Phase 1b Open-label Study of MK-7162 in Combination With Pembrolizumab (MK-3475) +/- Other Therapies in Participants With Advanced Solid Tumors
Phase: PHASE1
Conditions: Solid Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
Phase 1b Open-label Study of MK-7162 in Combination with 
Pembrolizumab (MK-3475) +/- other therapies in Participants 
with Advanced Solid Tumors
21-Jul-2020
NCT03364049

Product:  MK-7162 
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Confidential
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., 
WHITEHOUSE STATION, NJ, U.S.A.
Protocol Title: Phase 1b Open-label Study of MK-7162 in Combination with 
Pembrolizumab (MK-3475) +/- other therapies in Participants with Advanced Solid Tumors
Protocol Number: 002-02
Compound Number: MK-7162
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:  136641
EudraCT NUMBER: 2017-000418-49
Approval Date:  21 July 2020
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical trial 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
-02
21-JUL-2020
The overall rationale for the amendment is to allow participants who have 
completed the study to be discontinued and enrolled in a pembrolizumab 
extension study.
-01
09-NOV-2017
Revisions/updates incorporated based on feedback from regulatory agency and 
sites.
-00
02-OCT-2017
Original protocol
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment -02
Overall Rationale for the Amendment:
The overall rationale for the amendment is to allow participants who have completed the study to be discontinued and enrolled in a 
pembrolizumab extension study. 
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
1  Synopsis
5.1.2  Study Diagram
5.3  Beginning and End of Study 
Definition
9.1.7  Assignment of 
Treatment/Randomization 
Number
Language was added to allow participants who have completed 
the study to be discontinued and enrolled in a pembrolizumab 
extension study.
This change will allow this 
study to be closed.
 
 
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Table of Contents
DOCUMENT HISTORY ....................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 4
1.
Synopsis...................................................................................................................... 14
2.
Schedule of Activities (SoA)..................................................................................... 17
Dose Escalation and Confirmation...................................................................... 17
3.
Introduction............................................................................................................... 26
Study Rationale..................................................................................................... 26
Background ........................................................................................................... 26
Pharmaceutical and Therapeutic Background .................................................... 26
MK-7162 Pharmaceutical and Therapeutic Background............................. 26
Pembrolizumab 
(MK-3475) 
Pharmaceutical 
and 
Therapeutic 
Background.................................................................................................. 28
Preclinical Trials ................................................................................................. 29
MK-7162 Preclinical Trials ......................................................................... 29
Ongoing Clinical Trials....................................................................................... 29
MK-7162 Ongoing Clinical Trials............................................................... 29
Pembrolizumab (MK-3475) Ongoing Clinical Trials.................................. 29
Benefit/Risk Assessment....................................................................................... 29
4.
Objectives/Hypotheses and Endpoints.................................................................... 30
5.
Study Design.............................................................................................................. 31
Overall Design....................................................................................................... 31
Dose Escalation and Confirmation ..................................................................... 31
Study Diagram .................................................................................................... 34
Number of Participants........................................................................................ 34
Beginning and End of Study Definition.............................................................. 34
Clinical Criteria for Early Trial Termination...................................................... 35
Scientific Rationale for Study Design.................................................................. 35
Rationale for Endpoints ...................................................................................... 35
 
 
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Efficacy Endpoints....................................................................................... 35
Response Rate Assessed by RECIST version 1.1................................. 36
Response Rate Assessed by Immune-based RECIST (iRECIST)........ 36
Safety Endpoints.......................................................................................... 36
Pharmacokinetic Endpoints ......................................................................... 37
Pharmacodynamic Endpoints....................................................................... 37
Kynurenine (KYN):Tryptophan (TRP) ................................................ 37
Target Engagement ........................................................................ 37
Anti-Drug Antibodies (ADA)...................................................................... 37
Planned Exploratory Biomarker Research................................................... 37
Germline Genetic Analyses .................................................................. 37
Tumor Genetic Analyses ...................................................................... 38
Tumor and Blood Ribonucleic Acid Analyses ..................................... 38
Proteomic Biomarkers and Immunohistochemistry (IHC)................... 38
Peripheral Blood Mononuclear Cell (PBMC) Phenotypic Analysis .... 38
Other Blood-derived Biomarkers.......................................................... 39
Future Biomedical Research........................................................................ 39
Justification for Dose............................................................................................ 39
Rationale for Starting and Maximum Dose of MK-7162 ................................... 39
Maximum Dose of MK-7162.............................................................................. 40
Rationale for Dose Interval and Escalation Increments...................................... 41
Dose Finding Using a Modified Toxicity Probability Interval Design........ 41
6.
Study Population....................................................................................................... 43
Inclusion Criteria.................................................................................................. 44
Exclusion Criteria................................................................................................. 46
Lifestyle Restrictions ............................................................................................ 48
Dietary Restrictions ............................................................................................ 48
Contraception...................................................................................................... 48
Pregnancy............................................................................................................ 49
Use in Nursing Women....................................................................................... 49
Screen Failures...................................................................................................... 49
Participant Replacement Strategy ...................................................................... 49
 
 
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7.
Treatments................................................................................................................. 50
Treatments Administered .................................................................................... 50
Dose Modification (Escalation/Titration/Other)................................................ 52
Dose Administration/Escalation/Cohort Expansion ........................................... 52
Dose Administration (Preparation).............................................................. 52
Definition of Dose Limiting Toxicity................................................................. 52
Timing of Dose Administration.......................................................................... 53
Timing of Administration for MK-7162...................................................... 53
Timing of Administration for Pembrolizumab ............................................ 53
Guidelines for Dose Modification due to Adverse Events ................................. 54
Dose Modification for MK-7162................................................................. 54
Dose Modification for Pembrolizumab ....................................................... 56
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................... 56
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................... 60
Other allowed dose interruption(s) for pembrolizumab ....................... 61
Method of Treatment Assignment....................................................................... 61
Stratification........................................................................................................ 61
Blinding.................................................................................................................. 62
Preparation/Handling/Storage/Accountability .................................................. 62
Dose Preparation................................................................................................. 62
Handling, Storage and Accountability................................................................ 62
Treatment Compliance......................................................................................... 62
Concomitant Therapy........................................................................................... 63
Acceptable Concomitant Medication.................................................................. 63
Prohibited Concomitant Medications.................................................................. 63
Supportive Care .................................................................................................. 64
Treatment After the End of the Study................................................................ 64
Clinical Supplies Disclosure................................................................................. 64
8.
Discontinuation/Withdrawal Criteria..................................................................... 64
Discontinuation of Study Treatment................................................................... 64
Withdrawal from the Study................................................................................. 65
 
 
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Lost to Follow Up.................................................................................................. 66
9.
Study Assessments and Procedures......................................................................... 66
Administrative and General Procedures ............................................................ 67
Informed Consent................................................................................................ 67
General Informed Consent........................................................................... 67
Consent and Collection of Specimens for Future Biomedical Research ..... 67
Inclusion/Exclusion Criteria ............................................................................... 67
Participant Identification Card............................................................................ 68
Medical History .................................................................................................. 68
Prior and Concomitant Medications Review ...................................................... 68
Prior Medications......................................................................................... 68
Concomitant Medications............................................................................ 68
Assignment of Screening Number...................................................................... 68
Assignment of Treatment/Randomization Number............................................ 69
Treatment Administration................................................................................... 69
Timing of Dose Administration................................................................... 69
Timing of Dose Administration for MK-7162 ..................................... 69
Timing of Dose Administration for Pembrolizumab............................ 69
Withdrawal/Discontinuation............................................................................... 69
Withdrawal From Future Biomedical Research .......................................... 70
Participant Blinding/Unblinding......................................................................... 70
Calibration of Critical Equipment....................................................................... 70
Efficacy Assessments ............................................................................................ 70
Tumor Imaging and Assessment of Disease....................................................... 70
Initial Tumor Imaging......................................................................................... 71
Tumor Imaging During the Study....................................................................... 71
End of Treatment and Follow-up Tumor Imaging.............................................. 72
RECIST 1.1 Assessment of Disease ................................................................... 72
iRECIST 1.1 Assessment of Disease.................................................................. 72
Medical Photography (cutaneous lesions) .......................................................... 74
Eastern Cooperative Oncology Group (ECOG) Performance Scale .................. 74
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events..................................................................................................................... 75
 
 
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Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information.................................................................................... 75
Method of Detecting AE, SAE and Other Reportable Safety Events................. 77
Follow-up of AE, SAE and Other Reportable Safety Event Information........... 77
Regulatory Reporting Requirements for SAE .................................................... 77
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as AEs or SAEs................................................................................................... 77
Pregnancy and Exposure During Breastfeeding ................................................. 78
Events of Clinical Interest (ECI)......................................................................... 78
Treatment of Overdose......................................................................................... 78
Safety...................................................................................................................... 79
Physical Examinations........................................................................................ 79
Full Physical Exam ...................................................................................... 79
Directed Physical Exam............................................................................... 79
Vital Signs........................................................................................................... 79
Electrocardiograms ............................................................................................. 80
Clinical Safety Laboratory Assessments............................................................. 80
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 80
Pregnancy Test............................................................................................. 81
Pharmacokinetics.................................................................................................. 81
Blood Collection for Plasma for MK-7162 Pharmacokinetics........................... 81
Blood Collection for MK-7162 Metabolites....................................................... 81
Pharmacodynamics............................................................................................... 81
Future Biomedical Research Sample Collection................................................ 82
Biomarkers ............................................................................................................ 82
Planned Genetic Analysis Sample Collection..................................................... 82
Blood Collection for Anti-Drug Antibodies ....................................................... 82
Visit Requirements ............................................................................................... 82
Screening............................................................................................................. 82
Treatment Period................................................................................................. 83
Discontinued Participants Continuing to be Monitored in the Study ................. 83
Safety Follow-up Visit................................................................................. 84
 
 
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Survival Follow-up Visits............................................................................ 84
Survival Status .................................................................................................... 84
10.
Statistical Analysis Plan ........................................................................................... 84
Statistical Analysis Plan Summary ..................................................................... 85
Responsibility for Analyses/In-House Blinding ................................................. 86
Hypotheses/Estimation ......................................................................................... 86
Analysis Endpoints ............................................................................................... 86
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 86
Safety Endpoints ................................................................................................. 87
Analysis Populations............................................................................................. 87
Safety Analysis Populations ............................................................................... 87
Pharmacokinetic Analysis Populations............................................................... 87
Efficacy Populations ........................................................................................... 87
Statistical Methods................................................................................................ 87
Statistical Methods for Efficacy Analysis........................................................... 88
Statistical Methods for Safety Analysis.............................................................. 88
Summaries of Baseline Characteristics, Demographics and Other Analyses..... 88
Demographic and Baseline Characteristics ................................................. 88
Pharmacokinetic and Pharmacodynamic Modeling Analysis...................... 88
Interim Analyses ................................................................................................... 88
Multiplicity ............................................................................................................ 88
Sample Size and Power Calculations .................................................................. 88
Subgroup Analyses ............................................................................................... 89
Compliance (Medication Adherence).................................................................. 89
Extent of Exposure................................................................................................ 89
11.
References.................................................................................................................. 90
12.
Appendices................................................................................................................. 94
Appendix 1: Abbreviations and Trademarks .................................................... 94
Appendix 2: Clinical Laboratory Tests .............................................................. 98
Appendix 3: Study Governance Considerations.............................................. 100
Merck Code of Conduct for Clinical Trials .................................................................. 100
Financial Disclosure...................................................................................................... 102
 
 
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Data Protection.............................................................................................................. 102
Confidentiality of Data ................................................................................................. 102
Confidentiality of Participant Records.......................................................................... 102
Confidentiality of IRB/IEC Information....................................................................... 103
Publication Policy......................................................................................................... 103
Compliance with Trial Registration and Results Posting Requirements...................... 103
Compliance with Law, Audit and Debarment .............................................................. 103
Data Quality Assurance ................................................................................................ 104
Source Documents ........................................................................................................ 105
Study and Site Closure.................................................................................................. 105
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................. 106
Definition of AE ........................................................................................................... 106
Definition of SAE ......................................................................................................... 107
Additional Events reported in the same manner as SAE .............................................. 108
Recording AE and SAE ................................................................................................ 108
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............... 112
Appendix 5: Contraceptive Guidance and Pregnancy Testing ...................... 113
Contraception Requirements......................................................................................... 113
Pregnancy Testing......................................................................................................... 115
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research........................................................................................... 116
Appendix 7:  Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................. 120
 
 
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LIST OF TABLES
Table 1
Dose-finding Rules per mTPI Design........................................................................... 43
Table 2
Adequate Organ Function Laboratory Values.............................................................. 45
Table 3
Study Treatment............................................................................................................ 51
Table 4
MK-7162 Dose Modification and Treatment Discontinuation Guidelines for 
Drug-Related Adverse Events...................................................................................... 55
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.......................................................................... 57
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines..................................................................................................................... 60
Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive Disease ........ 74
Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events ............................................................................................. 76
Table 9
Protocol-Required Safety Laboratory Assessments ..................................................... 99
Table 10 Contraceptive Methods............................................................................................... 114
 
 
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LIST OF FIGURES
Figure 1 Study Diagram .............................................................................................................. 34
 
 
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1. Synopsis
Protocol Title:  
Phase 1b Open-label Study of MK-7162 in Combination with Pembrolizumab (MK-
3475) +/- other therapies in Participants with Advanced Solid Tumors
Short Title: 
Phase 1b MK-7162 in combinations with pembrolizumab (MK-3475) +/- other therapies 
in participants with advanced solid tumors
Objectives/Hypotheses and Endpoints:
Male/female participants of at least 18 years of age with advanced/metastatic solid tumors 
will be enrolled in this trial.
Objective
Endpoint
Primary
1. To determine the safety and 
tolerability and to establish a 
preliminary recommended Phase 2 
dose (RP2D) of MK-7162
administered in combination with 
pembrolizumab

Dose-limiting toxicity (DLT)

Adverse events (AEs)

Discontinuation of study treatment due 
to an AE
Secondary
1. To evaluate the pharmacokinetics 
(PK) of MK-7162 administered 
orally as monotherapy and in 
combination with pembrolizumab 
intravenous (IV) infusion

PK parameters, including area under the 
curve (AUC), minimum observed 
combination (Cmin), and maximum 
observed combination (Cmax)
2. To evaluate pharmacodynamics
(PD) of MK-7162 alone and in 
combination with pembrolizumab
through measurement of kynurenine 
(KYN) and tryptophan (TRP) levels

KYN and TRP will be measured as PD 
biomarkers of Indoleamine-2,3-
dioxygenase-1 (IDO1) inhibition
3. To evaluate the objective response 
rate (ORR) to MK-7162 in 
combination with pembrolizumab

ORR based on Response Evaluation 
Criteria In Solid Tumors version 1.1 
(RECIST 1.1) and immune-based 
RECIST (iRECIST) as assessed by the 
investigator
 
 
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Overall Design:
Trial Phase
Phase 1b
Clinical Indication
Treatment of participants with advanced solid tumors
Population
Participants with histologically or cytologically 
confirmed advanced solid tumors by pathology report 
who have received or been intolerant to all treatment 
known to confer clinical benefit will be enrolled.
Trial Type
Interventional
Type of Design
This is an open-label, multicenter, nonrandomized dose 
escalation and confirmation study of MK-7162 in
combination with pembrolizumab.
Type of Control
No treatment control
Trial Blinding
Unblinded open-label
Estimated Duration 
of Trial
The Sponsor estimates that the trial will require 
approximately 2 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related phone call or visit.
Number of Participants:
Approximately 40 participants will be enrolled in the dose escalation and confirmation 
phase of this trial. Enrollment of additional participants in expansion cohorts will be 
specified in a future protocol amendment.
 
