Conditions: Advanced Solid Tumors
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 27
Healthy volunteers: no

Brief summary:
The study will evaluate the safety, tolerability, and pharmacokinetics (PK) of MK-1088 in monotherapy and in combination with pembrolizumab in participants with advanced solid tumors who have not responded to conventional therapy. The effect of MK-1088 on tumor size will also be examined.

Detailed description:

Arms:
arm 1: Participants received MK-1088 daily (QD) orally at 100 mg on days 1-21 of each 21-day cycle for up to 35 cycles (up to \~24 months). arm 2: Participants received MK-1088 (QD) orally at 200 mg on days 1-21 of each 21-day cycle for up to 35 cycles (up to \~24 months) arm 3: Participants received MK-1088 (QD) orally at 400 mg on days 1-21 of each 21-day cycle for up to 35 cycles (up to \~24 months) arm 4: Participants received MK-1088 (QD) orally at 600 mg on days 1-21 of each 21-day cycle for up to 35 cycles (up to \~24 months) arm 5: Participants received MK-1088 daily (QD) orally at 100 mg on days 1-21 of each 21-day cycle plus pembrolizumab at 200 mg intravenous (IV) infusion every 3 weeks (Q3W), on Day 1 of each 21-day cycle for up to 35 cycles (up to \~24 months) arm 6: Participants received MK-1088 daily (QD) orally at 200 mg on days 1-21 of each 21-day cycle plus pembrolizumab at 200 mg intravenous (IV) infusion every 3 weeks (Q3W), on Day 1 of each 21-day cycle for up to 35 cycles (up to \~24 months)

Interventions: intervention 1: MK-1088 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Oral Tablet intervention 2: IV Infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1/Phase 2 Study to Evaluate the
Safety and Tolerability of MK-1088
as Monotherapy and in Combination with
Pembrolizumab in Participants with Advanced
Solid Tumors
NCT05394350
29-Jun-2022


