Conditions: Colorectal Neoplasms
Keywords: programmed cell death 1 (PD-1, PD1 ) programmed cell death ligand 1 (PD-L1, PDL1) microsatellite stable (MSS) colorectal cancer (CRC) chemokine receptor type 5 (CCR5)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 41
Healthy volunteers: no

Brief summary:
This trial will evaluate the safety and efficacy of vicriviroc (MK-7690) at 2 dose levels in combination with pembrolizumab (MK-3475) in participants with advanced/metastatic microsatellite stable (MSS) colorectal cancer (CRC).

Detailed description:

Arms:
arm 1: Participants receive vicriviroc 150 mg tablets per os (PO) every day (QD) of each 21-day cycle up to 35 cycles and pembrolizumab 200 mg as a 30-minute intravenous (IV) infusion on Day 1 of each 21 day cycle up to 35 cycles (cycle length: 21 days). arm 2: Participants receive vicriviroc 250 mg tablets PO QD of each 21-day cycle up to 35 cycles and pembrolizumab 200 mg as a 30-minute IV infusion on Day 1 of each 21 day cycle up to 35 cycles (cycle length: 21 days).

Interventions: intervention 1: Vicriviroc intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Vicriviroc tablets administered orally, QD at dose level 1 or 2. intervention 2: Pembrolizumab administered by IV infusion at 200 mg every 3 weeks (Q3W), given on cycle day 1.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 2 trial to evaluate the safety and efficacy of 
vicriviroc (MK-7690) in combination with pembrolizumab 
(MK-3475) in participants with advanced/metastatic
microsatellite stable (MSS) colorectal cancer (CRC)
07-Aug-2019
NCT03631407


PRODUCT: MK-7690 
1
PROTOCOL/AMENDMENT NO.: 046-02
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07-AUG-2019
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 2 trial to evaluate the safety and efficacy of vicriviroc (MK-7690) in 
combination with pembrolizumab (MK-3475) in participants with advanced/metastatic 
microsatellite stable (MSS) colorectal cancer (CRC)
Protocol Number: 046-02
Compound Number: MK-7690
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
139660
Approval Date: 07-August-2019
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 2
07-AUG-2019

Clarification of AE/SAE reporting of progression of cancer under 
study.

Minor clarifications of timepoints and windows of activities and 
sample collections in the Schedule of Activities
Amendment 1
22-AUG-2018

Clarification of Grade 3 DLT definition.

Clarification of study intervention dosing sequence.

Clarification of tumor imaging schedule in first year of study.
Original Protocol
28-JUN-2018

Not applicable.
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Clarification of AE/SAE reporting of progression of cancer under study, timepoints and windows of activities, and sample collections 
in the Schedule of Activities.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA)
Blood for genetic analysis
It is specified that blood for genetic analysis is to be 
collected at C1D1 predose from all randomized 
participants only. This is a requirement of the main 
study and is separate from the future biomedical 
research consent (as described in Sections 8.9 and 
8.10).
This clarifies the collection requirement 
of blood for genetic analysis at 
Screening for all randomized 
participants.
1.3 Schedule of Activities (SoA)
Blood for immune profiling 
(immunophenotyping)
It is specified that 2 distinct samples are to be 
collected for immunophenotyping with allowable 
windows for collection: 1 at Screening AND 1 at 
predose C1D1 to ensure a sample for biomarker 
analysis is collected AND analyzed at baseline prior 
to receiving drug.
Screening samples must be collected between -28 
days to -3 days.
During treatment, collect predose samples 30 
minutes before dosing on Day 1 of each cycle for 
Cycles 1, 2, and 4, and every 4 cycles thereafter.
This clarifies the blood collection 
timepoints and allowable windows
during Screening and treatment cycles 
for immune profiling.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities (SoA)
Serum for pembrolizumab PK
It is specified that the reference timepoint and 
allowable window for collection of 0.5 h is within 30 
minutes from the end of pembrolizumab infusion.
This clarifies the timing and allowable 
window of the 0.5 h post-dose PK 
sample collection.
1.3 Schedule of Activities (SoA)
Plasma for vicriviroc PK
It is specified that on C1D1 and C2D1, the post-dose 
vicriviroc PK samples collected at 8 h will have a 
±30 minute collection window.
This clarifies the allowable window for 
the vicriviroc 8 h post-dose sample 
collection.
1.3 Schedule of Activities (SoA)
Blood for Serum Cytokines
It is specified that Screening samples must be 
collected between -28 days to -3 days, 
During treatment samples are to be collected predose 
on Day 1 of each cycle for Cycles 1, 2, and 4, and 
every 4 cycles thereafter.
This clarifies the blood collection 
timepoints and allowable windows 
during Screening and treatment cycles 
for immune profiling.
1.3 Schedule of Activities (SoA)
Archival and/or newly obtained 
tissue collection
A ±3-day window for collection of the optional on-
treatment biopsy is added.
It is specified that collection of the Cycle 
3 optional tumor tissue biopsy has a 
window of  ±3 days. 
5.1 Inclusion Criteria
Criterion #5
It is specified that if submitting unstained cut slides, 
newly cut slides should be submitted within 7 days 
after the slides are cut.
This clarifies the timelines for 
submission of newly cut slides to reduce
shipment times and stability issues.
8.1.8 Study Intervention 
Administration - Vicriviroc
It is specified that during on-site visits, daily 
morning administration of vicriviroc should be 
withheld and taken when witnessed by the 
investigator and/or trial staff. It is also added that the 
date and time of the last dose of vicriviroc (taken at 
home) should be documented in the eCRF.
Instructions are added to withhold 
vicriviroc dosing at on-site visits and to 
capture vicriviroc dosing date/time prior 
to clinic visit. This will better define 
information for PK modeling.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
10.3.1 Definition of AE – Events 
meeting the AE definition
It is specified that progression of the cancer under 
study is not a reportable event.
This clarifies AE/SAE reporting of 
progression of cancer under study.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA)................................................................................20
2
INTRODUCTION..........................................................................................................32
2.1
Study Rationale....................................................................................................32
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
Inhibition of CCR5 as a Target for Cancer Treatment ......................34
Inhibition of PD-1 as a Target for Cancer Treatment........................34
2.2.2
Preclinical and Clinical Studies ...................................................................34
Vicriviroc Clinical Studies.................................................................34
Pembrolizumab Clinical Studies........................................................34
2.3
Benefit/Risk Assessment......................................................................................34
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................35
4
STUDY DESIGN............................................................................................................36
4.1
Overall Design......................................................................................................36
4.2
Scientific Rationale for Study Design.................................................................37
4.2.1
Rationale for Endpoints ...............................................................................38
Efficacy Endpoints.............................................................................38
Primary Efficacy Endpoint ................................................................38
4.2.1.2.1
Secondary Efficacy Endpoints.................................................38
4.2.1.2.2
Response Rate Assessed by RECIST 1.1 ................................38
4.2.1.2.3
Response Rate Assessed by iRECIST .....................................38
Safety Endpoints................................................................................39
PK Endpoints .....................................................................................39
Antidrug Antibodies...........................................................................39
Serum Cytokines................................................................................39
Planned Exploratory Biomarker Research.........................................40
Future Biomedical Research..............................................................42
4.3
Justification for Dose...........................................................................................42
4.3.1
Vicriviroc Dosing.........................................................................................42
4.3.2
Pembrolizumab Dosing................................................................................42
 
 
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4.4
Beginning and End of Study Definition .............................................................43
4.4.1
Clinical Criteria for Early Study Termination .............................................44
5
STUDY POPULATION ................................................................................................44
5.1
Inclusion Criteria.................................................................................................44
5.2
Exclusion Criteria................................................................................................47
5.3
Lifestyle Considerations......................................................................................50
5.3.1
Contraception...............................................................................................50
5.3.2
Pregnancy.....................................................................................................50
5.3.3
Use in Nursing Women................................................................................51
5.4
Screen Failures.....................................................................................................51
5.5
Participant Replacement Strategy......................................................................51
6
STUDY INTERVENTION............................................................................................51
6.1
Study Intervention(s) Administered...................................................................52
6.1.1
Medical Devices...........................................................................................53
6.2
Preparation/Handling/Storage/Accountability .................................................53
6.2.1
Dose Preparation..........................................................................................53
6.2.2
Handling, Storage, and Accountability........................................................53
6.3
Measures to Minimize Bias: Randomization and Blinding..............................54
6.3.1
Intervention Assignment..............................................................................54
6.3.2
Stratification.................................................................................................54
6.3.3
Blinding........................................................................................................54
6.4
Study Intervention Compliance..........................................................................54
6.5
Concomitant Therapy..........................................................................................54
6.5.1
Inhibitors/Inducers of CYP3A4...................................................................56
6.5.2
Rescue Medications and Supportive Care ...................................................57
6.6
Dose Modification ................................................................................................57
6.6.1
Dose Modification Guidelines.....................................................................57
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................64
Other Allowed Dose Interruption for Pembrolizumab ......................67
6.6.2
Evaluation of Safety.....................................................................................67
Dose-limiting Toxicity.......................................................................67
6.7
Intervention After the End of the Study............................................................69
6.8
Clinical Supplies Disclosure................................................................................69
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................69
7.1
Discontinuation of Study Intervention...............................................................69
7.2
Participant Withdrawal From the Study...........................................................70
 
 
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7.3
Lost to Follow-up .................................................................................................70
8
STUDY ASSESSMENTS AND PROCEDURES........................................................71
8.1
Administrative and General Procedures ...........................................................71
8.1.1
Informed Consent.........................................................................................71
General Informed Consent.................................................................72
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................72
8.1.2
Inclusion/Exclusion Criteria ........................................................................72
8.1.3
Participant Identification Card.....................................................................72
8.1.4
Medical History ...........................................................................................73
General Medical History....................................................................73
Oncologic Disease Details.................................................................73
8.1.5
Prior and Concomitant Medications Review...............................................73
Prior Medications...............................................................................73
Prior Oncologic Treatment ................................................................73
Concomitant Medications..................................................................73
8.1.6
Assignment of Screening Number...............................................................74
8.1.7
Assignment of Treatment/Randomization Number.....................................74
8.1.8
Study Intervention Administration ..............................................................74
Timing of Dose Administration.........................................................75
8.1.9
Discontinuation and Withdrawal .................................................................75
Withdrawal From Future Biomedical Research ................................75
8.1.10
Participant Blinding/Unblinding..................................................................75
8.1.11
Domiciling ...................................................................................................75
8.1.12
Calibration of Equipment.............................................................................76
8.2
Efficacy Assessments ...........................................................................................76
8.2.1
Tumor Imaging and Assessment of Disease................................................76
Initial Tumor Imaging........................................................................76
Tumor Imaging During the Study......................................................77
End of Treatment and Follow-up Tumor Imaging.............................77
RECIST 1.1 Assessment of Disease..................................................78
iRECIST Assessment of Disease.......................................................78
8.3
Safety Assessments...............................................................................................81
8.3.1
Physical Examinations.................................................................................81
Full Physical Examination.................................................................81
Directed Physical Examination..........................................................82
8.3.2
Vital Signs....................................................................................................82
8.3.3
Liver Function Tests ....................................................................................82
 
 
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8.3.4
Electrocardiograms ......................................................................................82
8.3.5
Clinical Safety Laboratory Assessments .....................................................82
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................83
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................83
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......86
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...86
8.4.4
Regulatory Reporting Requirements for SAE .............................................86
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................86
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................87
8.4.7
Events of Clinical Interest (ECIs) ................................................................87
8.5
Treatment of Overdose........................................................................................87
8.6
Pharmacokinetics.................................................................................................88
8.6.1
Blood Collection for PK ..............................................................................88
8.6.2
Blood Collection for Antipembrolizumab Antibodies.................................88
8.7
Pharmacodynamics..............................................................................................88
8.8
Future Biomedical Research Sample Collection...............................................88
8.9
Planned Genetic Analysis Sample Collection....................................................88
8.10
Biomarkers ...........................................................................................................89
8.11
Health Economics Medical Resource Utilization and Health Economics.......89
8.12
Visit Requirements...............................................................................................89
8.12.1
Screening......................................................................................................89
8.12.2
Treatment Period..........................................................................................90
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........90
8.12.4
Poststudy......................................................................................................90
Safety Follow-up Visit.......................................................................90
Imaging Follow-up.............................................................................90
Survival Follow-up ............................................................................91
8.12.5
Survival Status .............................................................................................91
9
STATISTICAL ANALYSIS PLAN .............................................................................91
9.1
Statistical Analysis Plan Summary.....................................................................91
9.2
Responsibility for Analyses/In-house Blinding .................................................93
9.3
Hypotheses/Estimation ........................................................................................93
9.4
Analysis Endpoints...............................................................................................93
9.4.1
Efficacy/Pharmacokinetics Endpoints .........................................................93
9.4.2
Safety Endpoints..........................................................................................94
 