 
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Treatment Groups and Duration:
Treatment Groups
Participants will be allocated via Interactive voice response 
system/integrated web response system (IVRS/IWRS) to dose-level 
cohorts of MK-7162, administered orally (PO). MK-7162 will be 
administered as monotherapy once a day (QD) every day of each 
21-day (3-week) cycle. Starting with treatment Cycle 2 until 
treatment Cycle 36, participants will receive MK-7162 daily QD in 
combination with pembrolizumab 200 mg IV every 3 weeks. Each
treatment cycle is 3 weeks.
The study will follow the modified toxicity probability interval 
(mTPI) method (Section 5.5.3.1) to identify a preliminary RP2D, 
maximum tolerated dose (MTD) and/or maximum administered 
dose (MAD) of MK-7162 in combination with pembrolizumab.
The dose limiting toxicity (DLT) evaluation period will be 2 cycles 
(6 weeks/42 days).
Upon identification of the preliminary RP2D of MK-7162 for use 
in combination with pembrolizumab, additional participants with 
solid tumors will be enrolled in the dose expansion phase of this 
trial. Participants in the expansion phase of this trial will receive 
MK-7162 in combination with pembrolizumab as dual therapy or 
in combination with additional chemotherapeutic or immune-
modulatory agents. The dose expansion phase of this trial will be 
initiated through an amendment to this protocol.
Duration of 
Participation
The participant duration in the trial is approximately 2 years from 
the time the participant signs the Informed Consent Form (ICF)
through the final contact.
After a screening phase of up to 28 days, each participant will 
receive assigned treatment for up to 36 treatment cycles 
(approximately 2 years). Treatment may continue until 1 of the 
following occurs: disease progression, unacceptable AEs, 
intercurrent illness that prevents further administration of 
treatment, investigator decision to withdraw the participant, 
participant withdraws consent, pregnancy of the participant, 
noncompliance with trials treatment or procedure requirements, 
or administrative reasons requiring cessation of treatment.
After the end of treatment, each participant will be followed for 
the occurrence of AEs and spontaneously reported pregnancy as 
described in Section 9.3.
Once the participant has achieved the study objective or the study 
has ended, the participant will be discontinued from this study 
and may be enrolled in an extension study to continue protocol-
defined assessments and treatment.
A list of abbreviations used in this document can be found in Appendix 1.
 
 
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2. Schedule of Activities (SoA)
Dose Escalation and Confirmation
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Administrative Procedures
Informed Consent
Form (ICF)
X
• Written consent must be obtained prior to 
performing any protocol-specific procedures.
• An ICF signed >28 days prior to C1D1 does 
not need to be replaced.
Informed Consent 
for Future 
Biomedical 
Research (FBR) 
(optional)
X
Participant 
Identification Card
X
Inclusion/Exclusio
n Criteria
X
Demographics and 
Medical History
X
Prior Medication 
and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
 
 
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Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Disease Details and 
Prior Oncology 
Treatment History
X
MK-7162 
Administration and 
Dispensing
X
X
X
X
X
• Participants are to be dosed within 3 days of 
allocation.  
• All treatment visits should follow an 
overnight fast. Some PK and PD samples must
to be obtained in the morning prior to 
administration of a morning dose of MK-7162.
C1D1: Minimum 8-hour observation period 
following initial MK-7162 monotherapy dose 
on C1D1
C2D1-C36D1: For pembrolizumab 
combination treatment day visits, MK-7162 
should be administered in clinic a minimum of 
1 h prior to initiation of pembrolizumab 
infusion. 
Pembrolizumab 
Administration
X
X
X
X
C2D1: Minimum 8-hour observation period 
following completion of pembrolizumab 
infusion
New Anticancer 
Therapy Status
X
X
 
 
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Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Survival Status
X
Treatment and Safety Follow-up Phase: 
Upon Sponsor request, participants may be 
contacted for survival status at any time during 
the course of the study
Survival Follow-up Phase: After Investigator 
determined PD or start of new anticancer 
treatment.
Efficacy Procedures
Tumor Imaging: 
RECIST 1.1 and 
iRECIST Response 
Assessment
X
X
X
X
• Imaging obtained via CT, PET/CT, or MRI.
• Medical Photography for cutaneous lesions:
Obtained on the same schedule as imaging
• On-treatment visit window: ± 7 days
Screening Visit: Baseline tumor imaging 
and/or medical photography for cutaneous 
lesions should be performed within 28 days 
prior to first dose of MK-7162.
Treatment Phase: Obtain first on-treatment 
imaging at Week 9 (C4D1); Obtain subsequent 
imaging every 9 weeks thereafter.
Medical 
Photography 
(cutaneous lesions)
X
X
X
X
Safety Assessments and Procedures
AE/SAE Review
X
X
X
X
X
Full Physical 
Examination
X
X
X
Directed Physical 
Examination
X
X
X
X
X
 
 
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Protocol/Amendment No.: 002-02 
MK-7162-002-02 Final Protocol
21-Jul-2020
Confidential
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Height
X
Weight
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Consists of temperature, pulse, respiratory rate, 
blood pressure, and oxygen (02) saturation.
C1D1: Predose: Obtain within 1 h (±  30 min) 
prior to  MK-7162 dose; Postdose: Obtain 2, 4, 
6, and 8 h (± 30 min) after dosing
C2D1: Predose: Obtain within 1 hour (±  
30 min) prior to  MK-7162 dose; Postdose:
Obtain 2, 4, 6, and 8 h (± 30 min) after 
completion of MK-7162 and pembrolizumab 
dosing
C3D1 and beyond: Predose: Obtain within 1 h 
(± 30 min) prior to  MK-7162 dose. 
12-lead ECG
X
X
X
X
C1D1 Postdose: Obtain within 30 min after 
dosing
C2D1 Postdose: Obtain within 30 min after the 
end of the pembrolizumab infusion
Eastern 
Cooperative 
Oncology Group 
(ECOG) Status
X
X
X
X
X
X
X
X
Assessment to confirm eligibility must be 
performed within 7 days prior to C1D1 dosing
 
 
05JV55
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Product:  MK-7162 
21
Protocol/Amendment No.: 002-02 
MK-7162-002-02 Final Protocol
21-Jul-2020
Confidential
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Safety: Local Laboratory Evaluations
Screening: Obtain and evaluate clinical laboratory tests within 7 days prior to first dose of study 
medication (C1D1) unless otherwise specified. Tests performed prior to the participant signing IC 
as part of routine clinical management are acceptable in lieu of a screening test, if the test is 
performed within the specified time frame.
Day 1 for All Treatment Cycles: Obtain samples prior to MK-7162 and pembrolizumab dosing, 
unless otherwise specified
See Procedures Manual for details regarding collection and management of samples
HIV, Hepatitis B 
and C screen
X
Historical results are acceptable unless testing 
is required by local regulation. Tests performed 
during the 28 day screening period are 
acceptable.
Hematology
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
X
X
Lipase and 
Amylase
X
X
LDH, GGT
X
X
X
X
X
X
PT/INR and 
PTT/aPTT
X
X
X
X
X
Consider ongoing testing for participants on 
routine warfarin treatment.
Thyroid Function 
(T3, T4, TSH) 
X
X
X
X
X
Tests performed during the 28-day screening 
period are acceptable for eligibility assessment.  
Treatment Cycles: Obtain every other 
treatment cycle, starting with C1: C1, C3, C5, 
etc.; Obtain at 30-day Safety Follow-up
 
 
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Product:  MK-7162 
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Protocol/Amendment No.: 002-02 
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21-Jul-2020
Confidential
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Tumor Markers
X
X
X
X
X
X
Obtain as clinically appropriate (eg, CEA, CA-
125, CA-19-9, alpha fetoprotein, etc.)
Pregnancy Test: 
Serum β-Human 
Chorionic 
Gonadotropin (β-
hCG) or Urine Test
X
X
X
• For women of childbearing potential 
(WOCBP) only
• 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.
•  Obtain urine pregnancy test within 72 hours
prior to the first MK-7162 dose
Pharmacokinetics/Pharmacodynamics/Biomarkers
C1D1: Obtain samples predose MK-7162
C2D1 thru C36D1: Predose = prior to MK-7162 administration and prior to pembrolizumab
infusion; Postdose = subsequent to MK-7162 administration and pembrolizumab infusion
See Procedures Manual for collection and management of samples
Blood (DNA) for 
Genetic Analysis
X
Obtain predose
Peripheral Blood 
Mononuclear Cell
X
X
X
X
X
X
X
X
Screening: Obtain predose on the same day as 
the Screening tumor biopsy
C2D1: Obtain predose on the same day as the 
tumor biopsy
C3D15:  Obtain predose on the same day as the 
tumor biopsy
C3D1-C36D1: Predose
 
 
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Product:  MK-7162 
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Protocol/Amendment No.: 002-02 
MK-7162-002-02 Final Protocol
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Confidential
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Plasma for
MK-7162 
Pharmacokinetics 
(PK)
X
X
X
X
X
X
X
X
X
X
C1D1 & C1D15: Predose: Obtain following an 
overnight fast.  Postdose: 1, 2, 4, and 8 hrs.
Participant to remain fasting for 1 hr
subsequent to dosing.
C2D1: Predose: Obtain following an overnight 
fast. Obtain same day as tumor biopsy.
C2D15: Predose: Obtain following an 
overnight fast.
C3D1: Predose: Obtain following an overnight 
fast. Postdose: 1, 2, 4, and 8 hrs. Participant to 
remain fasting for 1 hr subsequent to MK-7162
dosing. 
C3D15: Predose: Obtain following an 
overnight fast. Obtain on the same day as tumor 
biopsy. 
C4D1-C36D1: Predose every 4 cycles: C4, C8, 
C12, etc. Obtain following an overnight fast.
Collection time point windows: 1 hr. (± 15 
min), 2-8 hrs. (± 30 min)
Serum for 
Pembrolizumab 
Pharmacokinetics 
(PK)
X
X
X 
X
X
X
C2D1: Predose; Postdose: 0.5 hrs. (± 5 min) 
following completion of pembrolizumab 
infusion
C3D1: Predose
C4D1-C36D1: Obtain predose every 4 cycles: 
C4, C8, C12, etc.
 
 
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Product:  MK-7162 
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Protocol/Amendment No.: 002-02 
MK-7162-002-02 Final Protocol
21-Jul-2020
Confidential
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Serum for Anti-
pembrolizumab 
Antibodies
X
X
X 
X
X
X
C2D1 and C3D1: Predose 
C4D1-C36D1: Obtain predose every 4 cycles: 
C4, C8, C12, etc.
Blood for Plasma 
Pharmacodynamic 
(PD) and  
Biomarker 
Analyses
X
X
X
X
X
X
Screening: Obtain on the same day as the 
Screening tumor biopsy. Obtain following an 
overnight fast.
C1D1 & C1D15: Predose: Obtained following
an overnight fast. Postdose: 1, 2, 4, and 8 hrs.
C2D1: Predose: Obtain following an overnight 
fast.  Obtain on the same day as tumor biopsy.  
C3D1: Predose: Obtained following an 
overnight fast. Postdose: 1, 2, 4, and 8 hrs.
C3D15: Predose: Obtain following an 
overnight fast. Obtain the same day as tumor 
biopsy. 
Collection timepoint windows: 1 hr. (± 15 
min), 2-8 hrs. (± 30 min)
Whole Blood for 
Immune profiling
X
X
X
X
X
Obtain during Screening
Treatment Cycles: Obtain predose on C1D1,
C2D1, C3D1, and C4D1
Blood for Serum 
Biomarker 
Analysis
X
X
X
X
X
X
Treatment Cycles: Obtain predose on D1 of 
every Cycle.
Blood for RNA 
Analysis
X
X
X
X
X
Treatment Cycles: Obtain predose C1D1,
C2D1, C3D1, and C6D1 only
 
 
05JV55
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Product:  MK-7162 
25
Protocol/Amendment No.: 002-02 
MK-7162-002-02 Final Protocol
21-Jul-2020
Confidential
Trial Phase:
Screening
Treatment 
(Treatment Cycle = 21 days)
End of 
Treat-
ment 
(EoT)
Post-treatment
MK-7162 
Mono-
therapy
MK-7162 and Pembrolizumab 
Combination Therapy
Last Dose 
/ Discon-
tinuation
Safety 
Follow-
up
Survival 
Follow-
up
Visit or Cycle (C):
C1
C2
C3
C4
C5 
thru 
C36
30 days 
after 
the last 
dose
Every 12 
weeks 
after the 
last dose
Scheduling Day 
(D):
D1
D15
D1
D15
D1
D15
D1
D1
Schedule Window 
(Days):
-28 to -1
± 3
± 3
± 3
± 3
± 5
± 3
± 3
± 7
± 7
± 14
Notes
Tumor Tissue Collection
Archival Tumor 
Tissue
X
Archival tumor tissue is preferred. If archival 
tumor tissue is unavailable, freshly obtained 
biopsy tissue may be used (See Procedures 
Manual for details).
Tumor Biopsy
X
Collection of a newly biopsied tumor tissue 
specimen is required during screening prior to 
C1D1 dosing. Must be collected after overnight 
fast.  
Tumor Biopsy
X
X
• Initial requirement: C2D1 = mandatory and 
C3D15 = optional
• Upon site notification by Sponsor: C2D1 = 
optional and C3D15 = mandatory
• All biopsies must be collected after an 
overnight fast and prior to administration of 
either MK-7162 or pembrolizumab on the day 
of the biopsy.
C2D1: Obtain biopsy predose
C3D15: Obtain biopsy predose (after 5 
additional weeks of MK-7162 in combination 
with pembrolizumab following C2D1).
Abbreviations: AE = adverse event; CT = computed tomography; DNA = deoxynucleic acid; ECG = electrocardiogram; GGT = gamma glutamyl transferase; HIV = human 
immunodeficiency virus; LDH = Lactate dehydrogenase; MRI = magnetic resonance imaging; PET = ; positron emission tomography PT/INR = prothrombin time/international 
normalized ratio; PTT/aPTT = partial thromboplastin time/activated partial thromboplastin time; RECIST 1.1 = Response Evaluation Criteria In Solid Tumors version 1.1; 
iRECIST = immune-based RECIST; RNA = ribonucleic acid; SAE = serious adverse event; T3 = total triiodothyronine; T4 = total thyroxine; TSH = thyroid stimulating hormone.
 