PRODUCT: MK-1088  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 1/Phase 2 Study to Evaluate the Safety and Tolerability of MK-1088 
as Monotherapy and in Combination with Pembrolizumab in Participants with Advanced 
Solid Tumors
Protocol Number: 002-01
Compound Number: MK-1088
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
160204
EudraCT
2021-006712-93
Approval Date: 29 June 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
29-JUN-2022
Address agency comments
Original Protocol
15-DEC-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
The rationale for this amendment is to address agency feedback.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.3.1.1  Part 1, Arms 1 and 2, 
and Arm 1 Crossover to Arm 
2: Screening Through End-of-
Treatment Phase
Table 1: Modified the Scheduling Window for 
some of the scheduled visits
Updated for clarity
Provides clarity in the Notes and in footnotes for 
Cycle 1 and Cycle 2 evaluation collection in 
relation to intervention administration
Updated for clarity
5.1.1  Inclusion Criteria for 
Arm 1 and Arm 2
Inclusion Criterion number 8: Table 4: Adjusted 
renal evaluations and related laboratory values
Update addresses agency feedback
5.2.1  Exclusion Criteria for 
Arm 1 and Arm 2
Exclusion Criterion number 16: Provides 
specific details regarding clinically significant 
cardiovascular disease
Update addresses agency feedback
EC number 17:
Provides new criteria: QTcF
Update addresses agency feedback
EC number 18:
Provides new criteria: stem cell or organ 
transplant
Provides clarity for eligibility
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Section # and Name
Description of Change 
Brief Rationale 
EC number 23:
Deleted text due to conflicting language
Provides clarity for eligibility
EC number 24:
Revised text to reduce redundancy
Provides clarity for eligibility
EC number 26:
Revised text to clarify conflicting language
Provides clarity for eligibility
EC number 28:
Provides new criterion: recovery from surgery or 
ongoing complications
Provides clarity for eligibility
5.3.1  Meals and Dietary 
Restrictions
Update provides guidance for fasting 
requirements.
Update addresses agency feedback
5.3.3  Activity Restrictions
Update aligns with the IB content.
Update aligns with information provided in the 
most current MK-1088 IB
4.1 Overall Design
Updated language to indicate ‘adjusted’ mTPI
Update addresses agency feedback
4.3.1.2  Rationale for Dose 
Interval and Escalation 
Increments
Updated language to indicate ‘adjusted’ mTPI
Update addresses agency feedback
4.3.1.3  Dose Finding Using a 
Modified Toxicity Probability 
Interval Design
Updated language in text and also Table 3 
(Dose-finding Rules per Adjusted mTPI Design) 
to show the change in some actions/rules for 
given DLTs and AEs
Update addresses agency feedback
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Section # and Name
Description of Change 
Brief Rationale 
6.3.1 Intervention Assignment
Updated language to indicate ‘adjusted’ mTPI
Update addresses agency feedback
6.5  Concomitant Therapy
Table 6: Removed reference to CYP2C8
CYP2C8 substrates are permitted, not 
prohibited, as concomitant therapy
6.6.3 Cohort Expansion
Updated language to indicate ‘adjusted’ mTPI
Update addresses agency feedback
9.1 Statistical Analysis Plan 
Summary
Updated language to indicate ‘adjusted’ mTPI
Update addresses agency feedback
10.2  Appendix 2: Clinical 
Laboratory Tests
Updated to state laboratory evaluations are 
performed locally, not centrally.
Provides correct language
Table 12: Updated footnotes for lab evaluation 
collection and analysis
Provides clarity
Title Page
Updated the corporate name address
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ USA. This 
conversion resulted only in an entity name 
change and update to the address.
10.1.1  Code of Conduct for 
Clinical Trials
Updated the corporate name and address
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ USA. This 
conversion resulted only in an entity name 
change and update to the address.
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Section # and Name
Description of Change 
Brief Rationale 
8.4  Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
Update instructs the investigators to document if 
an SAE was associated with a medication error, 
misuse, or abuse
Per REGULATION (EU) No 536/2014 OF 
THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL
10.3.1 Definitions of 
Medication Error, Misuse, and 
Abuse
This is a new section that provides definitions 
for medication error, misuse, and abuse
Per REGULATION (EU) No 536/2014 OF 
THE EUROPEAN PARLIAMENT AND OF 
THE COUNCIL
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................21
1.3.1
Schedule of Activities for Part 1: Dose Escalation and Confirmation for 
Arm 1 (MK-1088 Monotherapy) and Arm 2 (MK-1088 in Combination 
With Pembrolizumab), and for Arm 1 Crossover to Arm 2 ........................21
1.3.1.1
Part 1, Arms 1 and 2, and Arm 1 Crossover to Arm 2: Screening 
Through End-of-Treatment Phase......................................................21
1.3.1.2
Part 1, Arms 1 and 2, and Arm 1 Crossover to Arm 2: 
Posttreatment Phase ...........................................................................29
2
INTRODUCTION..........................................................................................................30
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................31
2.2.1.1
MK-1088 Pharmaceutical and Therapeutic Background...................31
2.2.1.2
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 
Background........................................................................................32
2.2.2
Preclinical and Clinical Studies ...................................................................33
2.2.3
Ongoing Clinical Studies.............................................................................33
2.2.3.1
MK-1088 Clinical Studies .................................................................33
2.2.3.2
Pembrolizumab (MK-3475) Clinical Studies ￼...............................33
2.3
Benefit/Risk Assessment......................................................................................34
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................34
4
STUDY DESIGN............................................................................................................35
4.1
Overall Design......................................................................................................35
4.2
Scientific Rationale for Study Design.................................................................38
4.2.1
Rationale for Endpoints ...............................................................................39
4.2.1.1
Efficacy Endpoints.............................................................................39
4.2.1.1.1
Response Rate Assessed by RECIST Version 1.1...................39
4.2.1.2
Safety Endpoints................................................................................39
4.2.1.3
Pharmacokinetic Endpoints ...............................................................39
4.2.1.4
Planned Exploratory Biomarker Research.........................................40
4.2.1.5
Future Biomedical Research..............................................................41
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4.3
Justification for Dose...........................................................................................42
4.3.1
Starting Dose for This Study........................................................................42
4.3.1.1
Rationale for Starting and Maximum Dose of MK-1088..................42
4.3.1.2
Rationale for Dose Interval and Escalation Increments.....................43
4.3.1.3
Dose Finding Using a Modified Toxicity Probability Interval 
Design ................................................................................................43
4.4
Beginning and End-of-Study Definition ............................................................45
4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................46
5.1
Inclusion Criteria.................................................................................................46
5.1.1
Inclusion Criteria for Arm 1 and Arm 2 ......................................................46
5.2
Exclusion Criteria................................................................................................50
5.2.1
Exclusion Criteria for Arm 1 and Arm 2 .....................................................51
5.3
Lifestyle Considerations......................................................................................54
5.3.1
Meals and Dietary Restrictions....................................................................54
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................54
5.3.3
Activity Restrictions ....................................................................................54
5.4
Screen Failures.....................................................................................................54
5.5
Participant Replacement Strategy......................................................................54
6
STUDY INTERVENTION............................................................................................55
6.1
Study Intervention(s) Administered...................................................................55
6.1.1
Medical Devices...........................................................................................57
6.2
Preparation/Handling/Storage/Accountability .................................................57
6.2.1
Dose Preparation..........................................................................................57
6.2.2
Handling, Storage, and Accountability........................................................57
6.3
Measures to Minimize Bias: Randomization and Blinding..............................58
6.3.1
Intervention Assignment..............................................................................58
6.3.2
Stratification.................................................................................................59
6.3.3
Blinding........................................................................................................59
6.4
Study Intervention Compliance..........................................................................59
6.5
Concomitant Therapy..........................................................................................59
6.5.1
MK-1088 Supportive Care...........................................................................62
6.5.2
Rescue Medications and Supportive Care ...................................................63
6.5.3
Pembrolizumab Supportive Care.................................................................63
6.6
Dose Modification (Escalation/Titration/Other)...............................................63
6.6.1
Dose Administration/Escalation ..................................................................63
6.6.1.1
Dose Administration (Preparation)....................................................63
6.6.2
Definition of Dose‑limiting Toxicity ..........................................................63
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6.6.3
Cohort Expansion.........................................................................................64
6.6.4
Guidelines for Dose Modification due to Adverse Events for MK-1088....65
6.6.5
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................67
6.7
Intervention After the End of the Study............................................................74
6.8
Clinical Supplies Disclosure................................................................................74
6.9
Standard Policies..................................................................................................74
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................75
7.1
Discontinuation of Study Intervention...............................................................75
7.2
Participant Withdrawal From the Study...........................................................76
7.3
Lost to Follow-up .................................................................................................76
8
STUDY ASSESSMENTS AND PROCEDURES........................................................77
8.1
Administrative and General Procedures ...........................................................77
8.1.1
Informed Consent.........................................................................................77
8.1.1.1
General Informed Consent.................................................................78
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................78
8.1.2
Inclusion/Exclusion Criteria ........................................................................78
8.1.3
Participant Identification Card.....................................................................78
8.1.4
Medical History ...........................................................................................79
8.1.5
Prior and Concomitant Medications Review...............................................79
8.1.5.1
Prior Medications...............................................................................79
8.1.5.2
Concomitant Medications..................................................................79
8.1.6
Assignment of Screening Number...............................................................80
8.1.7
Assignment of Treatment/Randomization Number.....................................80
8.1.8
Study Intervention Administration ..............................................................80
8.1.8.1
Timing of Dose Administration.........................................................80
8.1.8.2
Timing of Administration for MK-1088............................................80
8.1.8.3
Timing for Administration of Pembrolizumab ..................................81
8.1.9
Discontinuation and Withdrawal .................................................................81
8.1.9.1
Withdrawal From Future Biomedical Research ................................81
8.1.10
Participant Blinding/Unblinding..................................................................82
8.1.11
Calibration of Equipment.............................................................................82
8.2
Efficacy/Immunogenicity Assessments ..............................................................82
8.2.1
Tumor Scans and Assessment of Disease....................................................82
8.2.2
Initial Tumor Scans......................................................................................83
8.2.3
Tumor Scans During the Study....................................................................83
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8.2.4
End of Treatment and Follow-up Tumor Scans...........................................84
8.2.5
RECIST 1.1 and PCWG-modified RECIST 1.1 Assessment of Disease ....84
8.3
Safety Assessments...............................................................................................86
8.3.1
Physical Examinations.................................................................................86
8.3.1.1
Full Physical Examination.................................................................86
8.3.1.2
Directed Physical Examination..........................................................87
8.3.2
Vital Signs....................................................................................................87
8.3.3
Electrocardiograms ......................................................................................87
8.3.4
Clinical Safety Laboratory Assessments .....................................................87
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................88
8.3.5
Pregnancy Testing........................................................................................88
8.3.6
Eastern Cooperative Oncology Group Performance Status.........................88
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................89
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................89
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......91
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...92
8.4.4
Regulatory Reporting Requirements for SAE .............................................92
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................92
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................93
8.4.7
Events of Clinical Interest............................................................................93
8.5
Treatment of Overdose........................................................................................93
8.6
Pharmacokinetics.................................................................................................93
8.6.1
Blood Collection for Plasma MK-1088 .......................................................94
8.7
Pharmacodynamics..............................................................................................94
8.8
Biomarkers ...........................................................................................................94
8.8.1
Planned Genetic Analysis Sample Collection..............................................94
8.9
Future Biomedical Research Sample Collection...............................................95
8.10
Health Economics Medical Resource Utilization and Health Economics.......95
8.11
Visit Requirements...............................................................................................95
8.11.1
Screening......................................................................................................95
8.11.2
Treatment Period/Vaccination Visit ............................................................95
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........95
8.11.4
Posttreatment Visit.......................................................................................95
8.11.4.1
Safety Follow-up Visit.......................................................................96
8.11.4.2
Efficacy Follow-up Visits..................................................................96
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8.11.4.3
Survival Follow-up Contacts .............................................................96
8.11.5
Poststudy......................................................................................................96
8.11.6
Vital Status...................................................................................................97
9
STATISTICAL ANALYSIS PLAN .............................................................................97
9.1
Statistical Analysis Plan Summary.....................................................................97
9.2
Responsibility for Analyses/In-house Blinding .................................................98
9.3
Hypotheses/Estimation ........................................................................................98
