criteria should be assessed at screening and confirmed prior to first 
dose.
Medical History
X
Tumor Tissue Sample (biopsy)
X
Sufficient tumor tissue (as determined by local pathologist) obtained before start of study 
treatment in the metastatic setting or from an unresectable site (block or minimum of 30slides, 
obtained from core biopsy, punch biopsy, excisional biopsy or surgical specimen). 
For subjects where a biopsy is not feasible, archival tumor material must be available. See 
Section 3.1.3.
For CohortsC3-C6,tumortissue submitted will be assessed for quality with a H&Estain and 
onlythose subjects who have met tissue quality thresholds canbe assigned study drug.
MSI Status
X
Sites must submit and document prior MSI testing and results. Tissue must be available for all 
subjects for repeat MSI testing. 
Confirm availability of pathology report containing MSI testing results. Report must contain 
MSI results and should also contain specific results per markers tested for MSI. 
For C6 Cohort:Subjects with phenotypes that are non-MSI-H may enroll and may be treated. 
Locally-obtained MSI testing results are not required prior to study treatment assignment. A 
MSI status mustultimately be determinedif a subject is assigned study treatment.   
Determine KRAS Mutation Status
X
Determine BRAF Mutation Status
X
Prior Medications
X
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Table 5.1-1:
Screening Procedural Outline (CA209142)
Procedure
Screening
Visit
Notes
Record History of Lynch Syndrome
(if tested or if not tested; record result if 
tested)
X
ECOG Performance Status
X
Within 14 days prior to first dose.
See Appendix 2 for ECOG Performance Status scale.
Safety Assessments
Physical Examination
X
Vital Signs 
X
Including BP, HR, and temperature. Obtain vital signs at the screening visit and within 
72hours prior to first dose.
Physical Measurements
X
Height and Weight. Within 14 days prior to first dose
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Echocardiogram
Performed for the C5 Cohort Only
X
LVEF assessment with documented LVEF 50% by either TTE or MUGA (TTE preferred 
test) within 6 months from first study drug administration
Performed for the C5 Cohort Only
ECG
X
Within 14 days prior to first dose. 
For C5 and C6 Cohorts: Subjects with screening 12-lead ECG showing a QT interval as 
corrected (QTc) >480 msec are excluded.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Protocol Amendment No: 09
Date: 27-Aug-2021
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930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-1:
Screening Procedural Outline (CA209142)
Procedure
Screening
Visit
Notes
Laboratory Tests
X
CBC w/differential and platelet count,
Chemistry panel including: LDH, AST, ALT, ALP, T.Bili, BUN or serum urea level, 
creatinine, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, TSH, Free T4, Free T3, Hepatitis B 
surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV 
RNA), within 14 days prior to first dose.
Safety laboratory tests do not need to be repeated if they were performed within 14 days of first 
dose.
Performed for the C5 Cohort Only:Cardiac Troponin Levels:T (cTnt) or I (cTnI)
Performed for C6 Cohort Only:Blood Type, Rh, and IAT should be done before the first dose 
of daratumumab. Subject RBC phenotyping (standard or extended) is an alternative option to 
the IAT test, if locally required. Either method must be completed prior to first daratumumab 
infusion.
Pregnancy Test (WOCBP only)
X
Serum or urine to be done at screening visit and repeated within 24 of first dose of study 
therapy
Efficacy Assessment
Baseline Tumor Imaging Assessment
X
CT or MRI chest, abdomen, pelvis and all known or suspected sitesof diseasewithin 28days 
prior to first dose of study therapy. 
IVRS
Register Subject in IVRS
X
A call must be made to the IVRS to register subject after signing informed consent.
Protocol Amendment No: 09
Date: 27-Aug-2021
128
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930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-2:
Short-Term Procedural Outline (Nivolumab Monotherapy, CA209142): MSI-H (Arm N, mStage 1/2)
Procedure
During Treatment
Day 1 every 4 weeks
See Section 3.1.4.1for treatment 
duration
Notes
Visit Window : 2 Days
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
Including BP, HR, and temperature. Obtain vital signs within 72 hours prior to 
first dose.
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status. 
See Appendix 2 for ECOG Performance Status scale.
Review of Concomitant Medication
X
Adverse Events Assessment
X
Laboratory Tests
X
On-study local CBC, chemistry, and thyroid laboratory assessments (after first 
dose) should be donewithin 72 hours prior to each dose and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH with 
reflexive Free T4, Free T3.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first dose, and 
then every 4 weeks (1 week) regardless of dosing schedule 
Protocol Amendment No: 09
Date: 27-Aug-2021
129
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-2:
Short-Term Procedural Outline (Nivolumab Monotherapy, CA209142): MSI-H (Arm N, mStage 1/2)
Procedure
During Treatment
Day 1 every 4 weeks
See Section 3.1.4.1for treatment 
duration
Notes
Visit Window : 2 Days
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Outcomes Research Assessment 
EORTC
QLQ-C30 & EQ-5D Questionnaires
Assessed following drug vial assignment but before first dose and every 6weeks when coinciding with clinic visits.
Assessed at follow-up visit 1 & 2.Assessments should be completed at the start of the study visit prior to any study-
related procedures or speaking with the physician.
For all subjects, except for those enrolled in the non-MSI-H Safety Cohort
Pharmacokinetic Assessments
Nivolumab PK blood sample
See separateTable 5.5.1-2
Immunogenicity Assessments
Nivolumab Immunogenicity blood 
sample collection
See separate Table 5.5.1-2
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separate Table 5.6.8-1
Peripheral Blood Mononuclear Cells 
(PBMCs) Immuno-phenotyping
See separateTable 5.6.8-1
Ex vivo Functional assay (PBMCs)
See separateTable 5.6.8-1
Tumor tissue sample (biopsy)
See separateTable 5.6.8-1
Whole blood gene expression
See separateTable 5.6.8-1
Stool sample
See separateTable 5.6.8-1
Plasma Sample
See separate Table 5.6.8-1
SNP (whole blood)
See separateTable 5.6.8-1
Protocol Amendment No: 09
Date: 27-Aug-2021
130
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-2:
Short-Term Procedural Outline (Nivolumab Monotherapy, CA209142): MSI-H (Arm N, mStage 1/2)
Procedure
During Treatment
Day 1 every 4 weeks
See Section 3.1.4.1for treatment 
duration
Notes
Visit Window : 2 Days
MSI Status Determination
Submit Redacted Pathology Report 
to BMS Containing Local MSI 
Results
To be submitted at Week 1 Day 1. Report must contain MSI results and should also contain specific results per 
markers tested for MSI. 
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from vial allocation, the subject must receive the first dose of 
study medication. Subjects may be dosed no less than 25 days between doses.
The dosing calculations should be based on the body weight. All doses should 
be rounded to the nearest milligram.
Protocol Amendment No: 09
Date: 27-Aug-2021
131
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-3:
Short-term Procedural Outline (Nivolumab Ipilimumab Combination, CA209142): MSI-H (Arm N +I, 
cStage 1/2) and non-MSI-H (Independent Safety Study)
Procedure
During Treatment
Day 1 (Dose 1/week 1, 
Dose 2/week 4, Dose 
3/week 7, Dose 
4/week 10)
During 
Treatment
Day 1 (week 13 
and every 4 
weeks
thereafter)
Notes
Visit Window : 2 Days
For MSH-H (Arm N+I) only, see Section 
3.1.4.1for treatment duration.
Safety Assessments
Targeted Physical Examination
X
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
X
Including BP, HR, and temperature. Obtain vital signs within 72 hours 
prior to first dose 
Physical Measurements (including 
performance status)
X
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
Review of Concomitant 
Medication
X
X
Adverse Events Assessment
X
X
Laboratory Tests
X
X
On-study local laboratory assessments(after first dose)should be done 
within 72 hours prior to each dose and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, 
TSH with reflexive Free T4, Free T3.
Protocol Amendment No: 09
Date: 27-Aug-2021
132
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-3:
Short-term Procedural Outline (Nivolumab Ipilimumab Combination, CA209142): MSI-H (Arm N +I, 
cStage 1/2) and non-MSI-H (Independent Safety Study)
Procedure
During Treatment
Day 1 (Dose 1/week 1, 
Dose 2/week 4, Dose 
3/week 7, Dose 
4/week 10)
During 
Treatment
Day 1 (week 13 
and every 4 
weeks
thereafter)
Notes
Visit Window : 2 Days
For MSH-H (Arm N+I) only, see Section 
3.1.4.1for treatment duration.
Pregnancy Test (WOCBP only)
X
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose, and then every 4 weeks (1 week) regardless of dosing schedule 
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Outcomes Research Assessment 
EORTC QLQ-C30 & EQ-5D
Questionnaires
Assessed following drug vial assignment but before first dose and every 6weeks when coinciding with clinic visits. 
Assessed at follow-up visit 1& 2.Assessments should be completed at the start of the study visit prior to any study-
related procedures or speaking with the physician.
For all subjects, except for those enrolled in the non-MSI-H Safety Cohort
Pharmacokinetic Assessments
Nivolumab PK blood sample
See separate Table 5.5.1-1
Ipilimumab PK blood sample
See separate Table 5.5.1-1
Immunogenicity Assessments
Nivolumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-1
Ipilimumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-1
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separate Table 5.6.8-2
Protocol Amendment No: 09
Date: 27-Aug-2021
133
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-3:
Short-term Procedural Outline (Nivolumab Ipilimumab Combination, CA209142): MSI-H (Arm N +I, 
cStage 1/2) and non-MSI-H (Independent Safety Study)
Procedure
During Treatment
Day 1 (Dose 1/week 1, 
Dose 2/week 4, Dose 
3/week 7, Dose 
4/week 10)
During 
Treatment
Day 1 (week 13 
and every 4 
weeks
thereafter)
Notes
Visit Window : 2 Days
For MSH-H (Arm N+I) only, see Section 
3.1.4.1for treatment duration.
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separate Table 5.6.8-2
Ex vivo Functional assay 
(PBMCs)
See separate Table 5.6.8-2
Tumor tissue sample (biopsy)
See separate Table 5.6.8-2
Whole blood gene expression
See separate Table 5.6.8-2
Stool sample
See separate Table 5.6.8-2
Plasma Sample
See separate Table 5.6.8-2
SNP (whole blood)
See separate Table 5.6.8-2
MSI Status Determination
Submit Redacted Pathology 
Report to BMS Containing Local 
MSI Results
To be submitted at Week 1 Day 1. Report must contain MSI results and should also contain specific results per 
markers tested for MSI. 
Protocol Amendment No: 09
Date: 27-Aug-2021
134
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-3:
Short-term Procedural Outline (Nivolumab Ipilimumab Combination, CA209142): MSI-H (Arm N +I, 
cStage 1/2) and non-MSI-H (Independent Safety Study)
Procedure
During Treatment
Day 1 (Dose 1/week 1, 
Dose 2/week 4, Dose 
3/week 7, Dose 
4/week 10)
During 
Treatment
Day 1 (week 13 
and every 4 
weeks
thereafter)
Notes
Visit Window : 2 Days
For MSH-H (Arm N+I) only, see Section 
3.1.4.1for treatment duration.
Clinical Drug Supplies
IVRS Drug Vial Assignment
X*
X**
Vials may be assigned up to 2 days prior to first dose date.
* Nivolumab Ipilimumab Combination
** Nivolumab Monotherapy
Dispense Study Drug
X*
X**
Within 3 days from vial allocation, the subject must receive the first dose 
of study medication. Subjects may be dosed no less than 19 days between 
doses during administration of nivolumab/ipilimumabin combination and 
no less than 25 days between doses once nivolumabonly is administered 
(ie, as of Week 13).
The dosing calculations should be based on the body weight. * Nivolumab 
Ipilimumab Combination
** Nivolumab Monotherapy
Protocol Amendment No: 09
Date: 27-Aug-2021
135
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-4:
Short-term Procedural Outline for C3 Cohort [Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W] 
No Prior Treatments in Metastatic Setting: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
Safety Assessments
Targeted Physical Examination
X
Targeted examination mustinclude at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
Including BP, HR, temperature. Obtain vital signs within 72 hours prior 
to first dose.
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
Review of Concomitant 
Medication
X
Adverse Events Assessment
X
Laboratory Tests
X
On-study local laboratory assessments (after first dose) should be done 
within 72 hours prior to each dose through Week 23 and every alternate 
dose thereafter and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH with reflexive Free T4, Free T3.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose,and then every 4 weeks (1 week) regardless of dosing schedule 
Protocol Amendment No: 09
Date: 27-Aug-2021
136
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-4:
Short-term Procedural Outline for C3 Cohort [Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W] 
No Prior Treatments in Metastatic Setting: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Outcomes Research Assessment 
EORTC QLQ-C30 & EQ-5D
Questionnaires
Assessed following drug vial assignment but before first dose and every 6 weeks thereafter. Assessed at follow-up visit 
1& 2.Assessments should be completed at the start of the study visit prior to any study-related procedures or speaking 
with the physician.
Pharmacokinetic Assessments
Nivolumab PK blood sample
See separate Table 5.5.1-3
Ipilimumab PK blood sample
See separate Table 5.5.1-3
Immunogenicity Assessments
Nivolumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-3
Ipilimumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-3
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separateTable 5.6.8-3
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separate Table 5.6.8-3
Ex vivo Functional assay 
(PBMCs)
See separateTable 5.6.8-3
Tumor tissue sample (biopsy)
See separateTable 5.6.8-3
Whole blood gene expression
See separateTable 5.6.8-3
Protocol Amendment No: 09
Date: 27-Aug-2021
137
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-4:
Short-term Procedural Outline for C3 Cohort [Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W] 
No Prior Treatments in Metastatic Setting: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
Stool sample
See separateTable 5.6.8-3
Plasma Sample
See separateTable 5.6.8-3
SNP (whole blood)
See separateTable 5.6.8-3
MSI Status Determination
Submit Redacted Pathology 
Report to BMS Containing Local 
MSI Results
To be submitted at Week 1 Day 1. Report must contain MSI results and should also contain specific results per 
markers tested for MSI. 
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from treatment assignment, the subject must receive the 
first dose of study medication. 
Subjects may be dosed no less than 12 days between nivolumab doses, 
and no less than 5 weeks between ipilimumab doses.
The dosing calculations should be based on the body weight. All doses 
should be rounded to the nearest milligram.
Protocol Amendment No: 09
Date: 27-Aug-2021
138
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-5:
Short-term Procedural Outline for C5 Cohort [Nivolumab + Anti-Lag-3 (BMS-986016)]: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Neurological Exam
X
Obtain neurological exam (performed by a neurologist) in subjects who 
experience a study drug related Grade 2 neurological AE.
Vital Signs 
X
Including BP, HR, temperature. Obtain vital signs within 72 hours prior 
to first dose 
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
12-lead electrocardiogram (ECG)
X
12-lead ECG to be performed within 72 hoursprior to dosing
Review of Concomitant 
Medication
X
Adverse Events Assessment
X
Protocol Amendment No: 09
Date: 27-Aug-2021
139
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-5:
Short-term Procedural Outline for C5 Cohort [Nivolumab + Anti-Lag-3 (BMS-986016)]: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
Laboratory Tests
X
On-study local laboratory assessments (after first dose) should be done 
within 72 hours prior to each dose through Week 23 and every alternate 
dose thereafter and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH with reflexive Free T4, Free T3.
Performed for the C5 Cohort Only:  Cardiac Troponin Levels:T (cTnt) 
or I(cTnI). Labs are performed locally, and may be collected within 
72hours prior to dosing. Results must be reviewed by the Investigator 
or appropriate designee prior to dose administration.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose, and then every 4 weeks (1 week) regardless of dosing schedule 
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Outcomes Research Assessment 
EORTC QLQ-C30 & EQ-5D
Questionnaire
Assessed following drug vial assignment but before first dose and every 6 weeks thereafter. Assessed at follow-up visit 
1& 2.Assessments should be completed at the start of the study visit prior to any study-related procedures or speaking 
with the physician.
Pharmacokinetic Assessments
Nivolumab PK blood sample
See separate Table 5.5.1-4
BMS-986016PK blood sample
See separate Table 5.5.1-4
Protocol Amendment No: 09
Date: 27-Aug-2021
140
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-5:
Short-term Procedural Outline for C5 Cohort [Nivolumab + Anti-Lag-3 (BMS-986016)]: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
Immunogenicity Assessments
Nivolumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-4
Ipilimumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-4
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separateTable 5.6.8-3
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separate Table 5.6.8-3
Ex vivo Functional assay 
(PBMCs)
See separate Table 5.6.8-3
Tumor tissue sample (biopsy)
See separate Table 5.6.8-3
Whole blood gene expression
See separate Table 5.6.8-3
Stool sample
See separate Table 5.6.8-3
Plasma Sample
See separate Table 5.6.8-3
SNP (whole blood)
See separate Table 5.6.8-3
MSI Status Determination
Submit Redacted Pathology 
Report to BMS Containing Local 
MSI Results
To be submitted at Week 1 Day 1. Report must contain MSI results and should also contain specific results per 
markers tested for MSI. 
Protocol Amendment No: 09
Date: 27-Aug-2021
141
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-5:
Short-term Procedural Outline for C5 Cohort [Nivolumab + Anti-Lag-3 (BMS-986016)]: MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 3.1.4.1for treatment duration
ClinicalDrug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from treatment assignment, the subject must receive the 
first dose of study medications.
Protocol Amendment No: 09
Date: 27-Aug-2021
142
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-6:
Short-term Procedural Outline for C6 Cohort [Nivolumab + Daratumumab] non-MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
Including BP, HR, and temperature. Obtain vital signs within 72 hours 
prior to first dose. Should be monitored extensively on Cycle 1 Day 1 
before, during, and after the first infusion of daratumumab. For all other 
infusions, vital signs should be measured before the start of the infusion 
and at the end of the daratumumab infusion. If a subject experiences 
any significant medical event, assess if overnight hospitalization is 
necessary. If the subject does not experience a significant medical event 
and is hospitalized overnight only for observation, do not consider as a 
serious adverse event. 
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
Review ofConcomitant 
Medication
X
Adverse Events Assessment
X
Laboratory Tests
X
On-study local laboratory assessments (after first dose) should be done 
within 72 hours prior to each dose:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin,alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH with reflexive Free T4, Free T3.
Protocol Amendment No: 09
Date: 27-Aug-2021
143
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-6:
Short-term Procedural Outline for C6 Cohort [Nivolumab + Daratumumab] non-MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose,and then every 4 weeks (1 week) regardless of dosing schedule 
Efficacy Assessments
Tumor Imaging Assessment
Tumor imaging assessments should occur every 6 weeks from the date of first dose (1 week) for the first 24 weeks, then 
every 12 weeks (1 wk) thereafter until disease progression or treatment is discontinued (whichever occurs later).