 
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9.4.3
Exploratory Endpoints .................................................................................94
9.5
Analysis Populations............................................................................................94
9.5.1
Efficacy Analysis Populations .....................................................................94
9.5.2
Safety Analysis Populations ........................................................................94
9.5.3
Pharmacokinetic Analysis Populations........................................................94
9.6
Statistical Methods...............................................................................................95
9.6.1
Statistical Methods for Efficacy Analysis....................................................95
9.6.2
Statistical Methods for Safety Analysis.......................................................95
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................95
Demographic and Baseline Characteristics .......................................95
Pharmacokinetic Analysis..................................................................95
9.7
Interim Analyses ..................................................................................................96
9.8
Multiplicity ...........................................................................................................96
9.9
Sample Size and Power Calculations .................................................................96
9.10
Subgroup Analyses...............................................................................................97
9.11
Compliance (Medication Adherence).................................................................97
9.12
Extent of Exposure...............................................................................................97
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.....................................................................................................98
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........98
10.1.1
Code of Conduct for Clinical Trials.............................................................98
10.1.2
Financial Disclosure...................................................................................100
10.1.3
Data Protection...........................................................................................100
Confidentiality of Data ....................................................................101
Confidentiality of Participant Records.............................................101
Confidentiality of IRB/IEC Information..........................................101
10.1.4
Publication Policy......................................................................................101
10.1.5
Compliance with Study Registration and Results Posting Requirements .102
10.1.6
Compliance with Law, Audit, and Debarmen ...........................................102
10.1.7
Data Quality Assurance .............................................................................103
10.1.8
Source Documents .....................................................................................103
10.1.9
Study and Site Closure...............................................................................104
10.2
Appendix 2: Clinical Laboratory Tests............................................................105
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................106
10.3.1
Definition of AE ........................................................................................106
10.3.2
Definition of SAE ......................................................................................107
 
 
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10.3.3
Additional Events Reported in the Same Manner as SAE.........................108
10.3.4
Recording AE and SAE .............................................................................109
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................112
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................114
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................115
10.5.1
Definitions..................................................................................................115
10.5.2
Contraception Requirements......................................................................115
10.5.3
Pregnancy Testing......................................................................................117
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................118
10.7
Appendix 7: Country-specific Requirements..................................................123
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................124
10.9
Appendix 9: Abbreviations ...............................................................................128
11
REFERENCES.............................................................................................................132
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values ...........................................46
Table 2
Study Interventions....................................................................................52
Table 3
Examples of CYP3A4 Inducers/Inhibitors Prohibited During the Trial....56
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
Related AEs Associated with Vicriviroc and/or Pembrolizumab..............59
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................65
Table 6
Imaging and Treatment after First Radiologic Evidence of PD ................80
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................85
Table 8
Probability of Observing More Than 3 DLTs with 10 Participants in 
Each Arm ...................................................................................................96
Table 9
CI of the True ORR Under Different Hypothetical Number of 
Observed Response Scenarios With 20 Participants in Each Arm............97
Table 10
Protocol-required Safety Laboratory Assessments..................................105
Table 11
Highly Effective Contraception Methods................................................117
 
 
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LIST OF FIGURES
Figure 1
Trial Design ...............................................................................................19
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the 
Investigator ................................................................................................81
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 trial to evaluate the safety and efficacy of vicriviroc (MK-7690) in 
combination with pembrolizumab (MK-3475) in participants with advanced/metastatic 
microsatellite stable (MSS) colorectal cancer (CRC)
Short Title: Vicriviroc plus pembrolizumab in advanced/metastatic MSS CRC
Acronym: NA
Hypotheses, Objectives, and Endpoints:
In participants with advanced/metastatic MSS CRC following administration of vicriviroc in 
combination with pembrolizumab by vicriviroc dosage treatment Arms A and B:
Primary Objectives
Primary Endpoints
- Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response Evaluation 
Criteria in Solid Tumors, version 1.1 
(RECIST 1.1).
- Objective response is a confirmed complete 
response (CR) or partial response (PR).
- Objective: To determine the safety and 
tolerability.
- Dose-limiting toxicity (DLT)
- Adverse event (AE)
- Discontinuation of study treatment due to 
an AE
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate ORR as assessed by 
the investigator based on modified Response 
Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics (iRECIST) 
[Seymour, L., et al 2017], progression-free
survival (PFS) as assessed by the investigator 
based on RECIST 1.1 and iRECIST, and 
overall survival (OS).
- Objective response is a confirmed CR or 
PR.
- PFS is the time from the first dose of study 
intervention to the first documented disease 
progression or death due to any cause, 
whichever occurs first.
- OS is the time from the first dose of study 
intervention to death due to any cause.
- Objective: To evaluate the 
pharmacokinetics (PK) of vicriviroc.
- PK parameters including AUC in nM·hr, 
maximum concentration (Cmax) in nM, and 
trough concentration (Ctrough) in nM
 
 
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Colorectal Cancer
Population
Participants with advanced/metastatic MSS CRC
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
None
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 2 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 40 participants will be enrolled.
 
 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Levels
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
Arm A
(N = 20)
Vicriviroc
(MK-7690)
30 mg
150 mg
Oral
QD
Experimental
Pembrolizumab
100 
mg/vial
200 mg
IV 
infusion
Q3W
Experimental
Arm B
(N = 20)
Vicriviroc
(MK-7690)
50 mg
250 mg
Oral
QD
Experimental
Pembrolizumab
100 
mg/vial
200 mg
IV 
infusion
Q3W
Experimental
Abbreviations: IV = intravenous; Q3W = every 3 weeks; QD = once daily.
Total 
Number
2 arms
Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the informed consent form (ICF) through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned to 
receive study treatment until disease progression is radiographically 
documented and, when clinically appropriate, confirmed by the site per 
iRECIST; unacceptable AEs; intercurrent illness that prevents further 
administration of treatment; investigator’s decision to withdraw the 
participant; administrative reasons requiring cessation of treatment; or until 
the participant has received 35 administrations of pembrolizumab 
(approximately 2 years [24 months]). Vicriviroc will be discontinued when 
pembrolizumab is discontinued.
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy, as described under 
Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1 and 
confirmed by the site per iRECIST, initiating a nonstudy cancer treatment, 
withdrawing consent, becoming lost to follow-up, or end of the study. All 
participants will be followed by telephone for OS until death, withdrawal of 
consent, becoming lost to follow-up, or the end of the study.
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Regulatory, ethical, and study oversight considerations are outlined in Appendix 1
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
 
 
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1.2
Schema
The trial design is depicted in Figure 1.
Figure 1
Trial Design
Abbreviations: CRC = colorectal cancer; DLT = dose-limiting toxicity; MSS = microsatellite stable; QD = once 
daily.
 
 
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1.3
Schedule of Activities (SoA)
Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Administrative Procedures
Informed consent
X
Reconsent at the first 
indication of radiographic 
progression
As assessed by the 
investigator.
Informed consent for future 
biomedical research
X
The participant may 
also provide consent for 
future biomedical 
research; however, the 
participant may 
participate in the main 
study without 
participating in future 
biomedical research.
Participant identification 
card
X
Inclusion/exclusion criteria
X
Demographic and medical 
history
X
Oncology disease details 
and prior oncology 
treatment history
X
Prior/concomitant 
medications review
X
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Treatment randomization
X
Dose within 3 days of 
randomization.
Vicriviroc administration
Arm A: 150 mg PO 
QD for 21 days per 
cycle
or
Arm B: 250 mg PO 
QD for 21 days per 
cycle
Pembrolizumab 
administration
X
X
X
X
200 mg IV Q3W
Tumor imaging and 
response assessment
X*
X
X
X
*Screening imaging 
completed within 
28 days before first 
dose.
On-treatment imaging 
every 9 weeks 
(±7 days) from first 
dose, or as clinically 
indicated, for the first 
year; and 
every 12 weeks 
thereafter.
Post-treatment 
imaging every 
12 weeks (±14 days) 
from first dose, or as 
clinically indicated.
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Efficacy Procedures
Subsequent antineoplastic 
therapy status
X
X
X
X
Survival status
X
After investigator 
determined PD or start 
of new anticancer 
treatment.
In addition, upon 
Sponsor request, 
participants may be 
contacted for survival 
status at any time 
during the course of 
the study.
Clinical Procedures/Assessments
All screening 
procedures should be 
performed within 
28 days of 
randomization, unless 
otherwise noted.
Full physical examination
X
X
X
Directed physical 
examination
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Vital signs
X
X
X
X
X
X
X
Heart rate, respiratory 
rate, blood pressure, 
temperature
12-lead ECG
X
Perform additional tests 
as clinically indicated.
ECOG performance status
X
X*
X
X
X
X
X
*Perform within 7 days 
of starting study 
intervention.
AE/SAE review
X
X*
*Collection during 
imaging follow-up 
would only be SAEs in 
the 90 days post-
treatment 
discontinuation or until 
beginning another 
antineoplastic therapy.
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Laboratory Procedures/Assessments: Analysis by Local Laboratory
All screening 
procedures should be 
performed within 
28 days of 
randomization, unless 
otherwise noted.
Serum β-HCG or urine 
pregnancy test
(WOCBP only)
X
Obtain urine 
pregnancy test within 
72 hours before first 
dose.
Additional 
urine/serum testing 
may be performed if 
clinically warranted, 
and/or as defined by 
local regulations.
If a urine pregnancy 
test cannot be 
confirmed as negative, 
a serum pregnancy 
test is required.
Serum FSH (WOCBP 
only)
X
If necessary, to check 
menopausal status.
HIV, hepatitis B and C 
screen
X
Acceptable to be based 
on history, unless 
testing is required by 
local regulation.
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Urinalysis
X
X*
X
X
X
*If screening 
assessment has been 
performed within 
72 hours before
initiation of dosing, it 
does not need to be 
repeated on Cycle 1 
Day 1. Otherwise, 
perform up to 72 hours 
before Day 1 dosing.
INR or PT and aPTT
X
Participants on 
anticoagulant therapy 
should be monitored 
throughout the trial as 
clinically indicated.
Comprehensive chemistry 
panel
X*
X
X
X
X
X
X
*If screening 
assessment has been 
performed within 
72 hours before
initiation of dosing, it 
does not need to be 
repeated on Cycle 1 
Day 1. Otherwise, 
perform up to 72 hours 
before Day 1 dosing.
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
CBC with differential
X*
X
X
X
X
X
X
*If screening 
assessment has been 
performed within 
72 hours before 
initiation of dosing, it 
does not need to be 
repeated on Cycle 1 
Day 1. Otherwise, 
perform up to 72 hours 
before Day 1 dosing.
Thyroid function (T3 or 
FT3, T4 or FT4, and TSH)
X
X
X
X
To be performed every 
other cycle (3, 5, 7, etc.)
Liver function
X
X
X
PK/PD/Future Biomedical Research/Biomarkers: Analysis by Central Laboratory
Blood for genetic analysis
X
Collected predose from 
all randomized 
participants only.
This is a requirement of 
the main study and is 
separate from the future 
biomedical research 
consent (as described in 
Sections 8.9 and 8.10).
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Blood for immune 
profiling 
(immunophenotyping)
X*
X*
X
X
X
*Collected at 2 distinct 
timepoints for Screening 
AND pre-dose C1D1.
Screening samples
must be collected 
between -28 days to -
3 days.
Collect predose 
samples 30 minutes 
before dosing on Day 
1 of each cycle for 
Cycles 1, 2, and 4, 
and every 4 cycles 
thereafter.
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Serum for pembrolizumab 
PK*
X
X
X
*Predose (trough) PK 
samples will be 
collected within 
24 hours before infusion 
at Cycles 1, 2, and 4, 
and every 4 cycles 
thereafter.
Cycle 1 Day 1: 
predose (0) and 0.5 h 
(within 30 minutes 
after end-of-infusion 
of MK-3475)
Cycle 2 Day 1: 
predose (0) and 0.5 h 
(within 30 minutes 
after end-of-infusion 
of MK-3475)
Cycle 4 Day 1: 
predose (trough)
After Cycle 4:
predose every 
4 cycles
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Plasma for vicriviroc PK*
X
X
X
X
X
*All predose vicriviroc 
PK samples must be 
collected within 10 min 
before dosing.
Cycle 1 Day 1: 
predose (0) and 1, 2, 4
(± 10 mins), and 8 h 
(± 30 mins) postdose
Cycle 2 Day 1: 
predose (0) and 1, 2, 4
(± 10 mins), and 8 h 
(± 30 mins) postdose
Cycle 4 Day 1: 
predose (trough)
After Cycle 4:
predose every 
4 cycles
Antipembrolizumab 
antibodies
X
X
X
Anti-pembrolizumab 
antibody samples will 
be collected within 
24 hours before infusion 
at Cycles 1, 2, and 4 and 
every 4 cycles thereafter
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Blood for serum cytokines
X
X
X
X
X
Screening samples 
must be collected 
between -28 days to   
-3 days.
Collect predose on 
Day 1 of each cycle 
for Cycles 1, 2, and 4, 
and every 4 cycles 
thereafter.
Blood for RNA analysis
X
X
X
X
Blood for RNA analyses 
should be collected 
predose on Day 1 of 
Cycle 1, Cycle 2, and 
Cycle 4 and at treatment 
discontinuation.
 