9.4
Analysis Endpoints...............................................................................................98
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................98
9.4.2
Safety Endpoints..........................................................................................99
9.5
Analysis Populations............................................................................................99
9.5.1
Safety Analysis Populations ........................................................................99
9.5.2
Pharmacokinetic Analysis Populations........................................................99
9.5.3
Efficacy Analysis Populations...................................................................100
9.6
Statistical Methods.............................................................................................100
9.6.1
Statistical Methods for Efficacy Analysis..................................................100
9.6.2
Statistical Methods for Safety Analysis.....................................................100
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................100
9.6.3.1
Demographic and Baseline Characteristics .....................................100
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........101
9.7
Interim Analyses ................................................................................................101
9.8
Multiplicity .........................................................................................................101
9.9
Sample Size and Power Calculations ...............................................................101
9.10
Subgroup Analyses.............................................................................................101
9.11
Compliance (Medication Adherence)...............................................................101
9.12
Extent of Exposure.............................................................................................101
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................102
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......102
10.1.1
Code of Conduct for Clinical Trials...........................................................102
10.1.2
Financial Disclosure...................................................................................104
10.1.3
Data Protection...........................................................................................105
10.1.3.1
Confidentiality of Data ....................................................................105
10.1.3.2
Confidentiality of Participant Records.............................................105
10.1.3.3
Confidentiality of IRB/IEC Information..........................................105
10.1.4
Publication Policy......................................................................................106
10.1.5
Compliance with Study Registration and Results Posting Requirements .106
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10.1.6
Compliance with Law, Audit, and Debarment ..........................................106
10.1.7
Data Quality Assurance .............................................................................107
10.1.8
Source Documents .....................................................................................108
10.1.9
Study and Site Closure...............................................................................108
10.2
Appendix 2: Clinical Laboratory Tests............................................................109
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................110
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................110
10.3.2
Definition of AE ........................................................................................110
10.3.3
Definition of SAE ......................................................................................111
10.3.4
Additional Events Reported in the Same Manner as SAE.........................113
10.3.5
Recording AE and SAE .............................................................................113
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................116
10.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................118
10.5
Appendix 5: Contraceptive Guidance..............................................................119
10.5.1
Definitions..................................................................................................119
10.5.2
Contraception Requirements......................................................................120
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................121
10.7
Appendix 7: Country-specific Requirements..................................................126
10.8
Appendix 8: Abbreviations ...............................................................................127
10.9
Appendix 9: Prostate Cancer Working Group Criteria ................................130
11
REFERENCES.............................................................................................................134
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LIST OF TABLES
Table 1
Schedule of Activities: Screening through End-of-Treatment Phase for 
Part 1, Arm 1 and Arm 2, and Arm 1 Crossover to Arm 2..............................21
Table 2
Schedule of Activities: Posttreatment Phase for Part 1, Arm 1 and Arm 2, 
and Arm 1 Crossover to Arm 2........................................................................29
Table 3
Dose-finding Rules per Adjusted mTPI Design ..............................................45
Table 4
Adequate Organ Function Laboratory Values .................................................49
Table 5
Study Interventions..........................................................................................56
Table 6
Examples of Medications, Supplements, and Other Substances Prohibited 
During the Trial................................................................................................61
Table 7
MK-1088 Monotherapy: Dose Modification and Treatment 
Discontinuation Guidelines for Treatment Emergent Adverse Events............66
Table 8
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy or 
IO Combinations..............................................................................................69
Table 9
Pembrolizumab Monotherapy or IO Combinations Infusion Reaction Dose 
Modification and Treatment Guidelines ..........................................................73
Table 10
Overall Radiographic Response per PCWG-modified RECIST 1.1 ...............85
Table 11
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................91
Table 12
Protocol-required Safety Laboratory Assessments........................................109
Table 13
Bone Response Abbreviations and Associated Definitions...........................131
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LIST OF FIGURES
Figure 1
Part 1 Study Design: Dose Escalation and Confirmation of MK-1088 as a 
Single Agent (Arm 1) and in Combination with Pembrolizumab (Arm 2); 
Part 2: Dose Expansion in 3 Selected Solid Tumor Cohorts ...........................20
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1/Phase 2 Study to Evaluate the Safety and Tolerability of MK-1088 
as Monotherapy and in Combination with Pembrolizumab in Participants with Advanced 
Solid Tumors
Short Title: Phase 1/Phase 2 Study of MK-1088 as Monotherapy and in Combination with 
Pembrolizumab in Participants with Solid Tumors
Acronym:
Hypotheses, Objectives, and Endpoints:
In male and female participants with advanced/metastatic solid tumors:
Objectives
Endpoints
Primary
•
To determine the safety and tolerability 
and to establish a preliminary maximum 
tolerated dose/recommended Phase 2 
dose of MK-1088 administered as 
monotherapy and in combination with 
pembrolizumab infusion in Part 1
•
Dose-limiting toxicity (DLT)
•
Adverse events (AE)
•
Discontinuing study intervention due to 
an AE
Secondary
•
To evaluate the PK of MK-1088 
administered as monotherapy and in 
combination with pembrolizumab 
infusion in Part 1 and in Part 2
•
PK parameters including AUC and 
Cmax
•
To evaluate the antitumor activity 
(objective response rate [ORR] based on 
PCWG-modified RECIST 1.1 [prostate 
cancer participants only] or RECIST 1.1 
[all other participants]) of MK-1088 as 
assessed by the investigator when used as 
monotherapy and in combination with 
pembrolizumab in Part 1 and in Part 2
•
Objective response (OR) is a complete 
response (CR) or partial response (PR)
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Overall Design:
Study Phase
Phase 1/Phase 2
Primary Purpose
Treatment
Indication
Treatment of advanced/metastatic solid tumors
Population
Participants with advanced/metastatic solid tumors
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant 
(or their legally acceptable representative) provides 
documented informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Approximately 80 participants will be allocated for participation in Part 1 of this study.
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Intervention Groups and Duration:
Intervention 
Groups
Interven-
tion 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Part 1:
Arm 1
and 
Arm 2
MK-1088
50 mg,
100 mg, 
QD
Oral
Day 1 to Day 21 
of each treatment 
cycle for up to 35 
cycles
Experi-
mental
Part 1:
Arm 2
Part 2: 
(to be 
speci-
fied)
Pembro-
lizumab 
(MK-3475)
100 mg 
per vial
Q3W
Intravenous
Day 1 of each 
treatment cycle 
for up to 35 
cycles
Experi-
mental
Part 2: 
(to be 
speci-
fied)
MK-1088
50 mg, 
100 mg
This will 
be based
on the 
RP2D
from
Part 1
Oral
Day 1 to Day 21 
of each treatment 
cycle for up to 35 
cycles
Experi-
mental
Total 
Number of 
Intervention 
Groups/
Arms
Total number of Intervention Groups: 2
Duration of 
Participation
Each participant will participate in the study for up to approximately 
28 months from the time the participant provides documented informed 
consent through the final contact. After a screening phase of up to 28 days, 
each participant will receive assigned intervention for up to 24 months. 
After the end of treatment, each participant will be followed for a minimum 
of 30 days.
During Part 1 (Dose Escalation and Confirmation), participants will receive 
treatment with MK-1088 as monotherapy (Arm 1) or as combination 
therapy with pembrolizumab (Arm 2). Study treatment will begin on Day 1 
of each 21-day cycle. Participants enrolled in Arm 1 and in Arm 2 may 
continue treatment for up to 35 cycles (approximately 2 years) from the 
start of treatment.
Participants in Arm 1 who experience disease progression by either clinical 
or radiographic evaluation, may cross over into Arm 2, provided they meet 
eligibility criteria. Participants who cross over to combination treatment 
will be eligible to receive a maximum of 35 cycles of combination 
treatment irrespective of the number of cycles of MK-1088 received in 
monotherapy.”
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After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy. 
All participants, except for those who withdraw consent or are lost to 
follow-up, will be followed up for survival. Participants who experience 
confirmed disease progression or start a new anticancer therapy, will move 
into the Survival Follow-up Phase and should be contacted every 12 weeks 
to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees for this study.
Study Accepts Healthy Volunteers: No
Abbreviations are not spelled out at first use. A list of abbreviations used in this document is 
in Appendix 8. Note that “subject” or “participant” may be used to refer to individuals 
enrolled in clinical trials.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Part 1 Study Design: Dose Escalation and Confirmation of MK-1088 as a Single 
Agent (Arm 1) and in Combination with Pembrolizumab (Arm 2); Part 2: Dose 
Expansion in 3 Selected Solid Tumor Cohorts
Abbreviations: DL = dose level; mTPI = modified Toxicity Probability Interval; N = participant population size; PK = 
pharmacokinetic; Q3W = every 3 weeks; 
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1.3
Schedule of Activities
1.3.1
Schedule of Activities for Part 1: Dose Escalation and Confirmation for Arm 1 (MK-1088 Monotherapy) and Arm 2 
(MK-1088 in Combination With Pembrolizumab), and for Arm 1 Crossover to Arm 2
1.3.1.1
Part 1, Arms 1 and 2, and Arm 1 Crossover to Arm 2: Screening Through End-of-Treatment Phase
Table 1
Schedule of Activities: Screening through End-of-Treatment Phase for Part 1, Arm 1 and Arm 2, and Arm 1 Crossover to
Arm 2
Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Administrative Procedures
Informed Consent
X
Documented IC must be 
obtained before performing 
protocol-specific procedures.
Participants may elect to 
continue study treatment beyond 
disease progression and will 
require additional consent.
Informed Consent for Optional 
Future Biomedical Research
X
This is optional for the 
participant.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Update with the treatment 
number at the time of treatment 
allocation.
Demography and Medical History
X
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Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
Treatment Allocation
X
Treatment allocation may occur 
up to 3 days before C1D1.
Part 1 Arm 1 and Arm 2:
MK-1088 
Administration/Dispense
X
X
X
X
MK-1088: taken orally QD from 
D1 through D21 of each 
treatment cycle.
Part 1 Arm 2:
Pembrolizumab Administration 
X
X
X
X
Pembrolizumab: administered IV
Q3W on D1 of each treatment 
cycle.
Anticancer Therapy Status
X
Any changes in new treatment 
will be collected.
Disease Status
X
Clinical Procedures/Assessments
Full Physical Examination
X
X
Directed Physical Examination
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
Vital Signs
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
Obtain heart rate, respiratory 
rate, blood pressure,
temperature.
12-lead Electrocardiogram
X
X
X
X
X
C1D1 and C2D1: Obtain
predose and 2 hrs postdose.
C1D2 and C2D2: Obtain 
predose.
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Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
ECOG Performance Status
X
X
X
X
X
X
Obtain within 72 hrs before the
first dose of study intervention
on D1 of each cycle.
AE Monitoring
X
X
Tumor Imaging Response 
Assessment
(PCWG-modified RECIST 1.1 for 
prostate cancer participants; 
RECIST 1.1 for all other 
participants)
X
X
Treatment phase schedule: 
Obtain every 9 weeks (±7 
days)
After 54 weeks, obtain every 
12 weeks (±7 days)
Prostate cancer participants only:
Bone Scan
X
X
Tc99 bone scintigraphy (nuclear 
medicine bone scan) is required 
at screening and on-study at all 
protocol-required tumor 
assessment visits and when 
clinically indicated.
Tumor assessments visits:
Obtain every 9 weeks (±7 
days)
After 54 weeks, obtain every 
12 weeks (±7 days)
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Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Non-prostate cancer participants:
Bone Scan
X
X
Examples of acceptable scans:
nuclear medicine bone scan, 
PET scan, PET-CT, etc. 
Obtain at screening for 
participants with history of bone 
metastases or if bone metastases
are suspected.
Obtain when clinically indicated 
or to confirm CR when bone 
metastases were present at 
screening.
CT/MRI chest, abdomen, pelvis 
X
X
Obtain at screening for all 
participants, at protocol-required 
tumor assessment visits, and 
when clinically indicated.
Tumor assessment visits:
Every 9 weeks (±7 days)
After 54 weeks, obtain every 
12 weeks (±7 days)
Brain Scan
X
X
Required at screening for 
participants with known history 
of brain metastases or if brain 
metastases are suspected.
On study, obtain when clinically 
indicated or to confirm CR when 
brain metastases were present at 
screening. 
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Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Vital Status
X
Participants may be contacted 
for survival information at any 
time during the study, on 
Sponsor request.
Laboratory Procedures / Assessments
Comprehensive Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
Microscopic analysis is required 
if dipstick results are abnormal.
HIV, hepatitis B and C screen 
(per site SOP)
X
Screening requirements are
based on history and local 
regulations.
Refer to Sections 5.1 and 5.2.
PT/INR and aPTT or PTT
X
Perform at screening, then as 
clinically indicated. 
Thyroid Function Tests 
(TSH, T3 or free T3, free T4)
X
X
X
X
X
After C2D1: testing will be 
performed D1 of every other 
cycle (ie, C4, C6, C8, etc.)
Prostate cancer participants 
only:
PSA
X
X
X
X
X
X
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Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Pregnancy test for WOCBP only: 
urine or serum β-hCG
X
X
X
X
X
Perform a highly sensitive 
pregnancy test (urine or serum 
per local guidelines) within 24
hrs before C1D1. If screening 
collection is conducted within 
this timeframe, no need to repeat 
for C1D1.
Pregnancy test should be 
performed before each treatment 
cycle (24 hrs for urine and 72 hrs
for serum test).
Obtain urine pregnancy test as 
indicated; if test is positive or 
cannot be confirmed as negative, 
a serum pregnancy test is 
required.
Additional pregnancy testing 
may be conducted if required by 
local regulations or if clinically 
indicated.
Pharmacokinetics / Pharmacodynamics / Future Biomedical Research / Biomarkers
Blood for Genetic Analysis 
X
Predose: See Section 8.8.
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Study Phase
Screening
Phase a
Treatment Phase (3-Week Cycles)
End of 
Treatment 
/Discon-
tinuation
Notes
Treatment Cycle/Title:
Screening 
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Cycles 
4 to 35
Treatment Days
per Cycle:
Up to 28 days
before
Day 1 Cycle 1
Day 
1b
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
2c
Day 
8
Day 
15
Day 
1
Day 
8
Day 
15
Day 1
At time of 
treatment 
discon-
tinuation
Treatment Phase: Procedures, 
assessments, and samples are 
collected predose unless 
otherwise specified.
Scheduling Window (Days) 
-28 to -1
0
0
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+3
Plasma for MK-1088 PK assay
X
X
X
X
X
X
X
On the day(s) of sample 
collection, participants must not 
take study medication until the 
predose PK and biomarker 
(Section 8.8) sample collections 
are complete. Document the time 
of the last MK-1088 dose (ie, at 
home) taken before PK 
collection.
C1D1 and C2D1: Obtain 
predose and 1, 2, 4, and 8 hrs 
postdose.
C1D2 and C2D2: Obtain 
predose (24 hrs after D1 dosing 
for C1 and C2)
C3, C4 and every 4 cycles (ie, 
C4, C8, etc): Obtain predose
Blood for Serum Biomarker 
Analysis
X
X
X
Obtain predose
Blood for RNA Analyses
X
X
X
Obtain predose
Tumor Tissue Collection
Archival or Newly Obtained
Tumor Tissue Collection
X
See detailed tissue collection 
requirements in the 
Procedure/Lab Manual.
Participants in Arm 1 who cross
over to Arm 2 do not need to 
provide an additional sample.