CT or MRI of chest, abdomen, pelvis and all known sites of disease. Use same imaging method as was used at 
screening/baseline.
Subjects with a history of brain metastasis may have surveillance MRI approximately every 12 weeks from the date of 
first dose, or sooner if clinically indicated
All PR or CR evaluations must be confirmed by a second scan performed 4weeks later.
Outcomes Research Assessment 
EORTC QLQ-C30 & EQ-5D
Questionnaires
Assessments should be completed at the start of the study visit prior to any study-related procedures or speaking with the 
physician. Assessed following drug vial assignment but before first dose and every 6 weeks through Week 24. Starting 
Week 25, assessments will be completed at each dose visit. Assessed at follow-up 
visit 1& 2.
Pharmacokinetic Assessments
Nivolumab PK blood sample
See separate Table 5.5.1-5
DaratumumabPK blood sample
See separate Table 5.5.1-6
Immunogenicity Assessments
Nivolumab Immunogenicity 
blood sample collection
See separate Table 5.5.1-5
DaratumumabImmunogenicity 
blood sample collection
See separate Table 5.5.1-6
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separateTable 5.6.8-3
Protocol Amendment No: 09
Date: 27-Aug-2021
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Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-6:
Short-term Procedural Outline for C6 Cohort [Nivolumab + Daratumumab] non-MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separate Table 5.6.8-3
Ex vivo Functional assay 
(PBMCs)
See separate Table 5.6.8-3
Tumor tissue sample (biopsy)
See separate Table 5.6.8-3
Whole blood gene expression
See separate Table 5.6.8-3
Stool sample
See separate Table 5.6.8-3
Plasma Sample
See separate Table 5.6.8-3
SNP (whole blood)
See separate Table 5.6.8-3
MSI Status Determination
Submit Redacted Pathology 
Report to BMS Containing Local 
MSI Results
Please submit report if local MSI testing was performed. Report must contain MSI results and should also contain 
specific results per markers tested for MSI. 
HerpesZoster Virus Antiviral 
Prophylaxis
See Section 3.4.2.3
Initiate antiviral prophylaxis within 1 week after starting daratumumab. Continue antiviral prophylaxis during the 
Treatment Phase as per institutional guidelines, and for 3 months following treatment discontinuation. 
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from treatment assignment, the subject must receive the 
first dose of study medication. 
See Table 4.3.3-1for daratumumab dosing window guidance
Subjects may be dosed no less than 12 days between nivolumab doses 
through Week 24(240 mg).
Subjects may be dosed no less than21 days between nivolumab doses 
beyond Week 25 (480 mg)
Protocol Amendment No: 09
Date: 27-Aug-2021
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10.0
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Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-6:
Short-term Procedural Outline for C6 Cohort [Nivolumab + Daratumumab] non-MSI-H
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
Thedosingcalculationsshouldbebasedonthebodyweight.Alldoses
should be rounded to the nearest milligram.
Protocol Amendment No: 09
Date: 27-Aug-2021
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v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Period (All treatment groups, CA209142)
Procedure
Follow Up, 
Visits 1 and 2a
Survival Follow-Up 
Visitsb
Notes
Safety Assessments
Targeted Physical Examination
X
To assess for potential late emergent study drug related issues
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Adverse Events Assessment
X
In Survival Follow-Up period only to include toxicities from 
study therapy
ECG
X
Only at FU1
Review of Concomitant Medication
X
X
Subsequent Cancer Therapy
Laboratory Tests
X
CBC w/ differential and platelet count, LFTs, BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, 
amylase, lipase, TSH (+reflex Free T4 and Free T3)
To be done at FU1. To be repeated at FU2 if study related 
toxicity persists.
Troponin
X
X*
Performed for the C5 Cohort Only. All results should be 
checked as soon as possible.
*Troponin testing as clinically indicated, at the discretion of 
the treating physician during survival follow-up.
Pregnancy Test (WOCBP only)
X
Serum or urine
Efficacy Assessments
Tumor Imaging Assessment
See note
See note
Refer toFigure 3.1.4.8-1.
See separate Table 5.1-14
Protocol Amendment No: 09
Date: 27-Aug-2021
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930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-7:
Follow-Up Period (All treatment groups, CA209142)
Procedure
Follow Up, 
Visits 1 and 2a
Survival Follow-Up 
Visitsb
Notes
Outcomes Research Assessment 
EORTC QLQ-C30 & EQ-5D
Questionnaires
X
X*
For all subjects except subjects in independent non-MSI 
safety cohort.
*Only EQ-5D
Questionnaire is required at Survival Follow-Up Visits
Herpes Zoster Virus Antiviral 
Prophylaxis 
X
See Section 3.4.2.3
Initiate antiviral prophylaxis within 1 week after starting 
daratumumab. Continue antiviral prophylaxis during the 
Treatment Phase as per institutional guidelines, and for 
3months following treatment discontinuation.
Subject Status
Survival Status
X
Every 3 months after F-U 2; may be accomplished by visit, 
phone contact or email, to assess subsequent anti-cancer 
therapyfor a minimum of 5 years, in all cohorts except the 
non-MSI-H Safety Cohort. (Please see Section 3.1.10for end 
of the study definition.)
a Subjects must be followed for at least 100 days after last dose of study therapy. Follow-up visit #1 (FU1) occurs approximately 35 days (7 days) after last dose 
or coinciding with the date of discontinuation (7 days) if date of discontinuation is greater than 35 days after last dose. Follow up visit #2 (FU2)occurs 
approximately 80 days (7 days) after FU1.
b Survival visits = every 3 months from FU2. Survival visits will be conductedfor all cohorts except the non-MSI-H SafetyCohort.
Protocol Amendment No: 09
Date: 27-Aug-2021
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1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-8:
Re-Initiation Screening Procedural Outline (CA209142)
Procedure
Screening
Visit
Notes
Eligibility Assessments
Informed Consent
X
Separate ICF required at time of re-initiation
Medical History
X
Investigator must verify subject is eligible for re-initiation per Section 4.3.9
Tumor Tissue Sample (biopsy)
X
Optional
ECOG Performance Status
X
Within 14 days prior to first dose.
See Appendix 2 for ECOG Performance Status scale.
Safety Assessments
Physical Examination
X
Vital Signs 
X
Including BP, HR, and temperature. Obtain vital signs at thescreening visit and within 
72hours prior to first dose.
Physical Measurements
X
Height and Weight. Within 14 days prior to first dose
Assessment of Signs and Symptoms
X
Within 14 days prior to first dose
Echocardiogram
Performed for the C5 Cohort Only
X
LVEF assessment with documented LVEF 50% by either TTE or MUGA (TTE preferred 
test) within 6 months from first study drug administration of re-initiation
Performed for the C5 Cohort Only
ECG
X
Within 14 days prior to first dose. 
For C5 Cohort: Subjects with screening 12-lead ECG showing a QT interval as corrected 
(QTc) >480 msec are excluded.
Concomitant Medication Collection
X
Within 14 days prior to first dose
Protocol Amendment No: 09
Date: 27-Aug-2021
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10.0
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Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-8:
Re-Initiation Screening Procedural Outline (CA209142)
Procedure
Screening
Visit
Notes
Laboratory Tests
X
CBC w/differential and platelet count,
Chemistry panel including: LDH, AST, ALT, ALP, T.Bili, BUN or serum urea level, 
creatinine, Ca, Mg, Na, K, Cl, Glucose, amylase, lipase, TSH, Free T4, Free T3, Hepatitis B 
surface antigen (HBV sAg), and hepatitis C antibody (HCV Ab) or Hepatitis C RNA (HCV 
RNA), within 14 days prior to first dose.
Safety laboratory tests do not need to be repeated if they were performed within 14 days of first 
dose.
Performed for the C5 Cohort Only:Cardiac Troponin Levels: T (cTnt) or I (cTnI)
Pregnancy Test (WOCBP only)
X
Serum or urine to be done at screening visit and repeated within 24 of first dose of study 
therapy
Efficacy Assessment
Re-initiation Baseline Tumor Imaging 
Assessment
X
CT or MRI chest, abdomen, pelvis and all known or suspected sites of disease within 28days 
prior to first dose of re-initiation treatment. 
Protocol Amendment No: 09
Date: 27-Aug-2021
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10.0
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Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-9:
Re-initiation Procedural Outline (Nivolumab Monotherapy, CA209142): MSI-H (Arm N, mStage 1/2)
Procedure
Nivolumab 480 mg Q4W
See Section 4.3.1for 
Re-initiation Treatment 
Schedule and Duration 
To Be Performed at Each 
Dosing Visit
Notes
Visit Window : 2 Days
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
Including BP, HR, and temperature. Obtain vital signs within 72 hours prior to 
first dose.
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status. 
See Appendix 2 for ECOG Performance Status scale.
Review of Concomitant Medication
X
Adverse Events Assessment
X
Laboratory Tests
X
On-study local CBC, chemistry, and thyroid laboratory assessments (after first 
dose) should be done within 72 hours prior to each dose every 4 weeks and 
include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase),BUN or serum urea 
level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH with 
reflexive Free T4, Free T3.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first dose, and 
then every 4 weeks(1 week) regardless of dosing schedule 
Protocol Amendment No: 09
Date: 27-Aug-2021
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930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-9:
Re-initiation Procedural Outline (Nivolumab Monotherapy, CA209142): MSI-H (Arm N, mStage 1/2)
Procedure
Nivolumab 480 mg Q4W
See Section 4.3.1for 
Re-initiation Treatment 
Schedule and Duration 
To Be Performed at Each 
Dosing Visit
Notes
Visit Window : 2 Days
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separateTable 5.6.8-4
Peripheral Blood Mononuclear Cells 
(PBMCs) Immuno-phenotyping
See separate Table 5.6.8-4
Ex vivo Functional assay (PBMCs)
See separate Table 5.6.8-4
Tumor tissue sample (biopsy)
(optional)
See separate Table 5.6.8-4
Whole blood gene expression
See separate Table 5.6.8-4
Plasma Sample
See separate Table 5.6.8-4
SNP (whole blood)
See separate Table 5.6.8-4
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from vial allocation, the subject must receive the first dose of 
study medication.Following first nivolumab dose, subsequent nivolumab dosing 
will be based on the actual date of administration of the previous dosing. 
Subjects may be dosed within a ± 3-day window of scheduled dose due to 
scheduling conflict.Subjects may be dosed no less than 25 days from the 
previous dose.
Protocol Amendment No: 09
Date: 27-Aug-2021
152
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Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-10:
Re-initiation Procedural Outline (Nivolumab Ipilimumab Combination, CA209142): MSI-H (Arm N+I, 
cStage 1/2)
Procedure
See Section 4.3.1for Re-initiation 
Treatment Schedule and Duration
To Be Performed at Each Dosing Visit
Notes
Visit Window : 2 Days
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
Including BP, HR, and temperature. Obtain vital signs within 72 hours 
prior to first dose 
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
Review of Concomitant
Medication
X
Adverse Events Assessment
X
Laboratory Tests
X
On-study local laboratory assessments (after first dose) should be done 
within 72 hours prior to each dose every 4 weeks and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, 
TSH with reflexive Free T4, Free T3.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose, and then every 4 weeks (1 week) regardless of dosing schedule 
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Protocol Amendment No: 09
Date: 27-Aug-2021
153
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Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-10:
Re-initiation Procedural Outline (Nivolumab Ipilimumab Combination, CA209142): MSI-H (Arm N+I, 
cStage 1/2)
Procedure
See Section 4.3.1for Re-initiation 
Treatment Schedule and Duration
To Be Performed at Each Dosing Visit
Notes
Visit Window : 2 Days
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separate Table 5.6.8-5
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separateTable 5.6.8-5
Ex vivo Functional assay 
(PBMCs)
See separate Table 5.6.8-5
Tumor tissue sample(biopsy)
(optional) 
See separate Table 5.6.8-5
Whole blood gene expression
See separate Table 5.6.8-5
Plasma Sample
See separate Table 5.6.8-5
SNP (whole blood)
See separate Table 5.6.8-5
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from vial allocation, the subject must receive the first dose 
of study medication.Following first nivolumab dose, subsequent 
nivolumab dosing will be based on the actual date of administration of the 
previous dosing. Subjects may be dosed within a ± 3-day window of 
scheduled dose due to scheduling conflict.Subjects may be dosed no less 
than 19 days between doses for the first 4 doses of nivolumab and 
ipilimumab. For the remaining doses, subjects may be dosed no less than 
25 days between doses of nivolumab.
Protocol Amendment No: 09
Date: 27-Aug-2021
154
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930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-11:
Re-initiation Schedule for C3 Cohort [Nivolumab 360 mg Q3W + Ipilimumab 1 mg/kg Q6W] No Prior 
Treatments in Metastatic Setting
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 4.3.1for Re-initiation Treatment Schedule and 
Duration
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Vital Signs 
X
Including BP, HR, temperature. Obtain vital signs within 72 hours prior 
to first dose.
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
Review of Concomitant 
Medication
X
Adverse Events Assessment
X
Laboratory Tests
X
On-study local laboratory assessments (after first dose) should be done 
within 72 hours prior to each dose through Week 23 and every dose 
thereafter and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH with reflexive Free T4, Free T3.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose, and then every 4 weeks (1 week) regardless of dosing schedule 
Protocol Amendment No: 09
Date: 27-Aug-2021
155
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-11:
Re-initiation Schedule for C3 Cohort [Nivolumab 360 mg Q3W + Ipilimumab 1 mg/kg Q6W] No Prior 
Treatments in Metastatic Setting
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
Separate Table
Notes
Visit Window : 2 Days
See Section 4.3.1for Re-initiation Treatment Schedule and 
Duration
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separate Table 5.6.8-5
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separateTable 5.6.8-5
Ex vivo Functional assay 
(PBMCs)
See separate Table 5.6.8-5
Tumor tissue sample (biopsy)
(optional) 
See separate Table 5.6.8-5
Whole blood gene expression
See separate Table 5.6.8-5
Plasma Sample
See separate Table 5.6.8-5
SNP (whole blood)
See separate Table 5.6.8-5
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from treatment assignment, the subject must receive the 
first dose of study medication. 
Subjects may be dosed no less than 19 days between nivolumab doses, 
and no less than 5 weeks between ipilimumab doses.
Protocol Amendment No: 09
Date: 27-Aug-2021
156
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-12:
Re-initiation for C5 Cohort (Nivolumab: MSI-H Nivolumab 240 mg Q2W + BMS-986016 [LAG3] 160 
mg Q2W)
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
SeparateTable
Notes
Visit Window : 2 Days
See Section 4.3.1for Re-initiation Treatment Schedule and 
Duration
Safety Assessments
Targeted Physical Examination
X
Targeted examination must include at a minimum the following body 
systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Neurological Exam
X
Obtain neurological exam (performed by a neurologist) in subjects who 
experience a study drug related Grade 2 neurological AE.
Vital Signs 
X
Including BP, HR, temperature. Obtain vital signs within 72 hours prior 
to first dose 
Physical Measurements (including 
performance status)
X
Weight and ECOG performance status.
See Appendix 2 for ECOG Performance Status scale. 
12-lead electrocardiogram (ECG)
X
12-lead ECG to be performed within 72 hoursprior to dosing
Review of Concomitant 
Medication
X
Adverse Events Assessment
X
Protocol Amendment No: 09
Date: 27-Aug-2021
157
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Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-12:
Re-initiation for C5 Cohort (Nivolumab: MSI-H Nivolumab 240 mg Q2W + BMS-986016 [LAG3] 160 
mg Q2W)
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
SeparateTable
Notes
Visit Window : 2 Days
See Section 4.3.1for Re-initiation Treatment Schedule and 
Duration
Laboratory Tests
X
On-study local laboratory assessments (after first dose) should be done 
within 72 hours prior to each dose through Week 23 and every alternate 
dose thereafter and include:
CBC w/differential and platelet count,
LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, 
lipase, TSH with reflexive Free T4, Free T3.
Performed for the C5 Cohort Only:  Cardiac Troponin Levels: T (cTnt) 
or I(cTnI). Labs are performed locally, and may be collected within 
72hours prior to dosing. Results must be reviewed by the Investigator 
or appropriate designee prior to dose administration.
Pregnancy Test (WOCBP only)
X
Serum or urine pregnancy test to be done within 24 hours prior to first 
dose, and then every 4 weeks (1 week) regardless of dosing schedule 
Efficacy Assessments
Tumor Imaging Assessment
See separate Table 5.1-14
Exploratory Biomarker Testing
Soluble Biomarkers (Serum)
See separateTable 5.6.8-6
Peripheral Blood Mononuclear 
Cells (PBMCs) Immuno-
phenotyping
See separate Table 5.6.8-6
Ex vivo Functional assay 
(PBMCs)
See separate Table 5.6.8-6
Tumor tissue sample (biopsy)
(optional)
See separate Table 5.6.8-6
Whole blood gene expression
See separate Table 5.6.8-6
Protocol Amendment No: 09
Date: 27-Aug-2021
158
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-12:
Re-initiation for C5 Cohort (Nivolumab: MSI-H Nivolumab 240 mg Q2W + BMS-986016 [LAG3] 160 
mg Q2W)
Procedure
To Be Performed at Each Dosing Visit, 
Unless Otherwise Specified in Notes or 
SeparateTable
Notes
Visit Window : 2 Days
See Section 4.3.1for Re-initiation Treatment Schedule and 
Duration
Plasma Sample
See separate Table 5.6.8-6
SNP (whole blood)
See separate Table 5.6.8-6
Clinical Drug Supplies
IVRS Drug Vial Assignment
X
Vials may be assigned up to 2 days prior to first dose date.
Dispense Study Drug
X
Within 3 days from treatment assignment, the subject must receive the 
first dose of study medication. 
Protocol Amendment No: 09
Date: 27-Aug-2021
159
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-13:
Follow-Up (Discontinuation of Re-initiated Treatment, CA209142)
Procedure
Re-initiation (R) 
Follow Up, 
Visits 1(R)  and 
2(R)a
Survival Follow-Up 
Visitsb
Notes
Safety Assessments
Targeted PhysicalExamination
X
To assess for potential late emergent study drug related issues
Targeted examination must include at a minimum the 
following body systems:
Cardiovascular
Gastrointestinal
Pulmonary
Neurological exam for subjects with brain metastases
Adverse Events Assessment
X
In Survival Follow-Up period only to include toxicities from 
study therapy
ECG
X
Only at FU1(R)
Review of Concomitant Medication
X
X
Subsequent Cancer Therapy
Laboratory Tests
X
CBC w/ differential and platelet count, LFTs, BUN or serum 
urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, Glucose, 
amylase, lipase, TSH (+reflex Free T4 and Free T3)
To be done at FU1(R). To be repeated at FU2(R) if study 
related toxicity persists.