 
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Protocol/Amendment No.: 002-02 
MK-7162-002-02 Final Protocol
21-Jul-2020
Confidential
3. Introduction
MK-7162 is a selective small-molecule inhibitor of Indoleamine-2,3-dioxygenase-1 (IDO1),
administered orally, in development for use in combination therapy with pembrolizumab for 
the treatment of advanced solid tumors.
Study Rationale 
The IDO1 protein contains a heme co-factor which is responsible for binding and activating 
oxygen to catalyze the ring opening of L-tryptophan (TRP) to generate N-formyl kynurenine
(KYN). The presence of heme is indispensable for IDO1 catalytic activity. MK-7162 inhibits 
IDO1 by either displacing heme from intact protein and/or preventing binding of heme 
during protein synthesis and folding. In human cancers, the enzyme IDO1 is upregulated and 
facilitates evasion of the immune system by tumor cells. MK-7162 is a small molecule which 
inhibits activity of IDO1, thereby reducing conversion of TRP to KYN, and facilitating T-
cell responses within the tumor microenvironment. 
While there is no prior experience with dosing of MK-7162 in humans with cancer, clinical 
proof of concept for IDO1 inhibition in cancer is provided by epacadostat, an IDO1-selective 
heme-binding inhibitor, that has been used clinically in combination with both anti-
programmed death 1 (PD-1) antibodies, including pembrolizumab [Gangadhar TC, Hamid O, 
Smith DC, Bauer, TM, Wasser, JS, Luke JJ 2015], and anti-CTLA4 antibody ipilimumab 
[Gibney GT, Hamid O, Lutzky, J, Olszanski, AJ, Gangadhar, TC 2015]. To date, epacadostat 
has demonstrated a favorable safety profile in humans.
Initiation of human studies of MK-7162 is supported by preclinical studies conducted in rats 
and dogs. Based on the dosing margins established in preclinical safety studies of MK-7162, 
there are no contraindications to conducting clinical trials in accordance with study protocols 
and applicable regulatory guidance. To date, the safety of single doses of MK-7162 up to 300
mg has been established in an ongoing normal human volunteer (NHV) single ascending 
dose (SAD) study.
IDO1 expression is highly correlated with programmed death ligand 1 (PD-L1) expression in 
human tumors. IDO1 expression is induced in preclinical models in response to anti- PD-1 
treatment as well as treatment with other immunomodulatory agents. Therefore, MK-7162 
will be developed for use in combination with pembrolizumab, an anti-PD-1 agent.
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-7162, 
and the MK-3475 IB/approved labeling for detailed background information on 
pembrolizumab.
Pharmaceutical and Therapeutic Background
MK-7162 Pharmaceutical and Therapeutic Background
Malignant cells are known to evade the human immune system through a process known as 
immune tolerance. In recent years, immunotherapeutics have been developed that 
successfully counteract various cellular processes involved in cancer immune tolerance. Such 
therapies have expanded the range of options for treatment of various cancers. For example, 
 
 
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Protocol/Amendment No.: 002-02 
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21-Jul-2020
Confidential
pembrolizumab is a monoclonal antibody that blocks the activity of PD-1, an immune 
checkpoint protein that promotes immune tolerance by suppressing T-cell activity against 
tumor cells. By blocking this pathway, pembrolizumab enables the antitumor immune 
response and has been shown to be efficacious in treatment of multiple malignancies 
including non-small cell lung cancer (NSCLC), malignant melanoma, head and neck 
squamous cell cancer (HNSCC), and Hodgkin lymphoma. However, despite the advances 
made in cancer immunotherapy, response to pembrolizumab treatment as well as to other 
immunotherapies is incomplete in many cases, and evidence suggests that malignant cells are 
able to utilize multiple other pathways to achieve immune escape.
IDO1 is an intracellular enzyme that catalyzes the first step of degradation of the essential 
amino acid TRP into KYN. Depletion of TRP and accumulation of KYN appear to interfere 
with multiple pathways required for T-cell activation and function. Studies demonstrate that 
expression of IDO1 by tumor cells in animal models leads to suppression of T-cell responses 
to tumor cells, contributing to immune tolerance.
MK-7162 is a selective small-molecule inhibitor of IDO1 that displaces the heme cofactor of 
IDO1, either by replacement of heme in the intact protein or by binding in place of heme 
during protein synthesis/folding. In vitro, MK-7162 shows potent inhibition of IDO1 in 
human cancer cells. Although MK-7162 is not directly cytotoxic to malignant cells, it is 
anticipated that inhibition of IDO1 activity will interfere with the immune tolerance 
phenomenon and enhance the antitumor effects of immunotherapeutic agents such as 
pembrolizumab.
 
MK-7162 NHV single ascending-dose study yielded the following safety data. There were no 
serious adverse events (SAEs) reported.  The reported AEs were low grade. Epacadostat is a
small-molecule inhibitor of IDO1 which is currently being studied in clinical cancer trials in 
combination with PD-1 blockade. While the mechanism of IDO1 inhibition by this 
compound is distinct from that of MK-7162, the common molecular target supports the 
projected effects common to both. 
Epacadostat Phase 1/2 data demonstrated the following: one DLT occurred at the dose of 300 
mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 3, 
fatigue). The most common adverse events in >20% of patients overall were fatigue, nausea, 
decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and 
cough. Treatment produced significant dose-dependent reductions in plasma KYN levels and 
in the plasma KYN:TRP ratio at all doses and in all patients. Epacadostat doses of 100 mg 
BID achieved >80% to 90% inhibition of IDO1 at peak and 50% inhibition at trough based 
on plasma KYN:TRP ratios. Although no objective responses were detected, stable disease 
lasting greater than or equal to 16 weeks was observed in 7 of 52 patients [Beatty, G. L., et al 
2017]. Grade 3 AST/ALT elevation was observed in 1 patient but was attributed to biliary 
duct obstruction consistent with progressive disease. A second patient also experienced grade 
3 AST/ALT elevations, but this was determined to be most likely related to acetaminophen 
ingestion over the maximum recommended daily dose for tumor fevers.  
 
 
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Protocol/Amendment No.: 002-02 
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21-Jul-2020
Confidential
BMS-986205, an IDO1 inhibitor with similar mechanism of action to that of MK-7162, is 
being evaluated in an ongoing clinical study in combination with the anti-PD-1 mAb 
nivolumab.  Forty-two treated patients were reported. All treatment-related adverse events 
were grade 1 or 2 except three grade 3 toxicities (autoimmune hepatitis [dose limiting; BMS-
986205 100 mg/nivolumab 240 mg], rash, and asymptomatic hypophosphatemia). Day 14 
individual trough concentrations began exceeding the human whole blood 50% maximal 
inhibitor concentration (IC50) starting with 25 mg QD, and the 90% maximal inhibitor 
concentration (IC90) starting with 50 mg QD.  All patients treated at 200 mg QD exceeded 
the IC90. Serum KYN was substantially reduced at all doses (>45% mean reduction at each 
dose), with >60% mean reduction at the 100 and 200 mg QD doses. Intratumoral KYN was 
reduced from between 23% and 90% in evaluable paired pre- and monotherapy on-treatment 
samples [Siu, L. L., et al 2017] [Hunt, J. T., et al 2017].
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001]. 
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
 
 
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[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in solid tumors.
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to PD-1, thus inhibiting its interaction with 
programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 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 an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications. Refer to the pembrolizumab IB/approved labeling for details.
Preclinical Trials
MK-7162 Preclinical Trials
Refer to the MK-7162 IB for detailed preclinical information.
Ongoing Clinical Trials
MK-7162 Ongoing Clinical Trials  
A NHV trial for MK-7162 is ongoing. Refer to the MK-7162 IB for clinical trial details.
Pembrolizumab (MK-3475) Ongoing Clinical Trials
Ongoing clinical trials with pembrolizumab are being conducted in multiple solid tumors. In 
addition, multiple other agents in combination with pembrolizumab are also being 
investigated. Refer to the pembrolizumab IB for clinical trial details.
Benefit/Risk Assessment
Participants in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
 
 
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4. Objectives/Hypotheses and Endpoints
In male and female participants at least 18 years of age with advanced solid tumors:
Objective
Endpoint
Primary
1. To determine the safety and tolerability 
and to establish a preliminary RP2D of 
MK-7162 administered in combination 
with pembrolizumab

Dose-limiting toxicity (DLT)

Adverse events (AEs)

Discontinuation of study treatment due to 
an AE
Secondary
1. To evaluate the pharmacokinetics (PK) of 
MK-7162 administered orally as 
monotherapy and in combination with 
pembrolizumab intravenous (IV) infusion

PK parameters of MK-7162, including 
area under the cure (AUC), Cmin, and 
Cmax
2. To evaluate pharmacodynamics (PD) of 
MK-7162 through measurement of KYN 
and TRP levels

KYN and TRP will be measured as PD 
markers of IDO1 inhibition.
3. To evaluate the objective response rate 
(ORR) of MK-7162 in combination with 
pembrolizumab

ORR based on Response Evaluation 
Criteria In Solid Tumors version 1.1 
(RECIST 1.1) and immune-based 
RECIST (iRECIST) as assessed by the 
Investigator
Tertiary/Exploratory
1. To evaluate overall survival (OS) and 
Progression Free Survival (PFS) of 
participants treated with MK-7162 in 
combination with pembrolizumab

OS

PFS based on Response Evaluation 
Criteria in Solid Tumors version 1.1 
(RECIST 1.1) and immune-based 
RECIST (iRECIST) as assessed by the 
Investigator
2. To evaluate the PK of pembrolizumab 
when administered in combination with 
orally administered MK-7162

PK parameters of pembrolizumab, 
including area under the cure (AUC), 
Cmin, and Cmax
3. To identify molecular (genomic, 
metabolic and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, PD activity, 
and/or the mechanism of action of 
MK-7162 as monotherapy and in 
combination with pembrolizumab

Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue; pembrolizumab anti-
drug antibodies (ADA).
 
 
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5. Study Design 
Overall Design 
This is a nonrandomized, multicenter open-label trial of MK-7162 in combination with 
pembrolizumab in participants with a histologically or cytologically confirmed diagnosis of 
advanced solid tumor.
Part A, the Dose Escalation and Confirmation Phase as outlined in this protocol, will follow 
the mTPI method (see Section 5.5.3.1) to identify a RP2D, MTD and/or MAD of MK-7162 
for use in combination with pembrolizumab. 
Upon identification of the preliminary RP2D of MK-7162 for use in combination with 
pembrolizumab, an amendment will be issued to this protocol. That amendment will contain 
the study details of Part B, the Dose Expansion Phase for participants with specified solid 
tumor types to receive MK-7162 in combination with pembrolizumab either as dual therapy 
or plus an additional chemotherapeutic or immune-modulatory agents.
Dose Escalation and Confirmation 
This study will evaluate the safety and tolerability of MK-7162 alone and the safety, 
tolerability, and preliminary efficacy of MK-7162 in combination therapy with 
pembrolizumab.
All participants will be required to undergo a newly performed tumor biopsy during 
Screening, unless deemed medically unsafe by the Investigator. An additional on-study 
biopsy at one of two timepoints will also be required, unless deemed medically unsafe by the 
Investigator, with the biopsy at the other time point being optional. Initially, this biopsy will 
be required to occur on Cycle 2 Day 1 predose (prior to administration of MK-7162 study 
medication and prior to administration of IV pembrolizumab on that day), with a Cycle 3 
Day 15 biopsy being optional.  This will allow full characterization of the MK-7162 dose and
intratumoral PD response relationship after three weeks of MK-7162 monotherapy. In 
addition, this tissue biopsy will facilitate characterization of the MK-7162 dose that 
maximally inhibits intratumoral IDO1. After a sufficient number of biopsy specimens at the 
Cycle 2 Day 1 timepoint have been collected, the Sponsor may notify the sites that the Cycle 
2 Day 1 biopsy will become optional and the Cycle 3 Day 15 biopsy will be required.
Characterization of the MK-7162 dose and intratumoral PD response relationship at this time 
point will confirm whether the intratumoral PD effect of a given MK-7162 dose is 
maintained during concurrent PD-1 blockade with pembrolizumab, since IDO1 upregulation 
occurs during immune responses.  
Treatment allocation will be accomplished by nonrandom assignment through the interactive 
voice response system/integrated web response system IVRS/IWRS. Participants will receive 
MK-7162 monotherapy during the first treatment cycle followed by MK-7162 in 
combination with pembrolizumab for subsequent cycles. 
MK-7162 will be administered PO QD, every day of each 21-day (3-week) cycle. Starting on 
Cycle 2, Day 1, MK-7162 will be administered in combination with pembrolizumab 200 mg 
IV, which will be administered on Day 1 of every cycle (every 3 weeks). The DLT 
evaluation period will be 2 cycles (6 weeks). Treatment of the first and second participants
 