 
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Trial Period
Screening 
Phase
Treatment Phase
(21-day Treatment Cycles)
EOT/
Discont.
Post-treatment Phase
Notes
Treatment Cycle
Screening
(Visit 1)
1
2
3
4 to 35
Safety 
Follow-
up
Imaging
Follow-
up
Survival
Follow-
up
Cycle Day
(±3 days unless otherwise 
specified)
-28 to -1
1
11
(±4)
1
11
(±4)
1
11
(±4)
1
At time
treatment
discont.
(+7)
30 days
post last
dose
(+14)
Every
12 weeks
(±14)
Every
12 weeks
(±14)
Procedure windows may 
vary
Stool for biomarker
analysis
X
(2 samples)
X
X
X
Samples to be collected 
at home for all time 
points:
Collect first predose 
sample (optional) any 
time during screening 
between 7 and 4 days 
before Cycle 1 Day 1.
Collect second 
predose sample 
(required) at least 
2 days after first 
predose sample. 
Collect postdose 
samples (required) 
2-5 days after dosing 
at Cycles 1, 2, 4, and 
8, if clinically 
feasible.
Tumor Tissue Collection
Archival and/or newly 
obtained tissue collection
X
X*
*Optional on-treatment 
biopsy (± 3 days). To be 
performed after 
scheduled blood draws.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of 
treatment; FSH = follicle-stimulating hormone; FT3 = free triiodothyronine; FT4 = free thyroxine; β-HCG = β human chorionic gonadotropin; HIV = human immunodeficiency 
virus; INR = international normalized ratio; IV = intravenous; PD = progressive disease; PK = pharmacokinetic(s); PO = per os (by mouth); PT = prothrombin time; QD = once 
daily; RNA = ribonucleic acid; SAE = serious adverse event; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing 
potential.
 
 
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2
INTRODUCTION
Vicriviroc maleate (also known as MK-7690, formerly SCH 417690 and SCH-D) is an orally 
available small molecule cysteine-cysteine motif chemokine receptor 5 (CCR5) antagonist. 
Once daily (QD) dosing of vicriviroc combined with pembrolizumab is currently being 
developed for the treatment of microsatellite stable (MSS) colorectal cancer (CRC).
2.1
Study Rationale
In both men and women, CRC is the third most commonly diagnosed type of cancer, and it is
a leading cause of cancer-related deaths globally. The American Cancer Society estimates 
that approximately 4.6% of men (1 in 22) and 4.2% of women (1 in 24) will be diagnosed 
with colorectal cancer in their lifetime [American Cancer Society 2017]. The global burden 
of CRC is expected to increase by 60% to more than 2.2 million new cases and 1.1 million 
deaths by 2030 [Arnold, M., et al 2017]. The relative survival rate for CRC is 65% at 5 years 
following diagnosis and 58% at 10 years [American Cancer Society 2017].
CRC is a heterogeneous disease with a number of etiological pathways, including the 
chromosomal instability (CIN) pathway, the microsatellite instability (MSI) pathway, and 
CpG island methylator phenotype (CIMP). CRC may be divided via molecular phenotyping 
into tumors with normal deoxyribonucleic (DNA) mismatch repair (MMR) function and 
those with DNA MMR deficient (MMR-D). Tumors showing the presence of MSI are 
classified as MSI-H (microsatellite instability-high), depending on the extent of instability in 
the markers tested; whereas tumors without this characteristic are classified as MSS. MSI 
CRC composes approximately 15% of sporadic CRC and 5% of Stage IV CRC, while MSS 
CRC composes the remainder. Based on clinical data for pembrolizumab monotherapy, the 
immune-related objective response rate (ORR) was 0% (0 of 18 patients) for MMR proficient 
(MMR-P) CRC and 40% (4 of 10 patients) for MMR-D CRC [Le, D. T., et al 2015].
Metastatic colorectal cancer (mCRC) is characterized by an immunosuppressive environment 
created by suppressive cell types, such as myeloid-derived suppressor cells (MDSCs) and 
macrophages. Macrophages can either be tumor fighting (M1-subtype) or tumor helping 
(M2-subtype). In CRC, macrophages within the tumor (tumor-associated macrophages 
[TAMs]) are often of the tumor promoting M2-subtype. One of the master switches for 
determining whether a macrophage is tumor promoting (M2-subtype) versus tumor fighting
(M1-subtype) is the CCR5 receptor. The G-protein–coupled receptor, CCR5, and its 
chemokine ligands (CCL3, CCL4, and CCL5) induce recruitment of stromal and 
inflammatory cells and promote immune evasion mechanisms. T cells at the invasive 
margins of human CRC liver metastases produce CCL5, which has tumor-promoting effects 
on tumor cells and TAMs (M2-subtype). In CRC explant models and human CRC tumor 
biopsies, CCR5 blockade led to repolarization of TAMs (M1-subtype), modulation of 
chemokines, a reduction of inflammatory cytokines (macrophage migration inhibitory factor 
[MIF], C-X-C motif ligand 8, interleukin-1 receptor antagonist, and vascular endothelial 
growth factor), an increase in interferon alfa (IFN-α) and interferon alfa-2a (IFN-α2a), and 
redistribution of infiltrating T cells. These alterations in the immune microenvironment could 
 
 
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potentially enhance the antitumor effects of antiprogrammed cell death 1 (anti-PD-1)
treatment [Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmo 2016].
Moreover, CCR5-CCL5 signaling promotes the homing of immunosuppressive regulatory 
T cells (Tregs) in CRC and pancreatic cancer, and disruption of this signaling results in 
decreased migration of Tregs into the tumor and reduced tumor growth. In addition to its 
expression on immunosuppressive cell types such as Tregs, MDSCs, and TAMs, CCR5 and 
its ligands can also be expressed on T cells and NK (natural killer) cells. Studies are 
underway to better understand how inhibition of this axis balances the immune milieu to 
prevent cancer dissemination and to destroy tumor cells. CCR5 can also be expressed on 
tumor cells and in the stroma by cancer-associated fibroblasts. CCR5 is highly expressed by 
mCRC tumor cells, and CCR5 blockade can induce cytotoxic and apoptotic effects in CRC 
cancer cells [Weitzenfeld P, Ben-Baruch A 2014].
CCR5 antagonism has been shown to impact tumor progression and metastases in several 
tumor types (eg, gastric, breast, prostate) in nonclinical studies using xenograft models 
[Velasco-Velazquez, M., et al 2012] [Ochoa-Callejero, L., et al 2013] [Mencarelli, A., et al 
2013]. In these models, the CCR5 antagonist maraviroc has been shown to reduce the 
potential for gastric and breast cancer cell dissemination, to prevent the development of 
gastric tumorigenesis, to reduce prostate cancer bone and brain metastases, and to impede 
recruitment of immunosuppressive TAMs in triple-negative breast cancer.
These data suggest that CCR5 antagonism might reverse tumor immune suppression caused 
by immune suppressive cell populations in the tumor microenvironment, such as MDSCs, 
Tregs, and TAMs. Reversal of this immunosuppression may allow immune checkpoint 
inhibitors (eg, PDL-1 antagonists) to be more effective against CRC, as well os other types of 
cancer. This proof-of-concept trial will investigate vicriviroc combined with pembrolizumab 
in advanced MSS CRC.
2.2
Background
Vicriviroc maleate is a potent CCR5 antagonist. Data for vicriviroc from human clinical trials 
for prior development in human immunodeficiency virus (HIV) indications demonstrated 
significant and substantial efficacy in reducing viral load and viral breakthrough by binding 
to CCR5 to block HIV entry. These data support on-target activity against CCR5. Safety data 
from these trials indicated vicriviroc was well tolerated in both healthy volunteers and 
patients with HIV. Development of vicriviroc was discontinued after pivotal studies failed to 
show improvement in HIV control with vicriviroc when added to optimized background 
therapy, compared with placebo.
Initial development of vicriviroc will focus on combinations with pembrolizumab. 
Pembrolizumab is a potent humanized immunoglobulin G4 monoclonal antibody (mAb) with 
high specificity of binding to the PD-1 receptor, thus inhibiting its interaction with 
programmed cell death ligand 1 (PD-L1) and 2 (PD-L2). Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1.
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
 
 
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an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) 
is indicated for the treatment of patients across a number of indications.
Refer to the Investigator’s Brochures (IBs) and/or approved labeling for detailed background 
information on vicriviroc and pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
Inhibition of CCR5 as a Target for Cancer Treatment
Vicriviroc is a CCR5 antagonist that has previously been investigated in anti-HIV 
indications. There have been no previous clinical trials in oncology indications. For more 
details refer to the vicriviroc IB.
Inhibition of PD-1 as a Target for Cancer Treatment
Keytruda (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. For more details on specific indications, refer to the pembrolizumab IB.
2.2.2
Preclinical and Clinical Studies
Vicriviroc Clinical Studies
Vicriviroc has been under development previously for HIV. More than 2100 participants
have been exposed to vicriviroc in Phase 1 through Phase 3 studies, including 2 Phase 3 trials 
where a total of 568 participants were treated. The PK, pharmacodynamics, and safety of 
vicriviroc have been well characterized. Refer to the vicriviroc IB for further information.
Pembrolizumab Clinical Studies
Ongoing clinical trials with pembrolizumab are being conducted in multiple solid tumors. In 
addition, multiple combinations with pembrolizumab are also being investigated. Refer to the 
pembrolizumab IB for trial details.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for those participating in this clinical 
study may be found in the accompanying IBs and ICF documents.
 
 
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
In participants with advanced/metastatic MSS CRC following administration of vicriviroc in 
combination with pembrolizumab by vicriviroc dosage treatment Arms A and B:
Objectives
Endpoints
Primary
•
Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response 
Evaluation Criteria in Solid Tumors,
version 1.1 (RECIST 1.1).
•
Objective response is a confirmed 
complete response (CR) or partial 
response (PR).
•
Objective: To determine the safety and 
tolerability.
•
Dose-limiting toxicity (DLT)
•
Adverse event (AE)
•
Discontinuation of study treatment due to 
an AE
Secondary
•
Objective: To evaluate ORR as assessed 
by the investigator based on modified 
Response Evaluation Criteria in Solid 
Tumors 1.1 for immune-based 
therapeutics (iRECIST) [Seymour, L., et 
al 2017], progression-free survival (PFS) 
as assessed by the investigator based on 
RECIST 1.1 and iRECIST, and overall 
survival (OS).
•
Objective response is a confirmed CR or 
PR.
•
PFS is the time from the first dose of 
study intervention to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
OS is the time from the first dose of study 
intervention to death due to any cause.
•
Objective: To evaluate the 
pharmacokinetics (PK) of vicriviroc.
•
PK parameters including AUC in nM·hr, 
maximum concentration (Cmax) in nM, 
and trough concentration (Ctrough) in nM
Tertiary/Exploratory
•
Objective: To evaluate the development 
of circulating antipembrolizumab 
antibodies.
•
Antipembrolizumab antibody level
•
Objective: To identify molecular 
(genomic, metabolic and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action.
•
Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood ribonucleic acid (RNA) variation, 
proteomics and immunohistochemistry 
(IHC), and other biomarkers.
 
 
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Objectives
Endpoints
•
Objective: To determine if differential 
gut microbiome signatures are associated 
with response to treatment or 
development of adverse events.
•
Gut microbiome composition, response, 
development of immune-related adverse 
events (irAEs), and changes in 
microbiome diversity.
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, open-label, global, multisite Phase 2 trial of vicriviroc in combination 
with pembrolizumab in participants with MSS CRC. This trial will evaluate the safety, 
tolerability, and efficacy of vicriviroc in combination with pembrolizumab at 2 doses of 
vicriviroc: 150 mg (Arm A) and 250 mg (Arm B). The dose of pembrolizumab will remain 
constant at 200 mg every 3 weeks (Q3W). Lower and/or higher doses of vicriviroc may be 
explored depending on the combined safety, PK, and pharmacodynamic data available.
Participants will be randomly allocated to receive vicriviroc (150 mg or 250 mg) in 
combination with pembrolizumab using an interactive response technology (IRT). In Arms A 
and B, vicriviroc will be administered per os (PO) every day (QD) of a 21-day cycle;
pembrolizumab will be administered IV Q3W on Day 1 of each cycle.
Initial enrollment in each dose arm will be staggered. The first 3 participants in Arm A or 
Arm B will be enrolled no more frequently than 1 participant per week, to allow for 
tolerability assessment between participants. Participants will be closely followed for 
unacceptable toxicities. After the first 10 evaluable participants in each arm have been 
enrolled, enrollment will be paused for safety and tolerability analysis until completion of the
DLT period. If this arm is well tolerated (≤3 of 10 evaluable participants experience DLTs in 
Cycle 1), this arm may be expanded by enrolling an additional 10 participants. A dose arm 
will be considered intolerable if >3 of 10 evaluable participants experience DLTs in Cycle 1. 
If the dose arm is not tolerated, the arm may be discontinued, and the protocol may be 
amended to include a lower vicriviroc dose. Otherwise, enrollment into an arm will be 
discontinued, and alternative doses may be considered. Additional cohorts may be added 
based on the totality of the efficacy and safety data.
Participants will be monitored carefully for the development of AEs, and for clinical and/or 
radiographic evidence of disease progression according to RECIST 1.1. However, iRECIST 
may be used by the investigator for treatment decisions. In participants who have initial 
evidence of radiological progressive disease (PD) by RECIST 1.1, it will be at the discretion 
of the investigator whether to continue a participant on study intervention until repeat 
imaging is obtained. This clinical judgment decision should be based on the participant’s 
overall clinical condition, including performance status, clinical symptoms, and laboratory 
data. Participants may continue to receive study intervention until tumor assessment is 
repeated 4 to 8 weeks later to confirm PD by iRECIST per site assessment.
 