Troponin
X
X*
Performed for the C5 Cohort Only. All results should be 
checked as soon as possible.
*Troponin testing as clinically indicated, at the discretion of 
the treating physician during survival follow-up.
Pregnancy Test (WOCBP only)
X
Serum or urine
Efficacy Assessments
Tumor Imaging Assessment
See note
See note
See separate Table 5.1-14
Protocol Amendment No: 09
Date: 27-Aug-2021
160
10.0
Approved
930073805
10.0
v
Approved
1.0
v

Clinical Protocol
CA209142
BMS-936558
nivolumab
Table 5.1-13:
Follow-Up (Discontinuation of Re-initiated Treatment, CA209142)
Procedure
Re-initiation (R) 
Follow Up, 
Visits 1(R)  and 
2(R)a
Survival Follow-Up 
Visitsb
Notes
Subject Status
Survival Status
X
Every 3 months after F-U 2 (R); may be accomplished by 
visit, phone contact or email, to assess subsequent anti-cancer 
therapy for a minimum of 5 years, in all cohorts.(Please see 
Section 3.1.10for end of the study definition.)
a Subjects must be followed for at least 100 days after last dose of study therapy. Follow-up visit #1after re-initiation(FU1R) occurs approximately 35 days (
7 days) after last dose or coinciding with the date of discontinuation (7 days) if date of discontinuation is greater than 35 days after last dose. Follow upafter 
re-initiationvisit #2 (FU2R)occurs approximately 80 days (7 days) after FU1(R).
b Survival visits = every 3 months from FU2(R). Survival visits will be conducted for all MSI-H subjects who have re-initiated treatment.
Table 5.1-14a:
Standard Tumor Imaging Assessment
Tumor imaging assessments will occur every 6 weeks from the date of first dose (± 1 week) for the first 24 weeks, then every 12 weeks (± 1 week) 
thereafter until disease progression or treatment is discontinued (whichever occurs later).
Table 5.1-14b:
Reduced Tumor Imaging Assessment
All Subjects (Except Re-initiation Subjects) 
Re-initiationSubjects
Scans every 12 weeks (± 1 week)for 3 years after first dose, then every 
24 weeks (± 2weeks)thereafter*
Scans every 12 weeks  (± 1 week) for 3 years after first dose following re-
initiation, then every 24 weeks (± 2weeks)thereaftera
a Scans may continue every 12 weeks (± 1 week) if clinically indicated.
Notes: CT or MRI chest, abdomen, pelvis and all known sites of disease. Use same imaging method as was used at screening/baseline.
Subjects with a history of brain metastasis may have surveillance MRI approximately every 12 weeks from the date of first dose, or sooner if clinically indicated.
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5.2
StudyMaterials
NCI CTCAE version 4.0
Nivolumab Investigator Brochure
Ipilimumab Investigator Brochure
BMS-986016 Investigator Brochure
Daratumumab Investigator Brochure
Pharmacy Binder
Laboratory manuals for collection and handling of blood (including biomarker and 
immunogenicity) and tissue specimens 
Site manual for operation of interactive voice response system, including enrollment 
worksheets
Manual for entry of local laboratory data
Pregnancy Surveillance Forms
RECIST 1.1 pocket guide
5.3
Safety Assessments
At baseline, a medical history will be obtained to capture relevant underlying conditions. The 
baseline examinations should include signs and symptoms, weight, height, ECOG Performance 
Status, BP, HR, and temperature, and they should be performed within 14days prior to first dose 
except where noted inTable 5.1-1. Concomitant medications will also be collected within 14 days 
prior to first dose and through thestudy treatment period (SeeTable 5.1-1, Table 5.1-2Table 5.1-
3,Table 5.1-4, 
Table 5.1-5, and Table 5.1-6)and during the re-initiation period if applicableTable 
5.1-8,Table 5.1-9, Table 5.1-10, Table5.1-11andTable 5.1-12.
Baseline local laboratory assessments should be done within 14 days prior to the first dose and 
include: CBC w/differential, LFTs (ALT, AST, total bilirubin, alkaline phosphatase), BUN or 
serum urea level, creatinine, Ca, Mg, Na, K, Cl, LDH, glucose, amylase, lipase, TSH, Free T4, 
Free T3, and Hep B and C testing (HBV sAg and HCV RNA or Ab) (seeTable 5.1-1). Pregnancy 
testing for WOCBP (done locally) should be done within 24 hours prior to first dose,and then 
every 4 weeks (1 week) regardless of dosing scheduleand during re-initiation period, as 
applicable,and at each safety follow-up visits after the original treatment phase and after re-
initiated treatment.
Subjects will be evaluated for safety if they have received any study drug. Toxicity assessments 
will be performed continuously during the treatment phaseand during re-initiated treatment if 
applicable.During the safety follow-up phase (Table 5.1-7andTable 5.1-13),toxicity assessments 
should be done in person. Once subjects reach the survival follow-up phase, either in-person visits 
or documented telephone calls to assess the subject’s status are acceptable.
Adverse events and laboratory values will be graded according to the NCI-CTCAE version 4.0.
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On-study weight, ECOG Performance Status, and vital signs should be assessed at each on-study 
visit prior to nivolumab dosing. Vital signs should also be taken as per institutional standard of 
care prior 
to, during and after dosing. The start and stop 
time of the nivolumab,ipilimumab, BMS-
986016, and daratumumabinfusionsshould be documented. Physical examinations are to be 
performed as clinically indicated. If there are any new or worsening clinically significant changes 
since the last exam, report changes on the appropriate non-serious or serious adverse event page.
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 
inducted liver enzyme elevations) 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.
Some of the previously referred to assessments may not be captured as data in the eCRF. They are 
intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations.
5.3.1
Imaging Assessment for the Study
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.
Collect any additional imaging that may demonstrate tumor response or progression (including 
scans performed at unscheduled timepoints and/or 
at an outside institution) for RECIST 1.1 
tumor 
assessment and submit to the BICR.
5.4
Efficacy Assessments
Study evaluations will take place in accordance with the flow charts in Section 5.1. Baseline 
assessments should be performed within 28 days prior to the first dose utilizing CT or MRI. In 
addition to chest, abdomen, and pelvis, all known sites of disease should be assessed at 
baseline. Subsequent assessments should include chest, abdomen, and pelvis, and all known 
sites of disease and should use the same imaging method as was used at baseline. Baseline 
MRI for brain should be done for known or suspected disease.Subjects with a history of brain 
metastasis should have surveillance MRI approximately every 12 weeks, or sooner if clinically 
indicated.Subjects will be evaluated for tumor response beginning 6 weeks (1 week) from 
first dose and continuing every 6 weeks (1 week) for the first 24 weeks and every 12 weeks 
(±1 week) thereafter, until disease progression is documented or treatment is discontinued 
(whichever occurs later). Tumor imaging assessments for ongoing study treatment decisions 
will be completed by the investigator using RECIST (Response Evaluation Criteria in Solid 
Tumors) 1.1 criteria, Appendix 3.Confirmation of PR and/or CR is required after at least 4 
weeks from the initial scan reporting response. Confirmation of progression is not required. 
For re-initiated subjects, assessments will only be performed locally and the imaging vendor will 
collect scans. During Re-initiation, tumor imaging assessments should occur every 6 weeks from 
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the date of re-initiation of treatment (1 week) for the first 24 weeks, then every 12 weeks (
1week) thereafter until disease progression or treatment is discontinued (whichever occurs later). 
In order to help reduce unnecessary participant burden and help optimize participant safety by 
reducing the possible radiation exposure risk of a secondary malignancy, investigators should 
reduce scan frequency for participants having disease control at 3 years,per Table 5.1-14b.3 years
after the first doseor 3 years after re-initiation dose, as the case may be,the participant’s tumor 
assessmentscheduleshouldbe modified toevery24weeksunless clinically indicated to continue 
tumor assessments every 12 weeks.
Immune-related response criteria using unidimensional measurements may be used to describe 
tumor shrinkage following disease progression.
107This phenomenon has been described for 
ipilimumab as well as for nivolumab.
5.4.1
Primary Efficacy Assessment
The primary endpoint is ORR in all subjects as determined by investigators. ORR is defined as the 
number of subjects with a best overall response (BOR) of complete response (CR) or partial 
response (PR) divided by the number of treated subjects. The investigator assessed ORR will be 
further characterized by the investigator-determined duration of response (DOR) and the 
magnitude of reduction in tumorvolume. 
5.4.2
Secondary Efficacy Assessment
The secondary endpoint is ORR based on IRRC determination. IRRC-assessed ORR will be 
further characterized by IRRC-determined DOR.
5.5
Pharmacokinetic and Immunogenicity Assessments
Samples for PK and immunogenicity assessments will be collected for all subjects receiving 
nivolumab monotherapy, nivolumab combined withipilimumab, nivolumab combined with BMS-
986016, and nivolumab combined with daratumumab. All timepoints are relative to the start of 
study drug administration. All on-treatment timepoints are intended to align with days on which 
study drug is administered.If dosing occurs on a different day, the PK and immunogenicity 
sampling should be adjusted accordingly. Further details of sample collection, processing, and 
shipment will be provided in the laboratory procedures manual.
Samples for PK and immunogenicity assessments will not be collected for subjects who have 
re-initiated treatment following discontinuation at maximum clinical benefit.
All samples which have been collected prior to protocol revision 08 will be analyzed. 
5.5.1
Pharmacokinetics and Immunogenicity Collection and Processing
A detailed schedule of PK and immunogenicity evaluations is provided inTable 5.5.1-1, Table 
5.5.1-2, Table 5.5.1-3, Table 5.5.1-4, Table 5.5.1-5, and Table 5.5.1-6. All time points in 
nivolumab/ipilimumab and nivolumab/BMS-986016 combination cohorts are relative to the start 
of nivolumab infusion. In the nivolumab/daratumumab combination cohort, predose sample for 
daratumumab should be drawn before administration of daratumumab (window of -2hours before 
thestart of daratumumabdosing). Daratumumab post-dose samples should be drawn within 
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2hours after the end of the infusion. PK samples will be analyzed for nivolumab, ipilimumab, 
BMS-986016, and daratumumab by validated assays. Immunogenicity samples will be analyzed 
for anti-nivolumab, anti-ipilimumab, and anti-BMS-986016, and anti-daratumumab antibodies by 
validated immunogenicity assays; samples may also be analyzed for neutralizing antibodies by 
validated methods. Serum samples may be analyzed by an exploratory method that measures these 
mAbs or anti-drug antibodies for technology exploration purposes; exploratory results will not be 
reported. Serum samples designated for PK or biomarker assessments may also be used for 
immunogenicity analysis if required (eg, insufficient volume for complete immunogenicity 
assessment or to follow up on suspected immunogenicity related AE).PK and immunogenicity 
samples after 2 years of treatment, and samples for post-treatment discontinuation follow-up visits
(1 & 2),will not be collected.
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Table 5.5.1-1:
PK Sampling-Pharmacokinetic & Immunogenicity Sampling Schedule -Arm N+I (Nivolumab in 
combination with Ipilimumab
Study Day
Event
Time 
(Relative to Start 
of Infusion)
Hour: Min
Nivolumab PK
Blood Sample
Nivolumab 
Immunogenicity 
Sample
Ipilimumab PK
Blood Sample
Ipilimumab 
Immunogenicity 
Sample
D1 Week 1
Predosea
00:00
X
X
X
X
D1 Week 4
Predosea
00:00
X
X
X
X
D1 Week 10
Predosea
00:00
X
X
X
X
D1 Week 13
Predosea
00:00
X
X
X
X
D1 Week 25
Predosea
00:00
X
X
X
X
Day 1 of every 24th week until 
discontinuation of study treatment
or up to 2 years of treatment
Predosea
00:00
X
X
a Predose samples should be collected just prior to the start of infusion on the day the study drug is administered
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Table 5.5.1-2:
PK Sampling-Pharmacokinetic & Immunogenicity Sampling 
Schedule -Arm N (Nivolumab monotherapy)
Study Day
Event
Time
(Relative to Start of 
Infusion)
Hour:Min
Nivolumab 
PK Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
D1 Week 1
Predosea
00:00
X
X
D1 Week 5
Predosea
00:00
X
X
D1 Week 13
Predosea
00:00
X
X
D1 Week 25
Predosea
00:00
X
X
Day 1 of every 24th week 
until discontinuation of 
study treatmentor up to 2 
years of treatment
Predosea
00:00
X
X
a Predose samples should be collected just prior to the start of infusion on the day the study drug is administered
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Table 5.5.1-3:
PK Sampling-Pharmacokinetic & Immunogenicity Sampling 
Schedule for Cohort C3 
(Nivolumab and Ipilimumab Sample Collections)
Study Day
(1 Cycle 
=6Weeks)
Event
Time 
(Relative 
to Start of 
Infusion)
Hour: Min
Nivolumab 
PK
Blood 
Sample
Nivolumab 
Immunogenicity 
Sample
Ipilimumab 
PK
Blood 
Sample
Ipilimumab 
Immunogenicity 
Sample
D1 Week 1
(D1 Cycle 1)
Predosea
00:00
X
X
X
X
D1 Week 3
(D15 Cycle 1)
Predosea
00:00
X
X
X
X
D1 Week 9
(D15 Cycle 2)
Predosea
00:00
X
X
X
X
D1 Week 15
(D15 Cycle 3)
Predosea
00:00
X
X
X
X
D1 Week 21
(D15 Cycle 4)
Predosea
00:00
X
X
X
X
Day 1 of every 
24th (4 cycles) 
week after 
week 21 until 
discontinuation 
of study 
treatmentor up 
to 2 years of 
treatment
Predosea
00:00
X
X
X
X
a Predose samples should be collected just prior to the start of infusion on the day the study drug is administered.
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Table 5.5.1-4:
Pharmacokinetic and Immunogenicity Sampling Schedule 
(Nivolumab and BMS-986016 Combination, Cohort C5)
Study Daya
Event 
(Relative to Start 
of Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
PK Blood 
Sample for 
Nivolumab 
and 
BMS-986016
Immunogenicity 
Sample for 
Nivolumab and 
BMS-986016
Cycle 1 Day 1 (Week 1 Day 1)
Predoseb
00:00
X
X
Cycle 5 Day 1(Week 9 Day 1)
Predoseb
00:00
X
X
Cycle 7 Day 1(Week 13 Day 1)
Predoseb
00:00
X
X
Day 1 of every 8th cycle (every 
16 weeks) until discontinuation 
of study treatment or up to2 
years of treatment
predoseb
00:00
X
X
a If BMS-986016is discontinued and nivolumab continues, BMS-986016PK and ADA should be collected only for 
the next 2 time points (corresponding to nivolumab sample collection) according to the PK table. If nivolumab is 
discontinued and BMS-986016continues, nivolumab PK and ADA should be collected only for the next 2 time 
points (corresponding to BMS-986016sample collection) according to the PK table.
b Pre-dose samples should be taken just prior to the start of infusion (preferably within 30 minutes). If the infusion
is delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample.
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Table 5.5.1-5:
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Nivolumab (Nivolumab and Daratumumab Combination, 
CohortC6)
Study Day
(1 Cycle =4 weeks starting 
Week 25)
Event 
(Relative to 
Start of 
Infusion/Event)
Time 
(Relative to Start 
of Nivolumab 
Infusion)
Hour:Min
PK Blood 
Sample for 
Nivolumab
Immunogenicity 
Sample for 
Nivolumab 
Cycle 3Day 1 (Week 3 Day 1)a
Predoseb
00:00
X
X
Cycle 9Day 1(Week 9 Day 1)
Predoseb
00:00
X
X
Cycle 11Day 1(Week 13 Day 1)
Predoseb
00:00
X
X
Cycle 17Day 1(Week 25 
Day1)c
Predoseb
00:00
X
X
Day 1 of every 4th cycle (every 
16 weeks) until discontinuation 
of study treatment or up to 2 
years of treatment
Predoseb
00:00
X
X
a Nivolumab will start at Week 3.
b Pre-dose samples should be taken just prior to the start of infusion (preferably within 30 minutes). If the infusion 
is delayed and a pre-dose sample is already collected, there is no need to collect an additional pre-dose sample.
c Starting from Week 25, nivolumab will be given 480 mg Q4W.
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Table 5.5.1-6:
Pharmacokinetic and Immunogenicity Sampling Schedule for 
Daratumumab (Nivolumab and Daratumumab Combination, 
Cohort C6)
Study Day
Event 
(Relative to Start 
of Daratumumab 
Infusion/Event) 
Time 
(Relative to Start 
of Daratumumab 
Infusion)
Hour:Min
PK Blood 
Sample for 
Daratumumab 
Immunogenicity 
Assessment for 
Daratumumab 
(taken from 
DaratumumabPK 
sample)a
Week 1 Day 1
Pre-doseb
00:00
X
X
Week 1 Day 1
Post-dose
EOI
X
Week 5 Day 1
Pre-dose
00:00
X
X
Week 5 Day 1
Post-dose
EOI
X
Week 9 Day 1
Predoseb
00:00
X
X
Week 13 Day 1
Predoseb
00:00
X
X
Week 25 Day 1
Predoseb
00:00
X
X
Week 41 Day 1
Predoseb
00:00
X
Week 57 Day 1
Predoseb
00:00
X
X
Week 73 Day 1
Predoseb
00:00
X
Week 89 Day 1
Predoseb
00:00
X
Week 105 Day 1
Predoseb
00:00
X
X
a Daratumumab immunogenicity will be assessed from an aliquot of the daratumumab PK blood sample –no 
additional blood draw is required.
b Daratumumab predose PK samples should be drawn before administration of either nivolumab or daratumumab 
(window of -2 hours before that start of dara dosing).  Daratumumab post dose samples should be drawn within 2 
hours after the end of the infusion.
5.6
Biomarker Assessments
Peripheral blood and tumor tissue will be collected prior to therapy and at selected timepoints on 
treatment. Residual sample material available after completion of the designated analyses may be 
used in the future for identification of additional pharmacodynamic or predictive markers or to 
enhance understanding of disease biology. If biomarker samples are drawn but study drug(s) is not 
administered, samples will be retained. A detailed description of each assay system is described 
below and a schedule of pharmacodynamic evaluations is provided inTable 5.6.8-1, Table 5.6.8-
2, Table 5.6.8-3, Table 5.6.8-4, Table 5.6.8-5, and Table 5.6.8-6.