 
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enrolled in each cohort will occur at least 7 days apart. Treatment of the second and third 
participants enrolled in each cohort will occur at least 3 days apart.
An mTPI design [Ji, Y. and Wang, S.-J. 2013] will be used to identify and confirm the RP2D 
of MK-7162 in combination with pembrolizumab. Participants will initially be enrolled in the 
first dose-level cohort, receiving MK-7162 monotherapy for Cycle 1, and then receiving 
MK-7162 in combination with pembrolizumab for subsequent cycles (Cycles 2 to Cycle 36). 
Lower and/or higher doses of MK-7162 may then be explored depending on the combined 
safety, PK, PD, and preliminary efficacy data available at each dose level. The dose of 
pembrolizumab will remain constant at 200 mg IV Q3W.
The final number of participants enrolled will depend on the DLT observations and what 
dose is ultimately identified as the RP2D using the mTPI design. For the purposes of dose 
escalation decisions from a safety perspective, participants will be considered evaluable for 
DLT if they have completed the 6-week DLT evaluation period (completed the first and 
second cycles or discontinued treatment due to a DLT).
Dose finding and confirmation in Part A of the trial will end after 14 participants have been 
treated at any of the selected doses (which may include optional doses). In the event the 
dose-finding decision is not to stay at the current dose based on the 14 participants, the dose 
may be escalated or de-escalated and additional participants may be treated. The 
pool-adjacent-violators algorithm [Ji, Y. and Wang, S.-J. 2013] will be used to estimate the 
DLT rates under the assumption of monotonicity between DLT rates and dose levels. The 
dose with an estimated DLT rate closest to 30% may be treated as a preliminary RP2D. The 
totality of the data will be considered before deciding on the dose(s) to carry forward to Part 
B (dose expansion).
The primary objective is to identify the RP2D of MK-7162 for use in combination with 
pembrolizumab. The preliminary RP2D may be the same as the MTD/MAD, or the 
preliminary RP2D may be selected based on overall exposure, emerging safety and 
tolerability data, PK data, PD data, and preliminary clinical benefit data from this study.
Upon identification of the preliminary RP2D of MK-7162 for use in combination with 
pembrolizumab, additional participants with solid tumors will be enrolled in the dose 
expansion phase (Part B) of this trial to receive MK-7162 in combination with 
pembrolizumab as dual therapy, or in combination with additional chemotherapeutic or 
immune-modulatory agents.  This dose expansion phase (Part B) of this trial will be initiated 
through a future protocol amendment.
Preliminary efficacy will be evaluated using objective response rate (ORR) and Progression 
Free Survival (PFS) assessed by the investigator based on the RECIST 1.1. ORR and PFS 
will also be assessed by iRECIST. ORR will be evaluated as a secondary objective. PFS and
overall survival (OS) will be evaluated as exploratory objectives. 
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 decision. In participants who have initial 
evidence of radiological progressive disease by RECIST 1.1, it will be at the discretion of the 
investigator whether to continue a participant on study treatment until repeat imaging is 
obtained. This clinical judgment decision should be based on the participant’s overall clinical 
 
 
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condition, including performance status, clinical symptoms, and laboratory data. Participants 
may continue to receive study treatment until tumor assessment is repeated ≥4 weeks later 
and confirms progressive disease by iRECIST per site assessment.
Adverse events will be evaluated by the investigator, according to criteria outlined in the 
National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0, to establish the safety and tolerability of MK-7162 when administered as
monotherapy and in combination with pembrolizumab, as per the primary objective of this 
study.
There will be no intra-participant dose escalation for participants enrolled in this study. The 
definition of DLTs and criteria for dose modification of MK-7162 are outlined in 
Sections 7.2.2 and 7.2.4. Pembrolizumab will be administered at a fixed dose of 200 mg IV 
every 3 weeks, which will not be modified.
Participants may receive study medication for up to 36 cycles. Participants will be treated 
until progressive disease, unacceptable toxicity, intercurrent illness that prevents further 
administration of treatment, Investigator’s decision to withdraw treatment, participant 
withdrawal of consent, pregnancy of the participant, noncompliance with study medication
or procedure requirements, 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 MK-7162 for AE 
monitoring. Serious adverse events will be collected for 90 days after discontinuation, 
30 days if the participant initiates new anticancer therapy less than 30 days after study 
treatment discontinuation, or the day new anticancer therapy is initiated if between 30 days 
and 90 days after study treatment discontinuation. Participants with an ongoing AE of Grade 
>1 at the time of treatment discontinuation will be followed until resolution of the AE to 
Grade 0-1, 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 progressive disease 
will have post-treatment follow-up for disease status (including imaging) until disease
progression, initiating a new anticancer therapy, withdrawing consent for study participation, 
or becoming lost to follow-up.
After confirmed disease progression, each participant who discontinues treatment will be 
contacted by telephone every 12 weeks (±14 days) for survival until withdrawal of consent to 
participate in the study, becoming lost to follow-up, death, or end of the study, whichever 
occurs first.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
This trial will use an adaptive design based on prespecified criteria. Interim analyses will be 
conducted to examine clinical trial data on a continuous basis to allow for dose-finding 
decisions, safety, tolerability, and efficacy analysis.
 
 
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Study Diagram
The trial design is depicted in Figure 1.
Figure 1
Study Diagram
MK-7162 in Combination with Pembrolizumab
MK-7162
@ 25 mg QD
MK-7162
@ 50 mg QD
MK-7162
@ 100 mg QD
MK-7162
@ 200 mg QD
MK-7162
@ 400 mg QD
Pembrolizumab
@ 200 mg IV 
Q3W
Pembrolizumab
@ 200 mg IV 
Q3W
Pembrolizumab
@ 200 mg IV 
Q3W
Pembrolizumab
@ 200 mg IV 
Q3W
Pembrolizumab 
@ 200 mg IV 
Q3W
Dose escalation and confirmation using an mTPI design based on a 6 week DLT 
observation period to identify a preliminary RP2D
One 3-week treatment cycle of MK-7162 monotherapy is followed by MK-7162 
combination with pembrolizumab for 35 treatment cycles (total of 36 cycles on 
treatment)
MK-7162 is administered orally QD.   Pembrolizumab is administered by IV infusion, 
and is administered on Day 1 of each 3 week treatment cycle
Treatment of the first and second participants enrolled in each cohort will occur at least 
7 days apart. Treatment of the second and third participants enrolled in each cohort will 
occur at least 3 days apart
Once participants have achieved the study objectives or the study has ended, they will be 
discontinued from this study and may be enrolled into an extension study to continue 
protocol-defined assessments and treatment.
IV=intravenous; mTPI=modified toxicity probability interval; QD=once daily; Q3W=every 3 
weeks; RP2D=recommended Phase 2 dose
Number of Participants
Approximately 40 participants will be allocated to the dose escalation and confirmation
phase (Part A) of this trial. An estimated additional 150 participants will be enrolled into the 
dose expansion phase (Part B) of this trial.
Beginning and End of Study Definition
The overall trial begins when the first participant signs the informed consent form (ICF).  
The overall trial ends when the last participant completes the last study-related phone-call or 
visit, withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be 
contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study.
 
 
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Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other trials suggest a potential 
health hazard to participants
2. Plans to modify or discontinue the development of the trial drug
3. Poor adherence to protocol and regulatory requirements
4. Quality or quantity of data recording is inaccurate or incomplete
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-7162 and/or pembrolizumab.
Scientific Rationale for Study Design 
This Phase 1b study is being conducted to evaluate the safety, tolerability, and efficacy of 
MK-7162 in individuals with solid tumors when administered in combination with 
pembrolizumab. In the dose expansion phase of this trial, which will be detailed in a future 
protocol amendment, MK-7162 will be administered with pembrolizumab as dual therapy or 
in combination with additional chemotherapeutic or immune-modulatory agents. 
This study is being conducted in male and female participants at least 18 years of age with
advanced solid tumors.
The precise timing of clinical/laboratory safety evaluations and/or efficacy evaluations 
currently outlined in the protocol may be modified during the study based on newly available 
MK-7162 clinical and/or preclinical safety, tolerability, or efficacy data. Additional visits 
may be required if changes are made to the PK/PD sampling scheme. Other modifications to 
the dosing and/or clinical procedures currently outlined in the protocol may be required to 
achieve the scientific goals of the study objectives and/or to ensure appropriate safety 
monitoring of the study participants.
Rationale for Endpoints
Efficacy Endpoints
A secondary objective for this trial is to evaluate the antitumor activity of MK-7162 in 
combination with pembrolizumab in participants with advanced or metastatic solid tumors. 
Tumor response in participants with solid tumors will be assessed by investigator using 
RECIST 1.1 and iRECIST. A central imaging vendor will also be used to collect, clean, and 
hold tumor imaging and medical photography for possible analysis by blinded, independent 
central review.
Sites are encouraged to have a multidisciplinary assessment plan to determine in advance 
which lesions will be biopsied and/or targeted for tumor assessment. If feasible, biopsied 
tumors should not be used for assessment by RECIST 1.1/iRECIST.
 
 
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Response Rate Assessed by RECIST version 1.1
RECIST 1.1 will be used to determine the objective response.
Response Rate Assessed by Immune-based RECIST (iRECIST)
RECIST 1.1 has been adapted to account for the unique tumor response characteristics seen 
following treatment with immunotherapeutic agents (Section 9.2.5). Immunotherapeutic 
agents 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 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 to 
immunotherapeutic agents. Based on an analysis of participants with melanoma enrolled in 
KEYNOTE-001 (KN001), 7% of evaluable participants experienced tumor pseudo-
progression. Of note, participants who had progressive disease (PD) by RECIST 1.1 but not 
by the immune-related response criteria [Wolchok, J. D., et al 2009] had longer overall 
survival 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 10% of participants. These findings support the need to apply a modification 
to RECIST 1.1 that takes into account the unique patterns of atypical responses in 
immunotherapy and enables treatment beyond initial radiographic progression, if the 
participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has therefore 
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 (US)
Food and Drug Administration (FDA) and the European Medicines Agency (EMA) 
[Seymour, L., et al 2017]. The unidimensional measurement of target lesions, qualitative 
assessment of non-target lesions, and response categories are identical to those of RECIST 
1.1, until progression is seen by RECIST 1.1. However, if a participant by RECIST 1.1 with 
progression is clinically stable, treatment may be continued until additional imaging is
performed that confirms radiographic progression. iRECIST will be used by Investigators to 
assess tumor response and progression and make treatment decisions 
For further information on iRECIST, see Section 9.2.5.
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of MK-7162 in 
participants with advanced/ metastatic solid tumors when administered in combination with 
pembrolizumab. The primary safety analysis will be based on participants who experience 
toxicities as defined by CTCAE Version 4.0 criteria. Safety will be assessed by quantifying 
the toxicities and grades of toxicities experienced by participants who have received MK-
7162 as monotherapy and in combination with pembrolizumab.
Safety parameters commonly used for evaluating investigational systemic anti-cancer 
treatments are included as safety endpoints for the study including, but not limited to, the 
incidence of, causality to, and outcome of AEs/SAEs; changes in vital signs and laboratory 
values. 
 
 
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Pharmacokinetic Endpoints
A secondary objective of this study is to characterize the PK profile of MK-7162 following 
administration as a single agent and to characterize the PK profiles of MK-7162 and 
pembrolizumab following administration as combination therapy. The concentrations of 
these agents will serve as the primary readout for the PK, and these data will be used to 
derive PK parameters of the agents when administered alone and in combination. 
Furthermore, the results of these analyses will be used in conjunction with the PD, safety,
and exploratory endpoint data to help assess future dosing strategies for MK-7162.
Pharmacodynamic Endpoints
Kynurenine (KYN):Tryptophan (TRP)
The ratio of KYN to TRP will be measured in both plasma and in tumor biopsy specimens as 
a downstream PD marker of target engagement. 
Target Engagement
An assay directly assessing target engagement will not be utilized and has therefore not been 
developed. Target engagement with be indirectly inferred by the KYN:TRP PD biomarker 
assay results.
Anti-Drug Antibodies (ADA)
Anti-pembrolizumab ADA response 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 to understand drug 
metabolism, exposure, and safety. The incidence of antidrug antibodies and neutralizing 
antidrug antibodies will be evaluated and summarized over time by dose. Correlations 
between the presence/absence of positivity for antidrug antibodies and PK and PD markers, 
activity, and safety will be explored.
Planned Exploratory Biomarker Research
In addition to the specified analyses, exploratory analyses of metabolite profiles may be 
conducted in plasma and/or serum.  
Germline Genetic Analyses
Germline (blood) genetic analyses (eg, single nucleotide polymorphism analyses, whole 
exome sequencing, whole genome sequencing): This research may evaluate whether genetic 
variation within a clinical trial 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 deoxynucleic acid (DNA) variation across the genome in order to interpret tumor-
specific DNA mutations. Finally, microsatellite instability (MSI) may be evaluated as this is 
an important biomarker of response to immunotherapy with pembrolizumab.
 
 
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Tumor Genetic Analyses
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 immune-oncology drug development include (for example) 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. MSI may also be evaluated as this is an important biomarker of response 
to immunotherapy with pembrolizumab.
Tumor and Blood Ribonucleic Acid Analyses
Tumor and blood ribonucleic acid (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. 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.
Proteomic Biomarkers and Immunohistochemistry (IHC)
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) has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this 
association may also be true in additional cancer types (eg, triple-negative breast cancer
[TNBC], head and neck squamous cell carcinoma [HNSCC], and gastric cancer). 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 may identify novel protein biomarkers that could aid in patient 
selection for MK-7162 and pembrolizumab (MK-3475) therapy.
Peripheral Blood Mononuclear Cell (PBMC) Phenotypic Analysis
Phenotypic characterization and enumeration of immune suppressive cells (eg, myeloid-
derived suppressor cells [MDSC], regulatory T cells [Treg]) and activated/proliferating T-
cell subsets (eg, Ki67, human leukocyte antigen – antigen D related [HLA-DR]) circulating 
in blood collected at pre- and post- treatment time points may be assessed by flow cytometry 
as a potential PD biomarker downstream of target engagement. 
 
 
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Other Blood-derived Biomarkers 
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 can 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-based biomarkers. This research would serve to develop such assays for 
future clinical use.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (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 trial) 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 sub-trial are presented in Appendix 6  –
Collection and Management of Specimens for Future Biomedical Research.
Justification for Dose 
Rationale for Starting and Maximum Dose of MK-7162
 
 
 
While the mechanism of IDO1 inhibition by MK-7162 is distinct from that of epacadostat, 
due to the common molecular target, there may be effects common to both. In published 
results of early clinical trials, epacadostat has been associated with common adverse effects 
(>20%) of fatigue, nausea, decreased appetite, and vomiting, constipation, abdominal pain, 
diarrhea, dyspnea, back pain, and cough. Two dose-limiting toxicities were observed, 
radiation pneumonitis and fatigue, both of which were grade 3 and were determined to be 
possibly related to therapy. This includes the following: one DLT occurred at the dose of 
300 mg BID (grade 3, radiation pneumonitis); another DLT occurred at 400 mg BID (grade 
3, fatigue). 
 