 
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The investigator will evaluate AEs according to criteria outlined in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, 
to establish the safety and tolerability of vicriviroc when administered in combination with 
pembrolizumab.
There will be no intraparticipant dose escalation for participants enrolled in this study. The 
definition of DLTs and criteria for dose modification of vicriviroc are outlined in Section 6.6.
Participants may receive study intervention for up to 35 cycles (24 months). Participants will 
be treated until PD, unacceptable toxicity, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw treatment, participant 
withdrawal of consent, pregnancy of the participant, participant completes treatment, or 
administrative reasons requiring cessation of treatment, at which point they will be 
discontinued from the study.
All participants will be followed for at least 30 days after their last dose of study drug 
therapy for AE monitoring. Serious adverse events (SAEs) will be collected for 90 days after 
discontinuation, 30 days if the participant initiates new anticancer therapy <30 days after 
discontinuation of study intervention, or the day new anticancer therapy is initiated if 
between 30 and 90 days after discontinuation of study intervention. Participants with an 
ongoing AE of Grade >1 at the time of treatment discontinuation will be followed until 
resolution of the AE to Grade 0 or 1, until considered stable by the treating physician, or until 
beginning a new anticancer therapy, whichever occurs first.
Participants who discontinue treatment for reasons other than confirmed PD will have 
post-treatment follow-up for disease status (including imaging) until PD, initiating a new 
anticancer therapy, withdrawing consent for study participation, or becoming lost to 
follow-up.
After confirmed PD, each participant will be contacted by telephone every 12 weeks 
(84 days ± 14 days) for survival until withdrawal of consent, lost to follow up, death, or end 
of the study, whichever occurs first.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This Phase 2 trial is being conducted to evaluate the safety, efficacy, and tolerability of 
vicriviroc in advanced/metastatic MSS CRC when administered in combination with 
pembrolizumab. Vicriviroc has been previously developed for HIV indications and found to 
have a favorable toxicity profile (see Sec. 4.3.1 and the vicriviroc IB for more information). 
Vicriviroc has not been developed for oncology indications. Two different doses of vicriviroc 
(150 mg and 250 mg QD) will be evaluated in combination with the standard dose of 
pembrolizumab (200 mg Q3W).
 
 
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4.2.1
Rationale for Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint
A primary objective for this trial is to evaluate the antitumor activity of vicriviroc in 
combination with pembrolizumab in participants with MSS CRC. Tumor response in 
participants with solid tumors will be assessed using RECIST 1.1 based on investigator 
assessment.
This study will use ORR based on RECIST 1.1 criteria, as assessed the investigator, as the 
primary endpoint. The ORR is an acceptable measure of clinical benefit that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable risk-benefit profile.
4.2.1.2.1
Secondary Efficacy Endpoints
Secondary objectives will include evaluation of PFS by RECIST 1.1 and ORR by iRECIST,
and OS of participants treated with vicriviroc in combination with pembrolizumab. For 
additional details about assessing efficacy endpoints using RECIST 1.1 and iRECIST, see 
Appendix 8.
4.2.1.2.2
Response Rate Assessed by RECIST 1.1
RECIST 1.1 will be used to determine the objective response. Although traditional 
RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol 
has implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in 
total and 5 per organ.
4.2.1.2.3
Response Rate Assessed by iRECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
after treatment with pembrolizumab (Section 8.2.1.5). Immunotherapeutic agents such as
vicriviroc and pembrolizumab may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents, and 
participants treated with pembrolizumab may manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. Thus, standard RECIST 1.1 
may not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Based on an analysis of participants with melanoma enrolled in 
KEYNOTE-001 (KN001), 7% of evaluable participants experienced delayed or early tumor 
pseudo-progression. Of note, participants who had PD by RECIST 1.1 but not by the 
immune-related response criteria [Wolchok, J. D., et al 2009] had longer OS than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
 
 
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account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable.
The iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the United States Food and Drug Administration and the European Medicines Agency 
[Seymour, L., et al 2017]. The unidimensional measurement of target lesions, qualitative 
assessment of nontarget lesions, and response categories are identical to RECIST 1.1, until 
progression is seen by RECIST 1.1. However, if a participant is clinically stable, additional 
imaging may be performed to confirm radiographic progression. The investigators will use 
iRECIST to assess tumor response and progression and make treatment decisions.
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments will be safety endpoints in this study, including, but not limited to, the incidence 
of, causality, and outcome of DLTs, AEs, and discontinuation of study treatment due to AEs.
PK Endpoints
A secondary objective of this study is to characterize the PK profile of vicriviroc after 
administration of vicriviroc in combination with pembrolizumab. The systemic 
concentrations of this agent maybe used in conjunction with the pharmacodynamic, safety, 
and exploratory endpoint data to help assess future dosing strategies for vicriviroc.
PK endpoints will include AUC, Cmax, and Ctrough.
Antidrug Antibodies
Antidrug antibodies (ADA) response with pembrolizumab will be determined to understand 
drug metabolism, exposure, and safety. Formation of ADAs can potentially confound drug 
exposures at therapeutic doses and prime for subsequent infusion-related toxicity. ADA 
response at the beginning of each specified treatment cycle will be determined. The incidence 
of ADA and neutralizing ADA will be evaluated and summarized over time by dose. 
Correlations between the presence or absence of positivity for antidrug antibodies and PK 
and pharmacodynamic markers, activity, and safety may be explored.
Serum Cytokines
Because treatment with vicriviroc can result in immune stimulation and resulting potential 
for cytokine release, serum cytokines will be monitored to provide supplementary 
information to assist in the evaluation of any safety events (eg, tumor necrosis factor alpha 
[TNF-α] and interleukin 2 [IL-2] and 6 [IL-6]).
 
 
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Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. In addition to studying variation 
across the human genome, variants in CCR5 may specifically be investigated as there are 
variants in CCR5 known to impact function of the receptor. Finally, microsatellite instability 
(MSI) may be evaluated as this is an important biomarker for some cancers (ie, colorectal 
cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
 
 
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Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system may also be evaluated (eg, IL-10). MicroRNA profiling 
may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) measure such proteins in serum. Correlation of expression with response to 
pembrolizumab therapy may identify new approaches for predictive biomarkers in blood, 
representing a major advance from today’s reliance on assessing tumor biomarkers. This 
research would serve to develop such assays for future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Blood for immune profiling
Blood for immunophenotyping: Real-time biomarker analysis of immune markers on 
circulating immune cells will be performed to aid recommended phase two dose (RPTD) 
analysis.
Stool for biomarker analysis
Recent research suggests that the diversity of bacteria in the GI tract (microbiome) might be 
associated with response to checkpoint inhibition therapy and development of irAEs. In 
addition, the gut microbita influences the response to cancer immunotherapy and 
chemotherapy by affecting the differentiation and functions of myeloid cells in the tumor 
microenvironment. To evaluate the potential for such association in this study, stool will be 
collected and the diversity and strains of bacteria comprising the gut microbiome may be 
evaluated in the context of irAEs, clinical response to MK-7690, and changes to the diversity 
of the microbiome that result from the study treatment.
 
 
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Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.3
Justification for Dose
4.3.1
Vicriviroc Dosing
Dose selection was based on available human clinical data. The 150-mg dose was selected 
because it provides equivalent AUC exposure to the Phase 3 dose of vicriviroc (30 mg PO 
QD boosted with ritonovir) used in the HIV trials. This exposure resulted in an 
approximately 3-log reduction in HIV RNA, and thus demonstrates significant viral activity. 
The higher dose of 250 mg, which may provide increased target coverage, was also shown to 
be well tolerated in previous human clinical trials.
The maximum preplanned dose of vicriviroc that will be used in this study is 250 mg QD. 
Higher doses may be considered if supported by clinical PK, pharmacodynamic, and efficacy 
data, although higher exposures are not likely to provide any substantial increase in target 
engagement. The study design allows for exploration of lower doses if the 150-mg dose level 
is not tolerated in combination with pembrolizumab.
The human starting dose and dosing interval of vicriviroc are based on an integration of 
nonclinical toxicologic, pharmacologic, and efficacy data. See the vicriviroc IB for more 
information.
4.3.2
Pembrolizumab Dosing
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications, regardless of tumor type. As outlined 
below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W).
 
 
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•
Clinical data showing meaningful improvement in benefit-risk including OS at 200 mg 
Q3W across multiple indications.
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically based PK [PBPK] analysis) at 
200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non–small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1-enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, 
KN010, and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W 
(KN001 Cohort B3, KN001 Cohort F2, and KN006). All of these studies demonstrated flat 
dose- and exposure-response relationships across the doses studied, representing an 
approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg dose (or 200-mg fixed-dose) 
Q3W provided similar responses to the highest doses studied. Subsequently, flat dose-
exposure–response relationships were also observed in other tumor types, including head and 
neck cancer, bladder cancer, gastric cancer, and classical Hodgkin lymphoma, confirming 
200 mg Q3W as the appropriate dose independent of the tumor type. These findings are 
consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
 
 
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4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male and/or female participants of at least 18 years of age with advanced/metastatic MSS
CRC will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Have a histologically proven locally advanced unresectable or metastatic (Stage IV) 
CRC.
2. Have locally confirmed MSS CRC. Participants with MSI-H/MMR-D or microsatellite 
unstable CRC are not eligible.
3. Have been previously treated with standard therapies, which must include 
fluoropyrimidine, oxaliplatin, and irinotecan, and have received, been intolerant to, or 
been ineligible for all treatment known to confer clinical benefit.
a.
Participants who have withdrawn from standard treatment because of unacceptable 
toxicity warranting discontinuation of that treatment and precluding retreatment with 
the same agent before progression of disease will be eligible.
b. Regimens given with adjuvant intent will be counted as treatment for metastatic 
disease if the participant’s disease had progressed within 6 months after treatment.
4. Have measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Target lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions.
5. Have provided archival tumor tissue sample or newly obtained core or excisional biopsy 
of a tumor lesion not previously irradiated. Formalin-fixed, paraffin-embedded tissue 
blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue.
Note: If submitting unstained cut slides, newly cut slides should be submitted to the 
testing laboratory within 7 days after the slides are cut (details pertaining to tumor 
tissue submission can be found in the Procedures Manual).
 
 
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6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
within 7 days of starting study intervention.
Demographics
7. Are Male or Female.
8. Are ≥18 years of age, inclusive, at the time of signing the ICF.
Male Participants
9. A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 120 days after the last dose of study 
intervention and refrain from donating sperm during this period.
Female Participants
10. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 of the following conditions applies:
c.
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
d. A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 120 days after the last dose of study intervention.
Informed Consent
11. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. The participant may also provide consent for future 
biomedical research; however, the participant may participate in the main study without 
participating in future biomedical research.
Laboratory Values
12. Have adequate organ function as defined by the following table (Table 1). Specimens 
must be collected within 28 days unless otherwise specified before the start of study 
intervention.
 
 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500/µL
Platelets
≥100 000/µL
Hemoglobina
≥9.0 g/dL or ≥5.6 mmol/L
Renal
Serum creatinine or
Measured or calculatedb CrCl (GFR can also 
be used in place of creatinine or CrCl)
≤1.5 × ULN or
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN or direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT and aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
ANC = absolute neutrophil count; aPTT = activated partial thromboplastin time; 
AST (SGOT) = aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
CrCl = creatinine clearance; GFR=glomerular filtration rate; INR = international normalized ratio; 
PT = prothrombin time; ULN = upper limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell 
transfusion within the last 2 weeks.
b CrCl should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and guidelines for 
the administration of specific chemotherapies.
 
 
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5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have a known additional malignancy that is progressing or has required active treatment 
within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
2. Have known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate provided 
they are radiologically stable (ie, without evidence of progression for at least 4 weeks by 
repeat imaging; note that the repeat imaging should be performed during study 
screening), clinically stable, and without requirement of steroid treatment for at least 
14 days before the first dose of study intervention.
3. Have severe hypersensitivity reaction (≥Grade 3) to treatment with any mAb or 
components of the study interventions.
4. Have an active autoimmune disease that has required systemic treatment in the past 
2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive 
drugs), except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed. Use 
of nonsystemic steroids is permitted.
5. Have a history of vasculitis.
6. Have an active infection requiring systemic therapy.
7. Have symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoracocentesis or 
paracentesis) is eligible.
8. Have interstitial lung disease that required oral or IV glucocorticoids to assist with 
management.
9. Have a history of pneumonitis (noninfectious) that required steroids, or has current 
pneumonitis.
10. Have a known history of HIV infection.
Note: No HIV testing is required unless mandated by local health authority.
 
 
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11. Have a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] 
reactive) or known active hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection.
Note: No testing for hepatitis B and hepatitis C is required unless mandated by local 
health authority.
12. Have a known history of active tuberculosis (TB; Bacillus tuberculosis).
13. Have a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, make administration of the study interventions
hazardous, or make it difficult to monitor AEs, such that it is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
14. Have a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
15. Are pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
the last dose of study intervention.
16. Are WOCBP who have a positive urine pregnancy test within 72 hours before 
randomization or treatment allocation (see Appendix 5). If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
Note: In the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study intervention, another pregnancy test (urine or serum) must 
be performed and must be negative for the participant to start receiving the study 
intervention.
17. Have undergone major surgery and have not recovered adequately from any toxicity 
and/or complications from the intervention before starting study intervention.
18. Have a seizure disorder requiring ongoing antiseizure therapy or with any condition that, 
in the judgment of the investigator, is likely to increase the risk of seizure (eg, CNS 
malignancy or toxoplasmosis).
19. Have known GI disease or GI procedures that could interfere with the oral absorption or 
tolerance of vicriviroc, such as esophageal, gastric, or duodenal ulceration or 
inflammatory bowel disease, or history of GI surgery.
20. Are using any drug (therapeutic or recreational), or withdrawal thereof, that poses an 
increased risk of convulsions, in the opinion of the investigator.
21. Have had an allogeneic tissue/solid organ transplant.
 