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AE=adverse event; aPTT= activated partial thromboplastin time; β-hCG=beta-human chorionic gonadotropin; C=Cycle; CR=complete response; CT=computed tomography; 
D=Day; ECOG=Eastern Cooperative Oncology Group; HIV= human immunodeficiency virus; MRI=magnetic resonance imaging; PCWG=Prostate Cancer Working Group; 
PET= positron emission tomography; PK=pharmacokinetic; PSA=prostate-specific antigen; PT/INR=prothrombin time/international normalized ratio; PTT= partial 
thromboplastin time; Q3W=every 3 weeks; QD=once daily; RECIST=Response Evaluation Criteria In Solid Tumors; RNA=ribonucleic acid; SOP=standard operating 
procedure; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
a
Arm 1 crossover to Arm 2: Screening assessments obtained during Arm 1 may be eligible for crossover screening for Arm 2 if the assessments were obtained within 28 days 
before Arm 2 treatment initiation.
b
Laboratory tests should be performed within 3 days before the first dose of study intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days before the first dose. Please refer to Section 8.3.4.1 for details.
c
C1D2 and C2D2 evaluations must be obtained withjn 24 hours after study intervention administration for C1D1 and C2D1.
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1.3.1.2
Part 1, Arms 1 and 2, and Arm 1 Crossover to Arm 2: Posttreatment Phase
Table 2
Schedule of Activities: Posttreatment Phase for Part 1, Arm 1 and Arm 2, and Arm 1 Crossover to Arm 2
Study Phase:
Posttreatment
Title:
Safety
Follow-up
Imaging
Follow-up
Survival 
Follow-up
Notes
Timing/frequency for Follow-up:
30 days after the
last dose of
study medication
Arm 2 only: 
90 days after the
last dose of
pembrolizumab
Every 12 weeks
Every 12 weeks
Scheduling Window (Days):
±7
±7
±7
±7
Administrative Procedures
Concomitant Medication Review
X
X
Arm 2: 90-day follow-up can be performed with a 
telephone call.
Anticancer Therapy Status
X
X
Any changes in new treatment will be collected.
Disease Status
X
X
X
See Sections 8.11.4.2 and 8.11.4.3.
Clinical Procedures / Assessments
Full Physical Examination
X
Vital Signs
X
Obtain heart rate, respiratory rate, blood pressure, 
temperature.
ECOG Performance Status
X
AE Reporting
Arm 2: 90-day follow-up can be performed with a 
telephone call.
Vital Status
On 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 vital status.
Tumor Imaging Response Assessment
X
PCWG-modified RECIST 1.1 for prostate cancer 
participants; RECIST 1.1 for all other participants.
Use the same type of scans obtained during treatment 
phase.
Laboratory Procedures / Assessments
Comprehensive Chemistry Panel
X
Hematology
X
Thyroid Function Tests
(TSH, T3 or free T3, free T4)
X
Pharmacokinetics 
Plasma for MK-1088 PK
X
AE=adverse event; ECOG=Eastern Cooperative Oncology Group; PCWG=Prostate Cancer Working Group; PK=pharmacokinetic; RECIST= Response Evaluation Criteria In Solid Tumors; 
TSH=thyroid-stimulating hormone.
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2
INTRODUCTION
MK-1088 is a novel small molecule that is a dual antagonist of the adenosine A2A and A2B
receptors. MK-1088 is under study for the treatment of solid tumors as monotherapy and as 
combination therapy with pembrolizumab. This is a dose-escalation and dose-finding study 
to assess the safety and tolerability of MK-1088, both as monotherapy and as combination 
therapy with pembrolizumab. The FIH single ascending dose study of MK-1088 in healthy 
volunteers (PN001) completed study enrollment on 01-JUN-2021. Refer to the MK-1088 IB 
for further information.
2.1
Study Rationale
Immunotherapy has dramatically improved treatment rates of some cancers. However, 
tumors have several mechanisms to limit an immune response and escape 
immunosurveillance. An immune suppressive TME contributes to the lack of response or 
resistance to T-cell immune checkpoint inhibitors such as pembrolizumab and ipilimumab 
[Chen DS, Mellman I. 2013]. Along with indoleamine 2,3-dioxygenase, arginase, and 
transforming growth factor-beta, adenosine and its receptors represent a key pathway 
contributing to an immune suppressive environment in tumors and allow tumors to escape 
from immune responses [Smyth, M. J., et al 2016] [Leone, R. D., et al 2015] [Hatfield, S. M. 
2016]. Therefore, an adenosine rich TME represents a major barrier for effective tumor 
immunotherapy and needs to be overcome to achieve more effective and broader clinical 
efficacy.
MK-1088 is a potent small molecule antagonist of the A2A and A2B receptors. Dual A2AR and 
A2BR antagonists may improve the immune status in the TME by both removing the 
suppression of T-cell effector functions via A2AR and blocking the inhibitory effects of 
myeloid cells via A2BR [Iannone, R., et al 2013] [Sorrentino, C., et al 2016] [Sitkovsky, M. 
V. 2020]. Internal preclinical data show that MK-1088 administration led to significant 
antitumor efficacy as a single agent in the mouse syngeneic CT26 tumor model. Furthermore, 
in the mouse syngeneic CM3 tumor model (Cloudman S-91 melanoma), treatment with 
MK-1088 in combination with anti-PD-1 muDX400 monoclonal antibody led to significant 
antitumor efficacy compared with treatment with MK-1088 alone, supporting the scientific 
rationale for this study.
This is the first trial of MK-1088 in oncology patients, preceded by a FIH single ascending 
dose study of MK-1088 in healthy volunteers. The study will evaluate the safety, tolerability, 
PK, and pharmacodynamics of escalating doses of MK-1088 in monotherapy and in 
combination with pembrolizumab in participants with advanced solid tumors who have not 
responded to conventional therapy. The effect of MK-1088 on tumor size will also be 
explored. 
Clinical proof-of-concept for adenosine receptor antagonism is emerging. There has been 
some early signal of efficacy both in monotherapy and in combination with anti-PD-L1 
specifically in mCRPC [Lim, E. A., et al 2020] [Buisseret, L., et al 2020]. These data support 
the potential for meaningful clinical activity in the mCRPC population by targeting 
adenosine signaling inhibition. Other disease indications with some early signal of efficacy 
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both in monotherapy and in combination with anti-PD-1/anti-PD-L1 include NSCLC 
[Chiappori, A., et al 2018] [Chiappori, A. 2018] and mCRC [Cecchini, M., et al 2020], 
among others. Additional clinical data supporting the role of the adenosine pathway in cancer 
therapy were recently presented. CD73 is involved in the generation of adenosine from 
adenosine diphosphate. Data with an anti-CD73 monoclonal antibody in combination with an 
anti-PD-L1 agent have shown promising efficacy in the treatment of Stage III NSCLC 
following chemoradiation over anti-PD-L1 agents alone [Martinez-Marti, A., et al 2021].
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-1088, and the 
MK-3475 IB for detailed background information on pembrolizumab. 
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
MK-1088 Pharmaceutical and Therapeutic Background
MK-1088 is a novel small molecule antagonist of the A2A and A2B receptors. Based on in 
vitro data, MK-1088 has potent binding affinity for human A2A and A2B receptors and lower
affinity for human A1 and A3 receptors. MK-1088 has an acceptable preclinical safety profile 
and is in clinical development as an oral immunotherapy for advanced solid tumors. This 
small molecule is being developed as a cancer immunotherapeutic with the potential to be 
used as monotherapy or to be combined with KEYTRUDA® (pembrolizumab; a humanized 
anti-PD-1 receptor antibody), to increase antitumor efficacy in participants with various 
tumor indications.
A2A is expressed on T cells whereas A2A and A2B are expressed on myeloid cells, and thus
development of a dual antagonist represents a single agent to target different cell types in the 
TME. Agonism of A2A directly suppresses T-cell proliferation and cytokine production, and 
agonism of A2B activates myeloid cells to produce immunosuppressive factors that 
secondarily inhibit T-cell function. Adenosine levels in the TME can be orders of magnitude 
higher than in normal tissues (reported to be 10 – 100 µM vs 10 – 100 nM). These 
concentrations are far above the Kd of adenosine for A2A and at times above its Kd for A2B as 
well (reported to be 300 nM and 15 µM, respectively). An A2A/A2B dual antagonist would 
provide coverage under high adenosine levels in the TME at baseline or during anti-PD-1 
treatment or any other therapy that induces tumor cell death. That A2B is expressed on 
myeloid cells suggests that benefit would be seen in tumors with high myeloid infiltrate or in 
combination with treatments that induce myeloid infiltration.
Significant antitumor efficacy, shown by tumor growth inhibition with MK-1088 as a single 
agent, was observed in the CT26 mouse syngeneic tumor model, which is known to express 
moderate levels of A2AR by RNA sequencing. These data provide the rationale to pursue 
MK-1088 as monotherapy. In addition to the CT26 model, the antitumor activity of the 
A2A/A2B dual antagonist MK-1088 was tested as a single agent and in combination with the 
murinized anti-PD-1 antibody, muDX400 in the CM3, Renca, and MCA205 mouse 
syngeneic tumor models.
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Adenosine promotes immunosuppression in the TME via its effects on both innate and 
adaptive immune cells as outlined above. Therefore, relief of this adenosine-mediated 
immunosuppression may potentiate T-cell activation and improve efficacy of T-cell targeted 
therapies such as pembrolizumab, even in tumors that do not normally respond to PD-1 
antagonist alone. This would suggest that removal of immune suppression induced by 
MK-1088 combined with the T-cell checkpoint inhibitor, pembrolizumab, can offer 
substantially augmented antitumor efficacy than either treatment alone. This scientific 
rationale provides justification to pursue MK-1088 and pembrolizumab as combination 
therapy.
2.2.1.2
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 Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on 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 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. After 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 CD3ζ, PKCθ, and 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] [Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an 
attractive target for therapeutic intervention in advanced/metastatic solid tumors.
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2.2.2
Preclinical and Clinical Studies
Please refer to the MK-1088 IB for a description of preclinical evaluations of MK-1088.
Please refer to the current pembrolizumab IB/approved labeling for a description of 
preclinical and clinical evaluations of pembrolizumab.
2.2.3
Ongoing Clinical Studies
Please refer to the current pembrolizumab IB/approved labeling for a description of ongoing
clinical evaluations of pembrolizumab.
2.2.3.1
MK-1088 Clinical Studies
The FIH study for MK-1088 was PN001, a single ascending dose study in healthy volunteers 
to assess the safety, tolerability, and PK of MK-1088. This study completed enrollment and 
achieved LPLV on 01-JUN-2021. The FIH study in healthy volunteers afforded the 
advantage of rapid dose escalation into the therapeutic dose range in the subsequent Phase 
1/Phase 2 study in oncology patients while also offering more comprehensive and reliable 
measurement of MK-1088 plasma exposures to thoroughly characterize the PK of MK-1088. 
Single doses of 1, 3, 10, 25, 50, 100, 150, and 224 mg of MK-1088 were evaluated in PN001. 
Doses up to 224 mg were generally well tolerated, with no major AEs and SAEs observed at 
the dose range of 1 to 224 mg. Increases in blood pressure of up to 14 mm Hg along with 
increases in heart rate of up to approximately 2 to 13 bpm were observed over the dose range 
of 10 to 224 mg. One participant at the highest dose of 224 mg had a greater systolic blood 
pressure/heart rate response than others (3× mean) and diastolic blood pressure increase 
similar to mean but did not report any associated symptoms.
Plasma exposures in PN001 were generally dose proportional at the 1 to 224 mg dose range,
with observed median Tmax of 2 hours and apparent terminal t1/2 between 6 to 11 hours. The 
minimum Ctrough concentration target of 0.3 µM corresponding to >99% TE for A2A and 
>80% for A2B was successfully achieved at a single dose of 150 mg while the aspirational 
trough target of 1 µM corresponding to >99% for A2A and >90% for A2B was attained at both 
the 12- and 24-hour time points at a dose of 224 mg of MK-1088, enabling QD dosing of 
MK-1088 in Phase 1b. Furthermore, no food effect was observed at the 50 mg dose. Data 
from this FIH study were applied to inform the starting dose and dose levels for PN002 based 
on overall safety, tolerability profile, and PK of MK-1088 from PN001.
Please refer to the IB for further details.
2.2.3.2
Pembrolizumab (MK-3475) Clinical Studies ￼
Ongoing clinical studies with pembrolizumab are being conducted in multiple solid tumors. 
In addition, multiple combinations with pembrolizumab are also being investigated. Refer to 
pembrolizumab IB for study details.
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In male and female participants with advanced/metastatic solid tumors:
Objectives
Endpoints
Primary
•
To determine the safety and tolerability 
and to establish a preliminary maximum 
tolerated dose/recommended Phase 2 
dose of MK-1088 administered as 
monotherapy and in combination with 
pembrolizumab infusion in Part 1
•
Dose-limiting toxicity (DLT)
•
Adverse events (AE)
•
Discontinuing study intervention due to 
an AE
Secondary
•
To evaluate the PK of MK-1088 
administered as monotherapy and in 
combination with pembrolizumab 
infusion in Part 1 and in Part 2
•
PK parameters including AUC and 
Cmax
•
To evaluate the antitumor activity 
(objective response rate [ORR] based on 
PCWG-modified RECIST 1.1 [prostate 
cancer participants only] or RECIST 1.1 
[all other participants]) of MK-1088 as 
assessed by the investigator when used as 
monotherapy and in combination with 
pembrolizumab in Part 1 and in Part 2
•
Objective response (OR) is a complete 
response (CR) or partial response (PR)
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Objectives
Endpoints
Tertiary/Exploratory
•
To evaluate progression-free survival 
(PFS) and overall survival (OS) of 
participants treated with MK-1088 both 
as monotherapy and in combination with 
pembrolizumab. In solid tumors, 
assessment will be based on RECIST 1.1 
as assessed by the investigator. 
Metastatic prostate cancer response 
assessments will also use PCWG criteria.
•
PFS: the time from treatment allocation 
to the first documented disease 
progression or death due to any cause, 
whichever is first
•
OS: The time from treatment allocation 
to death due to any cause
•
To evaluate the duration of response 
(DOR) per RECIST 1.1 as assessed by 
the investigator
•
DOR is defined as the time from the 
first documented evidence of CR or PR 
until progressive disease (PD) or death 
due to any cause, whichever occurs 
first, in participants demonstrating PR 
or CR
•
To identify molecular (genomic, 
metabolic and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of MK-1088 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
4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, global, open-label, nonrandomized Phase 1/Phase 2 study of MK-1088 
in monotherapy and in combination with pembrolizumab in participants with a histologically 
or cytologically confirmed diagnosis of advanced solid tumor who have received, been 
intolerant to, or have been ineligible for treatment known to confer clinical benefit. 
This study will evaluate the safety, tolerability, and preliminary efficacy of MK-1088 
monotherapy administration (Arm 1), and in combination with pembrolizumab (Arm 2). 
There are 2 parts in this study, dose escalation and confirmation (Part 1) (Section 6.6.2) and 
cohort expansion (Part 2) (Section 6.6.3).
Participants will receive MK-1088 in monotherapy (Arm 1) or in combination with 
pembrolizumab (Arm 2). In Arm 1 and Arm 2, MK-1088 will be administered po QD every 
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day of a 21-day cycle. In Arm 2, pembrolizumab will be administered IV Q3W, on Day 1 of 
each cycle.
In Part 1 of the study, an adjusted mTPI design [Ji, Y. 2013] will be used to identify and 
confirm the RP2D of MK-1088 in Arm 1 (MK-1088 as a single agent), and in Arm 2 
(MK-1088 in combination with pembrolizumab). Four to 6 dose levels of MK-1088 are 
planned to be evaluated independently in each arm, in the dose range of 100 to 800 mg QD. 
Intermediate and/or higher doses of MK-1088 than those indicated may be explored 
depending on the totality of the data, including safety and PK, available at each dose level. 
BID dosing may also be explored based on tolerability and/or PK data. If applicable, BID 
dosing will be implemented in treatment arms introduced in an amendment. The dose of 
pembrolizumab in Arm 2 will remain constant at 200 mg Q3W.
Participants will be allocated centrally through IVRS. Arm 1 monotherapy slots will be filled 
first to generate monotherapy safety data before enrolling participants at that dose in Arm 2. 
After Arm 2 combination therapy has opened, slots in Arm 1 at a higher MK-1088 dose than 
Arm 2, if available, will be allocated first before Arm 2 slots are assigned. If both arms are 
open at the same dose of MK-1088, then allocation to Arm 1 or Arm 2 will be alternated.
Participants will be initially enrolled to receive MK-1088 in monotherapy (Arm 1). 
Enrollment in Arm 1 (MK-1088 in monotherapy) at DL2 will begin once all participants 
complete Cycle 1 at DL1 of Arm 1 and a dose-escalation decision has been made. Enrollment 
in Arm 2 (MK-1088 in combination with pembrolizumab) at DL1 may begin after all 
participants complete Cycle 1 at DL1 of Arm 1 and a dose-escalation decision has been 
made. Thus, the starting dose of MK-1088 in the combination arm will be at least 1 level 
below the dose level being tested concurrently in the MK-1088 monotherapy arm. The final 
number of participants enrolled in Part 1 will depend on the empirical safety observations 
(DLT), and what dose is ultimately identified as the RP2D using the adjusted mTPI design.
Based on the adjusted mTPI design, it is anticipated that data from 14 participants at a dose 
level will provide sufficient data to declare an MTD or RP2D. However, should there be 
clinical PK or safety reasons, additional participants and/or dose levels may be evaluated. 
The pool-adjacent-violators algorithm [Ji Y, Li Y, Bekele BN 2007] will be used to estimate 
the DLT rates across doses in each treatment arm 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 2. The RP2D of MK-1088 in the combination arm 
(Arm 2) may equal, but will not exceed, the RP2D in the MK-1088 monotherapy arm 
(Arm 1).