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5.6.1
Serum
In this study,we plan to analyze serum samples collected at baseline, during, and after treatment 
from subjects enrolled on the trial to identify potential biomarkers with prognostic and predictive 
value for outcomes (response, PFS,OS, toxicity). Preliminary results from this studywill inform
estimates for the Phase II efficacy study. Soluble factors, such as cytokines, chemokines, soluble 
receptors, and antibodies to tumor antigens will be characterized and quantified by immunoassays 
in serum. Analyses may include, but not necessarily be limited to, soluble CD25, soluble PD-1, 
soluble LAG-3, and CXCL-9. Collected serum samples will also be used for the assessment of 
tumor antigen-specific responses elicited following treatment with monotherapy and combination 
therapy to 
explore 
which 
antitumorantibodies 
are 
most 
associated 
with clinical 
response. Antibody 
levels to cancer test antigens will be assessed by multiplex assays and enzyme-linked 
immunosorbent assay (ELISA).
5.6.2
Plasma
The presence of cell-free DNA in circulating blood is a well-documented phenomenon. Fragments 
of DNA are shed into the blood stream from dividing cells during cell proliferation or cell death. 
In subjects with cancer, a fraction of this DNA is tumor-derived and is termed circulating tumor 
DNA (ctDNA). Albeit small, fragments ofDNA average between 180 to 200base pairs,and 
specific genomic regions can be amplified with PCR. Moreover, several studies have detected 
mutations in ctDNA that exactly correspond to mutations from the parent tumor. Using tissue and 
plasma from subjects with known driver mutations in melanoma or head and neck cancer, 
BEAMing or similar technology will be utilized to 
count 
the frequency of mutations in circulation.
5.6.3
Immunophenotyping
The proportion of specific lymphocyte subsets and expression levels of T cell co-stimulatory 
markers in peripheral blood mononuclear cell (PBMC)and/or whole bloodpreparations will be 
quantified by flow cytometry. Analyses may include, but not necessarily be limited to, the 
proportion of T, B, MDSC, and NK cells, granulocytes, the proportion of memory and effector T 
cell subsets, and expression levels of PD-1, PD-L1, other B7 family members, ICOS, and Ki67.
The proposed immunophenotyping by flow cytometry, along with peripheral blood gene 
expression analysis and T cell repertoire analysis would constitute the “immune monitoring” of 
the systemic immunity. 
5.6.4
Ex vivo Functional Assays
To explore whether monotherapy and/or combination therapy will restore T cell activation and 
function, peripheral blood mononuclear cells (PBMCs) will be isolated and cryopreserved. Assays 
of the functional status of effector T cells will be performed, including but not limited to, assays 
for interferon-gamma (IFN-) and CD107. 
5.6.5
Peripheral Blood Gene Expression
The expression level of genes related to response to nivolumab monotherapy and nivolumab
combined with ipilimumab, BMS-986016, or daratumumab will be quantified molecular methods 
such as RNASeq, Affymetrix by microarray and/or quantitative reverse transcription polymerase 
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chain reaction (RT-PCR) analysis in whole blood samples. Analysis may include, but not 
necessarily be limited 
to, 
genes 
associated 
with immune-related 
pathways, such 
as 
T 
cell 
activation 
and antigen processing and presentation.
5.6.6
T Cell Repertoire Analysis
Low diversity of the peripheral T cell compartment has been shown to correlate with poor OSin 
metastatic breast cancer.
108A standing theory in immuno-oncology suggests a diverse and 
activated immune environment is better adept at eradicating tumor compared to a skewed 
repertoire of naïve and tolerized T cells. In order to explore whether a diverse T cell repertoire is 
predictive of response to therapy, next generation, high-throughput, DNA sequencing will be 
performed on DNA isolated from peripheral blood and tumor tissue to quantitate the composition 
of the T cell repertoire prior to, and during, monotherapy and combination therapy.
5.6.7
Microbiome Analysis
Colorectal cancer may be associated with the gut microbiome through several mechanisms, 
including promotion of disease via induction of chronic inflammation or catabolism of polyamines 
on other carcinogenic digestible material. In addition, the innate and adaptive immune system 
activation state and repertoire may be altered based on local microbiota leading to differential 
activityof nivolumab and/or ipilimumab in colorectal cancer subjects. 
DNA will be extracted from fecal samples taken prior to therapy and on-treatment. A 
gene-sequencing approach will be utilized to survey microbial species in the gut in order to define 
microbiota as a function of efficacy and safety. Overall changes in the gut microbiota will also be 
characterized in individual subjects that receive therapy.
5.6.8
Tumor Samples
Tumor-Based Biomarker Measures
Tumor biopsy specimens will be obtained from consenting subjects prior to and during treatment 
with nivolumab monotherapy, nivolumab combined with ipilimumab, nivolumab combined with 
BMS-986016, and nivolumab combined with daratumumab to characterize immune cell 
populations and expression of selected tumor markers.Biopsy collection is mandatory for subjects 
with accessible lesions prior to therapy and on-treatment biopsy samples are optional.For Cohorts
C3, C5, and C6, tissue submitted will be assessed for quality with anH&E stain,and only those 
subjects who have met tissue quality thresholds canbe assigned study drug.
Fresh biopsies will be provided for biomarker analysis if accessible and deemed safe by the 
investigator. An archived biopsy prior to therapy is acceptable if the fresh biopsy cannot be 
obtained and if the archived tissue meets the defined criteria as stated below. 
An archived biopsy (block or slides) must contain tumor tissue
The subject has not received systemic therapy subsequent to archived biopsy and prior to 
screening
If an archived blockis not available, 30 or more slides containing tumor are available for 
exploratory use
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NOTE: Exceptions to above requirements need to be discussed with the medical monitor and will 
be handled in a case by case basis. An additional source of tumor tissue must be available if the 
tissue obtained adhering to the above guidelines can’t be tested due to poor quality or quantity. 
Accordingly, all subjects must also have archive tumor tissue obtained prior to the last systemic 
therapy received in the metastatic setting or from an unresectable site of disease.
A biopsy sample of subjects that have confirmed progression is optional, but strongly encouraged 
for the purposes of understanding mechanisms of resistance to therapy. 
Biopsy samples may be used for the following assessments:
Characterization of tumor infiltrating lymphocytes (TILs) and tumor antigens
Immunohistochemistry (IHC) will be used to assess the number and composition of immune 
infiltrates in order to define the immune cell subsets present within formalin-fixed, 
paraffin-embedded (FFPE) tumor tissue before and after exposure to therapy. These IHC analyses 
will include, but not necessarily be limited to, the following markers: CD4, CD8, CD45RO, 
FOXp3, PD-1, PD-L1, and PD-L2. 
Characterization of T cell repertoire
As described above, DNA sequencing will be performed on pre-and post-treatment tumor tissue 
to assess the composition of the T cell repertoire. DNA will be isolated from either the FFPE 
tumor 
block or from RNAlater or equivalent preparations.
Gene expression profiling
Tumor biopsies that are collected in RNAlater or equivalent fixative will be examined for mRNA 
gene expression to detect expression of selected immune related genes.
Tumor sample collection details
Fresh biopsy:
Fresh biopsies atbaseline should be prioritized over archived samples and are strongly encouraged 
on-treatment.
Tumor samples obtained from bone metastases are not considered acceptable for PD-L1 testing 
because the PD-L1 assay does not include a decalcification step. Forany cases where the only 
tumor tissue available is from a bone metastasis lesion, please discuss further with the study 
Medical Monitor.
Biopsy samples should be excisional, incisional or core needle. Fine needle aspirates or other 
cytology samples are only allowed after discussion with the sponsor’s biomarker expert.
It is recommended that samples be fixed in 10% Neutral-buffered formalin for 24-48 hours. 
Tumor 
tissue samples should not be shipped in formalin as the temperature and length of fixation cannot 
be controlled during shipping. 
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If slides are submitted, the recommended tissue section thickness is 4 microns and the slides must 
be positively charged.Slides should be shipped refrigerated at 2-8C.
Sample shipments should include a completed requisition form containing collection date, 
collection method, primary/met, site, fixation conditions, and a copy of Pathology report, if 
available.
If a fresh biopsy is taken, up to 4 core biopsies are recommended. An assessment of biopsy quality 
by a pathologist is strongly encouraged at the time of the procedure. The tumor tissue that is 
obtained from these biopsies will be divided equally into FFPE samples and RNAlater. 
The investigator, in consultation with the radiology staff, must determine the degree ofrisk 
associated with the procedure and find it acceptable. Biopsies may be done with local anesthesia 
or conscious sedation. Institutional guidelines for the safe performance of biopsies should be 
followed. Excisional biopsies may be performed to obtain tumor biopsy samples. Invasive 
procedures that require general anesthesia should not be performed to obtain a biopsy specimen. 
However, if a surgical procedure is performed for a clinical indication, excess tumor tissue may 
be used for research purposes with the consent of the subject.
For subjectswho re-initiate treatment, biomarker sample collection should follow either Table 
5.6.8-4, Table 5.6.8-5,or Table 5.6.8-6, depending on the cohort.Detailed instructionscan be 
found in the lab manual.
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Table 5.6.8-1:
CA209142 Biomarker Sampling Schedule (Subjects Receiving Nivolumab Only)
Collection 
Timinga
Soluble 
Biomarkers
PBMC
Stool
Tumor
Whole Blood
Study Day 
Serum
Plasma
Immuno-
phenotyping 
Ex vivo Functional 
Assay 
Microbiome 
Analysis
Tumor 
Biopsy 
Gene 
Expression 
SNP 
Screening 
Xb
D1 Week 1 
X
X
X 
X 
X
X 
X 
D1 Week 2c
X
X 
D1 Week 3 
X
X 
D1 Week 5 
X
X 
D1 Week 7 
X
X 
X 
X
Xd
X 
D1 Week 13 
X
X 
D1 Week 15 
X
X 
X 
X 
Upon Progressione
X
X 
X 
X
Xd
X 
a All biomarker samples may be obtained 3 days from the indicated time.
b Tumor biopsy prior to therapy is mandatoryduring initial treatment period.If an archived biopsy (as defined in the protocol) is not available at screening, a fresh 
biopsy will be taken at any point prior to treatment.. 
c Day 1 Week 2 samples are optional, but strongly encouraged for biomarker analysis.
d Optional biopsies on-treatment and upon progression and can be taken 7 days at the discretion of the investigator.
e Samples from subjects that have confirmed progression although optional, are encouraged.
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Table 5.6.8-2:
Biomarker Sampling Schedule (Subjects Receiving Nivolumab + Ipilimumab Combination)
Collection 
Timinga
Soluble 
Biomarkers
PBMC
Stool
Tumor
Whole Blood
Study Day 
Serum
Plasma
Immuno-
phenotyping 
Ex vivo Functional 
Assay 
Microbiome 
Analysis
Tumor 
Biopsy 
Gene 
Expression 
SNP
Screening 
Xb
D1 Week 1 
X
X
X 
X 
X
X 
X
D1 Week 2c
X
X 
D1 Week 4 
X
X 
D1 Week 7 
X
X 
X 
X
Xd
X 
D1 Week 13 
X
X 
D1 Week 15 
X
X 
X 
X 
Upon 
Progressione
X
X 
X 
X
Xd
X 
a All biomarker samples may be obtained 3 days from the indicated time.
b Tumor biopsy prior to therapy is mandatoryduring initial treatment period.If an archived biopsy (as defined in the protocol) is not available at screening, a fresh 
biopsy will be taken at any point prior to treatment.
c Day 1 Week 2 samples are optional, but strongly encouraged for biomarker analysis.
d Optional biopsies on-treatment and upon progression and can be taken 7 days at the discretion of the investigator.
e Samples from subjects that have confirmed progression although optional, are encouraged.
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Table 5.6.8-3:
Biomarker Sampling Schedule (Cohorts C3, C5, and C6)
Collection 
Timinga
Soluble 
Biomarkers
PBMC
Stool
Tumor
Whole Blood
Study Day Serum
Plasma
Immuno-phenotyping, 
T Cell Repertoire 
Analysis and Others 
Ex vivo 
Functional 
Assay 
Microbiome 
Analysis
Tumor 
Biopsy 
Immune Monitoring (flow 
cytometry, gene expression 
analysis and other 
analysis)
SNP 
Screening 
Xb
D1 Week 1 
X
X
X 
X 
X
X 
X
D1 Week 3
X
For 
Cohort 6 
Only
X
X 
For Cohort 6 
Only
X
For Cohort 6 
Only
X
For Cohort 6 Only
X
For 
Cohort 6 
Only
X
D1 Week 5 
X
X 
For 
Cohorts 
C5 Only
Xc
For Cohorts C5 and C6 Only
X
D1 Week 7 
X
X
X 
X 
X
Xc
X 
D1 Week 13 
X
X
D1 Week 17 
X
X
X 
X 
X 
Upon 
Progressiond
X
X 
X 
X
Xc
X 
a All biomarker samples may be obtained 3 days from the indicated time.
b Tumor biopsy prior to therapy is mandatoryduring initial treatment period.If an archived biopsy (as defined in the protocol) is not available at screening, a fresh 
biopsy will be taken at any point prior to treatment.
c Optional biopsies on-treatment and uponprogression and can be taken 7 days at the discretion of the investigator.
d Samples from subjects that have confirmed progression although optional, are encouraged.
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Table 5.6.8-4:
Biomarker Sampling Schedules for Subjects in mStage 1/2 who Re-initiate Treatment
CollectionTimingduringRe-initiation(R)
TumorBiopsy
WholeBlood
Serum
Plasma
PBMC
Screening(R)
Xa
D1Week1(R)
X
X
X
X
D1Week5(R)
X
X
X
UponProgression
X
X
X
aOptional, but strongly encouraged.
Table 5.6.8-5:
Biomarker Sampling Schedules for Subjects in cStage 1/2and Cohort 3 who Re-initiate 
Treatment
CollectionTimingduringRe-
initiation (R) 
Tumor Biopsy
Whole Blood
Serum
Plasma
PBMC
Screening(R)
Xa
D1Week1(R)
X
X
X
X
D1Week4(R)
X
X
X
UponProgression
X
X
X
aOptional, but strongly encouraged.
Table 5.6.8-6:
Biomarker Sampling Schedule for Subjects in Cohort 5 who Re-initiate Treatment
CollectionTiming
during Re-initiation (R) 
Tumor Biopsy
Whole Blood
Serum
Plasma
PBMC
Screening(R)
Xa
D1Week1(R)
X
X
X
X
D1Week3(R)
X
X
X
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Table 5.6.8-6:
Biomarker Sampling Schedule for Subjects in Cohort 5 who Re-initiate Treatment
CollectionTiming
during Re-initiation (R) 
Tumor Biopsy
Whole Blood
Serum
Plasma
PBMC
D1Week5(R)
X
X
X
UponProgression
X
X
X
aOptional, but strongly encouraged.
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5.7
Outcomes Research Assessments
Outcomes research data including health-related quality of life and patient-reported symptom 
burden provide a more complete understanding of the impact of treatment by incorporating the 
patients’ perspective. These data 
offer insights into 
the patient experience that may not be captured 
through physician reporting. The EQ-5D will be collected in order to assess the impact of 
nivolumabon generic health-related quality of life,and the data will be used for populating health 
economic models,most notably, cost effectiveness analysis. The EORTC-QLQ C-30 will be 
collected in order to assess cancer-specific,health-related quality of life. The combination of the 
generic scale for general health status and economic evaluation and the cancer specific scale will 
provide a robust outcomes research package. 
The EORTC QLQ-C30isa 30-item instrument comprising six functional scales (physical 
functioning, cognitive functioning, emotional functioning, role functioning, social functioning and 
global quality of life) as well as nine symptom scales (fatigue, pain, nausea/vomiting, dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Except for the overall 
health status and global quality of life items, responses for all items are 4-point categorical scales 
ranging from 1 (Not at all) to 4 (Very much). The overall health status/quality of life responses are 
7-point Likert scales. It has gone through appropriate psychometric testing and is available in over 
81 languages.
General health status will be measured using the EQ-5D. The EQ-5D is a standardized instrument 
foruse as a measure of self-reported general health status. The EQ-5D comprises 5dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety) and a visual analog rating scale 
(VAS). The utility data generated from the EQ-5D is recommended for and commonly used in 
cost effectiveness analysis.
The EQ-5D and the EORTC-QLQ C-30 will be collected for Cohort N, Cohort N + I, and 
Cohorts3-6.
If exceptional circumstances preclude the continued administration of measures using planned 
modalities, then alternate administration methods may be required, after consultation with Sponsor 
or the Sponsor’s representative.
Please refer to procedural tables found in Section 5.1for information regarding the timing of 
outcomes research assessments using the EQ-5D and EORTC-QLQ C-30.
5.8
Results of Central Assessments
Not applicable.
6
ADVERSE EVENTS
An Adverse Event(AE)is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation subject administered an investigational 
(medicinal) product 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 investigational product, 
whether or not considered related to the investigational product.
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Events Meetingthe 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, consideredclinically 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 NOTMeeting 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).
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following:
Related: There is a reasonable causal relationship between study drug administration and 
the AE.
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE. 
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.)
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6.1
Serious Adverse Events
A Serious Adverse Event (SAE)is any untoward medical occurrence that at any dose: 
results in death
is life-threatening (defined as an event in which the subject 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 (seeNOTE
below)
results in persistent or significant disability/incapacity
is a congenital anomaly/birth defect 
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 6.6for the definition of potential DILI.)
Suspected 
transmission 
of 
an infectious 
agent 
(eg, 
pathogenic 
or nonpathogenic) via 
the 
study drug 
is an SAE. 
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (SeeSection6.1.1
for reporting pregnancies).
Any component of a study endpoint that is considered related to study therapy (eg, death is an 
endpoint, if death occurred due to anaphylaxis, anaphylaxis must be reported) should be reported 
as SAE (see Section6.1.1for reporting details).
NOTE: 
The following hospitalizations are not considered SAEs in BMS clinical studies: 
a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event)
elective surgery, planned prior to signing consent
admissions as per protocol for a planned medical/surgical procedure
routine health assessment requiring admission for baseline/trending of health status 
(eg,routine colonoscopy)
medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases
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admission encountered for another life circumstance 
that carries no bearing on health status 
and requires no medical/surgical intervention (eg, lack of housing, economic inadequacy,
caregiver respite, family circumstances, administrative reason)
admission for administration of anti-cancer therapy in the absence of any other SAEs
6.1.1
Serious Adverse Event Collection and Reporting
Following the subject’s written consent 
to participate in the study, all SAEs, whether related 
or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified 
procedures. All 
SAEs must 
be collected 
that 
occur 
during 
the screening 
period 
and 
within 
100 days of discontinuation of dosing. If applicable, SAEs must be collected 
that relate 
to any later 
protocol-specified procedure (eg, a follow-up skin biopsy). 