 
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Prior/Concomitant Therapy
22. Have received prior therapy with vicriviroc or other CCR5 antagonist (eg, maraviroc) or 
have received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent.
23. Have been treated with an agent directed to another stimulatory or co-inhibitory T-cell 
receptor (eg, cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137).
24. Have received prior systemic anticancer therapy, including investigational agents, or has
used an investigational device within 28 days before the first dose of study intervention.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy or alopecia may be 
eligible. Participants receiving ongoing replacement hormone therapy for endocrine 
irAEs (eg, thyroid-replacement therapy) will not be excluded from participation in 
this study.
25. Have received prior radiotherapy (not to target lesions) within 2 weeks of start of study 
intervention. Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
26. Are expected to require any other form of antineoplastic therapy while on study.
27. Have a diagnosis of immunodeficiency, is receiving chronic systemic steroid therapy in 
excess of replacement doses (prednisone ≤10 mg/day is acceptable), or is taking any 
other form of immunosuppressive medication within 7 days before the first dose of the 
study intervention.
Note: The use of physiologic replacement doses of corticosteroids may be approved 
after consultation with the Sponsor Medical Monitor or designee.
28. Have received a live-virus vaccine within 30 days before the first dose of the study 
intervention. Vaccines that do not contain live virus are permitted.
29. Are currently receiving either strong (eg, itraconazole, telithromycin, clarithromycin, 
protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, 
boceprevir, telaprevir) or moderate (eg. ciprofloxacin, erythromycin, diltiazem, 
fluconazole, verapamil) inhibitors of cytochrome P450 (CYP)3A4 that cannot be 
discontinued for the duration of the study. The required washout period before starting 
study intervention is 2 weeks.
30. Are currently receiving either strong (eg, phenobarbital, enzalutamide, phenytoin, 
rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine, St John’s Wort) or 
moderate (eg, bosentan, efavirenz, modafinil) inducers of CYP3A4 that cannot be 
discontinued for the duration of the study. The required washout period before starting 
study intervention is 5 weeks for phenobarbital and 3 weeks for other agents.
 
 
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Prior/Concurrent Clinical Study Experience
31. Are currently participating in or have participated in a study of an investigational agent,
or have used an investigational device within 28 days before the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
5.3
Lifestyle Considerations
Participants should avoid grapefruit, grapefruit juice, Seville oranges, Seville orange juice, 
and St. John’s Wort (tablet or tea) while receiving study intervention. Otherwise, participants 
should maintain a normal diet unless modifications are required to manage an AE such as 
diarrhea, nausea, or vomiting.
5.3.1
Contraception
The study intervention may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study intervention may involve unknown 
risks to the fetus (unborn baby) if pregnancy were to occur during the study. To participate in 
the study, WOCBP must adhere to the contraception requirement (Appendix 5) from the day 
of study intervention initiation (or 14 days before the initiation of study intervention for oral 
contraception) throughout the study period up to 120 days after the last dose of study 
intervention. If there is any question that a WOCBP will not reliably comply with the 
requirements for contraception, that participant should not be entered into the study.
5.3.2
Pregnancy
If a participant inadvertently becomes pregnant while on study intervention, the participant 
will be immediately discontinued from study intervention. The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is an SAE (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
study investigator will make every effort to obtain permission to follow the outcome of the 
pregnancy and report the condition of the fetus or newborn to the Sponsor. If a male 
participant impregnates a female partner, the study personnel at the site must be informed 
immediately, and the pregnancy must be reported to the Sponsor and followed as described 
in Section 8.4.5.
 
 
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5.3.3
Use in Nursing Women
It is unknown whether vicriviroc or pembrolizumab is excreted in human milk. Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, participants who are breastfeeding are not eligible for enrollment.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention(s) provided by the Sponsor) will be packaged to support 
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
 
 
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6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention
Name
Type
Dose 
Formulation
Unit Dose 
Strengths
Dosage 
Levels
Route of
Administration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Arm A
Experimental
Vicriviroc
(MK-7690)
Drug
Tablet
30 mg
150 mg
Oral
QD
Experimental
IMP
Provided 
centrally by 
the Sponsor
Arm B
Experimental
Vicriviroc
(MK-7690)
Drug
Tablet
50 mg
250 mg
Oral
QD
Experimental
IMP
Provided 
centrally by 
the Sponsor
Arm A
and B
Experimental
Pembrolizumab
(MK-3475)
Drug
Solution for 
infusion
100 mg/vial
200 mg
IV infusion
Q3W
Experimental
IMP
Provided 
centrally by 
the Sponsor
Abbreviations: IMP = investigational medicinal product; IV = intravenous; Q3W = every 3 weeks; QD = once daily.
All supplies indicated in Table 2 will be provided per the "Sourcing" row depending upon local country operational requirements. 
Every attempt should be made to source these supplies from a single lot/batch number. The study site is responsible for recording the 
lot number, manufacturer, and expiry date for any locally purchased product per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
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6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on the preparation and administration of pembrolizumab are provided in the 
Pharmacy Manual. There are no specific calculations or evaluations required to be performed 
to administer the proper dose of vicriviroc to each participant.
The rationale for selection of doses to be used in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
 
 
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study intervention arms. Participants will be assigned 
randomly in a 1:1 ratio to Arm A (150 mg vicriviroc QD plus pembrolizumab Q3W) or 
Arm B (250 mg vicriviroc QD plus pembrolizumab Q3W).
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the interventions administered.
6.4
Study Intervention Compliance
Interruptions from the protocol specified treatment plan for >3 weeks between vicriviroc or 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medication specifically prohibited, 
discontinuation from study treatment may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant's primary physician. However, the decision to 
continue the participant on study treatment requires the mutual agreement of the investigator, 
the Sponsor, and the participant.
Participants are prohibited from receiving the following concomitant therapies and 
vaccinations during the screening and treatment periods of the study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents not specified in this protocol
 
 
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•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion, provided that the participant
has not progressed (either clinically or radiographically by iRECIST) or the lesion is 
not a target lesion, may be allowed at the investigator’s discretion.
•
Live vaccines within 30 days before the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus 
Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest (ECI) that is suspected to have an immunologic etiology. The 
use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.
•
CYP3A4 inhibitors/inducers/substrates are listed in Table 3. The participant must not 
take the treatments listed in Table 3 during the trial after the start of the study treatment. 
Since this list is not comprehensive, the investigator should use his or her medical 
judgment when a participant presents with a medication not on the list, or call the 
Sponsor Clinical Director for clarification.
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the electronic case report form
(eCRF) including all prescription, over-the-counter products, herbal supplements, IV 
medications, and fluids. If changes occur during the study period, documentation of drug 
dosage, frequency, route, and date should also be included on the eCRF.
All concomitant medications received within 28 days before the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs, as defined in Section 8.4.7.
 
 
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6.5.1
Inhibitors/Inducers of CYP3A4
Vicriviroc is a metabolism-dependent inhibitor of CYP3A4 and a substrate of CYP3A4. 
CYP3A4 inducers notably reduce vicriviroc exposure, while potent CYP3A4 inhibitors 
increase vicriviroc exposure. As such, concomitant use of other drugs that are identified in 
Table 3 as strong inducers, moderate inducers, strong inhibitors, or moderate inhibitors of 
CYP3A4 is prohibited while the participant is enrolled in this study.
Investigators should check an actively updated list of drugs that are clinically relevant 
inducers, or inhibitors of CYP450, including CYP3A4, as well as the product labeling of 
these compounds for reference (refer to Table 3 and Table 3 footnote c).
Table 3
Examples of CYP3A4 Inducers/Inhibitors Prohibited During the Trial
Strong 3A4
Inducersa,e
Moderate 3A4
Inducersb,e
Strong CYP3A4
Inhibitorsc,e
Moderate 
CYP3A4
Inhibitorsd,e
carbamazepine
phenobarbital
phenytoin
rifabutin
rifampin
troglitazone
bosentan
efavirenz
etravirine
modafinil
alprazolam
atazanavir 
boceprevir 
cannabis (oral; IV) 
clarithromycin 
cobicistat 
conivaptan 
danoprevir and ritonavir
dasabuvir 
diltiazem 
elvitegravir and ritonavir
grapefruit juicee
idelalisib 
indinavir and ritonavir
itraconazole 
ketoconazole 
lopinavir and ritonavir
paritaprevir and ritonavir
(ombitasvir and/or 
dasabuvir)
posaconazole 
nefazodone
nelfinavir
ritonavir
nefazodone
saquinavir and ritonavir
telaprevir 
telithromycin
tipranavir and ritonavir
troleandomycin
voriconazole
amprenavir
aprepitant
cimetidine 
ciprofloxacin 
clotrimazole 
crizotinib 
cyclosporine 
dilitiazem
dronedarone 
erythromycin
fluconazole
fluvoxamine 
fosamprenavir
imatinib 
tofisopam 
verapamil
grapefruit juicef
star fruit juice
Abbreviations: AUC = area under the curve; CYP = cytochrome P450; IV = intravenous.
a
Strong CYP3A4 inducers are those that decrease plasma AUC values of CYP3A4 substrates by >80% or higher.
b
A moderate inducer decreases the AUC of a sensitive index CYP substrate by ≥50% to 80%.
c
Strong inhibitors are defined as causing a >5-fold increase in the plasma AUC values or more than 80% decrease in 
clearance.
d
Moderate inhibitors are defined as causing a ≥2- but <5-fold increase in the AUC values or 50% to 80% decrease in 
clearance of sensitive CYP3A substrates when the inhibitors were given at the highest approved dose and the shortest 
dosing interval in clinical evaluations. 
e
Compiled from the table of substrates, inhibitors and inducers available at: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0936
64.htm#table3-2 (“Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”).
f
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (eg, 
high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low dose, 
single strength).
 
 
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6.5.2
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6. Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes, such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab and/or vicriviroc.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 4 for 
guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of the event.
6.6
Dose Modification
6.6.1
Dose Modification Guidelines
CTCAE, version 4.03, must be used to grade the severity of AEs. If appropriate, the 
investigator may attribute each toxicity event to vicriviroc or pembrolizumab alone, or to the 
combination and use the dose modification table (Table 4). If a dose modification for toxicity 
occurs with any agent, the dose may not be re-escalated in that participant. Dose 
modifications are always based on the previous cycle.
Participants may have 1 dose modification to vicriviroc and/or pembrolizumab throughout 
the course of the study (for modification of pembrolizumab, it may be held but the dose of 
200 mg will not be changed). If further toxicity occurs or the criteria for resuming treatment 
are not met, the participant must be discontinued from study intervention. If a participant 
experiences several toxicities and there are conflicting recommendations, following the most 
conservative dose adjustment is recommended (dose reduction appropriate to the most severe 
toxicity).
If, in the opinion of the investigator, the toxicity is related to the combination of the 2 study 
interventions, both should be held according to recommended dose modifications in Table 4. 
If toxicity is strongly suspected to be due to 1 of the 2 study interventions, discuss with the 
Sponsor. For participant convenience, if 1 study intervention is delayed, then the second 
study intervention can be delayed until both can be administered.
 
 
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AEs associated with vicriviroc and pembrolizumab exposure may represent an immunologic 
etiology. These irAEs may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than 1 body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.
According to existing clinical study data, most irAEs were reversible and could be managed 
with interruptions of pembrolizumab, administration of corticosteroids, and/or other
supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology or 
exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, or 
skin biopsy may be included as part of the evaluation.
Vicriviroc and pembrolizumab will be held for Grade 4 hematologic toxicities, 
nonhematologic toxicities Grade 3 or higher including laboratory abnormalities, and severe 
or life-threatening AEs as per Table 4.
If toxicity does not resolve to Grade 0 or 1 within 12 weeks after the last dose of study 
intervention, study intervention should be discontinued after consultation with the Sponsor.
With investigator and Sponsor agreement, participants with a laboratory AE still at Grade 2 
after 12 weeks may continue treatment in the study only if the AE is asymptomatic and 
controlled.
After any Grade 4 treatment-related AE, participants should not restart study intervention 
without consultation with the Sponsor (toxicity must have resolved to Grade 0 or 1 or 
baseline before restarting).
 
 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-Related AEs Associated with Vicriviroc and/or 
Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where vicriviroc and/or pembrolizumab have been withheld, vicriviroc and/or pembrolizumab can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg of prednisone or equivalent per day within 12 weeks.
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
4.
If vicriviroc is withheld due to an AE (with or without withholding pembrolizumab) and is then restarted, it will be restarted at a lower dose. Participants at
the 150-mg PO QD dose will be lowered to 90 mg PO QD; and participants at the 250-mg PO QD dose will be lowered to 150 mg PO QD. Only 1 dose 
reduction will be allowed. If further dose reduction is required, the participant should permanently discontinue vicriviroc.
irAEs
Toxicity Grade or 
Conditions (NCI 
CTCAE v4.03)
Action Taken With 
Vicriviroca
Action Taken With 
Pembrolizumabb
irAE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow up 
Pneumonitis
Grade 2
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold 
−Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper.
−Monitor participants for signs and 
symptoms of pneumonitis.
−Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment.
−Add prophylactic antibiotics for 
opportunistic infections.
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Permanently 
discontinue
 
 
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irAEs
Toxicity Grade or 
Conditions (NCI 
CTCAE v4.03)
Action Taken With 
Vicriviroca
Action Taken With 
Pembrolizumabb
irAE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow up 
Diarrhea/colitis
Grade 2 or 3
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold
−Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper.
−Monitor participants for signs and 
symptoms of enterocolitis (ie, 
diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) 
and of bowel perforation 
(ie, peritoneal signs and ileus).
−Participants with ≥Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing
endoscopy to rule out colitis.
−Participants with diarrhea/colitis 
should be advised to drink liberal 
quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid 
and electrolytes should be substituted 
via IV infusion.
Grade 4
Permanently 
discontinue
Permanently 
discontinue
AST/ALT 
elevation or 
increased 
bilirubin
Grade 2
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold
−Administer 
corticosteroids (initial 
dose of 0.5-1 mg/kg
prednisone or 
equivalent) followed by 
taper.
−Monitor with liver function tests 
(consider weekly or more frequently 
until liver enzyme value returned to 
baseline or is stable).
Grade 3 or 4 
Permanently 
discontinue
Permanently 
discontinue
-
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed by 
taper.
 