 
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Treatment with epacadostat produced significant dose-dependent reductions in plasma KYN
levels and in the plasma KYN:TRP ratio at all doses and in all patients. Epacadostat doses of 
100 mg BID achieved >80% to 90% inhibition of IDO1 at peak and 50% inhibition at trough. 
Although no objective responses were detected, stable disease lasting greater than or equal to 
16 weeks was observed in 7 of 52 patients [Beatty, G. L., et al 2017]. Grade 3 AST/ALT 
elevation was observed in 1 patient but was attributed to biliary duct obstruction consistent 
with progressive disease. A second patient also experienced grade 3 AST/ALT elevations, 
but this was determined to be most likely related to acetaminophen ingestion over the 
maximum recommended daily dose for tumor-related fevers.  
 
The 
NHV study assessed a starting MK-7162 dose of 3 mg, which was based on the no-observed 
adverse effect level (NOAEL) determined in nonclinical safety studies performed in the most 
sensitive and relevant animal species, adjusted with allometric factors to calculate the Human 
Equivalent Dose (HED), reduced by appropriate safety factors according to the particular 
aspects of the molecule and the design of the clinical trials. The maximum dose selected for 
the NHV study is currently 300 mg, based on the exposures at the NOAEL dose level in the 
preclinical species of rat and dog, and was projected to have an exposure lower than the 
NOAEL exposure of either preclinical species. The analysis of clinical PK data from the 
NHV SAD study has been reviewed alongside safety and tolerability data. The PK data in 
normal healthy participants over the dose range of 3 to 300 mg will continue to inform the 
dosing range for this study. 
Based on data from in vitro experimentation, animal models, and human experience with 
other inhibitors of IDO1, MK-7162 is expected to have broad clinical efficacy against a 
variety of tumor types when used in conjunction with pembrolizumab. 
 
 
 Prior studies of IDO1 inhibition in cancer patients have shown that this level of 
IDO1 inhibition is well tolerated, and preliminary studies suggest that there may be 
enhancement of the anti-tumor response with PD-1/PD-L1 blockade at this level of IDO1 
inhibition.
 
This dose was found to be both safe 
and well tolerated when administered as a single dose to normal healthy participants. 
Therefore, an MK-7162 dose of 25 mg PO QD will be the starting dose for the dose 
escalation and confirmation phase (Part A) of this Phase 1b trial.
Maximum Dose of MK-7162
The determination of a preliminary RP2D for MK-7162 is a primary objective for this study.
This study will evaluate the following dose levels: 25 mg PO QD, 50 mg PO QD, 100 mg PO 
QD, 200 mg, and 400 mg PO QD.
Corresponding IDO1 inhibition 
 
 
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in tumor cells at the tested dose levels will be evaluated using the KYN:TRP PD biomarker 
and fresh tumor biopsy specimens.
 
. 
Rationale for Dose Interval and Escalation Increments
The starting dose and dosing interval in participants of the MK-7162 Phase 1b study are 
based on an integration of clinical, nonclinical, toxicological, PK, and PD data. Dose finding 
will proceed with a model-based dose mTPI approach with a minimum of 3 participants
treated per dose level: 25 mg QD, 50 mg QD, 100 mg QD, 200 mg, and 400 mg QD.
Dose Finding Using a Modified Toxicity Probability Interval Design
The mTPI design [Ji Y, Li Y, Bekele BN 2007] of this study will target a DLT rate of 30%. 
The starting dose for the mTPI will be MK-7162 25 mg QD. Dose escalation and de-
escalation decisions are based on the mTPI design and depend on the number of participants 
enrolled and number of DLTs observed at the current dose level. 
A minimum of 3 participants are required at each dose. However, depending on the accrual 
rate and the occurrence of DLTs, 3, 4, 5, or 6 participants may be enrolled at each new dose
level. In [Table 1], the columns indicate the numbers of participants treated at the current 
dose level, and the rows indicate the numbers of participants experiencing DLT. The entries 
of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, 
staying at the same dose, de-escalating the dose, and excluding the dose from the trial due to 
unacceptable toxicity, respectively. For example, if 0 out of 3 participants at a given dose 
level develop a DLT, then the dose can escalate to the next level. If 2 participants out of 3 
develop a DLT, the dose will be de-escalated to the next lower dose level. If 3 out of 3 
participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose 
should be de-escalated and the current dose will not be explored further. If 1 out of 3 
participants at a given dose level develops a DLT, then additional participants should be 
enrolled at that dose level following the rules below.
When adding participants to a dose level in response to a “stay” decision, the same principles 
will be applied whether 3, 4, 5, or 6 participants are initially enrolled at that dose level. First, 
the number of additional participants to be enrolled is capped to minimize the exposure to a 
dose that may be unacceptably toxic (denoted as DU in [Table 1]). Secondly, to determine 
how many more participants can be enrolled at the dose level, one can count steps in 
diagonal direction (down and to the right) from the current cell to the first cell marked DU. 
For example, if 1 of 3 participants have experienced a DLT at a given dose level, no more 
than an additional 3 participants should be enrolled at this dose level until additional DLT 
data are available. This is because this dose level would be considered unacceptably toxic if 
all 3 of the additional participants experience a DLT (ie, 4/6 participants with DLT in
[Table 1]).
 
 
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A D or DU decision at the lowest dose level will stop the trial. An E decision at the highest 
dose level will result in staying at that level. During dose finding, it may be acceptable to de-
escalate to an intermediate dose that was not predefined and not previously studied if 
evaluation of toxicity at such a dose is desired. If this approach is taken, 3 to 6 new 
participants may be enrolled at the new intermediate dose, and the aforementioned rules 
should be used to determine further enrollment at this dose level.
Dose finding will end after 14 participants have been enrolled at any of the tested doses 
(including intermediate doses).  In the event the dose-finding decision is not to stay at the 
current dose based on the 14 participants, the dose may be escalated or de-escalated and 
additional participants may be treated.
The pool-adjacent-violators-algorithm [Ji, Y. and Wang, S.-J. 2013] will be used to estimate 
the DLT rates across doses. The dose with an estimated DLT rate closest to 30% will be 
treated as a preliminary MTD. The final RP2D for future studies will be based on all 
available safety and tolerability assessments from the Dose Escalation and Confirmation 
Phase, Dose Expansion Phase, as well as PK and PD data, and preliminary efficacy 
assessments from this trial.
Note that although 30% was the target toxicity rate used to generate the guidelines in [Table 
1], the observed rates of participants with DLTs at the MTD may be slightly above or below 
30%.
 
 
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Table 1
Dose-finding Rules per mTPI Design
Number of Participants Evaluable for DLT at Current Dose
Number of 
participants with at 
least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
DLT = Dose limiting toxicity; D = De-escalate to the next lower dose; DU = The current 
dose is unacceptably toxic; E = Escalate to the next higher dose; S = Stay at the current dose.
Target toxicity rate = 30%
Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.03 [Ji Y, Li Y, Bekele 
BN 2007], [Ji, Y., et al 2007], [Ji, Y. and Wang, S.-J. 2013]
6. Study Population
Male and female participants at least 18 years of age with advanced solid tumors (of any 
type) will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
 
 
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Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Have a histologically- or cytologically-confirmed advanced/metastatic solid tumor by 
pathology report and have received, or been intolerant to, or been ineligible for all 
treatment known to confer clinical benefit. Participants with solid tumors of any type 
are eligible for enrollment.
2. Have stage III or stage IV disease that is not surgically resectable.
3. Have measureable disease by RECIST 1.1 criteria as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
4. Be ≥18 years of age on the day of signing informed consent.
5. Have one or more discrete malignant lesions that are amenable to a minimum of two 
separate biopsies guided by one of the following modalities: visual inspection, 
ultrasound guidance, or cross-sectional image guidance (computed 
tomography/magnetic resonance imaging [CT/MRI]). 
Note:  Participants should only be enrolled if during the screening assessment the 
investigator deems the biopsy of such lesions to be medically safe.
6. Have an evaluable baseline tumor sample to submit for analysis. Archival samples are 
preferred, if available. Details pertaining to tumor tissue submission can be found in 
the Procedures Manual.
7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
8. Demonstrate adequate organ function as defined by the following table ([Table 2])
All screening evaluations should be performed within the Screening period, and labs
are to be obtained within 7 days of initiation of treatment.
 
 
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L a
Renal
Serum creatinine or
creatinine clearance (CrCl) (measured or
calculated) b or
Glomerular Filtration Rate (GFR) in place 
of CrCl
≤1.5 X upper limit of normal (ULN) or
≥60 mL/min for participant with creatinine 
levels ≥1.5 X ULN
Hepatic
Total bilirubin (serum) 
≤1.5 X ULN or 
Direct bilirubin <ULN for participants with 
total bilirubin levels ≥1.5 X ULN
Aspartate aminotransferase (AST) and 
Alanine aminotransferase (ALT)
<2.5 X ULN or ≤5 X ULN for participants
with liver metastases
Coagulation
International Normalized Ratio (INR) or
Prothrombin Time (PT)
< 1.5 X ULN unless participant is receiving 
anticoagulant therapy
Activated Partial Thromboplastin Time 
(aPTT) or Partial Thromboplastin Time 
(PTT)
< 1.5 X ULN unless participant is receiving 
anticoagulant therapy
a Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 
weeks. Participants may be on stable doses of erythropoietin (≥ approximately 3 months).
b Creatinine clearance (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.
Demographics
Male participants:
9. A male participant must agree to use a contraception, and refrain from donating 
sperm, as detailed in Appendix 5 of this protocol during the treatment period and for 
at least 120 days, corresponding to time needed to eliminate any study treatments 
(MK-7162 and pembrolizumab), after the last dose of study treatment.
 
 
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Female participants:
10. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: A woman of 
childbearing potential (WOCBP) who agrees to follow the contraception guidance in 
Appendix 5 during the treatment period for at least 120 days (corresponding to time 
needed to eliminate any study treatment(s) (MK-7162 and pembrolizumab).
Informed Consent
11. The participant (or legally acceptable representative if applicable) provides written 
informed consent. The participant may also provide consent for future biological 
research (FBR). However, the participant may consent to the main trial without 
participating in FBR.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder 
cancer, in situ cervical cancer, or other in-situ cancers.
2. Has a known active central nervous system (CNS) metastasis 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 this repeat imaging should be performed during 
study screening), clinically stable and without requirement for steroid treatment for at 
least 14 days prior to first dose of study treatment.
3. Has had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody/components of the study drug(s).
4. Has 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 non-systemic steroids is permitted.
5. Has a history of vasculitis.
6. Has an active infection requiring systemic therapy.
7. Has symptomatic ascites or pleural effusion. A participant who is clinically stable 
following treatment for these conditions (including therapeutic thoracentesis or 
paracentesis) is eligible.
 
 
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8. Has interstitial lung disease that has required oral or intravenous glucocorticoids to 
assist with management.
9. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
10. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years.
Note: Participants who have had a stem cell transplant greater than 5 years ago are 
eligible as long as there are no symptoms of graft-versus-host disease (GVHD).
11. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
12. Has known active 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.
13. Has 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 drugs 
hazardous, or make it difficult to monitor adverse effects such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
16. Has not fully recovered from any effects of major surgery without significant 
detectable infection. Surgeries that required general anesthesia must have been
completed at least 2 weeks before first study drug administration. Surgery that 
required regional/epidural anesthesia must have been completed at least 72 hours 
before first study drug administration and participants should have recovered.
17. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 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 has elapsed between the screening pregnancy test 
(urine or serum) and the first dose of study treatment, repeat pregnancy testing 
must be performed and must be negative in order for participant to start 
receiving study medication.
 
 
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Prior/Concomitant Therapy
18. Has received prior systemic anti-cancer therapy including investigational agents or 
has used an investigational device within 28 days prior to the first dose of study 
treatment.
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 immune-related adverse events will not be excluded from 
participation in this study.
Note: Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 
inhibitors, provided the participant did not experience ≥Grade 3 drug-related 
toxicity on monotherapy with a PD-1 or PD-L1 inhibitor.
19. Has been previously treated with an IDO1 inhibitor (eg, epacadostat, BMS-986205)
20. Has received prior radiotherapy within 2 weeks of start of study treatment. 
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.
21. Is receiving an MAO-inhibitors (MAOI) or any drug which has significant MAOI 
activity (eg, meperidine, linezolid, methylene blue) within the 21 days before 
screening, or has a history of Serotonin Syndrome after receiving serotonergic drugs.
22. Is expected to require any non-protocol antineoplastic therapy while on study.
23. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
in excess of replacement doses (the equivalent of prednisone ≤10 mg/day is 
acceptable), or on any other form of immunosuppressive medication.
Note: The use of physiologic replacement doses of corticosteroids may be approved 
after consultation with the Sponsor Medical Monitor or designee.
24. Has received a live-virus vaccine within 30 days prior to first dose of study 
medication. Vaccines that do not contain live virus are permitted.
Lifestyle Restrictions
Dietary Restrictions
For C1D1, C1D15 and C3D1 participants are to remain fasted overnight. The participant 
must remain fasting up to 1 hour following treatment with MK-7162 on C1D1, C1D15, and 
C3D1; clear fluids are permitted.
There are no other diet restrictions.
Contraception
MK-7162 and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is 
not known if MK-7162 or pembrolizumab have transient adverse effects on the composition 
of sperm.
 
 
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For this study, male participants will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with MK-7162 and/or 
pembrolizumab, the participant will be immediately discontinued from study treatment. 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 a serious adverse 
experience (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 his 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 9.3.6.
Use in Nursing Women
It is unknown whether MK-7162 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.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled 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 adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
In order to adequately evaluate the safety of the doses administered in Part A (Dose 
Escalation and Confirmation Phase), all participants enrolled must meet the criteria for 
evaluability for the first 2 cycles (42 days from the first dose of study medication). Criteria 
for evaluability of participants in Part B (Dose Expansion Phase) will be clarified in a future 
protocol amendment.
Participants are considered non-evaluable and will be replaced if:

They are allocated but not treated

They discontinue from the trial prior to completing all the safety evaluations for 
reasons other than treatment-related AEs

They receive less than 90% of the total oral MK-7162 or pembrolizumab infusion in 
Cycle 1 and Cycle 2 and did not experience a DLT.
 