In Part 2, safety and efficacy of MK-1088 in combination with pembrolizumab at the RP2D 
defined in Part 1 Arm 2 will be assessed. At least 3 indication-specific expansion cohorts are 
planned based on evolving data and will be incorporated into an amendment before initiating 
Part 2. Additional lower and/or higher doses of MK-1088 in combination with 
pembrolizumab may also be explored in Part 2. The final RP2D for future studies will be 
confirmed using all available safety information (including early and late toxicities from 
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Parts 1 and 2), as well as PK and pharmacodynamic data, and preliminary efficacy 
assessments.
Preliminary efficacy will be evaluated using ORR assessed by the investigator based on 
PCWG-modified RECIST 1.1 or RECIST 1.1 as a secondary objective. PFS based on 
PCWG-modified RECIST 1.1 or RECIST 1.1 as assessed by the investigator and OS will be 
evaluated as exploratory objectives. 
Intermittent data assessments may be conducted to enable future study planning and dosing 
decisions.
Participants will be monitored carefully for the development of AEs, and for clinical and/or 
radiographic evidence of disease progression according to PCWG-modified RECIST 1.1 or 
RECIST 1.1. If a participant has evidence of radiological PD by PCWG-modified RECIST 
1.1 or RECIST 1.1, it will be at the discretion of the investigator whether to continue a 
participant on study intervention. This clinical judgment decision should be based on the 
participant’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.
AEs will be evaluated by the investigator, according to criteria outlined in the NCI CTCAE, 
version 5.0, to establish the safety and tolerability of MK-1088 when administered in 
monotherapy or in combination with pembrolizumab per the primary objective of this study.
There will be no intraparticipant dose escalation for participants enrolled in this study. The 
definition of DLTs and criteria for dose modification of MK-1088 are outlined in Section 
6.6.2. Pembrolizumab will be administered at a fixed dose of 200 mg Q3W, which will not 
be modified.
Participants may receive study intervention (monotherapy in Arm 1 or combination with 
pembrolizumab in Arm 2) for up to 35 cycles (~24 months). Participants will be treated until 
PD, unacceptable toxicity, intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw treatment, participant withdrawal of consent, 
pregnancy of the participant, noncompliance with study intervention or procedure 
requirements, participant completes treatment, or administrative reasons requiring cessation 
of treatment, at which point they will be discontinued from the study.
Participants who progress by radiographic evaluation on monotherapy with MK-1088 
(Arm 1) may, at the investigator’s discretion and after consultation with the Sponsor, cross
over to combination treatment arm of MK-1088 and pembrolizumab (Arm 2). 
A participant may not cross over from Arm 1 (monotherapy) into Arm 2 (combination 
therapy with pembrolizumab) until that participant has completed the DLT evaluation period 
(ie, 21 days) in Arm 1. Participants who are eligible for crossover from Arm 1 to Arm 2 will 
complete the Arm 2 screening phase to ensure eligibility. In participants who cross over to
Arm 2, screening assessments obtained for Arm 1 may be eligible for crossover screening if 
the assessments were obtained within 28 days before Arm 2 treatment initiation; an 
additional tumor biopsy specimen is not required. These participants will continue to undergo 
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their scheduled activities. Participants may receive the highest dose of MK-1088 that has 
already shown safety and tolerability in combination with pembrolizumab (DLT evaluation 
period completed for that combination dose).
Participants who are eligible to receive combination treatment due to radiographically 
confirmed PD while in Arm 1, will not be included in the adjusted mTPI dose-escalation 
determination for Arm 2, as that specific dose level cohort must have already shown safety 
and tolerability. However, their data may be included retrospectively in determination of the 
RP2D for the combination treatment. These participants’ safety and efficacy data will be 
analyzed separately from that of the participants enrolled in Arm 2. Once they discontinue 
from any part of the study, participants will be treated at the discretion of the physician.
Participants who cross over to combination treatment will be eligible to receive a maximum 
of 35 cycles of combination treatment irrespective of the number of cycles of MK-1088 
received in monotherapy.
Participants who discontinued monotherapy in Arm 1 due to a DLT are not eligible for 
crossover to Arm 2.
Participants who discontinue treatment for reasons other than radiographic PD will have 
posttreatment follow-up for disease status (including imaging) until PD, initiating a new 
anticancer therapy, withdrawing consent for study participation, or becoming lost to follow-
up.
After discontinuation of study therapy, each participant will be contacted by telephone every 
12 weeks (84 ±7 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 study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 (Table 1, Table 2) of the SoA. Details of 
each procedure are provided in Section 8.
4.2
Scientific Rationale for Study Design
MK-1088 is a novel small molecule antagonist dually targeting the A2A and A2B receptors. 
Inhibition of adenosine signaling in the TME can decrease the immunosuppressive signals on 
immune cells, thus resulting in their activation against tumor cells. Combining MK-1088 
with pembrolizumab has the potential to overcome resistance and/or deepen the antitumor
response to PD-1 blockade alone. In the dose-escalation, safety phase of this trial, 
participants with any advanced solid tumor are eligible for enrollment. In the expansion 
phase of the study, participants with specific solid tumors will be selected based on all 
available preclinical and clinical data and any preliminary clinical efficacy data of MK-1088 
in monotherapy and in combination with pembrolizumab.
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4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
One of the secondary endpoints is antitumor activity based on PCWG-modified RECIST 1.1 
or RECIST 1.1 criteria as determined by the investigator. ORR is an acceptable measure of 
clinical benefit that demonstrates superiority of a new antineoplastic therapy, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use 
of PCWG-modified RECIST 1.1 or RECIST 1.1 to assess ORR is typically considered 
acceptable by regulatory authorities.
Tumor response will be assessed using PCWG-modified RECIST 1.1 or RECIST 1.1 as 
assessed by investigator (see Section 8.2.5). Antitumor activity will be measured through 
such tertiary endpoints as PFS, OS, and DOR, which are described further in Section 9.4.1.
4.2.1.1.1
Response Rate Assessed by RECIST Version 1.1
PCWG-modified RECIST 1.1 or RECIST 1.1 will be used by the local site when determining 
eligibility (Section 8.2.2) and by the principal investigator when assessing scans for efficacy 
measures (Sections 8.2.3 and 8.2.4). PCWG-modified RECIST 1.1 or RECIST 1.1 will be 
used to determine the objective response. Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, this protocol has implemented a PCWG-modified 
RECIST 1.1 and modified RECIST 1.1 to allow a maximum of 10 target lesions in total and 
5 per organ (Section 8.2.5).
4.2.1.2
Safety Endpoints
The primary objective of this study is to characterize the safety and tolerability of MK-1088 
as monotherapy and as combination therapy with pembrolizumab in participants with 
advanced/metastatic solid tumors. The primary safety analysis will be based on participants 
who experience toxicities as defined by CTCAE Version 5.0 criteria. Safety will be assessed 
by quantifying the toxicities and grades of toxicities experienced by participants who have 
received MK-1088 as monotherapy and in combination with pembrolizumab.
For AEs, attribution to drug, time of onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs that will be analyzed include, 
but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
4.2.1.3
Pharmacokinetic Endpoints
A secondary objective of this study is to characterize the PK profile of MK-1088 after 
administration as a single agent, and to characterize the PK profile of MK-1088 and 
pembrolizumab after administration as combination therapy. The serum 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 safety and 
exploratory endpoint data to help assess future dosing strategies for MK-1088.
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4.2.1.4
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/pharmacodynamic biomarkers and generate information that may better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, biospecimens (ie, blood components, tumor material) will be collected to support 
analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating 
molecules. Investigations may include, but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations. Finally, MSI may be evaluated as this 
is an important biomarker for some cancers (ie, colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes called a ‘hyper-mutated’ 
state) may generate neoantigen 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 to understand tumor-specific mutations, it is necessary to compare the tumor genome 
with the germline genome. Microsatellite instability may also be evaluated as this is an 
important biomarker for some cancers (ie, colorectal cancer). Circulating tumor DNA and/or 
RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted 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 
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evaluated (eg, IL-10). MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and 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 IVD device has been developed 
for use with pembrolizumab in NSCLC. Preliminary data indicates that this association may 
also be true in additional cancer types (ie, triple negative breast cancer, head and neck, and 
gastric). Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include, but are not limited to, immunoassays and liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as ELISA measure such proteins in 
serum. Correlation of expression with response to pembrolizumab therapy may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on specimens for which consent was provided during this 
study. 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 FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR 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 FBR research are presented in
Appendix 6.
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4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.3.1
Starting Dose for This Study
4.3.1.1
Rationale for Starting and Maximum Dose of MK-1088
The planned starting dose of MK-1088 is 100 mg po QD. This starting dose was informed by 
the results of the FIH study MK-1088 PN001, which is a randomized, placebo controlled, 
double-blind, single ascending dose trial conducted in healthy males and females of non-
child-bearing potential to determine the safety and tolerability of MK-1088 as well as to 
characterize the PK of MK-1088 that can achieve acceptable exposure and trough 
concentrations for the desired level of target engagement of the A2A and A2B receptors. The
study was conducted with a tablet formulation (platform tablet of 40% drug load spray-dried
intermediate in hydroxypropyl methylcellulose acetate succinate LF) in Belgium.
Data from this study was incorporated into a pharmacokinetic model to project the 
anticipated pharmacokinetic profile for daily dosing and projected tolerable starting dose that 
balances safety with potential benefits.
The 100 mg dose is approximately 2-fold lower than the highest dose tested in PN001. Based 
on in vitro profiling, high levels of A2A inhibition (>99% TE) and A2B inhibition (>90% TE) 
are expected at a trough concentration of approximately 1 µM in the absence of adenosine. 
While this trough concentration was achieved by a single dose of 224 mg in PN001, changes 
in blood pressure/heart rate measurements in an individual subject, and a general trend for 
increased blood pressure and heart rate measurement over baseline values with increasing 
MK-1088 dose was noted. A starting dose of 100 mg was recommended as a conservative 
approach at which pharmacological activity for MK-1088 is expected to be observed (>90% 
TE for A2A and >80% TE for A2B ) and comprehensive evaluation of the safety profile upon
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repeat dosing in an oncology patient population will be enabled. A 100 mg single dose was 
well tolerated in healthy volunteers and this starting dose provides the ability to have 
appropriate monitoring of patients after repeat dosing, before steadily increasing the dose. 
Exposures have increased dose proportionately up to 224 mg single doses in MK-1088 
PN001.
The maximum planned dose of MK-1088 is 800 mg po QD although higher doses may be 
explored if safety and tolerability permit. In addition to inhibiting A2A, dosing to this level is 
projected to achieve significant inhibition of A2B comparable to levels that more selective 
A2B inhibitors can achieve, even in the presence of high levels of adenosine expected to exist 
in the TME. Dose escalation to this planned maximum dose and/or higher doses are 
dependent on tolerability as observed during the adjusted mTPI dose-escalation design and if 
MK-1088 exposures continue to increase with dose.
4.3.1.2
Rationale for Dose Interval and Escalation Increments
The human starting dose and dosing interval of MK-1088 are based on an integration of 
nonclinical toxicological, pharmacological, and efficacy data. Dose-finding will proceed with 
a model-based adjusted mTPI approach with 3 to 14 participants treated per dose level using 
dose increment increases of approximately 30% to 100% of the prior dose.
In cohorts of participants treated with a combination of MK-1088 and pembrolizumab, doses 
of MK-1088 used in combination with pembrolizumab will be at least 1 to 2 dose levels 
behind the monotherapy dose and will not exceed the MTD/RP2D for monotherapy. If an 
MTD/RP2D for the monotherapy arm is established, the dose of MK-1088 in combination 
with pembrolizumab may continue escalation up to that dose.
4.3.1.3
Dose Finding Using a Modified Toxicity Probability Interval Design
Further dose-finding will follow the adjusted mTPI design [Ji, Y. 2013] with a target DLT 
rate of 30%. Dose-escalation and deescalation decisions are based on the adjusted 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, 3, 4, 5, or 6 participants may be enrolled within 7 to 14 days of the opening of a dose 
cohort. In Table 3, 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 study due 
to unacceptable toxicity, respectively. For example, if 0 of 3 participants at a given dose level 
develop a DLT, then the dose can escalate to the next level. If 2 participants of 3 develop a 
DLT, the dose will be de-escalated to the next lower dose level. If 3 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 of 3 participants at a given dose level 
develop a DLT, then additional participants should be enrolled at that dose level following 
the rules below.
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When adding participants to a dose level in response to a “stay” decision, 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 3). Second, 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 3). The 
same principles will be applied whether 3, 4, 5, or 6 participants are initially enrolled at that 
dose level.
A D or DU decision at the lowest dose level will stop the study. 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.
After 14 participants have been enrolled at any of the tested doses (including intermediate 
doses), dose-finding will stop if the mTPI table indicates “S” for staying at current dose. 
Otherwise, up to 14 new participants may be enrolled at a lower dose if “D” or “DU” is 
indicated, or at a higher dose if “E” is indicated.
The pool-adjacent-violators algorithm [Ji Y, Li Y, Bekele BN 2007] 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. However, the totality of the data will be considered before 
deciding on the dose(s) to carry forward to Part 2. The dose-escalation schedule may be 
adjusted based on pharmacodynamic, PK, and safety data emerging throughout the study. 
The preliminary RP2D of MK-1088 in the combination arm (Arm 2) will not exceed, but 
may be equal to, the preliminary RP2D in the MK-1088 monotherapy arm (Arm 1).
Note that although 30% was the target toxicity rate used to generate the guidelines in 
Table 3, the observed rates of participants with DLTs at the MTD may be slightly above or 
below 30%). When selecting the RP2D of the monotherapy and combination therapy, the 
totality of the safety data (eg, duration, reversibility, severity, and nature of the DLTs and 
AEs) will be evaluated. 
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Table 3
Dose-finding Rules per Adjusted 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
D
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
D
D
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
D
D
S
S
S
S
5
DU
DU
DU
DU
DU
D
D
D
D
S
6
DU
DU
DU
DU
DU
DU
D
D
D
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
D = De-escalate to the next lower dose; DLT = dose-limiting toxicity; DU = Current dose is unacceptably 
toxic; E = Escalate to the next higher dose; mTPI = modified Toxicity Probability Interval; S = Stay at the 
current dose;.
Adjusted from the mTPI table with 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. 
2013] [Ji, Y., et al 2010]
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, 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, if available.
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems or the number of discontinuations for administrative reasons is 
too high.
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Early study termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other studies suggest a potential 
health hazard to participants
2. Plans to modify or discontinue the development of the study drug
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-1088 or pembrolizumab.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant meets the following 
criteria:
5.1.1
Inclusion Criteria for Arm 1 and Arm 2
The inclusion criteria apply to all participants unless otherwise indicated.
Type of Participant and Disease Characteristics
1. The participant must have a histologically or cytologically confirmed diagnosis of 
advanced/metastatic solid tumor by pathology report and have received, have been
intolerant to, or have been ineligible for treatment known to confer clinical benefit.
For metastatic castrate-resistant prostate cancer (mCRPC) only: 