The investigator should report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
An SAE report should be completed for any event where doubt exists regarding its seriousness. 
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form.
SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(ordesignee) within 24 hours. SAEs must be recorded on the SAE Report Form; pregnancies on a 
Pregnancy Surveillance Form (electronic or paper forms). When using paper forms, the reports are 
to be transmitted via email or confirmed facsimile (fax) transmission to:
SAE Email Address: Refer to Contact Information list.
SAE Facsimile Number: Refer to Contact Information list.
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only 
in the event the electronic system is unavailable for transmission. When paper forms are used, the 
original paper forms are to remain on site.
SAE Telephone Contact(required for SAE and pregnancy reporting): Refer to Contact 
Information list.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS 
(ordesignee) using the same procedure used for transmitting the initial SAE report.
All SAEs should be followed to resolution or stabilization.
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6.2
Nonserious Adverse Events
Anonserious adverse eventis an AE not classified as serious.
6.2.1
Nonserious Adverse Event Collection and Reporting
The collection of nonserious AE information should begin at initiation of study drug. 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 subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Section6.1.1). Follow-up is also required for nonserious AEs that cause
interruption or discontinuation of study drug 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). 
All nonserious adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 100 days following the last dose 
of study treatment.
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that 
are reported/identified during the course of the study.
6.3
Laboratory Test Result Abnormalities
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form (paper or electronic) as appropriate:
Any laboratory test result that is clinically significant or meets the definition of an SAE 
Any laboratory 
test 
result 
abnormality that 
required 
the 
subject 
to 
have study 
drug discontinued 
or interrupted
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value).
6.4
Pregnancy
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject 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 
(or designee) Medical Monitor of this event and complete and forward a Pregnancy Surveillance 
Form to BMS (or designee) within 24 hours and in accordance with the SAE reporting procedures 
described in Section6.1.1.
In most cases, the study drug will be permanently discontinued in an appropriate manner (eg,dose 
tapering if necessary for subject safety).
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In the rare event that the benefit of continuing study drug is thought to outweigh the risk, after 
consultation with BMS, the pregnant subject may continue study drug, after a thorough discussion 
of benefits and risk with the subject.
Protocol required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated.
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
6.5
Overdose
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. Occurrences of overdose should be reported 
as an AE/SAE perSection6definitions, Events Meeting the AE Definition, Events NotMeeting 
the AE Definition). 
6.6
Potential Drug Induced Liver Injury (DILI)
Wherever possible, timely confirmationof 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 Section6.1.1for reporting details).
Potential drug induced liver injury is defined as: 
1.ALT or AST elevation > 3 times upper limit of normal (ULN)
AND 
2.Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3.No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
6.7
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. 
7
DATA MONITORING COMMITTEE AND OTHER EXTERNAL 
COMMITTEES
An IRRC will be utilized in this study for determination of IRRC-assessed ORR. Details of IRRC 
responsibilities and procedures will be specified in the IRRC charter.
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8
STATISTICAL CONSIDERATIONS
8.1
Sample Size Determination
This 
study will consist 
of 
5cohorts: 
non-MSI-H safety 
cohort, MSI-H cohort(Cohort N and 
Cohort 
N+I), Cohort C3(MSI-H subjects who have not had prior therapy for their metastatic disease), 
Cohort MSI-H C5,and Cohort non-MSI-H C6. All information pertaining to the C4 cohort was 
added via a site-specific Amendment 06. It is expected to treat up to approximately 96 subjects 
(up to 29non-MSI-H and up to 67MSI-H) for the initial non-MSI-H and MSI-H cohorts. It is 
expected to treat approximately 30subjects in cohort C3.It is expected to treat approximately 40 
MSI-H subjects in C5 Cohort and 40 non-MSI-H subjects C6 Cohort.
Sample size determination forthe non-MSI-H safety Cohort and MSI-H Cohort:
The MSI-H cohort will include subjects who are defined as MSI-H based on standard diagnostic 
testing documented in the subject’s medical history and prospectively confirmed in the current 
study by repeat testing using a PCR test.
The non-MSI-H cohort will include all subjects testing non-MSI-H by the repeat PCR test, 
including those who were MSI-H by medical history but not confirmed by repeat testing.
For the non-MSI-H safety cohort, sample size is not based on power considerations and will 
depend on the observed toxicity.
For the MSI-H cohort, a Simon optimal two-stage design will be used to test the null hypothesis 
that the true ORR is 30% (not considered clinically compelling) with either nivolumab 
monotherapy or the combination of nivolumab/ipilimumab. In the first stage (mStage 1), 
19subjects will be treated with nivolumab monotherapy. If there are 2 or fewer responses in these 
first 19 treated subjects, the protocol will be closed to further enrollment. If there are more than 2 
but less than 7 responses in the first 19 treated subjects, accrual to the monotherapy arm will be 
stopped,and the combination arm will be opened for accrual. Otherwise, if there are 7 or more 
responses in the first 19 treated subjects, approximately 29 additional subjects will be accrued to 
the monotherapy arm (mStage 2) to target a total of 48 treated subjects. 
If accrual to the combination arm is opened to the MSI-H cohort as specified above, stage I of the 
Simon two-stage design will be initiated in the combination arm with 19 treated subjects 
(cStage1). If there are 6 or fewer responses in these first 19 treated subjects, accrual to the 
combination arm will be stopped. Otherwise, approximately 29 additional subjects will be accrued 
to the combination arm (cStage 2) to target a total of 48 subjects treated with combination therapy. 
Subjects whose repeat testing does not confirm MSI-H status will be replaced in order to obtain
the required number of subjects in each stage of the Simon design.Note that because of the delay 
in obtaining the centrally evaluated MSI status, more than 48 subjects may be treated with 
monotherapy and combination therapy in these initial cohorts. 
Thenull hypothesis will be rejected if 20 or more responses are observed in 48 treated subjects in 
the open arm (nivolumab monotherapy and/or nivolumab/ipilimumab combination). Within a 
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given treatment arm, this design yields a one-sided type I error rate of5% and power of 90% when 
the true response rate is 52%.
Sample size determination for Cohort C3:
The sample size determination for Cohort C3was not based on power consideration but 
to provide 
precision on estimation of ORR.Saltz and coworkersreported ORR of 49% and 38% in 
chemotherapy group, per investigator assessment and per independent response review committee 
assessment, respectively,in this patient population.
42Table 8.1-1presents the 95% CI for ORR 
ranging from 45% to 65%, which are considered meaningful clinical outcome, with a sample size 
of 30subjects.
Table 8.1-1:
Interval Estimation and Coverage Probability-Clopper-
Pearson Method(95% Confidence Interval)
Sample size
Number of 
responses
Response rate
Confidence interval
30
13
0.43333
(0.2546, 0.6257)
30
14
0.46667
(0.2834, 0.6567)
30
15
0.50000
(0.3130, 0.6870)
30
16
0.53333
(0.3433, 0.7166)
30
17
0.56667
(0.3743, 0.7454)
30
18
0.60000
(0.4060, 0.7734)
30
19
0.63333
(0.4386, 0.8007)
30
20
0.66667
(0.4719, 0.8271)
Sample size determination for Cohort C5:
The sample size determination for Cohort C5 was not based on power consideration but 
to provide 
precision on estimation of ORR. Table 8.1-2shows the precision of the estimation of ORR based 
on the two-sided 95% exact CI using Clopper Pearson methods based on 4, 8, 12, 16,and 20 
responders out of 40subjects. With 40 subjects, the 95% CI of observed 16 responders will be 
(24.9%, 56.7%), which has the lower bound excluding the 23% background ORR from previous 
interim results.
Table 8.1-2:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 40 subjects(For C5 
Cohort)
The number of 
observed 
responses
4
8
12
16
20
Observed 
Response Rate
4/40 (10.0%)
8/40 (20.0%)
12/40 (30.0%)
16/40 (40.0%)
20/40 (50.0%)
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Table 8.1-2:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 40 subjects(For C5 
Cohort)
The number of 
observed 
responses
4
8
12
16
20
95% exact CI
(2.8%, 23.7%)
(9.1%, 35.6%)
(16.6%, 46.5%) (24.9%, 56.7%) (33.8%, 66.2%)
Sample size determination for Cohort C6:
Thesample size determination for Cohort C6 was not based on power consideration but 
to provide 
precision on estimation of ORR. Table 8.1-3shows the precision of the estimation of ORR based 
on the two-sided 95% exact CI using Clopper Pearson methods based on 6, 7, 8, 9, and 12 
responders out of 40subjects. With 40 subjects, the 95% CI of observed 6 responders will be 
(5.7%, 29.8%), which has the lower bound excluding the 5% background ORR.
Table 8.1-3:
Two-sided 95% exact CI using Clopper-Pearson method based on 
the number of observed responses out of 40 subjects(For C6 
Cohort)
The number of 
observed 
responses
6
7
8
9
12
Observed 
Response Rate
6/40 (15.0%)
7/40 (17.5%)
8/40 (20.0%)
9/40 (22.5%)
12/40 (30.0%)
95% exact CI
(5.7%, 29.8%)
(7.3%, 32.8%)
(9.1%, 35.6%)
(10.8%, 38.5%) (16.6%, 46.5%)
8.2
Populations for Analyses
The following definitions will apply to all cohorts except where otherwise specified:
The MSI-H cohort will include subjects who are defined as MSI-H based on standard 
diagnostictesting documented in the subject’s medical history(MSI-H per local testing)
including thoseprospectively confirmed in the current study by repeat 
testing using a PCR test. 
Subjects in this cohort will be referred to as ‘confirmed MSI-H subjects.’Similarly, the non-
MSI-H cohort will include all subjects testing non-MSI-H by the repeat PCR test or standard 
diagnostic testing documented in the subject’s medical history.
All Treated Subjects: All subjects who received at least one dose of study medication within a
cohort. This is the primary population for safety and efficacy analysis in anycohort.
All response evaluable subjects: All treated subjects within a given cohort who have baseline 
and at least one on-study evaluable tumor measurement.
PK subjects: All subjects with available serum time-concentration data from subjects dosed 
with study drug.
Immunogenicity subjects: all treated subjects with available immunogenicity data.
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PD-L1 measurable subjects: all treated subjects with a measurable PD-L1 expression result.
Biomarker subjects: All treated subjects with available biomarker data.
Outcomes Research Subjects: all treated subjects who have an assessment at baseline (Visit1 
assessment prior to administration of drug) and at least 1 subsequent assessment (for EORTC 
QLQ-C30 and EQ-5D separately).
All Re-initiation Treated Subjects: All subjects who received at least one dose of study 
medication following re-initiation of treatment. 
8.3
Endpoints
8.3.1
Primary Endpoint(s)
The primary objective will be measured by the primary endpoint of investigator-assessed ORR in 
each cohort. It is defined as the number of subjects with a best overall response (BOR) of 
confirmed CR or PR, according to RECIST 1.1 criteria, divided by the number of treated subjects
in the related cohort. The final analysis of the primary endpoint will occur at least 6months after 
the last enrolled subject’s first dose of study therapy. The BOR is defined as the best response 
designation recorded between thedate of first dose and the date of initial objectively documented 
progression per RECIST v1.1 or the date of subsequent therapy, whichever occurs first. For 
subjects without documented progression or subsequent therapy, all available response 
designationswill contribute to the BOR determination. For purposes of analysis, if a subject 
receives one dose and discontinues the study without assessment or receives subsequent therapy 
prior to assessment, this subject will be counted in the denominator (asnon-respondent.)
The investigator-assessed ORR will be further characterized by the investigator assessed duration 
of response (DOR) and rate of complete response (CR). DOR is defined as the time from first 
confirmed response (CR or PR) to the date of the first documented tumor progression as 
determined using RECIST 1.1 criteria or death due to any cause, whichever occurs first. For 
subjects who neither progress nor die, the DOR censoring will be the same as PFS censoring (see 
Section8.3.3). In each cohort, DOR will be computed for subjects with a BOR of PR or CR.
8.3.2
Secondary Endpoint(s)
The secondary objective will be measured by the secondary endpoint of IRRC-assessed ORR in 
eachcohort. It is defined as the number of subjects with a best overall response (BOR) of 
confirmed CR or PR, according to RECIST 1.1 criteria, divided by the number of treated subjects
in the 
related 
cohort. 
The final analysis 
of 
the secondary 
endpoint 
will 
occur 
the 
time 
of 
the primary 
endpoint analysis. The BOR is defined as the best response designation recorded between the date 
of first dose and the date of initial objectively documented progression per RECIST v1.1 or the 
date of subsequent therapy, whichever occurs first. For subjects without documented progression 
or subsequent therapy, all available response designations will contribute to the BOR 
determination. For purposes of analysis, if a subject receives one dose and discontinues the study 
without assessment 
or receives subsequent 
therapy prior 
to 
assessment, 
this subject 
will be counted 
in the denominator (as non-respondent).
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The IRRC-assessed ORR will be further characterized by the IRRC-assessed duration of response 
(DOR) and rate of CR. DOR is defined as the time from first confirmed response (CR or PR) to 
the date of the first documented tumor progression as determined using RECIST 1.1 criteria or 
death due to any cause, whichever occurs first. For 
subjects who neither progress nor die, the DOR 
censoring will be the same as PFS censoring (see Section8.3.3). In each cohort, DOR will be 
computed for subjects with a BOR of PR or CR. 
Investigator-assessed and IRRC-assessed DCR will be reported. Disease control rate (DCR) is 
defined as the number of subjectswith a BOR of confirmed CR or PR or SDlasting at least 
12weeksdivided by the number of treated subjects. 
8.3.3
Exploratory Endpoint(s) 
Exploratory safety objectives will include safety and tolerability of nivolumab monotherapy 
(mStage 1 and 2) or nivolumab in combination with ipilimumab (cStage 1 and 2and the cohort 
C3) in subjects with metastatic MSI-H CRC, nivolumab in combination with anti-LAG-3 antibody 
(BMS-986016, Cohort C5) in subjects with metastatic dMMR/MSI-H mCRC, or nivolumab in 
combination with daratumumab(Cohort C6)in subjects with metastatic non-MSI-H (pMMR) 
mCRC, as measured by the incidence of adverse events and specific laboratory abnormalities 
(worst grade) in each treatment arm. In addition, the safety and tolerability of nivolumab in 
combination with ipilimumab in subjects with metastatic non-MSI-H CRC will also be evaluated. 
Toxicities will be graded using the National Cancer Institute (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0.
Exploratory efficacy objectives will be measured byexploratory endpoints of PFS (using 
investigator and IRRC assessments) and OS in all treated subjects with metastatic CRCwithin 
each cohort. PFS is defined as the time from first dosing date to the date of the first documented 
progression, or death due 
to any cause, whichever occurs first. 
Subjects who die without a 
reported 
prior progression will be considered to have progressed on the date of their death. Subjects who 
did not progress or die will be censored on the date of their last evaluable tumor assessment. 
Subjects who did not have any on-study tumor imaging assessments and did not die will be 
censored on the first dosing date. Subjects who started any subsequent anti-cancer therapy without 
a prior reported progression,including death,will be censored at the last evaluable assessment 
prior to initiation of the subsequent anti-cancer therapy. 
OS is defined as the time from first dosing date to the date of death. A subject who has not died 
will be censored at their last known date alive. OS will be followed continuously while subjects 
are on the study drug and every 3 months via in-person or phone contact after subjects discontinue 
the study drug.
The PK objective will be measured from serum concentration. Samples will be collected to 
characterize pharmacokinetics of nivolumab monotherapy, PK of nivolumab, ipilimumab, 
BMS-986016, and daratumumab when combined, and to explore exposure-response relationships
(Section5.5).
The discordance rate between repeat MSI testing and prior MSI testing will be characterized using 
test results from both MSI-H and non-MSI-H cohorts(mStage1/2 and cStage1/2).
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Other exploratory endpoints for immunogenicity, pharmacogenomics, and outcomes research are 
discussed in detail in Sections 5.5, 5.6,and5.7, respectively.
For the evaluation of clinical activity of nivolumab monotherapy or combination treatment re-
initiation, new endpoints will be considered: BOR-re-initiation (BOR-R), ORR-re-initiation 
(ORR-R), DCR-re-initiation (DCR-R), TTR-re-initiation (TTR-R), DOR-re-initiation (DOR-R), 
PFS-re-initiation (PFS-R) and OS-re-initiation (OS-R). These endpoints will be defined similarly 
as the original ones but using the new re-initiation start date or new baseline evaluations as 
reference, where apply. Detailed definition of these endpoints will be provided in the SAP.
8.4
Analyses
Analysis methodologies presented in this section will apply to all cohorts except otherwise 
specified.Each cohort will be analyzed separately and interdependently but pooling of certain 
cohorts may be performed. 
8.4.1
Demographics and Baseline Characteristics
Demographic and baseline laboratory results will be summarized for all treated subjects by cohort 
(MSI-H,non-MSI-H, C3, C4, C5, and C6) and treatment (monotherapy and combination therapy, 
if applicable) using descriptive statistics.
8.4.2
Efficacy Analyses
8.4.2.1
Primary Endpoint Methods 
The investigator-assessed ORR will be summarized bycohort and by treatment (monotherapy and 
combination therapy, if applicable). A response rate estimate and corresponding two-sided exact 
CI will be provided. For the reporting following a 2-stage design,the method proposed by 
Atkinson and Brown will be used to estimate a 90%CI. 
This confidence interval takes into account 
the group sequential nature of the two-stage Simon design, where applicable.Otherwise, the 
method of Clopper-Pearson will be used to estimate a 95% CI, regardless of the study design, if 
more subjects were treated beyondthe sample size per the original Simon’s 2-stage design.
Within each cohort, ORR will be further characterized by the DOR and rate of CR. DOR will be 
summarized for subjects who achieve confirmed PR or CR using the Kaplan-Meier (KM) product-
limit method. Median values of DOR, along with two-sided 95% CI (based on the log-log 
transformation), will also be calculated. Investigator-assessed CR will be summarized bycohort 
and by treatment (monotherapy and combination therapy, if applicable). An estimate of complete 
response rate (CRR) and corresponding two-sided 95% exact CI will be provided using Clopper-
Pearson method.