 
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Participants who are not evaluable will be replaced unless accrual to the cohort has stopped. 
Non-evaluable participants will not be counted toward the total number of participants in the 
cohort for DLT evaluation.
7. Treatments
Study treatment is defined as any investigational treatment(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 treatment(s) provided by the Sponsor] will be packaged to support 
enrollment and replacement participants as required.  When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies.  Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Treatments Administered
The study treatment(s) to be used in this trial are outlined below in Table 3.
 
 
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Table 3
Study Treatment
Study 
Treatment 
Name
Dosage 
Formulation
Unit Dose 
Strength(s)
Dose 
Frequency
Dosage 
Level(s)
Route of 
Administration
Regimen/ 
Treatment Period
Sourcing
MK-7162
Oral 
Compressed 
Tablet (OCT)
1, 10, and 100 mg 
potency tablets
QD 
25 mg up 
to 400 
mg
Oral
Cycles 1-36; 21-day 
treatment cycle
Provided centrally 
by the Sponsor.
Pembrolizumab 
(MK-3475)
Solution for 
Infusion
100 mg/4 mL
Q3W
200 mg
IV infusion
Cycles 2-36: Day 1 
of each 21-day 
treatment cycle
Provided centrally 
by the Sponsor.
For pembrolizumab combination treatment-day visits, MK-7162 should be administered in clinic a minimum of 1 h prior to initiation of pembrolizumab infusion.
 
 
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All supplies indicated in Table 3 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 trial site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other) 
Dose Administration/Escalation/Cohort Expansion
Dose Administration (Preparation)
Details on preparation and administration of MK-7162 and pembrolizumab are provided in 
the appropriate Pharmacy/Procedures Manual.
Definition of Dose Limiting Toxicity
All toxicities will be graded using CTCAE Version 4.0 based on the investigator assessment.
In this study, the DLT window of observation will be during the first 6 weeks of treatment 
(Cycles 1 and 2). The occurrence of any of the following toxicities will be considered a DLT, 
if assessed by the investigator to be possibly, probably, or definitely related to study drug 
administration, excluding toxicities clearly not related to the drug, such as disease 
progression, environmental factors, unrelated trauma, etc.:
1. Grade 4 nonhematologic toxicity (not laboratory)
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:

Grade 4 thrombocytopenia of any duration 

Grade 3 thrombocytopenia associated with bleeding.
3. Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per standard of care; Grade 3
fever and Grade 3 flu-like symptoms lasting ≤24 hours with negative infectious 
disease workup (including negative blood and urine cultures)
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if:

Clinically significant medical intervention is required to treat the participant, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week

The abnormality results in a Drug-induced Liver Injury (DILI) (see Sections 9.3.1 
and 9.3.7 for criteria)
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc.
 
 
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5. Febrile neutropenia Grade 3 or Grade 4

Grade 3 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour

Grade 4 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour, with life-threatening consequences and 
urgent intervention indicated.
6. Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1 or Cycle 2
7. Prolonged delay (>2 weeks) in initiating Cycle 2 or Cycle 3 due to treatment-related 
toxicity
8. Missing 25% of MK-7162 doses as a result of drug-related AE(s) during the first 2 
cycles of treatment
9. Grade 5 toxicity
Timing of Dose Administration
Timing of Administration for MK-7162
MK-7162 will be administered once a day. The reason for any variability in administration of 
MK-7162 outside of the protocol-specified window should be documented in the
participant’s chart and recorded on the electronic Case Report Forms (eCRFs).
Every effort should be made to begin the first dose of study treatment on the day of 
allocation, but if this is not achieved, trial therapy should be initiated no later than 3 days 
from the date the study treatment cohort is allocated. All study treatments will begin on Day 
1 of each cycle after all predose study procedures and assessments have been completed as 
detailed in Section 2 - Summary of Activities. On Day 1 of each cycle (Cycles 2-36), MK-
7162 should be administered in the clinic a minimum of 1 hour prior to initiation of 
pembrolizumab infusion. 
The Pharmacy Manual contains specific instructions for MK-7162 administration.
All study medications will be administered on an outpatient basis.
Timing of Administration for Pembrolizumab 
Trial treatment of pembrolizumab should be administered on Day 1 of each 3 week cycle, 
beginning at Cycle 2, after all procedures/assessments have been completed as detailed in the 
Trial Flow Chart (Section 2).
Trial treatment of pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons.
The Pharmacy Manual contains specific instructions for pembrolizumab administration.
All study medications will be administered on an outpatient basis.
 
 
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Guidelines for Dose Modification due to Adverse Events
Adverse events (both nonserious and serious) associated with MK-7162 and pembrolizumab 
exposure may represent an immunologic etiology. These AEs may occur shortly after the 
first dose or several months after the last dose of treatment.
CTCAE 4.0 must be used to grade the severity of adverse events. The investigator may 
attribute each toxicity event to MK-7162 alone, to pembrolizumab alone, or to the 
combination, and modify the dose according to Table 4 and Table 5. If a dose modification 
for toxicity occurs with MK-7162, the dose may not be re-escalated to the dose that preceded 
the dose modification.  Dose modifications are always based on the previous cycle.
Reduction or holding of 1 agent and not the other agent is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to 1 of the study medications and Sponsor 
consultation and approval is obtained. For example, if MK-7162 is held due to an adverse 
event attributed to that drug, then pembrolizumab may continue to be administered in 
consultation with the Sponsor. Appropriate documentation is required regarding the drug to 
which the investigator is attributing the adverse event. If, in the opinion of the investigator, 
the toxicity is related to the combination of 2 or more agents, then the corresponding drugs 
should be held according to recommended dose modifications.
Dose Modification for MK-7162
Participants may have up to 2 dose modifications of MK-7162 throughout the course of the 
study, as described in Table 4. If further toxicity occurs or the criteria for resuming treatment 
are not met, the participant must be discontinued from the attributed study treatment. If a 
participant experiences several toxicities and there are conflicting recommendations, the 
most conservative dose adjustment recommendations (dose reduction appropriate to the most 
severe toxicity) should be followed.
Exceptional circumstances to the following dose modification tables below may be 
considered after consultation with and approval by the Sponsor.
 
 
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Table 4
MK-7162 Dose Modification and Treatment Discontinuation Guidelines for 
Drug-Related Adverse Events
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation 
after Consultation 
with Sponsor
Hematological toxicities:
Any Grade 1 
hematological toxicity
No
N/A
N/A
N/A
Any Grade 2 
hematological toxicity, 
or Grade 3 toxicity that 
persists for ≤5 days
Per 
medical 
assessment 
of the 
investigator
If treatment 
held, may be 
restarted when 
AE resolves 
back to 
baseline or to 
Grade 1
Per medical assessment of 
the Investigator:  may 
decrease dose by 1 dose 
level
If AE persists for 
12 weeks without 
resolution following 
reduction in dose
Any Grade 3 
hematologic toxicity 
that persists for 
>5 days, or Grade 4 
hematological toxicity
Febrile neutropenia
Grade 3 
thrombocytopenia of 
any duration if 
associated with 
bleeding
Yes
Treatment may 
be restarted 
when AE 
resolves back 
to baseline or to 
Grade 1
Decrease dose by 1 dose 
level
If AE persists for 
12 weeks without 
resolution following 
reduction in dosing 
schedule
Permanent 
discontinuation 
should be 
considered for any 
severe or life-
threatening event
Nonhematological toxicities:
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation 
after Consultation 
with Sponsor
Any Grade 1 
nonhematological 
toxicity 
Grade 2 alopecia
Grade 2 fatigue
No 
N/A
N/A
N/A
Any Grade 2 
nonhematological 
toxicity except Grade 
2 alopecia and Grade 2 
fatigue
Per 
medical 
assessment 
of the 
investigator
If treatment 
held, may be 
restarted when 
AE resolves 
back to 
baseline or to 
Grade 1
Per medical assessment of 
the Investigator:  may 
decrease dose by 1 dose 
level
If AE persists for 
12 weeks without 
resolution following 
reduction in dose
 
 
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Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation 
after Consultation 
with Sponsor
Any Grade 3 or 4 
nonhematological 
toxicity (not including 
laboratory, unless 
clinically significant 
medical intervention is 
required to treat the 
participant, or the 
abnormality leads to 
hospitalization, or the 
abnormality persists 
for >1 week)
Yes
Treatment may 
be restarted 
when AE 
resolves back 
to baseline or to 
Grade 1
Decrease dose by 1 dose 
level
If AE persists for 
12 weeks without 
resolution following 
reduction in dose
Permanent 
discontinuation 
from study 
treatment should be 
considered for any 
severe or life-
threatening event
If toxicity is attributed to MK-7162, and requires a treatment hold and does not resolve to 
Grade 0-1 within 12 weeks after the last treatment, then MK-7162 should be discontinued.
With Investigator and Sponsor agreement, participants with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and 
controlled.
After any Grade 4, drug-related adverse event, participants should not restart study treatment 
without consultation with the Sponsor (Toxicity must have resolved to Grade 0-1 or baseline 
prior to restarting).
Pembrolizumab treatment will be modified for the adverse events described Section 7.2.4.2.
Dose Modification for Pembrolizumab
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology.
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical trial 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. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with pembrolizumab 
are provided in Table 5.
 
 
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with 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 pembrolizumab has been withheld, 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 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.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
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
Diarrhea / Colitis 
Grade 2 or 3
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
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
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

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
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 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
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
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
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 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Gullain-
Barre Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE resolves to ≤ Grade 2 
and is controlled with hormonal 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 on pembrolizumab-associated 
infusion reaction are provided in Table 6.
Table 6
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 h
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/h to 
50 mL/h).  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 study 
drug treatment
Participant may be 
premedicated 1.5h (± 30 min) 
prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg PO 
(or equivalent dose of 
antihistamine) and/or
Acetaminophen 500-1000 mg 
PO (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 drug treatment.
No subsequent dosing
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 Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption(s) for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study treatment. 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 patient's study record.
Method of Treatment Assignment 
Study treatment will be allocated via IVRS. Each new dose level will open for enrollment 
without delay once the 42-day DLT observation period of the previous dose cohort is 
completed, and a dose escalation decision is made.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
 
 
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Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
treatment administered.
Preparation/Handling/Storage/Accountability
Dose Preparation
The rationale for selection of doses to be used in this trial is provided in Section 5.5.1.  There 
are no specific calculations or evaluations required to be performed in order to administer the 
proper dose to each participant.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial 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 trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product 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 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Compliance will be assessed at each clinic visit.
All doses of pembrolizumab will be administered under the supervision of a qualified 
physician and/or qualified designee experienced in the use of anticancer agents.
Interruptions from the protocol specified treatment plan for 12 weeks between MK-7162 or 
pembrolizumab doses for non-drug related or administrative reasons require consultation 
 
 
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between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination 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.
Acceptable Concomitant Medication
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 except for those that are prohibited as described in Section 7.7.2. All 
concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date should also be included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered more than 30 days after the last dose of trial treatment should be 
recorded for SAEs and events of clinical interest (ECIs) as defined in Section 9.3.  The 
investigator or qualified designee will record medication, if any taken by the participant 
during the trial.  
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases (including retreatment for post-complete response relapse) of this trial:

Antineoplastic biological therapy not specified in this protocol

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents not specified in this protocol

Radiation therapy 
Note: Palliative radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion, but only after the DLT 
observation period in order for the participant to be considered evaluable for 
DLT.
 
 
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
Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. 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 
AE of suspected immunologic etiology. Physiologic doses of corticosteroids may be 
administered, but only after consultation with and approval by the Sponsor.

MAO-inhibitors (MAOI) or any drug which has significant MAOI activity (eg, 
meperidine, linezolid, methylene blue)
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Participants may receive other medications that the investigator deems to be medically 
necessary.
Treatment by local surgery (and/or radiation therapy) of isolated or symptomatic progressing 
lesions in the setting of improving baseline disease may be permitted for palliative or 
potentially curative management following completion of Cycle 2. All such interventions, 
including continuation of study treatment, should be discussed with the Sponsor.
Supportive Care
Supportive care for participants should follow the pembrolizumab supportive care guidelines
located in Section 7.2.4.2.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study treatment (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
8. Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 - SoA and Section 
9.11.3 – Discontinued Participants Continuing to be Monitored in the Study.
 
 
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Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
o
The participant or participant’s legally acceptable representative requests to 
discontinue study treatment.
o
The participant interrupts study medication administration for more than 12
consecutive weeks.
o
The participant interrupts MK-7162 for more than 84 (QD) cumulative missed doses.
o
The participant has a medical condition or personal circumstance which, in the 
opinion of the investigator and/or sponsor, places the participant at unnecessary risk 
from continued administration of study treatment.
o
The participant has a confirmed positive serum or urine pregnancy test.
o
Non-compliance with trial treatment or procedure requirements.
o
Confirmed radiographic disease progression outlined in Section 9.11 – Visit 
Requirements (Exception is if Sponsor approves treatment continuation).
o
Unacceptable adverse experiences as described in Section 9.3 – Adverse Events, 
Serious Adverse Events and Other Reportable Safety Events.
o
Intercurrent illness other than another malignancy as noted above (Section 5.1.1 –
Dose Escalation and Confirmation) that prevents further treatment administration.
o
Investigator’s decision to discontinue treatment.
o
Recurrent Grade 2 pneumonitis.
o
Progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment.
Completion of 36 treatment cycles.
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, see Section 2 –SoA, and Section 9.11.3 – “Discontinued Participants Continuing to 
be Monitored in the Study” for those procedures to be completed at each specified visit.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
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.
 
 
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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 9.1.9 – Withdrawal/Discontinuation. 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 8.3.
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:
o
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.
o
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone 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 amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
9. 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.
●
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.
The approximate amount of blood collected from each participant for laboratory evaluations 
is provided in the Procedures Manual.
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, etc.), 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.
 
 
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Efficacy and safety evaluations must be obtained prior to study treatment administration on 
treatment cycle visit days, unless otherwise specified in the SoA.
Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical trial or Future Biomedical Research. If there are changes to the participant’s status 
during the trial (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
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 trial.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the 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 trial.  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 trial and the trial 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 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 sub-trial.  A copy of the 
informed consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.
 