Must have previously received docetaxel, prior treatment with one other 
chemotherapy is allowed as well as up to 2 second-generation hormonal 
manipulations.

Have prostate cancer progression within 6 months before screening, as 
determined by the investigator, by one of the following: 
a.
PSA progression using local laboratory values as defined by a minimum of 
2 rising PSA levels with an interval of ≥1 week between each assessment 
where the PSA value at screening should be ≥2 ng/mL.
b. Radiographic disease progression in soft tissue based on PCWG-modified 
RECIST 1.1 or RECIST 1.1 criteria with or without PSA progression.
c.
Radiographic disease progression in bone defined as the appearance of 2 or 
more new bone lesions on bone scan with or without PSA progression.
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Note: Subjects with prostate cancer lesions solely confined to prostate without 
evidence of metastasis cannot be reliably imaged and therefore are not eligible for 
study
2. Disease per PCWG-modified RECIST 1.1 for mCRPC or measurable disease per 
RECIST 1.1 as assessed by the local site investigator/radiology. Target lesions situated in 
a previously irradiated area are considered measurable if progression has been shown in 
such lesions.
Note: Lesions situated in the brain are not considered measurable disease and may be
considered as nonmeasurable only.
Note: Subjects with prostate cancer lesions solely confined to prostate without evidence 
of metastasis cannot be reliably imaged and therefore are not eligible for study
For participants with metastatic castrate-resistant prostate cancer:
a.
Have PCWG-modified RECIST 1.1 measurable (soft tissue) prostate cancer on CT or 
MRI scans as assessed by the local site/investigator/radiology
OR
b. Detectable bone metastases by whole body bone scintigraphy as per PCWG guidance 
(see Section 10.9, Appendix 9)
Demographics
3. Is male or female, from minimum of 18 years of age inclusive, at the time of providing
informed consent.
Male Participants
4.
If male, agrees to the following during the intervention period and for at least 7 days after 
the last dose of MK-1088:
•
Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on 
a long-term and persistent basis) and agrees to remain abstinent
OR
•
Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to 
medical cause, documented from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview) as detailed below:
-
Uses a male condom plus partner use of an additional contraceptive method when 
having penile-vaginal intercourse with a WOCBP 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-
vaginal penetration.
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-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
5. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), with low user dependency, or be abstinent from heterosexual intercourse as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as 
described in Appendix 5 during the intervention period and for at least 7 days after 
the last dose of MK-1088 and for at least 120 days after the last dose of 
pembrolizumab, whichever occurs last after the last dose of study intervention. The 
investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
-
Has a negative highly sensitive pregnancy test ([urine or serum] as required by local 
regulations) within 24 hours before the first dose of study intervention. If a urine test 
cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation if the 
serum pregnancy result is positive. Additional requirements for pregnancy testing 
during and after study intervention are in Section 8.3.5.
-
Abstains from breastfeeding during the study intervention period and for at least 
7 days after study intervention with MK-1088 or 120 days from the last dose of
pembrolizumab.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
6. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
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Additional Categories
7. Archival tumor tissue sample or newly obtained core needle biopsy of a tumor lesion not 
previously irradiated has been provided. Details pertaining to tumor tissue submission 
can be found in the Procedures or Laboratory Manual.
8. Adequate organ function as defined in Table 4. Specimens must be collected within 
72 hours before the start of study intervention.
Table 4
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Measured or calculatedb creatinine clearance
≥30 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b
Creatinine clearance (CrCl) must be calculated using Cockcroft Gault formula.
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.
9. Have an ECOG Performance Status of 0 to 1 assessed within 72 hours before the first 
dose of study intervention.
10. HIV-infected participants must have well controlled HIV on ART, defined as:
a.
Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at the time of 
screening.
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b. Participants on ART must have achieved and maintained virologic suppression 
defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
detection) using the locally available assay at the time of screening and for at least 
12 weeks before screening.
c.
Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks before study entry (Day 1).
d. The combination ART regimen must not contain any antiretroviral medications other 
than: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or 
tenoforvir.
11. Participants who are HBsAg positive are eligible if they have received HBV antiviral
therapy for at least 4 weeks and have undetectable HBV viral load before treatment 
allocation.
Note: Participants should remain on antiviral therapy throughout study intervention 
and follow local guidelines for HBV antiviral therapy post completion of study 
intervention.
Hepatitis B screening tests are not required unless: 
•
Known history of HBV infection
•
As mandated by local health authority
12. Participants with history of HCV infection are eligible if HCV viral load is undetectable 
at screening.
Note: Participants must have completed curative antiviral therapy at least 4 weeks 
before treatment allocation. 
Hepatitis C screening tests are not required unless:
•
Known history of HCV infection 
•
As mandated by local health authority
13. Be able to swallow and retain oral medication and must not have any clinically 
significant gastrointestinal abnormalities that may alter absorption.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets the following 
criteria:
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5.2.1
Exclusion Criteria for Arm 1 and Arm 2
The exclusion criteria apply to all participants unless otherwise indicated.
Medical Conditions
1. Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks 
(2 weeks for palliative radiation) before the first dose of study intervention, or has not 
recovered to CTCAE Grade 1 or better from any AEs that were due to cancer 
therapeutics administered more than 4 weeks earlier (this includes participants with 
previous immunomodulatory therapy with residual immune-related AEs). Participants 
receiving ongoing replacement hormone therapy for endocrine immune-related AEs will 
not be excluded from participation in this study.
2. 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, squamous cell carcinoma of the 
skin, in situ cervical cancer, or other in situ cancers.
3. Has clinically active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain or meningeal metastases may participate and be eligible for 
treatment provided they are stable and asymptomatic (without evidence of progression by 
MRI scan of the brain separated by at least 4 weeks after treatment), have no evidence of 
new or enlarging brain metastases, are evaluated within 4 weeks before first study 
intervention administration, and are off immunosuppressive doses of systemic steroids at 
least 2 weeks before enrollment.
4. Has had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody/components of the study intervention.
5. Has an active infection requiring therapy.
6. Has a history of interstitial lung disease.
7. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis. 
8. 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 nonsystemic steroids is permitted.
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9. Has concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV 
DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV 
RNA) infection. 
Note: Hepatitis B and C screening tests are not required unless:
•
Known history of HBV and HCV infection
•
As mandated by local health authority
10. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease.
11. Has a history or current evidence of any condition, therapy, laboratory abnormality, or 
other circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
12. Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
13. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through the duration of 
contraception after the last dose of study intervention. 
14. Has not fully recovered from any effects of major surgery without significant detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study intervention administration. Surgery requiring regional/epidural 
anesthesia must be completed at least 72 hours before first study intervention 
administration and participants should be recovered.
15. Has a history or current evidence of a GI condition (eg, inflammatory bowel disease, 
Crohn’s disease, ulcerative colitis) or impaired liver function or diseases that in the 
opinion of the investigator may significantly alter the absorption or metabolism of oral 
medications; 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.
16. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention, including NYHA Class III or IV congestive heart failure, unstable 
angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia 
associated with hemodynamic instability. Note: Medically controlled arrhythmia would 
be permitted.
17. Has a QTcF >470 msec.
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18. History of an allogeneic stem cell transplant or a solid organ transplant.
Prior/Concomitant Therapy
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137), AND was discontinued from that treatment due to a Grade 3 or higher irAE.
20. Has received prior A2A or A2B receptor antagonist therapy.
21. Currently receiving strong/moderate CYP3A4 inducers or inhibitors.
22. Currently receiving H2 blockers or proton-pump inhibitors.
23. Has received prior systemic anticancer therapy including investigational agents within 4 
weeks before allocation.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants 
with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may 
be eligible.
24. Has received prior radiotherapy within 2 weeks of start of study intervention, or had 
radiation-related toxicities requiring corticosteroids.
Note: Two or fewer weeks of palliative radiotherapy for non-CNS disease, with a 1-week 
washout, is permitted.
25. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines are allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
26. Has received an investigational agent or has used an investigational device within 
4 weeks prior to intervention administration.
Other Exclusions
27. Has a “superscan” bone scan. This is defined as an intense symmetric activity in the 
bones and diminished renal parenchymal activity on screening bone scan such that the 
presence of additional metastases in the future could not be evaluated.
28. Has not adequately recovered from major surgery or has ongoing surgical complications.
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants are required to fast 2 hours predose and 1 hour postdose.
Foods that are CYP3A inhibitors must not be consumed during the study. Grapefruit and star 
fruit are known to be CYP3A inhibitors, and should not be consumed for 2 weeks before the 
first dose of MK-1088 and for the entire duration of the study. Consumption of CYP3A4 
inhibitors, such as grapefruit juice, may significantly increase the levels of MK-1088 and 
cause increased toxicity. St. John's Wort is a CYP3A inducer, and the consumption of 
St. John's Wort or products containing St. John's Wort may reduce the levels of MK-1088. A 
partial list of examples of CYP3A inhibitors is provided in Section 6.5.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.3.3
Activity Restrictions
Patients should avoid prolonged exposure to sun. 
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
Participant Replacement Strategy
To adequately evaluate the safety of the doses administered in this study, all participants 
enrolled must meet the criteria for evaluability for Cycle 1. Participants are considered 
nonevaluable and will be replaced if:
•
They are allocated, but not treated.
•
They discontinue from the study without the occurrence of a DLT, before completing all 
the safety evaluations for reasons other than treatment-related AEs.
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•
They receive less than 75% of the total MK-1088 (or pembrolizumab infusion, if 
appropriate) in Cycle 1 (eg, if the infusion had to be discontinued due to an infusion 
reaction) and did not experience a DLT.
Participants who are not evaluable will be replaced unless accrual to the cohort has stopped. 
Nonevaluable participants will not be counted toward the total number of participants in the 
cohort for DLT evaluation.
If a participant experiences a DLT in Cycle 1, study intervention may be discontinued after 
discussion between the Sponsor and investigator. However, if the participant is deriving 
clinical benefit from the study intervention, the participant may be allowed to continue after 
discussion between the Sponsor and the investigator.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention[s]) provided by the Sponsor will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted before dosing the replacement 
participant. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 5.
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Table 5
Study Interventions
Arm 
Name
Arm 
Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Planned 
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment Period
Use
IMP/
NIMP
Sourcing
Part 1: 
Arm 1
and 
Arm 2
Experi
mental
MK-1088
Drug
Tablet
50 mg,
100 mg
DL1: 100 mg
DL2: 200 mg
DL3: 400 mg
DL4: 600 mg
DL5: 800 mg
Oral
Day 1 to Day 21 of 
each treatment 
cycle for up to 35 
cycles; QD dosing
Experi
mental
IMP
Provided 
centrally 
by the 
Sponsor
Part 1: 
Arm 2
Experi
mental
Pembro-
lizumab
(MK-3475)
Drug
Solution for 
Infusion
100 mg 
per Vial
200 mg
IV 
Infusion
Day 1 of each 
treatment cycle for 
up to 35 cycles; 
Q3W dosing
Experi
mental
IMP
Provided 
centrally 
by the 
Sponsor
Part 2: 
(To be 
speci-
fied)
Experi
mental
MK-1088
Drug
Tablet
50 mg 
100 mg
Will be based 
on the RP2D 
from Part 1
Oral
Day 1 to Day 21 of 
each treatment 
cycle for up to 35 
cycles; QD dosing
Experi
mental
IMP
Provided 
centrally 
by the 
Sponsor
Part 2: 
(To be 
speci-
fied)
Experi
mental
Pembro-
lizumab
(MK-3475)
Drug
Solution for 
Infusion
100 mg 
per Vial
200 mg
IV 
Infusion
Day 1 of each 
treatment cycle for 
up to 35 cycles; 
Q3W dosing
Experi
mental
IMP
Provided 
centrally 
by the 
Sponsor
DL=dose level; EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP=noninvestigational medicinal product; QD=once daily;
Q3W=every 3 weeks; RP2D=recommended Phase 2 dose.
The classification of IMP and NIMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect 
to the definition/classification of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Part 2 Arm Names will be specified in an amendment once the RP2D is determined in Part 1.
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All supplies indicated in Table 5 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
Throughout the study, the first intake of MK-1088 will occur at the trial site on Day 1 of each 
cycle for Arm 1 and Arm 2 (shortly before the pembrolizumab infusion in Arm 2). MK-1088 
will be administered orally, once daily. While in the clinic setting, pembrolizumab will be 
administered through an IV infusion as described in the Pharmacy Manual. Subsequent 
dosing of MK-1088 will be administered once daily QD by the participant (ie, unsupervised 
at their home) at approximately the same time each day, until Day 1 of the next cycle. For the 
MK-1088 dose on Day 2 of Cycles 1 and 2, the participant should refrain from MK-1088 
administration until required study procedures on this day (eg, blood draw for MK-1088 PK 
assay) have been completed.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-1088 (and pembrolizumab) are provided in 
the appropriate Pharmacy/Procedures Manual.
Concomitant chemotherapeutic/immunotherapeutic agents will be prepared and administered 
per the approved product label(s).
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an IVRS. There are 2 intervention arms. 
Participants will be allocated to 1 of 2 intervention arms: MK-1088 monotherapy (Arm 1) or 
MK-1088 in combination with pembrolizumab (Arm 2) using an IVRS in Part 1.
Participants will be allocated centrally through IVRS. Arm 1 monotherapy slots will be filled 
first to generate monotherapy safety data before enrolling participants at that dose in Arm 2. 
After Arm 2 combination therapy has opened, slots in Arm 1 at a higher MK-1088 dose than 
Arm 2, if available, will be allocated first before Arm 2 slots are assigned. If both arms are 
open at the same dose of MK-1088, then assignment to Arm 1 or Arm 2 will be alternated.
In Part 1 of the study, intervention will be allocated by nonrandom assignment. Enrollment 
into the MK-1088 in combination with pembrolizumab combination intervention arm (Arm 
2) may begin once all participants complete 1 cycle of MK-1088 monotherapy (Arm 1) at 
DL1, complete the DLT evaluation period, and a dose-escalation decision to the next dose 
level has been made. This ensures that the starting dose of MK-1088 in the combination arm 
will be at least one dose level below that being tested concurrently in the MK-1088
monotherapy arm. If both Arm 1 and Arm 2 are open for enrollment at different doses Arm 1 
will be allocated first. If, according to the adjusted mTPI algorithm, a dose de-escalation is 
recommended in Arm 1 (MK-1088 monotherapy) resulting in both monotherapy and 
combination arms open at the same dose, IVRS will alternate participant assignment between 
Arm 1 and 2 starting with Arm 1. For example, if the guidance of the adjusted mTPI 
indicates a dose de-escalation to the prior dose level of 200 mg after at least 3 DLT-evaluable 
participants at the 400 mg dose cohort of Arm 1 (MK-1088 monotherapy) have completed 
Cycle 1 and the 200 mg dose cohort of Arm 2 (MK-1088 in combination with 
pembrolizumab) is enrolling, then both arms are open for enrollment at the same dose. In that 
situation, the first participant will be allocated to Arm 1, the second participant will be 
allocated to Arm 2, the third participant will be allocated to Arm 1, etc. An observation 
period of at least 24 hours will occur between intervention initiation in participants enrolled 
within each dose level. Each new dose cohort will open for enrollment without delay once 
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the 21-day DLT observation period of the previous dose cohort is completed and a dose-
escalation decision is made.
When Part 2 is open for enrollment, IVRS will allocate participants by tumor type.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
•
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning
and counting returned tablets during the site visits and documented in the source documents 
and CRF. Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
•
A record of the number of MK-1088 tablets dispensed to and taken by each participant 
must be maintained and reconciled with study intervention and compliance records. 
Intervention start and stop dates, including dates for intervention delays and/or dose 
reductions will also be recorded in the CRF.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor’s 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 intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic chemotherapy or biological therapy
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•
Participants with mCRPC should not remain on androgen receptor blockers such as 
enzalutamide, abiraterone, nilutamide, etc. Participants are allowed to remain on GnRH/ 
LHRH agents after progression as part of standard of care (as allowed by local 
regulations).
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed
at the investigator’s discretion after the DLT observation period for the participant to be 
considered evaluable for DLT.
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. 
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral vaccines, 
or inactivated vaccines. These vaccines will be treated just as any other concomitant 
therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
-
To treat COPD exacerbations (only short-term oral or IV use in doses >10 mg/day 
prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
•
Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or COPD
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•
H2 Blockers or PPI
The participant must not take H2 blockers or PPI during the trial from 5 days before the 
start of the study treatment to 5 days after the last administration of MK-1088. The 
investigator should use their medical judgment when a participant presents with an H2 
blocker or PPI treatment or call the Sponsor Clinical Director for clarification.
Of note, antacids, such as calcium carbonate or aluminum hydroxide-based product, will 
be allowed during the study, and are recommended to be taken either 4 hours before or 
after dosing of MK-1088. 
•
Strong/moderate inhibitors/inducers/substrates of the CYP3A4 enzymes.
Investigators should check an actively updated list of drugs that are clinically relevant 
substrates, inducers or inhibitors of cytochrome P450, including CYP3A4 
(http://medicine.iupui.edu/clinpharm/ddis/table.asp) as well as the product labeling of 
these compounds for reference.
CYP3A4 inhibitors/inducers/substrates are listed below. The participant must not take the 
treatments listed in Table 6 during the trial after the start of the study treatment. Since 
this list is not comprehensive, the investigator should use their medical judgment when a 
participant presents with a medication not on the list or call the Sponsor Clinical Director 
for clarification.
Table 6
Examples of Medications, Supplements, and Other Substances Prohibited During 
the Trial
Strong 3A4
Inducersa,d
Strong CYP3A4
Inhibitorsb,d
Moderate CYP3A4 
Inhibitorsb,d
CYP3A4 Substrates With Narrow 
Therapeutic Rangec,d
carbamazepine
phenobarbital
phenytoin
rifabutin
rifampin
troglitazone
indinavir
nelfinavir
ritonavir
clarithromycin
itraconazole
ketoconazole
nefazodone
atazanavir
saquinavir
telithromycin
amprenavir
aprepitant
diltiazem
erythromycin
fluconazole
fosamprenavir
verapamil
grapefruit juice
alfentanilc
ergotaminec
diergotaminec
cyclosporine c
fentanylc
pimozidec
quinidinec
sirolimusc
tacrolimusc
astemizolec,e
terfenadinec,e
cisapridec,e
paclitaxelc
repaglinidec
lurasidonec
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Strong 3A4
Inducersa,d
Strong CYP3A4
Inhibitorsb,d
Moderate CYP3A4 
Inhibitorsb,d
CYP3A4 Substrates With Narrow 
Therapeutic Rangec,d
Abbreviation: CYP = cytochrome P450.
a
Strong 3A4 inducers listed are those that decrease plasma AUC values of 3A4 substrates by 30% or higher.
b
Moderate inhibitors are defined as causing a ≥2- but <5-fold increase in the AUC values or 50-80% decrease in 
clearance of sensitive CYP3A substrates when the inhibitors were given at the highest approved dose and the 
shortest dosing interval in clinical evaluations. Strong inhibitors are defined as causing a ≥5-fold increase in the 
plasma AUC values or more than 80% decrease in clearance.
c
CYP3A4 substrates with narrow therapeutic range refers to drugs whose exposure-response indicates that increases 
in their exposure levels by the concomitant use of CYP3A4 inhibitors may lead to serious safety concerns. For 
specific information, see the Classification of Substrates tables available at:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/  
(then click “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”)
d
Compiled from the in vivo inhibitors and inducers, inhibitor classification, and substrate classification tables 
available at:  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ (then 
click “Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”) and from the 
CYP450 drug interaction table (accessed June 2012) available at: 
http://medicine.iupui.edu/clinpharm/DDIs/table.aspx 
e
Not available in the United States, and limited availability in the European Union.
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention must be discontinued.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter products, herbal supplements, and IV medications and fluids. 
If changes occur during the study period, documentation of drug dosage, frequency, route 
and date should also be included on the eCRF.
All concomitant medications received within 28 days before the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
Prohibited medications should not be used during the treatment phase of the study.
6.5.1
MK-1088 Supportive Care
Medications required to treat AEs or concurrent illnesses, other than those listed as
prohibited, (Section 6.5), are allowed during the study. These include antiemetics, growth 
factors, and other supportive care medications. Contraceptive medications as described in 
Appendix 5 are allowed.
Any supportive care cancer treatment should not be CYP3A4 inhibitors/inducers (Table 6).
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Every medication taken by the participant during the study and the reason for use must be 
recorded in the eCRF. Note that the use of any concomitant medication must relate to the 
documented medical history, prophylaxis, or an AE of the participant.
6.5.2
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
6.5.3
Pembrolizumab Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including, but not limited to, the items outlined below.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Administration/Escalation
6.6.1.1
Dose Administration (Preparation)
Details on preparation and administration of MK-1088 (and pembrolizumab) are provided in 
the appropriate Pharmacy/Procedures Manual.
6.6.2
Definition of Dose‑limiting Toxicity
All toxicities will be graded using NCI CTCAE Version 5.0 based on the investigator 
assessment.
The DLT window of observation will be during Cycle 1. 
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to study 
intervention administration.
•
Grade 4 nonhematologic toxicity (not laboratory).
•
Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:
Grade 4 thrombocytopenia of any duration
Grade 3 thrombocytopenia associated with clinically significant bleeding
•
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 
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vomiting without use of antiemetics or antidiarrheals per standard of care; Grade 3 rash 
without use of corticosteroids or anti-inflammatory agents per standard of care.
•
Any Grade 3 or Grade 4 nonhematologic 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 DILI (see Section 8.4.7 for criteria)
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc.
•
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.
•
Prolonged delay (>2 weeks) in initiating Cycle 2 due to intervention-related toxicity.
•
Any intervention-related toxicity that causes the participant to discontinue intervention 
during Cycle 1.
•
Missing >25% of MK-1088 doses as a result of drug-related AEs during the first cycle.
•
Grade 5 toxicity.
6.6.3
Cohort Expansion
In Part 2 of the study, approximately 30 additional participants will be treated in each of the 
cohorts of participants with select advanced tumors. Participants in these cohorts will be 
treated at the RP2D identified using the adjusted mTPI design in Arm 2 of Part 1 (MK-1088
in combination with pembrolizumab). The dose of pembrolizumab in Arm 2 will remain 
fixed at 200 mg Q3W. Part 2 may proceed after a protocol amendment.
Part 2 will begin once an RP2D for Arm 2 has been identified. When Part 2 is open for 
enrollment, IVRS will assign participants to 1 of the cohorts by tumor type.
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6.6.4
Guidelines for Dose Modification due to Adverse Events for MK-1088
Adverse events (both nonserious and serious) associated with MK-1088 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.
For individual participants, dose delays and modifications of study treatment will be based on 
treatment-related toxicity, laboratory test results before treatment administration, and clinical 
assessments.
Participants may have up to 2 dose modifications of MK-1088 throughout the course of the 
study, as described in Table 7. Participants at dose level 1 who require dose reduction may 
reduce their dose to 50 mg. Participants who require dose reductions below 50 mg should be 
discontinued from study treatment. If further toxicity occurs or the criteria for resuming 
treatment are not met, the participant must be discontinued from the study intervention. If a 
participant experiences several toxicities and there are conflicting recommendations, follow 
the most conservative dose adjustment recommended (dose reduction appropriate to the most 
severe toxicity). Dose reductions are not permitted during the DLT evaluation period.
The NCI CTCAE, version 5.0 must be used to grade the severity of AEs. The investigator 
may attribute each toxicity event to MK-1088 alone, to pembrolizumab alone, or to the 
combination. However, dose modifications should be implemented according to Table 7, 
Table 8, and Table 9 regardless of investigator/Sponsor causality assessment and attribution 
to either or both drugs, unless clearly related to disease progression or intercurrent illness. If 
an irAE is observed in a participant enrolled on Arm 2, dose modifications for both 
pembrolizumab and MK-1088 should be followed according to the Grade associated with the 
AE in the respective dose-modification tables. If a participant experiences several toxicities 
and there are conflicting recommendations, follow the most conservative dose adjustment 
guidance.
Exceptional circumstances to following the dose-modification tables below may be 
considered after consultation with the Sponsor. 
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Table 7
MK-1088 Monotherapy: Dose Modification and Treatment Discontinuation 
Guidelines for Treatment Emergent 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 after 
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 after 
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 after 
reduction in dose
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 after 
reduction in dose.
Permanent 
discontinuation 
should be considered 
for any severe or life-
threatening event.
AE=adverse event; N/A=not applicable.
If toxicity does not resolve to Grade 0 to 1 within 12 weeks after last intervention, MK-1088 
should be discontinued after consultation with the Sponsor.
With investigator and Sponsor agreement, participants with a laboratory AE still at Grade 2 
after 12 weeks may continue intervention in the study only if asymptomatic and controlled.
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After any Grade 4, drug-related AE, participants should not restart study intervention without 
consultation with the Sponsor. (Toxicity must have resolved to Grade 0 to 1 or baseline 
before to restarting.)
Dose reductions are not permitted during Cycle 1.
Pembrolizumab treatment will be modified for the AEs described Section 6.6.5.
6.6.5
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination 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 study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination 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, skin biopsy may be included as part of 
the evaluation.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
Holding Study Interventions:
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
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Restarting Study Interventions:
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 8.
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Table 8
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy or IO Combinations
General instructions:
1.  Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.   Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment.
3.   The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
   Add prophylactic antibiotics 
for opportunistic infections
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent 
Grade 2, Grade 3 
or 4 
Permanently discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1 to 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
Recurrent Grade 
3 or Grade 4
Permanently discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2 a
Withhold
   Administer corticosteroids 
(initial dose of 0.5 to 
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 b or 4 c
Permanently discontinue
   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or Grade 
3 or 4 
hyperglycemia 
associated with 
evidence of 
-cell failure
Withhold d
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer 
antihyperglycemic in 
participants with 
hyperglycemia
   Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
   Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
   Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
   Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by 
taper
   Monitor changes of renal function
Grade 3 or 4
Permanently discontinue
Neurological 
Toxicities
Grade 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
Myocarditis
Grade 1
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently discontinue
All Other irAEs
PersistentGrade2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or discontinue 
based on the event e
Recurrent 
Grade 3 or 
Grade 4 
Permanently discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b     AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c     AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e     Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations or IO Combinations (MK-1088) 
Pembrolizumab monotherapy, coformulations or IO combinations (MK-1088) 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 monotherapy, coformulations or IO combinations
(MK-1088) associated infusion reactions are provided in Table 9.
Table 9
Pembrolizumab Monotherapy or IO Combinations 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 intervention.
Participant may be premedicated 1.5 
h (±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 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 after initial 
improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
h=hour; IV=intravenous; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Note:  Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.3, or if available, Protocol Clarification Letter.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation before restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance that, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.2.3 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond disease progression).
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
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•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in Section 
6.6.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Arm 1 participants who progress on monotherapy MK-1088 may crossover into Arm 2 at the 
screening phase if they have completed the DLT evaluation period and a dose level in Arm 2 
has shown safety and tolerability.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention 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 FBR, are outlined in Section 
8.1.9. The procedures to be performed should a participant repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
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 used for screening or baseline purposes 
provided the procedure met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised 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 their legally acceptable representative should be informed in a timely manner if 
new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of their
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
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the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
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 important. Details regarding the disease for which the 
participant has enrolled in the study will be recorded separately and not listed as medical 
history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
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 first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.
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 intervention(s), 
the study intervention(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 study intervention, the 30-day Safety Follow-up Visit should occur 
before the first dose of the new therapy.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur before intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. The assigned screening 
number will become the participants’ treatment/randomization number. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention should begin within 3 days of treatment allocation.
8.1.8.1
Timing of Dose Administration
For infusion:
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the Pharmacy Manual. The total volume of study intervention 
infused will be compared with the total volume prepared to determine compliance with each 
dose administered.
Oral medication:
During on-site visits, study intervention(s) will be administered by the investigator and/or 
study staff according to the specifications within the Pharmacy Manual. 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 nonvisit days, MK-1088 will be taken at home. The participant will note the number of 
tablets taken, the time of administration, as well as any reactions including the date/time.
When a participant attends a study visit, they will bring any unused tablets.
8.1.8.2
Timing of Administration for MK-1088
MK-1088 is a tablet administered orally once a day from Day 1 to Day 21 of each treatment 
cycle. The reason for any variability in administration of MK-1088 outside the protocol-
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specified window should be documented in the participant’s medical chart and recorded on 
the eCRFs.
Every effort should be made to begin the first dose of study intervention on the day of 
allocation, but if this is not achieved, study intervention should be initiated no later than 
3 days from the date of allocation. All subsequent cycles of study intervention may be 
administered up to 3 days before or 3 days after the scheduled Day 1 of each cycle due to 
administrative reasons per the investigator’s judgment. All study interventions will begin on 
Day 1 of each cycle after all predose study procedures and assessments have been completed 
as detailed in Section 1.3.
The Pharmacy Manual contains specific instructions for MK-1088 dose calculation and
administration.
8.1.8.3
Timing for Administration of Pembrolizumab
For those subjects enrolled in Arm 2 (MK-1088 and pembrolizumab), study treatment with 
pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the SoA (Section 1.3). All study 
treatments of pembrolizumab will be administered on an outpatient basis. Study treatment of 
pembrolizumab may be administered up to 3 days before or after the scheduled Day 1 of each 
cycle due to administrative reasons except for C1D1, where the window is +3 days from 
allocation.
Please refer to the Pharmacy Manual for specific instructions regarding preparation of the 
pembrolizumab infusion fluid, and administration.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA (Section 1.3) and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR 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 
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already performed before the request being received by the Sponsor will continue to be used 
as part of the overall research study data and results. No new analyses would be generated 
after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the study records) or the specimens have been 
completely anonymized, there will no longer be a link between the participant’s personal 
information and their specimens. In this situation, the request for specimen withdrawal 
cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Scans and Assessment of Disease
Throughout this section, the term 'scan' refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, bone imaging, or other methods as specified in this protocol. 
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for scan collection and retention and/or transfer can be found 
in the SIM. 
Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-enhanced 
MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by 
local practice. The same imaging technique 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 response assessment based on scans. 
Note: For the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
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Brain imaging is required at screening for participants with a history of brain metastases or 
when clinically indicated and on-study when clinically indicated or to confirm CR when 
brain metastases were present at screening.