 
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irAEs
Toxicity Grade or 
Conditions (NCI 
CTCAE v4.03)
Action Taken With 
Vicriviroca
Action Taken With 
Pembrolizumabb
irAE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow up 
T1DM or 
hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold
-
Initiate insulin 
replacement therapy for 
participants with T1DM.
-
Administer 
antihyperglycemic in 
participants with 
hyperglycemia.
-
Monitor participants for 
hyperglycemia or other signs and 
symptoms of diabetes.
Hypophysitis
Grade 2
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold
-
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated.
-
Monitor for signs and symptoms of 
hypophysitis (including 
hypopituitarism and adrenal 
insufficiency).
Grade 3 or 4 
Withhold or 
permanently 
discontinue (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)b
Withhold or 
permanently 
discontinueb
Hyperthyroidism 
Grade 2
Continue
Continue
-
Treat with nonselective 
β-blockers (eg, 
propranolol) or 
thionamides as 
appropriate.
-
Monitor for signs and symptoms of 
thyroid disorders.
Grade 3 or 4 
Withhold or 
permanently 
discontinue (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)b
Withhold or 
permanently 
discontinueb
 
 
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irAEs
Toxicity Grade or 
Conditions (NCI 
CTCAE v4.03)
Action Taken With 
Vicriviroca
Action Taken With 
Pembrolizumabb
irAE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow up 
Hypothyroidism
Grade 2-4
Continue
Continue
-
Initiate 
thyroid-replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care.
-
Monitor for signs and symptoms of 
thyroid disorders.
Nephritis and 
renal dysfunction
Grade 2
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold 

Administer 
corticosteroids 
(prednisone 1-2 mg/kg 
or equivalent) followed 
by taper.

Monitor changes of renal function.
Grade 3 or 4 
Permanently 
discontinue
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold
-
Based on severity of AE 
administer 
corticosteroids.
-
Ensure adequate evaluation to 
confirm etiology. and/or exclude 
other causes.
Grade 3 or 4
Permanently 
discontinue
Permanently 
discontinue
 
 
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irAEs
Toxicity Grade or 
Conditions (NCI 
CTCAE v4.03)
Action Taken With 
Vicriviroca
Action Taken With 
Pembrolizumabb
irAE Management With 
Corticosteroid and/or 
Other Therapies 
Monitor and Follow up 
All other irAEs
Intolerable/ 
persistent Grade 2
Withhold (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)
Withhold
-
Based on type and 
severity of AE 
administer 
corticosteroids.
-
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes.
Grade 3
Withhold or 
permanently 
discontinue based 
on the type of event. 
Events that require 
discontinuation 
include and are not 
limited to Guillain-
Barré syndrome, 
encephalitis (if 
pembrolizumab is 
restarted, restart 
vicriviroc at the 
lower dose level)b
Withhold or 
permanently 
discontinue based 
on the type of event. 
Events that require 
discontinuation 
include and are not 
limited to Guillain-
Barré syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
Permanently 
discontinue
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; irAE = immune-related adverse event; IV, intravenous; NCI = National Cancer Institute; PO = per os (by mouth); QD = daily; T1DM = type 1 diabetes 
mellitus.
a
If pembrolizumab is withheld, vicriviroc will also be withheld.
b
To withhold or permanently discontinue is at the discretion of the investigator or treating physician.
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤Grade 2 and is controlled with hormone replacement therapy or achieved metabolic control (in case of T1DM).
 
 
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Dose Modification and Toxicity Management of Infusion Reactions Related 
to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines for pembrolizumab-associated 
infusion reactions are provided in Table 5.
 
 
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Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hours
Stop Infusion.
Additional appropriate medical therapy may include, but is not limited to:
−
IV fluids
−
Antihistamines
−
NSAIDs
−
Acetaminophen
−
Narcotics
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion rate (eg, from 100 mL/hour to 
50 mL/hour). Otherwise dosing will be held until symptoms resolve, and the 
participant should be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further treatment with study 
intervention.
Participant may be premedicated 1.5 hours
(± 30 minutes) before infusion of 
pembrolizumab with:
−
Diphenhydramine, oral, 50 mg (or 
equivalent dose of antihistamine)
−
Acetaminophen, oral, 500-1000 mg 
(or equivalent dose of analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
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
Stop Infusion.
Additional appropriate medical therapy may include, but is not limited to:
−
Epinephrine**
−
IV fluids
−
Antihistamines
−
NSAIDs
−
Acetaminophen
−
Narcotics
−
Oxygen
−
Pressors
−
Corticosteroids
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used immediately.
Participant is permanently discontinued from further study intervention
treatment.
No subsequent dosing
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NCI = National Cancer Institute; NSAID = nonsteroidal 
anti-inflammatory.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE, version 4.03, at http://ctep.cancer.gov
 
 
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Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical or surgical events or logistical reasons not related to study therapy. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's eCRF.
6.6.2
Evaluation of Safety
To adequately evaluate the safety of the doses administered, all participants enrolled must 
meet the criteria for evaluability for Cycle 1.
Participants are considered nonevaluable for DLT evaluation if:
•
They are randomized but not treated.
•
They discontinue from the study before completing all the safety evaluations in Cycle 1 
for reasons other than treatment-related AEs.
•
They receive <75% of the total pembrolizumab infusion (eg, if the infusion had to be 
discontinued due to an infusion reaction) and/or vicriviroc in Cycle 1 and they did not 
experience a DLT.
Dose-limiting Toxicity
Formal DLT evaluation will be performed at the interim safety analysis, following 
completion of 1 cycle of treatment by 10 evaluable participants in each dose arm. DLT 
nonevaluable participants will not be replaced. For example, if 1 of the first 10 participants in 
an arm is nonevaluable for DLT, then the next DLT-evaluable participant enrolled and 
treated in the arm will be included in the interim safety analysis. The DLT evaluation period 
will be for 1 cycle (Day 1 to Day 21; Day 1 is considered the date a study intervention was 
first administered and not the date of randomization if dosing did not occur on the date of 
randomization). During this time, supportive treatment with granulocyte-colony stimulating 
factor (G-CSF) will not be allowed.
A dose arm will be considered intolerable if >3 of 10 evaluable participants experience DLTs 
in Cycle 1. If the dose arm is not tolerated, the arm may be discontinued, and the protocol 
may be amended to include a lower vicriviroc dose.
All toxicities will be graded based on investigator assessment (Appendix 3, Assessment of 
intensity).
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to study treatment:
1. Grade 4 nonhematologic toxicity (not laboratory)
 
 
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2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia associated with bleeding
3. Any nonhematologic AE Grade 3 severity (not laboratory) should be considered a DLT, 
with the following exceptions:

Grade 3 fatigue lasting ≤3 days;

Grade 3 diarrhea, nausea, or vomiting without use of antiemetics or antidiarrheals per 
standard of care;

Grade 3 rash without the use of corticosteroids or anti-inflammatory agents per 
standard of care.
4. Any Grade 3 or Grade 4 nonhematologic laboratory value (except clinically 
nonsignificant, treatable, or reversible laboratory abnormalities including uric acid) if:
•
Medical intervention is required to treat the participant, or
•
The abnormality leads to hospitalization, or
•
The abnormality persists for >72 hours.
5. Any of the following liver test abnormalities are observed (Hy’s Law):
•
ALT or AST >3 × ULN with total bilirubin >2 × ULN with no elevation in alkaline 
phosphatase (<2 × ULN)
•
No other reasons can be found to explain the combination of increased 
aminotransferases and total bilirubin, such as viral hepatitis A, B, or C, preexisting or 
acute liver diseases, or another drug capable of causing the observed injury
6. Febrile neutropenia Grade 3 or Grade 4:
•
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
7. Inability to administer ≥75% of the planned vicriviroc dose because of drug-related 
tolerability.
8. Delay in starting Cycle 2 by >2 weeks due to toxicity.
 
 
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6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.12.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant interrupts study treatment administration for more than 12 consecutive 
weeks, unless approved with written documentation from the Sponsor.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive urine or serum pregnancy test (see 
Section 10.5.3).
 
 
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•
Confirmed radiographic disease progression outlined in Section 8.11 (exception if the 
Sponsor approves treatment continuation).
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
•
Recurrent Grade 2 pneumonitis.
•
Discontinuation of treatment may be considered for participants who have attained a
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving 
2 cycles of the combination, including 2 doses of pembrolizumab and at least 80% of 
the planned doses of vicriviroc beyond the date when the initial CR was declared.
•
Completion of 35 treatments (approximately 2 years) with vicriviroc and pembrolizumab.
Note: The number of treatments is calculated starting with the first dose.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.Note: A participant is not considered lost 
to follow-up until the last scheduled visit for the individual participant. The missing data 
for the participant will be managed via the prespecified statistical data handling and 
analysis guidelines.
 
 
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
 
 
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General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
 
 
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
General Medical History
A medical history will be obtained by the investigator or qualified designee.
Medical history will include all active conditions, drug allergies, significant medical 
procedures, and any condition diagnosed within the prior 10 years that are considered to be 
clinically significant by the investigator. Any cancer, other than the cancer under study, will 
be recorded as medical history even if diagnosed greater than 10 years before enrollment. 
Details regarding the cancer under study will be recorded separately and not listed as medical 
history.
Oncologic Disease Details
The investigator or qualified designee will obtain historic and current details of the 
participant’s cancer under study. This information will include, but is not limited to, date of 
diagnosis, stage, histology, locations of primary lesions, and location of metastases if 
applicable.
8.1.5
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Any medications taken to treat a cancer other than 
the cancer under study will be recorded as a prior medication even if taken greater than 
28 days before the first dose of study medication. All treatments for the cancer under study 
will be recorded separately and not listed as a prior medication.
Prior Oncologic Treatment
The investigator or qualified designee will review and record all treatments for the cancer 
under study, including systemic and local treatment, vaccinations, radiation, and surgeries. 
Additional information collected on these treatments will include, but is not limited to, 
reason for discontinuation, best response, and date of progression after each treatment as 
applicable.
Concomitant Medications
The investigator or qualified designee will record any medication taken by the participant 
during the study.
 
 
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All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.3.
Any new anticancer therapy started after the participant’s discontinuation from the treatment 
period will be recorded separately. Additional information collected on this treatment will 
include, but is not limited to, best response and date of progression.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Vicriviroc
During on-site visits, daily morning administration of vicriviroc should be withheld and 
taken when witnessed by the investigator and/or trial staff. The administration, the dose, the 
time of administration, as well as any immediate reactions at the time of intake will be 
documented in the eCRF. The date and time of the last dose of vicriviroc (taken at home) 
should be documented in the eCRF.
For nonvisit days, vicriviroc will be taken at home.
When a participant attends a study visit, he or she will bring any unused tablets.
Refer to Section 8.1.8.1 (Timing of Dose Administration) for dose and treatment details.
Pembrolizumab
Administration of pembrolizumab will be witnessed by the investigator and/or study staff. 
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
Study treatment should begin within 3 days of randomization.
 
 
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Timing of Dose Administration
Vicriviroc may be taken with or without food. Vicriviroc should be taken at approximately 
the same time each day.
On Day 1 of each 21-day cycle, after potential vicriviroc administration in the morning, 
pembrolizumab will be administered at a fixed dose of 200 mg as a 30-minute IV infusion.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the Final Study Visit should be performed (at the time of withdrawal). Any 
AEs that are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 8.4 .
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
Participants will not be domiciled.
 
 
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8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. Tumor imaging is strongly preferred to be acquired by 
computed tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic 
resonance imaging (MRI) may be used when CT with iodinated contrast is contraindicated, 
or when mandated by local practice. MRI is the strongly preferred modality for imaging the 
brain. The same imaging technique regarding modality, ideally the same scanner, and the use 
of contrast should be used in a participant throughout the study to optimize the 
reproducibility of the assessment of existing and new tumor burden and improve the 
accuracy of the assessment of response or progression based on imaging. Note: for the 
purposes of assessing tumor imaging, the term “investigator” refers to the local investigator 
at the site and/or the radiological reviewer located at the site or at an offsite facility.
All scheduled images for all study participants from the sites will be submitted to the central 
imaging vendor. In addition, images (including via other modalities) that are obtained at an 
unscheduled time point to determine disease progression, as well as imaging obtained for 
other reasons, but captures radiologic progression based on investigator assessment, should 
also be submitted to the central imaging vendor.
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days before the date of 
randomization. The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 28 days prior to 
the date of randomization.
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
 
 
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Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ± 7 days) 
from the date of first dose. Subsequent tumor imaging should be performed every 9 weeks 
(±7 days), or more frequently if clinically indicated, for the first year (through Week 54); and 
every 12 weeks thereafter. First post-treatment imaging assessment, after 105 weeks 
(735 days ±7 days), participants who remain on treatment will have imaging performed every 
12 weeks (±14 days). Imaging timing should follow calendar days and should not be adjusted 
for delays in cycle starts. Imaging should continue to be performed until disease progression 
is identified by the investigator (unless the investigator elects to continue treatment and 
follow iRECIST), the start of new anticancer treatment, withdrawal of consent, death, or 
notification by the Sponsor, whichever occurs first. All supplemental imaging must be 
submitted to the central imaging vendor.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point.
Note: Response does not typically need to be verified in real time by the central imaging 
vendor.
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 
8 weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site, provided they have 
met the conditions detailed in Section 8.2.1.5. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study treatment. Exceptions are detailed in Section 8.2.1.5.
End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (± 14-day window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging, using 
the same imaging schedule used while on treatment every 12 weeks (± 14 days) until the start 
of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, 
or the end of the study, whichever occurs first.
 