8.4.2.2
Secondary Endpoint Methods
ORR based on IRRC assessment will be summarizedsimilarly as above and will be characterized 
by IRRC-assessed DOR and IRRC-assessed CRR similarly as above.
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8.4.2.3
Exploratory Endpoint Methods
PFS andOS will be summarized descriptively for eachcohort 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. 
8.4.3
Safety Analyses
Safety analyses will be performed in all treated subjects by cohort (MSI-H,non-MSI-H
independent safety cohort, and C3, C4, C5, and C6) and treatment (monotherapy and combination 
therapy, if applicable). Descriptive statistics of safety will be presented using NCI CTCAE version 
4.0. All on-study AEs, drug-related AEs, SAEs, and drug-related SAEs will be tabulated using 
worst grade per NCI CTCAE v4.0 criteria by system organ class and MedDRA preferred term. 
On-study lab parameters including hematology, chemistry, liver function, thyroid function, and 
renal function will be summarized using worst grade per NCI CTCAE v4.0 criteria.
8.4.4
Pharmacokinetic Analyses
The nivolumab, ipilimumab, BMS-986016, and daratumumabconcentration data obtained in this 
study may be combined with data from other studies in the clinical development programs to 
develop or refine a population PK model. These models may be used to evaluate the effects of 
intrinsic and extrinsic covariates on the PK of nivolumab or other compounds and to determine 
measures of individual exposure. In addition, model determined exposures may be used for 
exposure-response analyses. If performed, results of population PK and exposure 
response-analyses will be reported separately.
8.4.5
Biomarker Analyses
Methodology for exploratory biomarker analyses, including characterization of discordant rates 
for MSI testing, is described in the statistical analysis plan.
8.4.6
Outcomes Research Analyses
EQ 5D
Subject’s overall health state on a visual analog scale (EQ-VAS) at each assessment time point 
will be summarized using descriptive statistics, for each cohortassessed,by treatment 
(monotherapy and combination therapy, if applicable). The proportion of subjects reporting 
problems for the 5EQ-5D dimensions at each assessment time point will be summarized by level 
of problem eachcohort by treatment (monotherapy and combination therapy, if applicable). 
Percentages will be based on number subjects assessed at assessment time point.
A by-subject listing of EQ-5D with the problem levels for each of the 5 dimensions (mobility, 
self-care, usual activities, pain/discomfort and anxiety/depression), health state (5dimensions 
digits combined in a 5-digit number),and EQ-VAS will be provided.
EORTC QLQ C-30
The analysis of EORTC QLQ C-30 will be performed in all treated subjects in each cohort who 
have an assessment at baseline and at least one follow-up assessment.
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All scales and single items are scored on a categorical scale and linearly transformed to 
0-to-100scales with higher scores for a functional scale representing higher levels of functioning, 
higher scores for the global health status/quality of life representing higher levels of global health 
status/quality of life, 
and higher 
scores for 
a 
symptom 
scale 
representing higher level 
of symptoms. 
EORTC QLQ 
C-30 
global health 
status/QoL composite 
scale 
data 
and 
the 
remaining 
EORTC QLQ 
C-30 scale data will be summarized by timepoint using descriptive statistics for eachcohort
assessed.
8.4.7
Other Analyses 
8.4.7.1
Immunogenicity Analyses
Immunogenicity may be reported for ADA positive status (such as persistent positive, transient 
positive, 
only last 
sample 
positive, baseline 
positive) 
and ADA negative status, 
relative to 
baseline. 
In addition, presence of neutralizing antibody may be reported, if applicable. Effect of 
immunogenicity on safety/efficacy and biomarkers and PK may be explored.
8.4.7.2
Analyses of Re-initiation Treated Subjects
The same methodologies as used for the primary, secondary and exploratory efficacy endpoints 
will be used to analyze the specific endpoints defined to evaluate the clinical activity of nivolumab 
monotherapy or combination treatmentafterre-initiation. 
Selected safety analyses will be repeated using the new re-initiation start date or new baseline 
evaluations as reference, to evaluate the safety of nivolumab monotherapy or combination 
treatment re-initiation. 
All these analyses will be using the population of All Re-initiation Treated Subjects and will be 
presented by cohort. 
In addition, 
time from initial discontinuation to 
re-initiation will be described. 
The 
detailed 
of these 
analyses will be provided in the SAP.
8.5
Interim Analyses
For each treatment arm in the MSI-H cohort (mStage 1 monotherapy and combination therapy, if 
applicable),one interim analysis of investigator-assessed ORR will be performed on the first 
19treated subjects with confirmed MSI-H CRC.If there are 6 or fewer responses in these first 
19treated subjects, accrual to the corresponding treatment arm will be stopped. Otherwise, 
approximately 29additional confirmed MSI-H subjects will be accrued into the corresponding 
treatment arm to target a total of 48 treated subjects in that arm. 
Subjects in mStage 1 or cStage 1 who remain on treatment should complete a 24-week follow up 
for an assessment of ORR.The final analyses of these initial MSI-H cohort will take place after 
sufficient follow-up has been achieved for most or all of the subjects (eg, 6 months of treatment 
for the monotherapy cohort and 9 months of treatment for the combination therapy cohort). 
Anticipating a different enrollment rate in cohortsC3-C6, thesecohortswill be analyzed 
independently. Interim analyses will be conducted approximately 6months after the last subject
treated in the corresponding cohort.
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In addition, other interim analyses may be conducted to seek initial efficacy signal or for external 
data disclosurefor these cohorts. 
9
STUDY MANAGEMENT
9.1
Compliance
9.1.1
Compliance with the Protocol and Protocol Revisions
The study shall be conducted as described in this approved protocol. All revisions to the protocol 
must be discussed with, and be prepared by, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented approval/favorable 
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an immediate 
hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be
submitted to:
IRB/IEC for review and approval/favorable opinion
BMS
Regulatory Authority(ies), if required by local regulations
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must be 
sent to BMS.
If an amendment substantially alters the study design or increases the potential risk to the subject: 
(1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review and 
approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment.
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s).
9.1.2
Monitoring
Monitoring details describing strategy, including definition of study critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan.
Representatives of BMS must be allowed to visit all study site locations periodically to assess the 
data quality and study integrity. On site they will review study records and directly compare them 
with source documents, discuss the conduct of the study with the investigator, and verify that the 
facilities remain acceptable.
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In addition, the study may be evaluated by BMS internal auditors and government inspectors who 
must be allowed access to CRFs, source documents, other study files, and study facilities. BMS 
audit reports will be kept confidential.
The investigator 
must 
notify 
BMS promptly 
of 
any inspections scheduled by regulatory 
authorities, 
and promptly forward copies of inspection reports to BMS. 
9.1.3
Investigational Site Training
Bristol-Myers Squibb will provide quality investigational staff training prior 
to study initiationand 
prior to implementation of any significant protocol revision. Training topics will include but are 
not limited to: GCP, AE reporting, study details and procedure, electronic CRFs, study
documentation, informed consent, andenrollment of WOCBP.
9.2
Records
9.2.1
Records Retention
The investigator must retain all study recordsand source documents for the maximum period 
required by applicable regulations and guidelines, or institution procedures, or for the period 
specified by BMS, whichever is longer. The investigator must contact BMS prior to destroying 
any records associated with the study.
BMS will notify the investigator when the study records are no longer needed.
If the investigator withdraws from the study (eg, relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice of such 
transfer will be given in writing to BMS.
9.2.2
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by BMS) is maintained at each study site where study drug 
are inventoried and dispensed. 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 subject, including unique subject identifiers
amount transferred to another area/sitefor dispensing or storage
nonstudy disposition (eg, 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.
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BMS will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements.
9.2.3
Case Report Forms
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study.
For sites using the BMS electronic data capture tool, electronic CRFs will be prepared for all data 
collection fields except for fields specific to SAEs and pregnancy, which will be reported on the 
paper or electronic SAE form and Pregnancy Surveillance form, respectively. Spaces may be left 
blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by BMS. 
The 
confidentiality of records that 
could identify subjects must 
be protected, 
respecting 
the 
privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s).
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs. 
The completed CRF, including any paper or electronic 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 .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 mustmeet BMS training requirements and 
must only access the BMS electronic data capture tool using the unique user account provided by 
BMS. User accounts are not to be shared or reassigned to other individuals.
9.3
Clinical Study Report and Publications
Clinical Study Report:
A Signatory Investigator must be selected to sign the clinical study report. 
For each clinical study reportrelated to this protocol, the following criteria will be used to select 
the signatory investigator: 
Subject recruitment (eg, among the top quartile of enrollers)
Involvement in trial design
Publications:
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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 agreementgoverning [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 clinical trial agreement.
Scientific Publications (such as abstracts, congress podium presentations and posters, and 
manuscripts) of the study results will be a collaborative effort between the study Sponsor and the 
external authors.  No public presentation or publication of any interim results may be made by any 
principal investigator, sub-investigator,or any other member of the study staff without the prior 
written consent of the Sponsor.  
Authorship of publications at BMS is aligned with the criteria of the International Committee of 
Medical Journal Editors (ICMJE, www.icmje.org). Authorship selection is based upon significant 
contributions to the study (ie, ICMJE criterion #1). Authors must meet all 4 ICMJE criteria for 
authorship:
1)Substantial intellectual contribution to the conception or design of the work; or the acquisition 
of data (ie, evaluable subjects with quality data), analysis, or interpretation of data for the work 
(eg, problem solving, advice, evaluation, insights and conclusion); AND
2)Drafting the work or revising it critically for important intellectual content; AND
3)Final approval of the version to be published; AND
4)Agreement to be accountable for all aspects of the work in ensuring that questions related to 
the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Those who make the most significant contributions, as defined above, will be considered by BMS 
for authorship of the primary publication. Sub-investigators will generally not be considered for 
authorship in the primary publication. Geographic representation will also be considered.  
Authors will be listed by order of significant contributions (highest to lowest), with the exception 
of the last 
author. 
Authors 
in first 
and last 
position have 
provided the most 
significant 
contributions 
to the work. 
For secondary analyses and related publications, author list and author order may vary from 
primary to reflect additional contributions.
9.4
Dissemination of Clinical Study Data
In order to benefit potential study participants, patients, healthcare providers and researchers, and 
to help BMS honor its commitments to study participants, BMS will make information about 
clinical research studies and a summary of their results available to the public as per regulatory 
and BMS requirements. BMS will post study information on local, national,or regional databases 
in compliance with national and international standards for disclosure. BMS may also voluntarily 
disclose information to applicable databases.
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GLOSSARY OF TERMS
Term
Definition
Adverse Reaction
An adverse event that is considered by either the investigator or BMS as 
related to the investigational product
Unexpected Adverse Reaction
An adverse reaction, the nature or severity of which is not consistent with 
the applicable productinformation (eg, Investigator Brochure for an 
unapproved investigational product)
Serious Adverse Event
Serious adverse event defined as any untoward medical occurrence that at 
any dose: results in death; is life threatening (defined as an event in which
the subject 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; 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 subject 
or may require intervention [eg, medical, surgical] to prevent one of the 
other serious outcomes listed in the definition above). Examples of such 
events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization.). For reporting purposes 
only, BMS also considers the occurrence of pregnancy, overdose 
(regardless of association with an AE), and cancer as important medical 
events.
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LIST OF ABBREVIATIONS
Term
Definition
ADA
antidrug antibody
ADL 
activities of daily living 
AE
adverse event
ACLS
advanced cardiac life support
AI
accumulation index
AI_AUC
AUCaccumulation index; ratio of AUC(TAU) at steady state to 
AUC(TAU) after the first dose
AI_Cmax
Cmax accumulation index; ratio of Cmax at steady state to Cmax after 
the first dose
AI_Ctau
Ctau Accumulation Index; ratio of Ctau at steady state to Ctau after the 
first dose
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANOVA
analysis of variance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AT
aminotransaminases
AUC
area under the concentration-time curve
AUC(INF)
area under the concentration-time curve from time zero extrapolated to 
infinite time
AUC(0-T)
area under the concentration-time curve from time zero to the time of the 
last quantifiable concentration
AUC(TAU)
area under the concentration-time curve in one dosing interval
A-V
atrioventricular
-HCG
beta-human chorionic gonadotrophin
BA/BE
bioavailability/bioequivalence
%BE
percent biliary excretion
BID, bid
bis in die, twice daily
BLQ
below limit of quantification 
BMI
body mass index
BMS
Bristol-Myers Squibb
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Term
Definition
BOR-R
best overall response-re-initiation phase
BP
blood pressure
BRt
total amount recovered in bile
%BRt
total percent of administered dose recovered in bile
BSA 
body surface area 
BUN
blood urea nitrogen
C
celsius
C12
concentration at 12 hours
C24
concentration at 24 hours
Ca++
calcium
Cavg
average concentration
Cavgss
average serum concentration at steady state
Cavg28
average serum concentration at Day 28
CBC
complete blood count
Cexpected-tau
expected concentration in a dosing interval
CFR
Code of Federal Regulations 
CI
confidence interval
C1-
chloride
CLcr
creatinine clearance
CLD
dialysate clearance of drug from plasma/serum
CLNR
nonrenal clearance
CLR
renal clearance
CLT
total body clearance
CLT/F (or CLT)
apparent total body clearance
CLT/F/fu or 
CLT/fu
apparent clearance of free drug or clearance of free drug (if IV)
cm
centimeter
Cmax, CMAX
maximum observed concentration
Cmin, CMIN
trough observed concentration
CNS
central nervous system
COVID-19
coronavirus disease 2019
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Term
Definition
CRC
colorectal cancer
CRF
Case Report Form, paper or electronic
Ct
expected concentration at a certain time, usually at the end of an expected 
future dosing interval (eg, concentration at 24 hours, concentrationat 12 
hours, etc.)
Ctau
concentration in a dosing interval (eg, concentration at 24 hours, 
concentration at 12 hours, etc.)
Ctrough
trough observed plasma concentration
CR
complete response
CT
computed tomography
cTnI
cardiac troponin I
cTnT
cardiactroponin T
CV
coefficient of variation
CYP
cytochrome p-450
D/C
discontinue
dL
deciliter
dMMR
deficient mismatch repair
DOR-R
duration of response-re-initiation phase
DRt
total amount recovered in dialysate
%DRt
total percent of administered dose recovered in dialysate
DSM IV
Diagnostic and Statistical Manual of Mental Disorders (4th Edition)
EA
extent of absorption
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
electronic data capture
EEG
electroencephalogram
eg
exempli gratia (for example)
ESR
Expedited Safety Report
F
bioavailability
Fb
fraction of bound drug
FDA
Food and Drug Administration
FI
fluctuation Index ([Cmax-Ctau)/Cavg])
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Term
Definition
FRt
total amount recovered in feces
%FRt
total percent of administered dose recovered in feces
FSH
follicle stimulating hormone
%FE
percent fecal excretion
fu
fraction of unbound drug
fT4 
free thyroxine 
g
gram
G 
grade 
GC
gas chromatography
GCP
Good Clinical Practice
G criteria
adjusted R2 value of terminal elimination phase
GGT
gamma-glutamyl transferase
GFR
glomerular filtration rate
h
hour
H&E
hematoxylin and eosin
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCO3-
bicarbonate
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
I-O 
immuno-oncology 
IAT
indirect antiglobulin test
IC
informed consent form
ICD
International Classification of Diseases
ICH
International Conference on Harmonisation 
ICMJE
International Committee of Medical Journal Editors
ID 
infectious disease 
ie
id est (that is)
IEC
Independent Ethics Committee
IMP
investigational medicinal products
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Term
Definition
IND
Investigational New Drug application
IRB
Institutional Review Board
IRRC
independent radiology review committee
IU
international unit
IV
intravenous
IVIG 
intravenous immunoglobulin 
IVRS
Interactive Voice Response System
K
slope of the terminal phase of the log concentration-time curve
K3EDTA
potassium ethylenediaminetetraacetic acid
K+
potassium
kg
kilogram
z
terminal disposition rate constant
L
liter
LC
liquid chromatography
LDH
lactate dehydrogenase
LFT 
liver function tests 
ln
natural logarithm
LVEF
left ventricular ejection fraction
Lz_Start
the time point starting the log-linear elimination phase defining the 
terminal half life
Lz_End
the 
time 
point 
ending 
the log-linear 
elimination phase 
defining 
the 
terminal 
half life
Lz_N
number of time points in the log-linear elimination phasedefining the 
terminal half life
mg
milligram
Mg++
magnesium
MIC
minimum inhibitory concentration
min
minute
mL
milliliter
mmHg
millimeters of mercury
MMR
mismatch repair (of DNA)
MR_AUC(0-T)
ratio of metabolite AUC(0-T) to parent AUC(0-T), corrected for 
molecular weight
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Term
Definition
MR_AUC(INF)
ratio of metabolite AUC(INF) to parent AUC(INF), corrected for 
molecular weight
MR_AUC(TAU)
ratio of metabolite AUC(TAU) to parent AUC(TAU), corrected for 
molecular weight
MR_Cmax
ratio of metabolite Cmax to parent Cmax, corrected for molecular weight
MR_Ctau
ratio of metabolite Ctau to parent Ctau, corrected for molecular weight
MRI
magnetic resonance imaging
MRT
mean residence time
MS
mass spectrometry
MSI
microsatellite instability
MSI-H
microsatellite instability-high
MTD
maximum tolerated dose
MUGA
multiple-gated acquisition
g
microgram
N
number of subjects or observations
Na+
sodium
N/A
not applicable
ng
nanogram
NIMP
non-investigational medicinal products 
NSAID
nonsteroidal anti-inflammatory drug
ORR-R
overall response rate-re-initiation phase
pAUCe
extrapolated partial AUC from last quantifiable concentration to infinity
Pb
percent of bound drug
PD
pharmacodynamics
PFS-R
progression-free survival-re-initiation phase
PK
pharmacokinetics
pMMR
proficient mismatch repair
PO
per os (by mouth route of administration)
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
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Term
Definition
Pu
percent of unbound drug
QC
quality control
QD, qd
quaque die, once daily
Q2W
every 2 weeks
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
R2
coefficient of determination
RBC
red blood cell
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SCCHN
squamous cell carcinoma of the head and neck
SD
standard deviation
SMT
safety management team
SOP
standard operating procedures
sp.
species
Subj
subject
t
temperature
T
time
TAO
Trial Access Online, the BMS implementation of an EDC capability
T. bili 
total bilirubin 
T-HALF
half life
T-HALFeff_AUC
effective elimination half life that explains the degree of AUC 
accumulation observed
T-HALFeff_Cmax effective elimination half life that explains the degree of Cmax 
accumulation observed)
TID, tid
ter in die, three times a day
Tmax,TMAX
time of maximum observed concentration
TR_AUC(0-T)
AUC(0-T) treatment ratio
TR_AUC(INF)
AUC(INF) treatment ratio
TR_Cmax
Cmax treatment ratio
TSH 
thyroid stimulating hormone 
TTE
transthoracic echocardiogram
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Term
Definition
TTR-R
time to response-re-initiation phase
ULN 
upper limit of normal 
UR
urinary recovery
%UR
percent urinary recovery
URt
total amount recovered in urine
%URt
total percent of administered dose recovered in urine
UV
ultraviolet
Vss/F (or Vss)
apparent volume ofdistribution at steady state
Vz
volume of distribution of terminal phase (if IV and if multi-exponential 
decline)
W
washout
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
x g
times gravity
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55 Grosso JF, Kelleher CC, Harris TJ, et al. LAG-3 regulates CD8+T cell accumulation and 
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CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc Natl 
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62 Gandhi MK, Lambley E, Duraiswamy J, et al. Expression of LAG-3 by tumor-infiltrating 
lymphocytes is coincident with the suppression of latent membrane antigen-specific CD8+ T-
cell function in Hodgkin lymphoma patients. Blood. 2006;108:2280-2289
63 Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early 
lethality in mice deficient in CTLA-4. Science 1995;270:985-988.