 
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Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research trial. The card will contain trial site contact information (including 
direct telephone numbers) to be utilized 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 treatment 
allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease 
for which the participant has enrolled in the study will be recorded separately and not listed 
as medical history.
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 the first dose of study medication.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 9.3 (Adverse Events, Serious Adverse Events and Other Reportable Safety Events).
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study treatment(s), the 
study treatment(s) should be discontinued and the participant will move into the survival 
follow-up phase; if a participant initiates a new anticancer therapy within 30 days after the 
last dose of the trial treatment, the 30-day Safety Follow-up visit should occur before the first 
dose of the new therapy.
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 treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
 
 
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Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.11.1.  
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.
Treatment Administration
All study treatments will be administered on an out-patient basis. Study treatment should 
begin within 3 days of allocation or as close as possible to the allocation date.
Timing of Dose Administration
Timing of Dose Administration for MK-7162
During on-site visits, administration of study medication will occur at the study site under the 
direction of 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.
For non-visit days, MK-7162 will be taken at home. When a participant attends a study visit, 
he/she will bring any unused tablets.
Refer to Section 7.2.4 (Timing of Dose Administration) for dose and treatment details.
Timing of Dose Administration for Pembrolizumab
The first dose of pembrolizumab is administered on C2D1. Pembrolizumab is administered 
once every 21 days during a morning visit in the clinic. Details on administration of 
pembrolizumab are provided in the appropriate Pharmacy/Procedures Manual. Refer to 
Section 7.2.4 (Timing of Dose Administration) for dose and treatment details. 
Withdrawal/Discontinuation
Participants who discontinue study treatment 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 trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of withdrawal.  Any adverse 
events which are present at the time of withdrawal should be followed in accordance with the 
safety requirements outlined in Section 9.3 - Adverse Events.
 
 
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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 trial.  If 
medical records for the main trial 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 trial data and 
results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 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.
Participant Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment as required for inclusion laboratory assessments and for safety 
laboratory assessments

Imaging equipment as required for disease assessments relevant to trial objectives

Infusion equipment as required for administering study treatment
Additional guidance regarding critical equipment (if applicable) is provided in the 
Procedures Manual, Pharmacy Manual, and Site Imaging Manual.
Efficacy Assessments 
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 (SIM). Tumor imaging of the chest, abdomen, and pelvis is 
strongly preferred to be acquired by computed tomography (CT) with IV contrast. Contrast-
enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated contrast 
 
 
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is contraindicated. 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.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the allocation 
date. The study site team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1.
Imaging performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
allocation date.
Participants with previously-treated brain metastases may participate provided they have 
stable brain metastases, ie, without evidence of progression by imaging (confirmed by MRI if 
MRI was used at prior imaging or confirmed by CT imaging if CT used at prior imaging) for 
at least 4 weeks prior to the first dose of trial treatment. Any neurologic symptoms must have 
returned to baseline and participants must have no evidence of new or enlarging brain 
metastases, as per local radiology assessment, and have not used steroids for brain metastases 
for at least 14 days prior to trial initiation. This exception does not include carcinomatous 
meningitis, as participants with carcinomatous meningitis are excluded regardless of clinical 
stability.
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (±7 days) from the 
date of first dose of study treatment (C1D1). Subsequent tumor imaging should be performed 
every 9 weeks (±7 days) or more frequently if clinically indicated. 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, the start 
of new anticancer treatment, withdrawal of consent, or death, whichever occurs first. All 
supplemental imaging for study participants and related to disease progression/response 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.  
Per iRECIST (Section 5.4.1.1.2), 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 
 
 
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met the conditions detailed in Section 5.4.1.1.2. 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 
5.4.1.1.2.
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 (±4 week 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 9 weeks) until the start of a new 
anticancer treatment, disease progression, death, withdrawal of consent, or the end of the 
study, whichever occurs first. Such imaging should be submitted to the central imaging 
vendor.
RECIST 1.1 Assessment of Disease
RECIST 1.1 per Investigator assessment will be used as the primary measure for assessment 
of tumor response, 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 1.1 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 to 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 7. This allowance 
to continue treatment despite initial radiologic progressive disease (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.
 
 
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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 later to confirm PD by 
iRECIST, per Investigator assessment. Images should continue to be sent in to the central 
imaging vendor for potential retrospective BICR. 
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 
should continue to be performed following the intervals as outlined in Section 2 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 7.
Additional details about iRECIST are referenced in Merck TIP Sheet for RECIST 1.1 and 
iRECIST.
 
 
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Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat tumor 
imaging a
minimum of 4 
weeks later to 
confirm PD.
May continue study 
treatment at the 
Investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat tumor 
imaging a
minimum of 4 
weeks later 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 
tumor imaging 
required.
Not applicable
Repeat tumor 
imaging shows 
iUPD by iRECIST 
per Investigator 
assessment
Repeat tumor 
imaging a
minimum of 4 
weeks later to 
confirm PD.  May 
occur at next 
regularly scheduled 
imaging visit.
Continue study 
treatment at the 
Investigator’s 
discretion.
Repeat tumor 
imaging a
minimum of 4 
weeks later 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 tumor
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.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response 
Evaluation Criteria in Solid Tumors 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 1.1; 
VOP=verification of progression
Medical Photography (cutaneous lesions)
If applicable, medical photography should be obtained. The collection time points follow the
same schedule as imaging and may be performed more often if clinically indicated. 
Collection timepoints specified in the SoA are based on calendar days and are not adjusted 
for delays in treatment cycle start dates. Imaging and/or medical photography continues to be 
captured until disease progression or discontinuation (end of treatment [EoT]). The Site 
Imaging Manual (SIM) provides guidance in obtaining and submitting medical photography
to the central imaging vendor.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment, and during the follow-up period as specified in 
Section 2 - SoA. Additional ECOG assessments may be performed as clinically indicated.
 
 
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Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
The definitions of an adverse event (AE) or serious adverse event (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 4.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, 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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, 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 9.3.3.
Adverse events will not be collected for participants during the pre-screening 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.
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 causes the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
From the time of treatment allocation/randomization through 14 days following cessation of 
treatment, all AEs, SAEs and other reportable safety events 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 in the previous paragraph must be reported immediately to the Sponsor 
if the event is considered to be 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 treatment 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 timeframes as indicated in Table 8.
 
 
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Table 8
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up 
Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(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
Serious Adverse 
Event (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:
- drug/vaccine 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
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential DILI
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do 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
 
 
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Method of Detecting AE, SAE 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 non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
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, 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 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
1. 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 treatment under clinical investigation are met. 
2. The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, i.e., 
per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
3. Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
4. An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Progression of the cancer under study is not considered a reportable event. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
 
 
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Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the trial 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.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.
2. 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 may 
require an additional evaluation for an underlying etiology. The trial site 
guidance for assessment and follow up of these criteria can be found in the 
Investigator Trial File Binder (or equivalent).
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose). 
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-7162 by ≥20% of the indicated dose. No specific information is available on the 
treatment of overdose of MK-7162. In the event of overdose, MK-7162 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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Safety 
Details regarding specific safety procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial 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.
Physical Examinations
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exam are described in Section 2 (SoA). Height is 
recorded only at Screening; weight is recorded at Screening and at the visits indicated in the 
SoA. After the first dose of trial treatment, new clinically significant abnormal findings 
should be recorded as AEs.
Directed Physical Exam
The time points for a directed physical exam are outlined in Section 2 (SoA). The 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to study treatment administration. Weight is recorded at Screening and at the 
visits indicated in the SoA. New clinically significant abnormal findings should be recorded 
as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment on Day 1 of each Cycle and during the follow-
up period as specified in Section 2, SoA. Vital signs (VS) include temperature, pulse rate, 
respiratory rate, oxygen (02) saturation and blood pressure.
On Cycle 1 Day 1, collect VS within 1 hour (± 30 minutes) prior to MK-7162 administration 
and postdose MK-7162 at 2 hours, 4 hours, 6 hours, and 8 hours (± 30 minutes for each time 
point).  On Cycle 2 Day 1, VS will be monitored within 1 hour (± 30 minutes) prior to MK-
7162 and pembrolizumab administration, and after completion of dosing of both MK-7162
and infusion of pembrolizumab at 2 hours, 4 hours, 6 hours, and 8 hours (± 30 minutes for 
each time point). For Day 1 of each subsequent Cycle, VS will be monitored within 1 hour (± 
30 minutes) prior to MK-7162 and pembrolizumab administration. Additional VS monitoring 
may be obtained as clinically indicated.
 
 
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Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures. The ECG collection time points are outlined in the SoA. Clinically significant 
abnormal findings should be recorded as medical history. Additional ECGs may be 
performed as clinically necessary. Clinically significant abnormal findings seen on any ECGs 
performed after Screening should be recorded as AEs.
The Screening ECG will be obtained within 7 days prior to MK-7162 administration on 
C1D1.
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 must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
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.
●
If laboratory values from non-protocol 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 
treatment, 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. 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided in Appendix 2. The total amount of blood/tissue to be drawn/collected over the 
course of the trial (from pre-trial to post-trial visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant can be found in the 
Study Procedures Manual. Refer to Section 2 (SoA), for the schedule of laboratory 
assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
study treatment. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. After Cycle 1, predose laboratory safety tests can be 
 
 
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conducted up to 72 hours prior to that Cycle Day 1 dosing, unless otherwise noted on the 
SoA.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Unresolved abnormal 
laboratory values that are drug-related AEs should be followed until resolution. Laboratory 
tests do not need to be repeated after the end of treatment if laboratory results are within 
normal range.
Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to first dose 
of study treatment. If a urine test is positive or not evaluable, a serum test will be required. 
Participants must be excluded/discontinued from the study in the event of a positive test 
result. Pregnancy test (such as monthly testing) may be conducted if required by local 
regulations. 
Pharmacokinetics
To further evaluate the PK profile of MK-7162, sample collection is currently planned as 
shown in Section 2 (SoA). Maximum concentration (Cmax) and minimum concentration 
(Ctrough) at planned visits and times will be summarized.
Blood Collection for Plasma for MK-7162 Pharmacokinetics
Sample collection, storage and shipment instructions for plasma samples will be provided in 
the Procedures Manual. 
Blood Collection for MK-7162 Metabolites
Exploratory analysis of metabolites may also be conducted. 
Pharmacodynamics
Venous blood samples will be collected after an overnight fast for measurement of plasma 
levels of KYN and TRP in participants treated with MK-7162. Sample collection, storage 
and shipment instructions for blood samples will be provided in the Procedures Manual.
Urine samples will be collected for measurement of MK-7162. Sample collection, storage 
and shipment instructions for urine samples will be provided in the Procedures Manual.
Intratumoral KYN and TRP will be measured using required as well as optional on-study 
tumor biopsy specimens. Unless deemed medically unsafe by the Investigator, all 
participants will be required to undergo a baseline biopsy during Screening, following an 
overnight fast. Unless deemed medically unsafe by the Investigator, participants will be 
required to undergo one of two additional biopsies. Initially this second biopsy will occur on 
Cycle 2 Day 1, after an overnight fast and prior to the initial dose of pembrolizumab.  The 
additional optional biopsy on Cycle 3 Day 15, will also occur following an overnight fast. As 
the trial progresses, the Sponsor may designate the Cycle 3 Day 15 biopsy as required, with 
the Cycle 2 Day 1 biopsy designated as optional.
 
 
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Future Biomedical Research Sample Collection 
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover samples listed in Section 9.7 (Pharmacodynamics) and 9.9 (Biomarkers)
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research will be collected from all participants in this study as 
specified in the SoA:
1. Blood (DNA) for genetic analysis
2. Peripheral Blood Mononuclear Cells (PBMC)
3. Blood for plasma biomarker analyses
4. Whole blood for immune profiling
5. Blood for serum biomarker analyses
6. Blood for RNA analyses
7. Archival tumor specimen
8. Tumor tissue biopsies
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. Samples should be collected for planned analysis 
of associations between genetic variants in germline/tumor DNA and drug response. If a 
documented law or regulation prohibits (or local Institutional Review Board/Independent 
Ethics Committee [IRB/IEC] does not approve) sample collection for these purposes, then 
such samples should not be collected at the corresponding sites. Leftover DNA extracted 
from planned genetic analysis samples will be stored for future biomedical research only if 
participant signs the Future Biomedical Research consent.
Blood Collection for Anti-Drug Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the procedure manual. ADA samples should be drawn according to the ADA collection 
schedule for all participants (Section 6.0). Simultaneous PK sampling is required for 
interpretation of ADA analysis.
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Approximately 28 days prior to treatment allocation/randomization, potential participants 
will begin evaluation to determine that they fulfill the entry requirements as set forth in 
 
 
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Sections 6.1 (Inclusion Criteria) and 6.2 (Exclusion Criteria). Screening procedures may be 
repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests are to be performed within 7 days prior to the first dose of study 
medication. Exceptions are hepatitis and thyroid testing, which may be done up to 28 
days prior to the first dose of trial treatment.
o
Tests performed prior to the participant signing the informed consent (IC) as part 
of routine clinical management are acceptable in lieu of a screening text, if the 
test is performed within the specified time frame.

Evaluation of ECOG (for eligibility confirmation) is to be performed within 7 days 
prior to the first dose of trial treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study medication. 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 submission is not required within 28 days prior to the first 
dose of trial treatment. This tissue may be confirmed as available and submitted up to 
90 days after treatment initiation.

Screening evaluations/procedures and Cycle 1 Day 1 (C1D1) cannot be on the same 
day.
Treatment Period
Visit requirements are outlined in Section 2 (SoA). Specific procedure-related details are 
provided above in Section 9 (Study Assessments and Procedures).
Participants with a clinical benefit (ie, stable disease, partial response, or complete response) 
as determined by the Investigator may receive up to 36 cycles (approximately 2 years) of 
treatment: 1 cycle of MK-7162 monotherapy followed by 35 cycles of MK-7162 
combination therapy with pembrolizumab.
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 Section 2 (SoA). Additional details regarding participant withdrawal and 
discontinuation are presented in Section 8 (Discontinuation/Withdrawal Criteria).
 
 
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Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first.
All AEs that occur prior to the Safety Follow-Up Visit should be recorded (up to 30 days 
following end of treatment). Participants with an AE of Grade >1 will be followed until the 
resolution of the AE to Grade 0 to 1 or until the beginning of a new anticancer therapy, 
whichever occurs first. SAEs that occur within 30 days (90 days following administration of 
pembrolizumab) of the end of treatment or before initiation of a new anticancer treatment 
should also be followed and recorded.
Survival Follow-up Visits
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 every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first.
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 prior to 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).
10. Statistical Analysis Plan 
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other non-confirmatory 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 non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, 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.
 