 
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RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used as the primary measure for assessment of tumor response and date 
of disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment). Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in total 
and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study treatment should be discontinued; however, if the participant is achieving a clinically 
meaningful benefit, an exception to continue study treatment may be considered following 
consultation with the Sponsor. In this case, if study treatment is continued, tumor imaging 
 
 
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should continue to be performed following the intervals as outlined in the SoA (Section 1.3)
and submitted to the central imaging vendor.
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 6 and illustrated as a flowchart in Figure 2.
 
 
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Table 6
Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic evidence of PD 
by RECIST 1.1
Repeat imaging at 4 to 
8 weeks to confirm PD.
May continue study treatment, after 
patient reconsent, at the 
investigator’s discretion while 
awaiting confirmatory tumor 
imaging by site by iRECIST
Repeat imaging at 4 to 
8 weeks to confirm PD per 
investigator’s discretion only
Discontinue treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per investigator 
assessment
No additional imaging 
required.
Discontinue treatment (exception is 
possible upon consultation with 
Sponsor)
No additional imaging 
required
Not applicable
Repeat tumor imaging shows 
iUPD by iRECIST per 
investigator assessment
Repeat imaging at 4 to 
8 weeks to confirm PD. May 
occur at next regularly 
scheduled imaging visit.
Continue study treatment at the 
investigator’s discretion
Repeat imaging at 4 to 
8 weeks to confirm PD per
investigator’s discretion only
Discontinue treatment
Repeat tumor imaging shows 
iSD, iPR, or iCR by iRECIST 
per investigator assessment
Continue regularly scheduled 
imaging assessments.
Continue study treatment at the 
investigator’s discretion
Continue regularly scheduled 
imaging assessments
May restart study treatment if 
condition has improved and/or 
clinically stable per investigator’s 
discretion. Next tumor imaging should 
occur according to the regular imaging 
schedule.
Abbreviations: iCPD = iRECIST-confirmed progressive disease; iCR = iRECIST complete response; iPR = iRECIST partial response; iRECIST = modified Response Evaluation 
Criteria in Solid Tumors version 1.1 for immune-based therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; 
RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1.
 
 
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated with 
Pembrolizumab after First Radiologic Evidence of PD Assessed by the Investigator
Abbreviations: iRECIST = modified Response Evaluation Criteria in Solid Tumors, version 1.1, for immune-
based therapeutics; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, 
version 1.1.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedures
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical examination are described in the SoA (Section 1.3). 
After the first dose of trial treatment, new clinically significant abnormal findings should be 
recorded as AEs.
 
 
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Directed Physical Examination
For cycles that do not require a full physical examination per the SoA (Section 1.3), the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated before trial treatment administration. New clinically significant abnormal findings 
should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, before the 
administration of each dose of trial treatment and during the follow-up period, as specified in 
the SoA. Vital signs include temperature, pulse, respiratory rate, weight, and blood pressure. 
Height will be measured at Visit 1 only.
8.3.3
Liver Function Tests
Liver function tests will be performed as specified in the SoA to check for potential liver 
toxicity in the combination therapy.
8.3.4
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA (Section 1.3). Clinically significant abnormal findings should 
be recorded as medical history. Additional ECGs may be performed as clinically necessary.
8.3.5
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
 
 
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•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc., the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
 
 
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•
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
 
 
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Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to Sponsor
Consent to 
Randomization
Randomization 
Through 
Protocol-specified 
Follow-up Period
After the 
Protocol-specified 
Follow-up Period
NSAE
Report if:
-
due to protocol-
specified 
intervention
-
causes exclusion
-
participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE including cancer 
and overdose
Report if:
-
due to protocol-
specified 
intervention
-
causes exclusion
-
participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
-
intervention
related.
(Follow ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/lactation 
exposure
Report if:
-
due to 
intervention
-
causes exclusion
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 
24 hours of 
learning of 
event
ECI (requires
regulatory reporting)
Report if:
-
due to 
intervention
-
causes exclusion
Report:
-
Potential DILI
-
Require 
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
ECI (Does not require 
regulatory reporting)
Report if:
-
due to 
intervention
-
causes exclusion
Report:
-
non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
Abbreviations: ECI = event of clinical interest; DILI = drug-induced liver injury; NSAE = nonserious adverse 
event; SAE = serious adverse event.
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
 
 
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in Section 8.2 will not be reported to the Sponsor, as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 

An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for vicriviroc of ≥600 mg/day (≥2 times the maximum indicated dose) or for 
pembrolizumab of ≥1000 mg (≥5 times the indicated dose). No specific information is 
available on the treatment of overdose of vicriviroc and pembrolizumab. In the event of 
overdose, vicriviroc and pembrolizumab should be discontinued and the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
 
 
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8.6
Pharmacokinetics
The decision as to which plasma and/or urine samples collected will be assayed for 
evaluation of PK will be collaboratively determined by the Sponsor (eg, samples at lower 
doses may not be assayed if samples at higher doses reveal undetectable drug 
concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an 
exploratory manner for metabolites and/or additional pharmacodynamic markers.
8.6.1
Blood Collection for PK
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Procedure Manual. PK samples should be drawn according to the PK collection schedule 
for all participants. Every effort should be taken to collect samples at 30 days after end of 
study treatment.
8.6.2
Blood Collection for Antipembrolizumab Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Procedure Manual. Antipembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for all participants (SoA). Every effort should be taken to 
collect samples at 30 days after end of study treatment for ADA. Simultaneous PK sampling 
is required for interpretation of ADA analysis.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover DNA for future research
•
Leftover RNA from blood for RNA analysis
•
Leftover stool and/or its derivatives from stool for biomarker analysis
•
Leftover main study tumor tissue
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample will be drawn for CCR5 genotyping and for planned 
analysis of the association between genetic variants in DNA and drug response. If the 
IRB/IEC does not approve of the planned analysis of the association between DNA variation 
and drug response, or if there is a local law or regulation prohibiting the same, data analysis 
will be limited to CCR5. Leftover extracted DNA will be stored for future biomedical 
research if the participant signs the future biomedical research consent.
 
 
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Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the operations/laboratory manual.
8.10
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for genetic analysis
•
Blood for immune profiling (immune-phenotyping)
•
Blood for serum cytokines
•
Blood for RNA analysis
•
Stool for biomarker analysis
•
Archival and/or newly obtained tissue collection
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the operations/laboratory manual].
8.11
Health Economics Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics are not evaluated in this study.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.12.1
Screening
Approximately 28 days before treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1. 
Screening procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained before performing any protocol-specific procedure. Results
of a test performed before the participant signs the ICF as part of routine clinical
management are acceptable in lieu of a screening test if performed within the specified time
frame. Screening procedures are to be completed within 1 day before the first dose of study
treatment except for the following:
•
Laboratory tests are to be performed within 10 days before the first dose of study
treatment. An exception is hepatitis testing, which may be done up to 28 days before the
first dose of study treatment.
 
 
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•
Evaluation of ECOG is to be performed within 7 days before date of
allocation/randomization.
•
For WOCBP, a urine or serum pregnancy test will be performed within 72 hours before
the first dose of study treatment. If urine pregnancy results cannot be confirmed as
negative, a serum pregnancy test will be required (performed by the local study site
laboratory).
•
Archival tumor sample collection is not required to be obtained within 28 days before the
first dose of study treatment. Newly obtained tumor tissue may be obtained within
90 days of treatment initiation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.12.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 9.1.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in the SoA. Additional details regarding participant withdrawal and discontinuation 
are presented in Section 8.1.9.
8.12.4
Poststudy
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 (+14) days 
after the last dose of trial intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
Imaging Follow-up
Participants who discontinue study treatment for a reason other than disease progression per 
RECIST 1.1/iRECIST will move into the Follow-Up Phase and should be assessed as 
outlined in the SoA (Section 1.3) to monitor disease status. The Sponsor may request survival 
status to be assessed at additional time points during the course of the study (not to exceed 
approximately 12 weeks). Every effort should be made to collect information regarding 
 
 
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disease status until the start of new anticancer therapy, disease progression, death, or end of 
study. Information regarding poststudy anticancer treatment will be collected if new 
treatment is initiated.
Survival Follow-up
Participants who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested prior to an 
efficacy interim analysis, and/or final analysis. All participants who are not known to have 
died prior to the request for these additional survival status time points will be contacted at 
that time.
8.12.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested before, but not limited to, an interim 
and/or final analysis. Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor-defined time period will be 
contacted for their survival status (excluding participants that have a previously recorded 
death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental statistical analysis plan (sSAP).
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but before final database lock, will be documented in 
the sSAP as needed and referenced in the clinical study report (CSR) for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full details are
provided in the Statistical Analysis Plan (SAP), Section 9.2 through Section 9.12.
 
 
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Study Design Overview
Phase 2 trial of vicriviroc in combination with pembrolizumab 
in participants with advanced/metastatic MSS CRC.
Analysis Populations
Efficacy (Primary and Secondary): Full Analysis Set (FAS)
Safety (Primary): All Participants as Treated (APaT) and DLT 
evaluable population
PK (Secondary): Per-Protocol (PP)
Primary Endpoint(s)
Efficacy: objective response is a confirmed CR or PR.
Safety: 
DLT
AE
Discontinuing study treatment due to an AE
Secondary Endpoint(s)
Objective response is a confirmed CR or PR.
PFS is the time from the first dose of study intervention to the 
first documented disease progression or death due to any 
cause, whichever occurs first.
OS is the time from the first dose of study intervention to 
death due to any cause.
PK parameters of vicriviroc in combination with 
pembrolizumab, including AUC in nM·hr, Cmax in nM, and 
Ctrough in nM·hr
Statistical Methods for 
Efficacy/ 
Pharmacokinetic 
Analyses
ORR will be estimated by treatment arm using an exact 
method based on the binomial distribution together with its 
95% confidence interval (CI) (Clopper-Pearson interval).
Methods for the secondary efficacy analyses will be
documented in an sSAP.
PK parameters of study interventions will be summarized by 
planned visit and time for each arm.
Treatment Assignment
Participants will be randomized centrally through IRT to the 
2 arms (doses) of vicriviroc in combination with
pembrolizumab.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided by treatment arm for the 
safety endpoints as appropriate (eg, counts, percentages).
 
 
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Interim Analyses
An interim safety analysis is planned for each arm after the 
first 10 evaluable participants have finished at least 1 cycle of 
therapy in a given arm.
Additional interim safety analysis may be conducted to enable 
future trial planning at the Sponsor’s discretion, and data will 
be examined on a continuous basis to allow for timely 
decisions.
Multiplicity
No multiplicity adjustment is planned in this Phase 2 trial.
Sample Size and Power 
The total sample size is 20 participants per arm. No formal 
hypothesis testing will be conducted.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the
Clinical Biostatistics department of the Sponsor.
The trial is open-label (ie, participants, investigators, and Sponsor personnel will be aware of
participant treatment assignment after each participant is enrolled and treatment is assigned). 
Allocation to treatment will be randomized.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3 – Objectives/Hypotheses
and Endpoints.
9.4
Analysis Endpoints
9.4.1
Efficacy/Pharmacokinetics Endpoints
ORR as assessed by the investigator based on RECIST 1.1 is the primary endpoint. ORR as
assessed by the investigator based on iRECIST, PFS as assessed by the investigator based on
RECIST 1.1 and iRECIST, and OS are the secondary endpoints in this study. A description 
of efficacy measures is provided in Section 8.2 – Efficacy Assessments.
ORR is defined as the proportion of participants who achieve a confirmed CR or PR.
PFS is defined as the time from the first dose of study intervention to the first documented 
disease progression or death due to any cause, whichever occurs first.
OS is defined as the time from the first dose of study intervention to death due to any cause.
The PK endpoints include serum concentrations of vicriviroc, as well as derived PK 
parameters.
 