64 Saloura V, Zuo Z, Koeppen H, et.al. Correlation of T-cell inflamed phenotype with 
mesenchymal subtype, expression of PD-L1, and other immune checkpoints in head and neck 
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65 Chen J, Chen Z. The effect of immune microenvironment on the progression and prognosis of 
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66 Matthew 
Reilley, Jorge 
M Blando, Riham Katkhuda, 
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al. Immunologic 
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67 Study of Nivolumab (BMS-936558) in Combination With Gemcitabine/Cisplatin,
Pemetrexed/Cisplatin, Carboplatin/Paclitaxel, Bevacizumab Maintenance, Erlotinib,
Ipilimumab or as Monotherapy in Subjects With Stage IIIB/IV Non-small Cell Lung Cancer
(NSCLC) (CheckMate 012) ClinicalTrials.gov Identifier: NCT01454102
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68 ASCO GI 2018 Overman presentation, Monotherapy long-term follow up. Overman M, 
Bergamo F, McDermott R et al. Journal of Clinical Oncology 36, no. 4_suppl(February 1 
2018) 554-554.
69 Brahmer J, Horn L, Jackman D, et al. Five-year follow-up from the CA209-003 study of
nivolumab in previously treated advanced non-small cell lung cancer: clinical characteristics
of long-term survivors. Oral presentation presented at: American Association for 
CancerResearch (AACR) Annual Meeting, April 1-5, 2017, Washington, DC.
70 Felip Font E, Gettinger SN, Burgio MA, et al. Three-year follow-up from Checkmate 017/057:
Nivolumab versus docetaxel in patients with previously treated advanced non-small lung
cancer (NSCLC). Poster discussion presentation at the European Society of Medical Oncology
Annual Meeting, September 8-12, 2017, Madrid, Spain.
71 Herbst R. Garon E, Kim DW etal. KEYNOTE-010: Durable clinical benefit in patients with
previously treated, PD-L1-expressing NSCLC who completed pembrolizumab. Poster
presentation at the World Conference on Lung Cancer 2016 Dec 4-7; Vienna, Austria.
72 R S Herbst, GaronEB, Kim, D-W,et al. (LBA4)Long-term follow-up in the KEYNOTE-010 
study of pembrolizumab (pembro) for advanced NSCLC, including in patients (pts) who 
completed 2 years of pembro and pts who received a second course of pembro. Annals of 
Oncology, Volume 29, Issue suppl_10, 1 December 2018, mdy511.003, 
https://doi.org/10.1093/annonc/mdy511.003.
73 OPDIVO US Prescribing Information. Bristol-Myers Squibb, Princeton, NJ. March 2020.
74 Opdivo® Annex 
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Product Characteristics. 
Bristol-Myers 
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75 Zhao X, Suryawanshi S, Hruska M, et al. Assessment of nivolumab benefit–risk profile of a 
240-mg flat dose relative to a 3-mg/kg dosing regimen in patients with advanced tumors. Ann 
Oncol 2017;28:2002–8.
76 BMS-936558 Flat Dose Efficacy and Safety Report. DCN:930156964.
77 de Weers M, Tai YT, van der Veer MS, et al. Daratumumab, a novel therapeutic human CD38 
monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J 
Immunol. 2011;186(3):1840-1848.
78 Overdijk MB, Verploegen S, B¨ogels M, et al. Antibody-mediated phagocytosis contributes to 
the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple
myeloma. MAbs. 2015;7(2):311-321.
79 Lokhorst HM, Plesner T, Laubach JP, et al. Targeting CD38 with daratumumab monotherapy
in multiple myeloma. N Engl J Med. 2015;373(13): 1207-1219.
80 Lonial S, Weiss BM, Usmani SZ, et al. Daratumumab monotherapy in patients withtreatment-
refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 
2016;387(10027):1551-1560.
81 McKeage K. Daratumumab: first global approval. Drugs. 2016;76(2):275-281.
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82 Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune regulatory cells, 
promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 
2016;128(3):384-94.
83 Karakasheva TA, Waldron TJ, Eruslanov E, et al. CD38-Expressing Myeloid-Derived 
Suppressor Cells Promote Tumor Growth in a Murine Model of Esophageal Cancer. Cancer 
Res. 2015;75(19):4074-85. 
84 Chen, 
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of the PD-1/PD-L1 axis. J Clin Oncol 2017; 35: suppl 7S, abstract 79
85 Tosolini M, Kirilovsky A, Mlecnik B, et al. Clinical Impact of Different Classes of Infiltrating 
T Cytotoxic and Helper Cells (Th1, Th2, Treg, Th17) in Patients with Colorectal Cancer; 
Cancer Res February 15 2011 (71) (4) 1263-1271
86 Merck Sharp & Dohme Corp. A Study of Pembrolizumab (MK-3475) in Combination With 
Chemotherapy or Immunotherapy in Participants With Lung Cancer (MK-3475-
021/KEYNOTE-021)[ClinicalTrials.gov Identifier: NCT02039674] US NationalInstitutes of 
Health, ClinicalTrials.gov. 2014.
87 Eisenhauer 
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(version 1.1), European Journal of Cancer, 2009, Vol. 45, p 228-247.
88 Ji RR, Chasalow SD, Wang L, Hamid O, et al.An immune-active tumor microenvironment 
favors clinical response to ipilimumab. Cancer Immunol Immunother. 2012;61:1019-31. 
89 Hodi FS, O'
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with Metastatic Melanoma; N Engl J Med. 2010 Aug 19;363(8):711-23.
90 Robert C, Thomas L, Bondarenko et al.NEJM, 2011, Ipilimumab plus Dacarbazine for 
Previously Untreated Metastatic Melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26.
91 Ipilimumab Investigator Brochure Version 19. Mar-2015. DCN: 930017531.
92 Horenstein AL, Chillemi A, Zaccarello G, et al. A CD38/CD203a/CD73 ectoenzymatic 
pathway independent of CD39 drives a novel adenosinergic loop in human T lymphocytes. 
Oncoimmunology. 2013: 2(9): e26246. 
93 Lokhorst, H., Laubach, J. P., Nahi, Hareth, Plesner, T., Gimsing, P., Hansson, M, Minnema, 
M. C., and Lassen, U. Dose-dependent efficacy of daratumumab (DARA) as monotherapy in 
patients with relapsed or refractory multiple myeloma (RR MM). J Clin Oncol 32:5s(2014), 
8513. 2014.
94 Lokhorst, 
H., 
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M. Targeting 
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95 Lonial, S., Usmani, S., Singha, U. K., Chari, A, and Bahlis, N. J. Phase II study of 
daratumumab (DARA) monotherapy in patients with = 3 lines of prior therapy or double 
refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol 33 
(supplement), LBA8512. 2015.
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96 Nijhof IS, Groen RW, Noort WA et al. Preclinical evidence for the therapeutic potential of 
CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to 
lenalidomide and bortezomib. Clin.Cancer Res. 2014clincanres.
97 Nijhof IS, van Noort W, Lammerts van Bueren J et al. CD38-Targeted Immunochemotherapy 
Of Multiple Myeloma: Preclinical Evidence For Its Combinatorial Use In Lenalidomide and 
Bortezomib Refractory/Intolerant MM Patients. Blood 2013;122:277.
98 van der Veer MS, de WM, van KB et al. Towards effective immunotherapy of myeloma: 
enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 
monoclonal antibody daratumumab. Haematologica. 2011;96:284-290.
99 Plesner T, Arkenau T, Lokhorst H et al. Preliminary Safety and Efficacy Data Of 
Daratumumab In Combination With Lenalidomide and Dexamethasone In Relapsed Or 
Refractory Multiple Myeloma. Blood 2013;122:1986.
100Plesner, T., Arkenau, T, Lokhorst, Henk M., Gimsing, P., and Krejcik, J. Safety and efficacy 
of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory 
multiple myeloma. Blood 124(21), 84. 2014.
101Dimopoulos, M., Oriol, A., Nahi, H., San Miguel, J. F., Bahlis, N. J., Rabin, N., and Orlowski, 
R. An open-label, randomized phase 3 study of daratumumab, lenalidomide, and 
dexamethasone (DRd) versus lenalidomide and dexamethasone (Rd) in relapsed or refractory 
multipel myeloma (RRMM): POLLUX. Haematologica EHA, LB2238. 2016.
102Palumbo, A., Chanan-Khan, A., Weisel, K., Nooka, Ajay K., and Masszi, T. Phase III 
randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus 
bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple 
myeloma (RRMM): CASTOR study. J Clin Oncol ASCO. 2016.
103DARZALEX [package insert]. Janssen Biotech, Inc, Horsham PA; 2016.
104Umar A, Boland Cr, Terdiman JP, et al. Revised Bethesda Guidelines for Hereditary 
Nonpolyposis Colorectal Cancer (Lynch Syndrome) and Microsatellite Instability. J Nat 
Cancer Inst 2004;96:261-68.
105Claudia I. Chapuy, Rachel T Nicholson, Maria D Aguad et al : Resolving the daratumumab 
interference with blood compatibility testing TRANSFUSION 2015;55;1545–1554.
106Wolchok JD, Hoos A, O’Day S, et al. Guidelines for 
the evaluation of immune therapy activity 
in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15: 7412-20.
107Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS.  Developing a 
Common Language for Tumor Response to Immunotherapy: Immune-Related Response 
Criteria Using Unidimensional Measurements..  Clin Cancer Res. 2013 Jun 26.
108Manuel, M. 2012 Oncoimmunology
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APPENDIX 1
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 2
ECOGPERFORMANCE STATUS 
These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, 
assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and 
prognosis. They are included here for health care professionals to access. 
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light 
or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
* As published in Am. J. Clin. Oncol.:
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And 
Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. 
The ECOG Performance Status is in the public domain therefore available for public use. To duplicate the scale, 
please cite the reference above and credit the Eastern Cooperative Oncology Group, Robert Comis M.D., Group 
Chair. 
How to contact ECOG:
All contents copyright © 1998-2000 Eastern Cooperative Oncology Group.
All rights reserved.
Revised: July 27, 2006
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APPENDIX 3
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES(VERSION 1.1) WITH BMS MODIFICATIONS
1.
EVALUATION OF LESIONS
Solid tumors will be evaluated using Response Evaluation Criteria InSolid Tumors version 1.1 
(RECIST1.1)guideline with BMS modifications.
1
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as 
follows:
1.1
Measurable
Tumor lesions:Mustbe accurately measured in at least one dimension(longest diameter in the 
plane of the measurement to be recorded) with a minimum size of:
10 mm byCT/MRIscan-(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/MRIscan (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 
15mmby CT/MRIscan. 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 isreported as being 20 mm x 30 mm has a short axis of 20mm 
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 lesionsare 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 in 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 or plain films are notconsidered 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 identifiablesofttissuecomponents, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the softtissuecomponentmeets 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 ofdiameters 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 thatis 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 ofTarget Lesions
2.1.1.1
Lymph nodes
Lymph nodesidentified 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’. Whenthis occurs it is important 
that a value be recorded 
on the case report form. If it is the opinion of the radiologist that 
the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned
as the reference diameter.(Note:It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 
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default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error.To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm.
2.1.1.3
Lesions that split or coalesce on treatment
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalescedsuch 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 ornon-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare.
2.2.1.2
When the patient has only non-measurable disease
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into 
the 
interpretation of an increase in non-measurable 
disease burden. 
Because 
worsening in non-target 
disease 
cannot 
be easily quantified 
(by 
definition: 
if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal 
progression is 
to 
consider if 
the increase in 
overall 
disease burden based 
on 
the 
change 
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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 
describedas ‘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 nospecific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not.
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD).
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible 
‘new’ disease). New lesions 
on 
the 
basis 
of FDG-PET 
imaging 
can 
be identified 
according 
to the following algorithm:
1.Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion.
2.No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 
CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
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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 
confirmationand 
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 2.3.2-1provides 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 2.3.2-2is to be used. 
Table 2.3.2-1:
Time Point Response: Patients With Target (±Non-Target) Disease
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable
Table 2.3.2-2:
Time Point Response: Patients with Non-target Disease Only
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
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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
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 soto assign this category when no lesions can be measured is not advised.
2.3.3
Best Overall Response 
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date.
For example, if the first scheduled follow-up imaging visit is Week 6 (±7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified.
Special note on response assessment:When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstateprogression 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 CRand PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BestOverall Response
CR
CR
CR
CR
PR
SD, PD OR PRa
CR
SD
SD provided minimum criteria for SD duration met, otherwise, 
PD
CR
PD
SDprovided minimum criteria for SD duration met, otherwise, 
PD
CR
NE
SD provided minimum criteria for SD duration met, otherwise, 
NE
PR
CR
PR
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Table 2.3.3-1:
Best Overall Response (Confirmation of CRand PR Required)
Overall Response 
First Time Point
Overall Response 
Subsequent Time Point
BestOverall Response
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 durationmet, otherwise, 
NE
NE
NE
NE
CR=completeresponse,PR=partialresponse,SD=stabledisease,PD=progressivedisease,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 subsequentrepeat assessments that should be performed no 
less than 28days after the criteria for response are first met. Subsequent documentation of a CR 
may provide confirmation of apreviously identified CR even with an intervening NEor PR(eg, 
CR NE CRor 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/CRsfor confirmation.
Verification of Progression:Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease.
REFERENCES
1Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors:
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47.
.
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APPENDIX 4
MSI STATUS TESTING
TESTING PANEL DESCRIPTIONS (PCR AND IHC)
Bethesda method (PCR) Panel Description and Classification of MSI Status
Reference panel: 
BAT25 (mononucleotide)
BAT26 (mononucleotide)
D5S346 (dinucleotide)
D2S123 (dinucleotide)
D17S250 (dinucleotide)
Alternative loci: 
BAT40
BAT34C4
TGF-β-RII
ACTC (635/636)
Classification: 
If 5 loci tested (reference panel):
MSI-H:2 markers with instability
MSI-L: 1 marker with instability
MSS or MSI-L:0 markers with instability
If >5 loci tested (reference panel plus alternative loci):
MSI-H:30-40% markers with instability
MSI-L: <30-40% markers with instability
MSS or MSI-L:0 markers with instability
In the case of 1 PCR amplification failure:
If 3 markers of 4 MSI-H
If 1 marker of 4 re-amplify
IHC method -Panel Description and Classification of MSI Status
Panel 
hMSH2 
hMLH1
hMSH6
hPMS2 
Classification: 
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MSI-H:1 markers with instability
MSS:0 markers with instability
MSI-L:not evaluable with this technique
Prioritization of Tumor Tissue Samples for MSI Testing
1)Archive tissue (Preferred)
a)For MSI status confirmation
b)Archived tissue is required for all subjects. See main protocol and protocol Administrative 
Letter 02 dated 22Jan2015 for more information.
2)Fresh biopsy
a)For biomarker evaluations
b)For MSI status confirmation (if archive tissue is determined not suitable for testing by 
BMS-contracted Lab)
Important Reminders:
Refer to Central Lab Flow Chart and protocol for specific sample requirements
A normal control ACD whole blood sample is required as well as tumor tissue
Please contact BMS or The Central Lab if there are any questions.
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APPENDIX 5
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 
45years 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 
>40mIU/mL to confirm menopause.
Note:Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic FSH 
level. The duration of the washout period is a function of the type of HRT used. The duration of 
the washout period below are suggested guidelines and the investigators should use their 
judgement in checking serum FSH levels. 
1 week minimum for vaginal hormonal products (rings, creams, gels)
4 week minimum for transdermal products
8 week minimum for oral products
Other parenteral productsmay require washout periods as long as 6 months. If the serum FSH 
level is > 40 mIU/mLat any time during the washout period, the woman can be considered 
postmenopausal.
End of Relevant Systemic Exposure
End of relevant systemic exposure is the time pointwhere the IMP or any active major 
metabolites has decreased to a concentration that is no longer considered to be relevant for 
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human teratogenicity or fetotoxicity.This should be evaluated in context of safety margins 
from the no-observed adverse effect level (NOAEL) or the time required for 5 half-lives of the 
IMP to pass.
METHODS OF CONTRACEPTION
Local laws and regulations may require use of alternative and/or additional contraception methods.
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly.
a
Combined (estrogen-and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationand/or implantation (Thismethodof contraception canonlybe used 
by WOCBP participants in studies where hormonal contraception is permitted by the study 
protocol)
b 
oral (birth control pills)
intravaginal (vaginal birth control suppositories, rings, creams, gels)
transdermal
Combined (estrogen-and progestogen-containing) hormonal contraception must begin at 
least 30 days prior to initiation of study therapy
Progestogen-only hormonal contraception associated with inhibition of ovulation(Thismethodof 
contraception canonlybe used by WOCBP participants in studies where hormonal 
contraception is permitted by the study protocol)
b 
oral 
injectable 
Progestogen-only hormonal contraception must begin at least 30 days prior to initiation of 
study therapy
HighlyEffectiveMethodsThatAreUserIndependent
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationand/or implantation (Thismethodof contraception canonlybe used by WOCBP 
participants in studies where hormonal contraception is permitted by the study protocol)
b
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)(Thismethodof contraception canonlybe 
used by WOCBP participants in studies where hormonal contraception is permitted by the 
study protocol)
b,c
Bilateral tubal occlusion
Vasectomizedpartner 
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBPand the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.