 
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Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Additional
details follow in Sections 10.2 through 10.9.
Study Design Overview
Phase 1b trial of MK-7162 in combination with 
pembrolizumab in participants with advanced/metastatic solid 
tumors.
Dose Escalation and Confirmation (Part A) applies a 
modified TPI design to determine a preliminary RP2D.
Dose Expansion cohorts (Part B) will be the subject of a 
future amendment.
Analysis Populations
Safety (Primary): All-Subjects-as-Treated (ASaT)
PK (Secondary): Per-Protocol (PP)
Efficacy (Secondary/ Exploratory): Full Analysis Set (FAS) 
Primary Endpoint(s)
Safety:
DLT
AE
Discontinuation of study treatment due to an AE
Secondary Endpoints
PK parameters of MK-7162 monotherapy and MK-7162 in 
combination with pembrolizumab; PK parameters of 
pembrolizumab in combination with MK-7162
ORR based on RECIST 1.1 and iRECIST as assessed by 
investigator
KYN and TRP will be measured as PD markers of IDO1 
inhibition
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic 
Analyses
ORR will be estimated using an exact method based on the 
binomial distribution (Clopper-Pearson interval). Exploratory 
efficacy analyses are documented in the sSAP.
PK parameters of study medicines will be summarized by 
planned visit and time for each dose separately.
Treatment Assignment
Participants will be allocated centrally through IVRS/IWRS 
to single agent MK-7162 followed by MK-7162 in 
combination with pembrolizumab. Participants will be 
allocated by nonrandom assignment. The trial is open-label.
 
 
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Statistical Methods for 
Safety Analyses
Summary statistics (counts, percentages, means, standard 
deviations, etc.) will be provided for the safety endpoints as 
appropriate. The pool-adjacent-violators-algorithm [Ji Y, Li 
Y, Bekele BN 2007] will be used to estimate the DLT rates 
across doses. The estimate of the DLT rate among 
participants treated at MTD (or MAD) of MK-7162 in 
combination with pembrolizumab and the 80% Bayesian 
credible intervals for the estimate will be provided.
Interim Analyses
Interim analyses will be conducted to examine clinical trial 
data on a continuous basis to allow for dose-finding 
decisions, safety, tolerability, and efficacy analysis.
Multiplicity
No multiplicity adjustment is planned in this Phase 1 trial.
Sample Size and Power 
The overall sample size for this study depends on the 
observed DLT profiles of MK-7162 in combination with 
pembrolizumab. A target sample size of approximately 40
participants will be used for study planning purposes for the 
Dose Escalation and Confirmation. 
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 not be randomized.
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 4.
Analysis Endpoints
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
ORR, based on RECIST 1.1 and iRECIST as assessed by the investigator, is a secondary 
endpoint, and PFS and OS are exploratory endpoints in this study. A description of efficacy 
measures is provided in Section 9.2.
PK endpoints include concentrations of MK-7162 and pembrolizumab, as well as derived PK 
parameters, and are described in Section 9.6.
The exploratory evaluation of biomarkers to be measured in the trial is described in Section 
9.9.
 
 
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Safety Endpoints
The primary safety endpoint is the incidence of DLTs. In addition, safety and tolerability will 
be assessed by clinical review of all relevant parameters including adverse events (AEs), 
laboratory tests, and vital signs.
A description of safety measures is provided in Section 9.3 and 9.5.
Analysis Populations
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all participants who received at least one dose of study treatment. In 
case of treatment administration errors, participants will be analyzed according to the 
treatment they actually received. The DLT evaluable population includes ASaT participants 
that were observed for safety for 42 days after the first dose of assigned treatment or 
experienced a DLT prior to 42 days after the first dose of assigned treatment. The 
replacement participants will also be considered evaluable if the above specified criteria are 
met. See Section 6.5 for details.
At least one laboratory or vital sign measurement obtained subsequent to at least one 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.
Pharmacokinetic Analysis Populations
The per protocol (PP) population will be used for the analysis of PK and target engagement 
data in this study. The PP population consists of the subset of participants who complied with 
the protocol sufficiently to ensure that the data generated will likely exhibit the effects of 
treatment, according to the underlying scientific model. Compliance includes such 
considerations as exposure to treatment, availability of measurements, and the absence of 
major protocol violations. Any participant 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 one treatment will be included in the PP analysis dataset.
Efficacy Populations
The FAS population will be used for the analyses of exploratory efficacy data in this study. It 
consists of all participants with a baseline scan that demonstrated measurable disease by the 
investigator’s assessment, and who were administered at least one dose of study treatment.
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory endpoints will be described in the sSAP.
 
 
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Statistical Methods for Efficacy Analysis
ORR will be estimated using an exact method based on the binomial distribution (Clopper-
Pearson interval). The statistical methods for analyses of PFS and OS will be documented in 
the sSAP.
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, deaths, laboratory tests, VS, ECG measurements, and physical examinations.
Adverse events will be summarized by counts and frequencies for each dose level. 
Laboratory tests, VS, and other safety endpoints will be summarized as appropriate.
Dose limiting toxicities will be listed and summarized by dose level. The pool adjacent-
violators-algorithm [Ji Y, Li Y, Bekele BN 2007], which forces the DLT rate estimates to be 
non-decreasing with increasing dose levels and pools adjacent violators for weighted 
estimates by sample size, will be used to estimate the DLT rates across doses. The estimate 
of the DLT rates among participants treated at the MTDs (or MADs) and the 80% Bayesian 
credible interval based on a prior distribution of Beta (1,1) for the estimate will be provided.
Summaries of Baseline Characteristics, Demographics and Other Analyses
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Serum concentrations of study treatment will be summarized by planned visit and time for 
each dose separately; PK parameters will be summarized by dose.
Details of statistical analysis on peripheral blood receptor and other PK and 
pharmacodynamics modeling analyses will be documented in the sSAP.
Interim Analyses
Interim analyses will be conducted to examine clinical trial data on a continuous basis to 
allow for dose-finding decisions, safety, tolerability, and efficacy analysis.
Multiplicity
There will be no multiplicity control in this study.
Sample Size and Power Calculations
The sample size for the Dose Escalation and Confirmation is expected to be approximately 
40 participants for study planning purposes. Based on the occurrence of DLTs, up to 14 
participants may enroll per dose level in the mTPI phase. The final sample size is dependent 
on the number of dose levels tested and emerging safety data. For example, in the absence of 
DLTs, 3 participants per dose level would be treated at 25 mg QD, 50 mg QD, 100 mg QD,
 
 
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and 200 mg QD and 14 participants would be treated at a dose level of 400 mg QD in the 
mTPI phase. In this scenario, the total sample size for Part A would be 26 participants.
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
 
 
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12. Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation
Definition
ADA
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
AMP
Adenosine monophosphate
aPTT
Activated partial thromboplastin time
ASaT
All-Subjects-as-Treated
AST
Aspartate aminotransferase
AUC
Area under the curve
βhCG
Beta-human chorionic gonadotropin
BID
Twice per day
C
Cycle
CBC
Complete blood count
CD
Cluster of differentiation (eg, CD8, CD28)
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
CRF
Case report form
CrCl
Creatinine clearance
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
D
Day
DLT
Dose-limiting toxicity
DNA
Deoxynucleic acid
ECG
Electrocardiogram
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EMA
European Medicines Agency
EoT
End of treatment
 
 
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Abbreviation
Definition
FBR
Future biomedical research
FDA
Food and Drug Administration
FDAA
Food and Drug Administration Amendments Act
GCP
Good clinical practice
GFR
Glomerular filtration rate
GGT
Gamma glutamyl transferase
GVHD
Graft-versus-host disease
HBsAg/HBV
Hepatitis B surface antigen/Hepatitis B virus
HIV
Human immunodeficiency virus
HNSCC
Head and neck squamous cell cancer
IB
Investigator’s Brochure
IC50
50% maximal inhibitor concentration
IC90
90% maximal inhibitor concentration
ICF
Informed consent form
ICH
International Conference on Harmonisation
IHC
Immunohistochemistry
INR
International normalized ratio
IRB/IEC
Institutional Review Board/Independent Ethics Committee
iRECIST
Immune Response Evaluation Criteria In Solid Tumors
IT
Intratumoral
IV
Intravenous
IVD
In vitro diagnostic
IVRS/IWRS
Interactive voice response system/integrated web response system
KYN
Kynurenin
LDH
Lactate dehydrogenase
MAD
Maximum administered dose
MRI
Magnetic Resonance Imaging
mRNA
Messenger ribonucleic acid
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
 
 
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Abbreviation
Definition
MSI
Microsatellite instability
NCI 
National Cancer Institute
NHV
Normal healthy volunteer
NSCLC
Non-small-cell lung cancer
ORR
Overall response rate
OS
Overall survival
OTC
Over-the-counter
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease
PD-1
Programmed cell death-1
PD-L1
Programmed cell death-1 ligand 1
PD-L2
Programmed cell death-1 ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetic
PO
Per os; by mouth
PP
Per-Protocol
pRBC
Packed red blood cells
PT
Prothrombin time
PTT
Partial thrombin time
QD
Once per day
Q3W 
Every 3 weeks
RCC
Renal cell cancer
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAD
Single ascending dose
SAE
Serious adverse events
SIM
Site Imaging Manual
SoA
Schedule of Activities
 
 
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Abbreviation
Definition
sSAP
Supplemental Statistical Analysis Plan
TRP
Tryptophan
ULN
Upper limit of normal
US
United States
WOCBP
Woman of Childbearing Potential
 
 
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Appendix 2: Clinical Laboratory Tests 

The tests detailed in Table 9 will be performed by the local laboratory. 

Laboratory safety tests for screening should be performed within 28 days prior to first 
dose of study medication. After Cycle 1, predose laboratory tests can be performed up 
to 72 hours prior to dosing. Results must be reviewed by the Investigator or qualified 
designee and found to be acceptable prior to dosing.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 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.
 
 
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Table 9
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Follicle Stimulating 
Hormone (FSH)
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-human chorionic 
gonadotropin (β-hCG) a
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Hepatitis
WBC (total and 
differential) b
Aspartate aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine 
(T3) (or Free T3 [FT3]) b
RBC
Carbon Dioxide or 
Bicarbonate
Microscopic exam, if 
abnormal results are 
noted
Total thyroxine (T4) (or 
Free T4 [FT4])
PT or INR
Calcium
Urine pregnancy test a
Thyroid Stimulating 
Hormone (TSH)
aPTT or PTT
Chloride
Cytokines
Creatinine c
Gamma glutamyl 
transpeptidase (GGT)
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total 
bilirubin is elevated above the 
upper limit of normal
Total protein
Blood Urea Nitrogen d
Lactic dehydrogenase
Uric acid
a Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.
b Absolute or % acceptable per institutional standard  
c For participants with a baseline calculated creatinine clearance that is below the normal institutional laboratory range, a 
baseline measured creatinine clearance should be performed.
d Blood Urea Nitrogen is preferred; if not available urea may be tested
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 3: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 participant safety is the overriding concern 
in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck 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.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants may withdraw from a Merck 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
Merck is committed to safeguarding participant confidentiality, to the greatest extent possible.  Unless required by 
law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential 
medical records that might identify the research participant by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck 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.
Merck does not pay for participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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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.
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 which 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.
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 institutional review board, ethics review committee (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 trial 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 trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
 
 
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial 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 trial.  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.
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.
Compliance with Trial 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 trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow participants to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial 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 trial or its results to those 
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
 
 
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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 trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in this appendix 
under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
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 trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
 
 
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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. 
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.
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 trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment (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 treatment 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 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, 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.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
 
 
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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 9.3.5 for protocol specific exceptions
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 
A 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 a serious adverse event.  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a Merck product and is documented in the patient’s 
medical history.
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) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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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 one 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.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
In addition to the above criteria, adverse events 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.
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 Adverse Event 
case report forms/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.
 
 
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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 4.0. Any adverse event which changes CTCAE 
grade over the course of a given episode will have each change of grade recorded on 
the adverse event case report forms/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 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.
Assessment of Causality
●
Did the Sponsor's product cause the adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event 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 adverse event 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 adverse event:
●
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 trials with investigational 
medicinal product)?
 
 
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●
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 trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
If yes, did the AE recur or worsen?
●
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 trial is a single-dose drug trial); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH 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 INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment 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. 
 
 
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●
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.
●
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 one 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 adverse event causality to the 
combination regimen or to a single agent of the combination.  In general, causality 
attribution should be assigned to the combination regimen (i.e., 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 adverse 
event 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.
 
 
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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 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
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 electronic data collection 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 electronic data collection 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 Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection 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 Trial File Binder (or equivalent).
 
 
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
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 follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal 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.
Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 6.1: 
●
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
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 10 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant.
○
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.
 
 
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Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use 
one of the contraception methods described in Table 10 consistently and correctly during the 
protocol-defined time frame in Section 6.1.
Table 10
Contraceptive Methods
Acceptable Contraceptive Methods 
Failure rate of >1% per year when used consistently and correctly.
●
Male or female condom with or without spermicide
●
Cervical cap, diaphragm or sponge with spermicide
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing) hormonal contraception b
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c
●
Intrauterine hormone-releasing system (IUS) b
●
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 treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
 
 
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Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.
a) Typical use failure rates are higher than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for 
at least 120 days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential, after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. 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.1
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.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
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.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
trial 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 trial flow chart.  If delayed, present consent at next possible Participant Visit.  
 
 
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Consent forms signed by the participant will be kept at the clinical trial site under 
secure storage for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be 
captured in the electronic Case Report Forms (eCRFs). Any specimens for which 
such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. 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 trial purposes.
4. 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 trial 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 trial 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 trial site.  No personal identifiers will 
appear on the specimen tube.  
5. 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 sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
 
 
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6. 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 trial. If 
medical records for the main trial 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 trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 
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. 
7. 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 trial 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 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial 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.
 
 
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9. 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.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for Future Biomedical Research (i.e., only leftover samples are being 
retained).’
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.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; http://www.ich.org/LOB/
media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
 
 
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Appendix 7:  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 [X]). 
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 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. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
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 non-target lesion(s) identified at baseline

Development of new lesion(s)
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 non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
 
 
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New lesions will be classified as measurable or non-measurable, 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 – Non-target.
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 initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
o
For non-target 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
o
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 non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
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.
 
 
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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 Section 2 and submitted to the central imaging vendor.
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
o
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.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
 
 
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Confidential

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
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
o
Previously identified non-target 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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