 
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9.4.2
Safety Endpoints
The primary safety endpoint is the number and proportion of participants with DLTs, AEs, 
and discontinuation of study treatment due to AEs. In addition, safety and tolerability will be 
assessed by clinical review of all relevant parameters including AEs, laboratory tests, and 
vital signs.
A description of safety measures is provided in Section 8.3 – Safety.
9.4.3
Exploratory Endpoints
Exploratory endpoints include:
•
Antipembrolizumab antibody level
•
Germline genetic variation, genetic (DNA) mutations from tumor, tumor and blood 
ribonucleic acid (RNA) variation, proteomics and IHC, and other biomarkers
•
Gut microbiome composition, response, development of irAEs, and changes in 
microbiome diversity
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The FAS population will be used for the analyses of efficacy data in this study. It consists of 
all participants with a baseline scan that demonstrate measurable disease by the investigator’s 
assessment and who are administered at least 1 dose of study intervention.
9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT
population consists of all participants who receive at least 1 dose of study intervention.
The DLT evaluable population includes APaT participants that meet the criteria for DLT
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See
Section 6.6.2.1 for details.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of
study treatment is required for inclusion in the analysis of each specific parameter. To assess
change from baseline, a baseline measurement is also required.
9.5.3
Pharmacokinetic Analysis Populations
The PP population will be used for the analysis of PK data in this study. The PP population 
consists of the subset of participants who comply with the protocol sufficiently to ensure that 
their data will be likely to exhibit the effects of treatment, according to the underlying 
 
 
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scientific model. Compliance includes such considerations as exposure to treatment, 
availability of measurements, and the absence of major protocol violations. Any participants 
or data values excluded from the analyses will be identified, along with the reasons for 
exclusion, in the CSR. At the end of the study, all participants who were compliant with the 
study procedures and have available data from at least 1 treatment will be included in the PP 
analysis dataset.
9.6
Statistical Methods
This section describes the statistical methods that address the primary objectives. Methods
related to secondary and exploratory objectives will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analysis
ORR will be estimated by treatment arm using an exact method based on the binomial 
distribution together with its 95% CI (Clopper-Pearson interval).
Methods for the secondary efficacy analyses will be documented in the sSAP.
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters,
including DLTs, AEs, SAEs, laboratory tests, vital signs, and physical examinations.
DLT and AEs will be summarized by counts and frequencies for each arm. Laboratory tests, 
vital signs, and other safety endpoints will be summarized as appropriate (eg, counts, 
percentages).
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
Demographic variables and baseline characteristics will be summarized.
Pharmacokinetic Analysis
The PK parameters of the study interventions will be summarized by planned visit and time 
for each arm separately.
 
 
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9.7
Interim Analyses
An interim safety analysis is planned for each arm after the first 10 evaluable participants 
have finished at least 1 cycle of therapy in a given arm. If no more than 3 participants of the 
first 10 evaluable participants have experienced DLTs during the first cycle in a given arm, 
this arm may be expanded by enrolling an additional 10 participants. Otherwise, this arm 
may be terminated for safety concern.
Additional interim safety analysis may be conducted to enable future trial planning at the 
Sponsor’s discretion, and data will be examined on a continuous basis to allow for timely 
decisions.
9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
The probability of observing more than 3 DLTs with 10 participants in each arm is shown in 
Table 8. When the true DLT incidence is 20%, there is a 12% chance to observe more than 
3 DLTs with 10 participants in 1 arm.
The hypothetical ORR estimates and the CI (Clopper-Pearson interval [Clopper, C. J. 1934]) 
based on a sample size of 20 are shown in Table 9. Because of the small sample size, even an 
ORR as high as 20% (4 of 20) could be coming from a true signal as low as 7%. A higher 
ORR, such as 7 of 20, would be more indicative of a true response rate above 16%.
Table 8
Probability of Observing More Than 3 DLTs with 10 Participants in Each Arm
True DLT Incidence
Probability of Observing More Than 3 DLTs
10%
1.3%
15%
5.0%
20%
12.1%
25%
22.4%
30%
35.0%
Abbreviation: DLT = dose-limiting toxicity.
 
 
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Table 9
CI of the True ORR Under Different Hypothetical Number of Observed Response 
Scenarios With 20 Participants in Each Arm
Hypothetical Number of Responses
(CR or PR)
ORR
95% CI of ORR
2
10%
(0.1%, 24.9%)
3
15%
(1.2%, 31.7%)
4
20%
(3.2%, 37.9%)
5
25%
(5.7%, 43.7%)
6
30%
(8.7%, 49.1%)
7
35%
(11.9%, 54.3%)
8
40%
(15.4%, 59.2%)
9
45%
(19.1%, 63.9%)
10
50%
(23.1%, 68.5%)
Abbreviations: CI = confidence interval; CR = complete response; ORR = objective response rate; PR = partial 
response.
9.10
Subgroup Analyses
Efficacy endpoints will be analyzed by arm. Additional subgroup analyses (eg, by age, 
gender, and race) may be conducted as needed and will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study interventions will be collected during the trial. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
 
 
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.6
Compliance with Law, Audit, and Debarmen
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, 
rules and regulations relating to the conduct of the clinical study. The Code of Conduct, a 
collection of goals and considerations that govern the ethical and scientific conduct of 
clinical investigations sponsored by MSD, is provided in this appendix under the Code of 
Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
 
 
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10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
 
 
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10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 10 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 10
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
Platelet count
ALT
Protein
PT/INR
WBC count with differentiald:
Neutrophils
AST
Specific gravity
aPTT or PTT
Bicarbonate
Microscopic 
examination, if 
abnormal results are 
noted
Total T3 (or FT3), total T4 
(or FT4), and TSHb,c
Lymphocytes
Calcium
Monocytes
Chloride
Eosinophils
Creatinine
Basophils
Glucose
RBC count
Phosphorus
RBC indices:
Potassium
MCV
Sodium
MCH
Total bilirubin
% Reticulocytes
Direct bilirubin
Total protein
Blood urea nitrogen
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate 
aminotransferase; FT3 = free triiodothyronine; FT4 = free thyroxine; INR = international normalized ratio; MCH = mean 
corpuscular hemoglobin; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin time; 
RBC = red blood cell; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WBC = white blood cell; 
WOCBP = women of childbearing potential.
a
Perform on WOCBP only 72 hours before Day 1 of Cycle 1. Pregnancy tests must be repeated before every cycle if 
required or as specified per local regulatory guidance.
b
T3 is preferred; if not available, free T3 may be tested.
c
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Procedure Manual.
d
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent, or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
•
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.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
 
 
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Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.7 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
 
 
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d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
 
 
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10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.03. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs//worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL)
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL
-
Grade 4: Life threatening consequences; urgent intervention indicated
-
Grade 5: Death related to AE
 
 
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite 
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
-
(Note: This criterion is not applicable if: (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; (3) the study is a single-dose drug study; or (4) Sponsor’s 
product(s) is/are only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
 
 
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-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose drug study); or (3) Sponsor’s product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
IRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the 
AE onset relative to the administration of the Sponsor’s product is reasonable. The 
AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the AE 
is more likely explained by another cause than the Sponsor’s product. (Also entered 
for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
 
 
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•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1  for reporting time requirements.
 
 
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•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
This section is not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
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 no menses for 12 months without an alternative 
medical cause.
-
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with 2 FSH measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
10.5.2
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol-defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
 
 
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•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhea method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception, as described in 
Table 11, during the protocol-defined time frame in Section 5.1.
 
 
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Table 11
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●Combined (estrogen- and progestogen-containing) hormonal contraceptionb,c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●Progestogen only hormonal contraceptionb,c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
●Progestogen- only contraceptive implantb,c
●Intrauterine hormone-releasing systemb
●Intrauterine device (IUD)
●Bilateral tubal occlusion
●Vasectomized partner
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.
●Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. 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.
Notes:
a
Use should be consistent with local regulations regarding the use of contraceptive methods for participants 
of clinical studies.
b
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
If hormonal contraception efficacy is potentially decreased due to interaction with study intervention, 
condoms must be used in addition to the hormonal contraception during the intervention period and for at 
least 120 days after the last dose of study intervention. If locally required, in accordance with Clinical Trial 
Facilitation Group (CTFG) guidelines, acceptable hormonal contraceptives are limited to those that inhibit 
ovulation.
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Following initiation of treatment additional pregnancy testing will be performed if clinically 
warranted, and/or as defined by local regulations.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research

Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition. 
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.

Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.10 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways drugs/vaccines may interact with
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.

Summary of Procedures for Future Biomedical Research.
1. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
 
 
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2. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
3. eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
4. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.

Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.

Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.

Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
 
 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.

Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.

Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.

Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.

Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.

Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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
References
−
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
−
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
−
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
−
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
This section is not applicable.
 
 
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management [see Table 6
and Figure 2]). This decision by the investigator should be based on the participant’s overall 
clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant PD
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
•
Note: the iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
 
 
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point 

Visible growth of new nontarget lesions 

The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
 
 
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in the SoA (Section 1.3).
 
 
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire trial, either before or 
after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
nontarget lesions, taken as a whole.
•
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
 
 
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living
AE
adverse event
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
ANC
absolute neutrophil count
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
AUC
area under the curve
β-HCG
β human chorionic gonadotropin
BCG
Bacillus Calmette-Guérin
CCR5
cysteine-cysteine motif chemokine receptor 5
CI
confidence interval
CIMP
CpG island methylator phenotype
CIN
chromosomal instability
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
Case Report Form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
 
 
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Abbreviation
Expanded Term
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection
EOT
end of treatment
FAS
Full Analysis Set
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
FT3
free triiodothyronine
FT4
free thyroxine
GCP
Good Clinical Practice
G-CSF
granulocyte-colony stimulating factor
GFR
glomerular filtration rate
GI
gastrointestinal
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonization
iCPD
confirmed radiographic progression
IEC
Independent Ethics Committee
IFN-α
interferon alfa
IFN-α2a
interferon alfa-2a
IHC
immunohistochemistry
IL-2
interleukin 2
IL-6
interleukin 6
INR
international normalized ratio
irAEs
immune-related adverse events
 
 
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Abbreviation
Expanded Term
IRB
Institutional Review Board
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-
based therapeutics
IRT
interactive response technology
IV
intravenous
mAb
monoclonal antibody
mCRC
metastatic colorectal cancer
MDSC
myeloid-derived suppressor cell
MMR
mismatch repair
MMR-D
mismatch repair deficient
MMR-P
mismatch repair proficient
MRI
magnetic resonance imaging
MSI
microsatellite instability
MSI-H
microsatellite instability-high
MSS
microsatellite stable
NCI
National Cancer Institute
NK
natural killer (cells)
NSAID
nonsteroidal anti-inflammatory
NSCLC
non–small cell lung cancer
ORR
objective response rate
OS
overall survival
PBPK
physiologically based PK
PD
progressive disease
PD-1
programmed cell death ligand 1
PFS
progression-free survival
PK
pharmacokinetic(s)
PO
per os (by mouth)
PP
Per-protocol
PR
partial response
PT
prothrombin time
 
 
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Abbreviation
Expanded Term
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
once daily
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
ribonucleic acid
SAE
serious adverse event
SoA
schedule of activities
sSAP
supplemental statistical analysis plan
T3
triiodothyronine
T4
thyroxine
TAM
tumor-associated macrophage
TB
tuberculosis
TNF-α
tumor necrosis factor alpha
Tregs
regulatory T cells
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
WOCBP
woman/women of childbearing potential
 
 
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11
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[Seymour, L., et al 2017]
Seymour L, Bogaerts J, Perrone A, Ford R, 
Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in 
trials testing immunotherapeutics. Lancet 
Oncol. 2017 Mar;18(3):e143-52.
04P9RV
[American Cancer Society 
2017]
American Cancer Society. Colorectal cancer 
facts & figures 2017-2019 [Internet]. Atlanta 
(GA): American Cancer Society; 2017. 
Available from: 
https://www.cancer.org/content/dam/cancer-
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statistics/colorectal-cancer-facts-and-
figures/colorectal-cancer-facts-and-figures-
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04X63W
[Arnold, M., et al 2017]
Arnold M, Sierra MS, Laversanne M, 
Soerjomataram I, Jemal A, Bray F. Global 
patterns and trends in colorectal cancer 
incidence and mortality. Gut. 2017;66:683-
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04X5MY
[Le, D. T., et al 2015]
Le DT, Uram JN, Wang H, Bartlett BR, 
Kemberling H, Eyring AD, et al. PD-1 
blockade in tumors with mismatch-repair 
deficiency. N Engl J Med. 2015 Jun 
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04YCNZ
[Halama N, Zoernig I, 
Berthel A, Kahlert C, Klupp 
F, Suarez-Carmo 2016]
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Klupp F, Suarez-Carmona M, et al.  Tumoral 
Immune Cell Exploitation in Colorectal 
Cancer Metastases Can Be Targeted 
Effectively by Anti-CCR5 Therapy in 
Cancer Patients.  Cancer Cell. 2016 Apr 
11;29(4):587-601.
04XS33
[Weitzenfeld P, Ben-Baruch 
A 2014]
Weitzenfeld P, Ben-Baruch A.  The 
chemokine system, and its CCR5 and 
CXCR4 receptors, as potential targets for 
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[Velasco-Velazquez, M., et 
al 2012]
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M, Pestell TG, Ertel A, Lisanti MP, et al. 
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04X8LC
[Ochoa-Callejero, L., et al 
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Ochoa-Callejero L, Perez-Martinez L, 
Rubio-Mediavilla S, Oteo JA, Martinez A, 
Blanco JR. Maraviroc, a CCR5 antagonist, 
prevents development of hepatocellular 
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04X5F2
[Mencarelli, A., et al 2013]
Mencarelli A, Graziosi L, Renga B, Cipriani 
S, D'Amore C, Francisci D, et al. CCR5 
antagonism by maraviroc reduces the 
potential for gastric cancer cell 
dissemination. Transl Oncol. 2013 
Dec;6(6):784-93.
04X5DF
[Wolchok, J. D., et al 2009]
Wolchok JD, Hoos A, O'Day S, Weber JS, 
Hamid O, LebbéC, et al. Guidelines for the 
evaluation of immune therapy activity in 
solid tumors: immune-related response 
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