Sexual abstinence
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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 studytreatment.
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.
Continuous abstinence must begin at least 30 days prior to initiation of study therapy
It is not necessary to use any other method of contraception when complete abstinence is 
elected. 
WOCBP participants who choose complete abstinence must continue to have pregnancy
tests, as specified in Section 5. 
Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence
Periodic abstinence (including but not limited to calendar, symptothermal, post-ovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM) are not acceptable methods of contraception for this study.
NOTES:
a Typical use failure rates may differ from those whenused 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
LessThanHighlyEffectiveContraceptiveMethodsThatAreUserDependent
Failure rate of >1% per year when used consistently and correctly.
Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously
Diaphragm with spermicide
Cervical cap with spermicide
Vaginal Sponge with spermicide
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action(This method of contraception cannot be used by WOCBP 
participants in studies where hormonal contraception is prohibited)
UnacceptableMethodsofContraception
Periodic abstinence (calendar, symptothermal, post-ovulation methods)
Withdrawal(coitus interruptus).
Spermicide only
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Lactation amenorrhea method (LAM)
COLLECTION OF PREGNANCY INFORMATION
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 6.4and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting.
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APPENDIX 6
REVISED PROTOCOL SUMMARY OF CHANGE HISTORY
Overall Rationale for Revised Protocol 08, 08-Jun-2020
In this protocol revision, the study follow-up period is extended to obtain at least 5 years of data, 
to enable better characterization of the long-term efficacy of the study treatment. Nivolumab 
pharmacokinetics (PK) and immunogenicity (IMG)properties have been well characterized across 
the entire nivolumab program. Sufficient PK and IMG data havebeen collected in CA209142, 
therefore these sample collections beyond 2 yearshave been removedfrom Arm N, Arm N+I, 
Cohort C3, and Cohort C6. In these same arms and cohorts, PK and IMG collection during Follow-
up Visits 1 & 2 have also been removed. All samples which have been collected prior to revision 
08 will be analyzed.
Summary of key changes for Revised Protocol 08
Section Number & Title
Description of Change
Brief Rationale
Title Page
Changed Medical Monitor from 
Ajlan Atasoy to Sandzhar Abdullaev
Added Jing Yang as Study Director
To report important 
personnel changes
Synopsis, Investigational 
Product(s), Dose and Mode 
of Administration, Duration 
of Treatment with 
Investigational Products
1.1.4.8 Rationale for Shorter 
Nivolumab and Ipilimumab 
Infusion Times 
4.1.3.1 BMS-936558 
Nivolumab
4.1.3.2 Ipilimumab
Nivolumab infusion duration 
reduced to 30 minutesforArms N 
and N+I
To align with current
nivolumab and 
ipilimumab program 
standards 
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Summary of key changes for Revised Protocol 08
Section Number & Title
Description of Change
Brief Rationale
Synopsis, Study Design 
Schematic
Figure 3.1-1 Study Design 
Schematic
3.1.9.1 Follow-up for all 
Cohorts After Initial Study 
Treatment
Table 5.1-7 Follow-Up 
Period (All treatment 
groups, CA209142)
Table 5.1-13 Follow-Up 
(MSI-H Cohorts at 
Discontinuation of Re-
initiated Treatment, 
CA209142)
Revised text to increase Survival 
Follow-up from a maximum of 3 
years to a minimum of 5 years 
The studyfollow-up is 
extended to have at least 
5 years of data.  
The longer time frame 
will enable better 
characterization of the 
long-term efficacy of the 
study treatment.
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Summary of key changes for Revised Protocol 08
Section Number & Title
Description of Change
Brief Rationale
3.1.9.1 Follow-up for all 
Cohorts After Initial Study 
Treatment
Table 5.1-7 Follow-Up 
Period (All treatment 
groups, CA209142)
5.5.1 Pharmacokinetics and 
Immunogenicity Collection 
and Processing
Table 5.5.1-1 PK Sampling-
Pharmacokinetic & 
Immunogenicity Sampling 
Schedule -Arm N+I 
(Nivolumab in combination 
with Ipilimumab)
Table 5.5.1-2 PK Sampling-
Pharmacokinetic & 
Immunogenicity Sampling 
Schedule -Arm N 
(Nivolumab monotherapy)
Table 5.5.1-3 PK Sampling-
Pharmacokinetic & 
Immunogenicity Sampling 
Schedule for Cohort C3 
(Nivolumab and Ipilimumab 
Sample Collections)
Table 5.5.1-6 
Pharmacokinetic and 
Immunogenicity Sampling 
Schedule for Daratumumab 
(Nivolumab and 
Daratumumab Combination, 
Cohort C6)
Removed PK andIMG collection 
during Survival Follow-up Visits 1 
& 2 collection
Removed collection 
during survival follow-
up to align with current 
BMS standards
3.1.10 End of Study 
Definition
Added new subsection
To provide definitionof 
end of study, to align
with current BMS 
standards
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Summary of key changes for Revised Protocol 08
Section Number & Title
Description of Change
Brief Rationale
4.3.3 Dose Delay Criteria
Added that nivolumab and BMS-
986016 (C5 Cohort treatment) 
administration should be delayed for 
elevated troponin and Grade 2 
myocarditis
To align with current 
BMS-986016 and 
nivolumab program 
standards
4.3.3.1 Management 
Algorithms for Immuno-
Oncology Agents
Add Myocarditis algorithm
Provided Myocarditis 
algorithm per recent 
Nivolumab Investigator 
Brochure update
4.3.6 Discontinuation 
Criteria
Added details to Grade 4 drug-
related adverse events or laboratory 
abnormalities
Revised consultation to re-initiate 
dosing after a dosing interruption to 
include Medical Monitor “or 
designee”
Added text regarding any adverse 
event, laboratory abnormality, or 
intercurrent illness that the 
Investigator judges topresents a 
substantial clinical risk to the subject
To align with current
nivolumab program 
standards
4.3.8 Treatment Beyond 
Disease Progression
Specified a minimum of 5 mm 
absolute increase to definition of 
further progression
Added that treatment should be 
discontinued permanently upon 
documentation of further 
progression
Added criteria to determine 
progression for treatment 
discontinuation
To align with current 
nivolumab program 
standards
5.5 Pharmacokinetics and 
Immunogenicity 
Assessments
Addedthat all samples which have 
been collected prior to revision 08 
will be analyzed (see below) 
For clarity
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Summary of key changes for Revised Protocol 08
Section Number & Title
Description of Change
Brief Rationale
5.5.1 Pharmacokinetics and 
Immunogenicity Collection 
and Processing
Table 5.5.1-1 PK Sampling-
Pharmacokinetic & 
Immunogenicity Sampling 
Schedule -Arm N+I 
(Nivolumab in combination 
with Ipilimumab
Table 5.5.1-2 PK Sampling-
Pharmacokinetic & 
Immunogenicity Sampling 
Schedule -Arm N 
(Nivolumab monotherapy)
Table 5.5.1-3 PK Sampling-
Pharmacokinetic & 
Immunogenicity Sampling 
Schedule for Cohort C3 
(Nivolumab and Ipilimumab 
Sample Collections)
Add that PK and immunogenicity 
samples after 2 years of treatment 
will not be collected
Nivolumab PK and IMG 
properties have been 
well characterized 
across the entire 
nivolumab program. 
Sufficient PK and IMG 
data havebeen collected 
in CA209142, therefore 
samples beyond 2 years 
will no longer be 
collected in Arm N, 
Arm N+I, Cohort C3, 
and Cohort C6.
6 Adverse Event
Updated information on events 
meeting and not meeting the adverse 
events definition
Updated per BMS 
standard
6.5 Overdose
Revised overdose reporting 
instructions 
To align with updated 
information on events 
meeting and not meeting 
the adverse events 
definition in Section 6 
(above)
9.3 Clinical Study Report 
and Publications
Revised to include greater detail 
regarding publications
To align with current 
BMS standards
Appendix 1 Management 
Algorithms
Added Myocarditis algorithm; 
revised date of the other algorithms
Provided Myocarditis 
algorithm per recent 
Nivolumab Investigator 
Brochure update
All
Minor typographical changes or
clarifications
Minor, so not noted
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CA209142
BMS-936558
nivolumab
Overall Rationale for Revised Protocol 07,05-Feb-2019
Clinical study CA209-142 was originally designed to continue nivolumab monotherapy and 
nivolumab 
combination treatments 
until 
progression 
or 
toxicity in all cohorts. 
The 
optimal 
duration 
of immunotherapy still remains an important question and continues to be investigated. At 
the 
time 
of Revised Protocol 07, some subjects with MSI-H metastatic colorectal cancer have experienced 
durable clinical benefit and have remained on study treatment for longer than 24 months. 
Accumulating data suggest that 24 months of PD-1 checkpoint inhibitor treatment may be 
sufficient for long term benefit.Per Revised Protocol 07, because astrict stopping rule was not 
considered ideal for CA209-142, the option to stop treatment in case of maximum clinical benefit 
as assessed by the Investigator has been incorporated into 
the study. To minimize the potential risk 
of disease recurrence as a result of premature treatment discontinuation, all MSI-H/dMMR 
subjects who achieve objective response within the second year of treatment will be required to 
continue to receive study therapy for an additional 12 months before they have theoption to 
discontinue for maximum clinical benefit (Section 3.1.4.1). A minimum of 24 months of treatment 
along with other protocol defined criteria (Section 3.1.4.1) are required for eligibility for 
discontinuation at maximum clinical benefit. In addition, Revised Protocol 07 allows for the 
re-initiation of study treatment for subjects in MSI-H/dMMR cohorts who progress within 1 year 
(52 weeks) after treatment discontinuation at maximum clinical benefit.Eligibility for re-
initiation of treatment for subjects in MSI-H cohorts has been included in Section 3.1.4.8 and 
Section 4.3.9. 
Evaluation of clinical activity and safety of nivolumab monotherapy or combination treatment re-
initiation has been added as an exploratory objective.
Administrative Letters 07, 06, and 05 as specified in the document history presented on the 
previous page have been incorporated and are not listed below. 
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Synopsis: Investigational 
Product(s), Dose and Mode 
of Administration, Duration 
of Treatment with 
Investigational Product(s):  
Section 3.1 Study Design 
and Duration 
For each MSI-H cohort, text 
and section references to 
modifications made to 
treatment durations have 
been added. 
Supports modification in 
treatment duration for MSI-H 
subjects
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CA209142
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Synopsis: Investigational 
Product(s), Dose and Mode 
of Administration, Duration 
of Treatment with 
Investigational Product(s):  
Section 4.3.1 Re-initiation of 
Dose Schedules 
New Section: Re-initiation 
dose and schedules are 
presented.  
Treatment duration after re-
initiation will be a 
maximum of 24 months, 
except for subjects who 
achieve CR after re-
initiation. Subjects who 
achieve CR will be 
permitted to stay on therapy 
until progressive disease if 
clinically indicated per 
Investigator.
Details of dosing during re-
initiation of treatment.
Synopsis Study Design 
MSI-H cohorts updated to 
include reference to 
modified treatment duration 
section.
Supports modification in 
treatment duration for MSI-H 
subjects
Section 1.1.4.6 Dose and 
Scheduling Rationale 
(Nivolumab and Ipilimumab)
On the basis of modification 
of treatment duration for 
MSI-H cohorts, text was 
modified.
Text modified to reflect new 
treatment duration options
Section 1.1.4.7 Rationale for 
Treatment Duration and 
Introducing Re-Initiation in 
MSI-H/dMMR Cohorts
New Section: Text added to 
support modification of 
treatment duration and 
introduction of treatment re-
initiation for subjects in 
MSI-H cohorts
Describes rationale for 
introducing the option to 
discontinue treatment for  
maximum clinical benefit 
following a minimum treatment 
duration and the option for 
re-initiation
Section 1.1.4.10 Rationale 
for Nivolumab Dose 480mg 
Q4W during Re-initiation 
Treatment
New Section: Text added to 
support nivolumab dose 
during re-initiation of 
treatment.
Nivolumab 480 mg Q4W dose 
during re-initiation is supported 
by pharmacokinetic data. 
Section 1.3.3, Exploratory 
Objectives
Clinical activity and safety 
of nivolumab monotherapy 
or combination treatment re-
initiation will be evaluated 
as an exploratory objective.
Evaluation of re-initiation 
treatment is exploratory. 
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CA209142
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Section 1.5 Overall 
Risk/Benefit Assessment
Text added to support 
modification of treatment 
duration in MSI-H cohorts
The option to discontinue for 
maximum clinical benefit after 
a minimum of 24 months of 
treatment does not affect the 
risk/benefit assessment.
Section 3.1.4.1, Study 
Treatment Duration (MSI-H 
Cohorts Only)
This section specifies 
duration of treatment for 
these cohorts and includes 
criteria which define 
maximum clinical benefit.
Supports modification in 
treatment duration for MSI-H 
subjects
Section 3.1.4.2, MSI-H 
Nivolumab Monotherapy 
(Arm N): mStage 1 and 2
Section 3.1.4.3MSI-H 
Nivolumab + 
Ipilimumab(Arm N+I): 
cStage 1 and 2
Section  3.1.4.5MSI-H, 
C3 Cohort (No Prior 
Treatment in Metastatic 
Setting, Nivolumab + 
Ipilimumab)
Section 3.1.4.6 MSI-H 
C5, Cohort (2L in 
Metastatic Setting, 
Nivolumab + BMS-
986016)
These sections have been 
renumbered and updated to 
include referencesto 
modified treatment duration 
section. 
Required update for change in 
treatment duration for MSI-H 
subjects
Section 3.1.4.8: Treatment 
Options Upon Progression 
after Treatment 
Discontinuation For 
Maximum Benefit
New Section.
Text added to specify treatment 
options after progression based 
on time of progression and 
treatment duration
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CA209142
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Section 3.4.1 Prohibited 
and/or Restricted Treatment
Live/attenuated vaccines 
(eg, varicella, zoster, yellow 
fever, rotavirus, oral polio 
and measles, mumps, 
rubella [MMR]) are 
prohibited during the study. 
Updated per program wide 
standard for Nivolumab
Section 4.1 Study Treatment 
Table 4.1-1 Product 
Description Treatment Period
Throughout this section and 
table, content and data have 
been updated to drug supply 
standards.
Update per BMS standard
Section 4.2 Method of 
Assigning Subject 
Identification 
Text added to support 
subjects who re-initiate 
treatment.
Section 4.3 Selection and 
Timing of Dose for Each 
Subject 
Tables 4.3-1, 
4.3-3, 4.3-4 and 4.3-5.
Section 5.1 Flow Chart/Time 
and Events Schedules
Tables 5.1-2  
Tables 5.1-3  Table 5.1-4
Note added to each table as 
reference for modification 
of treatment duration for 
these cohorts.
Supports changes in treatment 
duration for MSH-I cohorts
Section 4.3.3, Dose Delay 
Criteria
Text updated
Updated per program wide 
standard for Nivolumab
Section 4.3.6 Discontinuation 
Criteria
Grade 3 drug myocarditis, 
of any duration has been 
added to drug-related 
adverse events that require 
discontinuation
Section 4.3.8 Treatment 
Beyond Disease Progression
The treatment administered 
beyond progression to 
re-initiated subjects will be 
the treatment received 
during re-initiation. 
Section aligned with option to 
re-initiate treatment for eligible 
MSI-H subject
Protocol Amendment No: 09
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Clinical Protocol
CA209142
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Section 4.3.9 Treatment Re-
initiation: MSI-H Cohorts
Section added to specify 
eligibility requirements for 
re-initiation of treatment for 
MSI-H subjects who 
progress within 1 year (52 
weeks) of discontinuation at 
Maximum Clinical Benefit
Section was added to align with 
option to re-initiate treatment 
for eligible MSI-H subjects.
Section 4.7Retained 
Samples for Bioavailability / 
Bioequivalence
Paragraph deleted: not 
applicable to the study.
Correction
Section 5.1Flow Chart/Time 
and Events Schedules
Table 5.1-8 through 5.1-11
Schedule of Procedures 
during re-initiation of 
treatment have been added 
for each MSI-H cohort.  
Note: during re-initiation 
there will be no collection 
of samples for 
PK/immunogenicity;
Assessments during re-
initiation are included for 
each MSH-I cohort.
Additional data collection of 
PK/immunogenicity are not 
necessary.
Optional tumor biopsy 
material will support analysis 
of biomarker evolution and 
potentially to identify 
characteristics of subjects 
who benefit from re-
initiation.
Section 5.1, Table 5.1-5
Short-term Procedural 
Outline for C5 Cohort 
[Nivolumab (BMS-936558) 
+ Anti-Lag-3 (BMS-
986016)]: MSI-H
Row: Dispense Study Drug 
row
Text in note column that 
was not applicable to this 
combination was deleted. 
Correction.
Section 5.4. Efficacy 
Assessments.
Text added to specify 
imaging during re-initiation.
Efficacy section update to align 
with change in study design
Protocol Amendment No: 09
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Clinical Protocol
CA209142
BMS-936558
nivolumab
Summary of key changes for Revised Protocol 07
Section Number & Title
Description of Change
Brief Rationale
Section 5.6.8 Tumor Samples 
Table 5.6.8-1, 
Table 5.6.8-2 
Table 5.6.8-3
New tables added to support 
biomarker sampling for 
those MSI-H subjects who 
re-initiate treatment.  
Tumor biopsy at re-initiation is 
optional due to the exploratory 
nature of analysis. Change in 
MSI status is not expected. 
Biopsy material will support 
analysis of biomarker evolution 
and, potentially, to identify 
characteristics of subjects who 
benefit from re-initiation
Section 8.2 Population for 
Analyses 
Section 8.3.3 Exploratory 
Endpoints
Section 8.4.7.2 Analyses of 
Re-initiation Treated 
Subjects
These sections have been 
updated or added (Section 
8.4.7.2) to address re-
initiation of treatment for 
subject in MSI-H cohorts. 
Aligned with changes in study 
design
Section 9.1.3 Investigational 
Site Training 
Added text to include 
training of sites prior to 
implementation of 
significant protocol 
revisions
Text added to align with site 
training practices for protocol 
revisions.
Appendix 1: Hepatic Adverse 
Event Management 
Algorithm 
Deletion of footnote stating 
I-O therapy may be delayed 
rather than discontinued if 
AST/ALT ≤ 8 x
ULN or T.bili ≤ 5 x ULN
Updated per BMS standard for 
all studies with nivolumab
Throughout the protocol
Minor editorial corrections and clarifications with no impact on 
protocol content.
Protocol Amendment No: 09
Date: 27-Aug-2021
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