If brain scans are performed, magnetic resonance imaging is preferred; however, CT 
imaging will be acceptable, if MRI is medically contraindicated.
Prostate Cancer
Bone scintigraphy (eg, nuclear medicine bone scan, Tc99 bone scan, bone scan, etc.) of the 
whole body is required for all participates at screening and on-study for all scheduled 
imaging visits and to confirm PCWG-modified RECIST 1.1 bone PD.

Other bone imaging modalities (eg, FDG-PET, PET, PSMA PET, MRI, SPECT, etc.) 
cannot be a substitute for the bone scan (see Appendix 9, Section 10.9).
Non-Prostate Cancer
Bone imaging (e.g. bone scan, PET scan, etc.) should be performed to evaluate bone 
metastases when clinically indicated at screening and on-study or to confirm CR when bone 
metastases were present at screening. 
8.2.2
Initial Tumor Scans
Initial tumor scans at screening must be performed within 28 days before the date of 
allocation. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The investigator must review screening scans to confirm the participant has 
measurable disease per RECIST 1.1, for mCRPC participants by PCWG-modified 
RECIST 1.1.
If brain scans are required to document the stability of existing metastases, the brain scan 
should be acquired during screening. The specific methods permitted for this study are 
described in the SIM.
Bone scintigraphy (eg, Tc99 bone scan, etc.) is required for all participants with prostate 
cancer. For all other participants, bone imaging (eg, bone scan, PET scan, etc.) is required 
only when clinically symptomatic (eg, with new bone pain, etc.).
8.2.3
Tumor Scans During the Study
The first on-study scan should be performed at 9 weeks (63 days ±7 days) from the C1D1
date. Subsequent tumor scans should be performed every 9 weeks (63 days ±7 days) or more 
frequently if clinically indicated. After 54 weeks (378 days ±7 days), participants who 
remain on treatment will have scans performed every 12 weeks (84 days ±7 days). Scan 
timing should follow calendar days and should not be adjusted for delays in cycle starts.
Scans are to be performed until disease progression is identified by the investigator,
withdrawal of consent, pregnancy, or death, whichever occurs first.
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Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
For non-prostate cancer participants, on-study brain or bone scans should be performed if 
clinically indicated or to confirm CR (if other lesions indicate CR and brain or bone lesions 
existed at screening).
For prostate cancer participants, radiographic progression will be determined according to 
PCWG-modified RECIST 1.1. Disease progression in bone lesions should be confirmed by 
another bone scan ≥6 weeks after site assessed first radiographic evidence of bone disease 
progression.
8.2.4
End of Treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to documented disease 
progression, this is the final required tumor scan.
If participants discontinue study intervention without documented disease progression, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of allocation, refer to Section 8.2.3.
Scans are to be continued until one of the following conditions are met:

Disease progression as defined by RECIST 1.1 or PCWG-modified RECIST 1.1

The start of a new anticancer treatment

Pregnancy

Death

Withdrawal of consent

The end of the study
8.2.5
RECIST 1.1 and PCWG-modified RECIST 1.1 Assessment of Disease
For participants other than those with prostate cancer, RECIST 1.1 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 
intervention). Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 
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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.
For participants with prostate cancer, the primary measure for assessment of tumor response, 
date of disease progression and as the basis for all protocol guidelines related to disease 
status (eg, discontinuation of study intervention) will be PCWG-modified RECIST 1.1. 
Assessment of treatment response in the soft tissue will be according to RECIST 1.1, 
modified as above. Assessment of treatment response in the bone will be according to the 
rules of PCWG as described in Appendix 9.
Soft tissue response and bone response assessments will be combined to produce an overall 
radiographic response, as shown in Table 10.
Table 10
Overall Radiographic Response per PCWG-modified RECIST 1.1
Soft Tissue 
Response
Bone Scan
Result
PCWG-modified RECIST 1.1 
Time Point Response Entered 
into CRF
PD
Any
PD
Any
PD
PD
Any (except PD)
PDu
PDu
NE
Non-PD, NED or NE
NE
NED
NE
NE
NED
Non-PD
Non-CR/Non-PD
NED
NED
NED
SD
Non-PD, NED, or NEa
SD
Non-CR/Non-PD 
Non-PD, NED, or NEa
Non-CR/Non-PD
PR
Non-PD, NED or NE*
PR
CR
Non-PD or NE*
PR
(if target lesions were present at 
screening)
Non-CR/Non-PD
(if no target lesions at screening)
CR
NED
CR
Abbreviations: CR = complete response; CRF = case report form; NE = nonevaluable; NED = no evidence of 
disease; PCWG = Prostate Cancer Working Group; PD = progressive disease; PDu = progressive disease 
unconfirmed; PR= partial response; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors Version 
1.1; SD = Stable disease. 
a If the bone scan is entirely missing or was not conducted, and bone lesions were present at screening, then 
the overall response is NE.
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For all participants (prostate cancer and non-prostate cancer), if disease progression is 
established by the investigator, the process continues as follows:

Investigator judgment will determine action

If the participant is clinically stable and study intervention is to continue, communication 
with the Sponsor is required and a reconsent addendum must be signed 

Obtain scans per original protocol schedule
For the purpose of this decision process, lack of clinical stability is defined as:

Unacceptable toxicity

Clinical signs or symptoms indicating clinically significant disease progression

Decline in performance status

Rapid disease progression or threat to vital organs or critical anatomical sites (eg, CNS 
metastasis, respiratory failure due to tumor compression, spinal cord compression) 
requiring urgent alternative medical intervention
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory
or Study Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard .
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Clinically significant abnormal findings should be recorded as medical 
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history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated before study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, before the 
administration of each dose of study intervention at study visits and during the follow-up 
period as specified in the SoA. Vital signs include temperature, heart rate, respiratory rate, 
and blood pressure. Height will be measured at Visit 1 only. Weight will be measured at Visit 
1; Day 1 of Cycles 1, 2, and 3; and during follow-up as specified in the SoA.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA. Clinically significant abnormal findings should be recorded as 
medical history. Additional ECGs may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the 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 nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
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considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests should be performed within 3 days before the first dose of study 
intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days before the first dose. After Cycle 1, predose laboratory safety tests can be 
conducted up to 72 hours before dosing unless otherwise noted on the flow charts.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable before administration of each dose of study intervention. 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.
See the Operations/Laboratory Manual for additional details.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be 
conducted at monthly intervals during intervention.
-
Pregnancy testing ([urine or serum] as required by local regulations) should be 
conducted at the end of relevant systemic exposure and correspond with the time 
frame for female participant contraception in Section 5.1.
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the subject's participation in the study.
8.3.6
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc.) with grades 0 to 5.
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The investigator or qualified designee will assess ECOG status at screening, before the 
administration of each dose of study intervention at study visits, and during the follow-up 
period as specified in the SoA (Section 1.3).
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE unless it results in 
hospitalization or death as described in Section 8.4.6 and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse. Investigators remain responsible for following up AEs, SAEs, and other reportable 
safety events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation through 30 days after cessation of study 
intervention must be reported by the investigator.
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•
All AEs meeting serious criteria, from the time of intervention allocation through 90 days 
after cessation of study intervention or 30 days after cessation of study intervention if the 
participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
allocation through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 11.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 11
Reporting Time Periods and Time Frames 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
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is receiving 
placebo run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any protocol-
specified intervention 
(eg, procedure, washout 
or run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable event.
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
ECI (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
ECI (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
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Progression of the cancer under study is not considered a reportable event unless it results in 
hospitalization or death.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include: 
3.
An overdose of Sponsor's product, as defined in Section 8.5.
4.
An elevated AST or ALT laboratory value that is greater than or equal to 3X the ULN 
and an elevated total bilirubin laboratory value that is greater than or equal to 2X the 
ULN and, at the same time, an alkaline phosphatase laboratory value that is less than 
2X the ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.*
*Note: These criteria are based on 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 study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-1088 by ≥20% of the indicated dose. No specific information is available on the 
treatment of overdose of MK-1088. In the event of overdose, MK-1088 may be discontinued 
and the participant should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated.
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.
8.6
Pharmacokinetics
To further evaluate MK-1088 exposure in this indication, and also to evaluate exposure of 
the proposed dosing regimen, sample collections for analysis of PK are currently planned as 
shown in Section 1.3. Blood samples will be obtained to measure PK of serum MK-1088. 
The MK-1088 serum Cmax and Cmin at planned visits and times will be summarized. Blood 
samples collected may be stored and further analysis may be performed, if required.
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On the day(s) of sample collection, participants must not take study medication until the 
predose PK and biomarker (Section 8.8) sample collections are complete. Every effort should 
be taken by the investigative center to document the time of the last MK-1088 dose (ie, at 
home) before PK collection.
8.6.1
Blood Collection for Plasma MK-1088
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Operations/Laboratory Manual.
Pharmacokinetic samples should be drawn according to the PK collection schedule for all 
participants. Every effort should be taken to collect samples at 30 days after end-of-study
intervention.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:
•
Blood (DNA) for genetic analysis
•
Blood for serum biomarker analyses
•
Blood for RNA analyses
•
Archival or newly obtained tumor tissue
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
8.8.1
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 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 FBR
only if participant signs the FBR consent.
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8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover samples listed in Section 8.8
8.10
Health Economics Medical Resource Utilization and Health Economics
This section is not applicable.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Approximately 28 days before treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 1.3. Screening 
procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days before the 
first dose of study intervention.
8.11.2
Treatment Period/Vaccination Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided above in Section 8..
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, 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 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.11.4
Posttreatment Visit
Participants will be required to return to the clinic approximately 30 days after the last dose 
of study intervention for the poststudy visit. If the poststudy visit occurs less than 30 days 
after the last dose of study intervention, a subsequent follow-up telephone call should be 
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made at 30 days post the last dose of study intervention to determine if any AEs have 
occurred since the poststudy clinic visit.
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
All AEs that occur before the Safety Follow-up Visit should be recorded (up to 30 days after 
the end of treatment).
8.11.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin Efficacy
Follow-up. Participants who discontinue study intervention for reasons other than PD should 
continue with imaging assessments per the protocol-defined schedule until: (1) radiographic 
PD is assessed by the investigator, (2) initiation of a new anticancer treatment, (3) death, (4) 
withdrawal of consent, (5) pregnancy, or (6) study conclusion or early termination, 
whichever occurs first. Follow-up should be assessed as defined in Section 8.11.4.3, to
monitor disease status. Information regarding poststudy anticancer treatment will be 
collected if new treatment is initiated. Participants who completed all efficacy assessments 
and/or will not have further efficacy assessments must enter survival follow-up.
8.11.4.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:

For participants who discontinue treatment intervention and who will not enter 
Efficacy Follow-up, the first survival follow-up contact will be scheduled 12 weeks 
after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).

For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
8.11.5
Poststudy
Participants will be required to return to clinic approximately 30 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 30 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at
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30 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.11.6
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. On 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 vital status.
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate sSAP.
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but before the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
Full details are in the SAP, Section 9.2 through 9.12.
Study Design Overview
Phase 1/Phase 2 study of MK-1088 monotherapy (Arm 1) and 
MK-1088 in combination with pembrolizumab (Arm 2) in 
participants with advanced/metastatic solid tumors. The study 
applies an adjusted mTPI design for dose-finding.
Intervention
Assignment
Participants will be allocated centrally through IVRS by 
nonrandom assignment.
Analysis Populations
•
Safety (Primary): All-Participants-as-Treated 
•
PK (Secondary): Per-Protocol 
•
Efficacy (Secondary and Exploratory): Full Analysis Set 
Primary Endpoint(s)
•
Dose-limiting toxicity 
•
Adverse event 
•
Discontinuing study treatment due to an AE
Secondary Endpoints
•
PK parameters including AUC, Cmin, and Cmax
•
ORR based on RECIST 1.1 as assessed by the investigator
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Statistical Methods for 
Efficacy/
Immunogenicity/ 
Pharmacokinetic 
Analyses
•
ORR based on RECIST 1.1 will be estimated using an exact 
method based on the binomial distribution (Clopper-Pearson 
interval).
•
Exploratory efficacy (eg, PFS, OS, and DOR) analyses are 
documented in the sSAP.
•
PK parameters of study medicines will be summarized by 
planned visit and time for each dose separately.
Statistical Methods for 
Safety Analyses
Summary statistics 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 RP2D of MK-1088 and the 90% Bayesian credible 
intervals for the estimate will be provided for each treatment 
arm.
Interim Analyses
No interim analyses are planned. Data will be examined on a 
continuous basis to allow for dose-finding decisions.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power
The overall sample size for this study depends on the observed 
DLT profiles of MK-1088 monotherapy and MK-1088 in 
combination with pembrolizumab. A target sample size of 80
participants in Part 1 will be used for study planning purposes.
Sample size for Part 2 Expansion will be determined once the 
RP2D is determined.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study is open-label (ie, participants, investigators, and Sponsor personnel will be aware 
of participant intervention assignment after each participant is enrolled and treatment is 
assigned). Participants will be allocated by nonrandom assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Efficacy endpoints are secondary (ORR) and exploratory (PFS, OS, and DOR) endpoints in 
this study. The ORR is defined as the percentage of participants who achieve a confirmed CR 
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or PR per PCWG-modified RECIST 1.1 or RECIST 1.1 as assessed by the investigator. 
Participants without response assessment will be counted as nonresponders. Details of the 
analysis plan will be documented in the sSAP for the exploratory objectives. A description of 
efficacy measures is provided in Section 8.2.
Pharmacokinetic endpoints include plasma concentrations of MK-1088 (and 
pembrolizumab), as well as derived PK parameters.
9.4.2
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 AEs, laboratory tests, and 
vital signs.
A description of safety measures is provided in Section 8.3.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all participants who received at least 1 dose of study intervention.
Participants who receive the incorrect study intervention will be summarized according to the 
actual study intervention they receive.
The DLT-evaluable population includes APaT participants that meet the criteria for DLT 
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 5.5 for details. Participants who are DLT nonevaluable will be eligible for inclusion 
in other analysis populations if they meet the respective criteria. 
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. A baseline 
measurement is also required to assess change from baseline.
Safety data from participants who experienced disease progression in the monotherapy arm 
and crossed over into the combination arm will be summarized in their initial monotherapy 
dose group until the time of cross over and will be summarized separately thereafter.
9.5.2
Pharmacokinetic Analysis Populations
The per-protocol population will be used for the analysis of PK and target engagement data 
in this study. The per-protocol population consists of the subset of participants who complied 
with the protocol sufficiently to ensure that their data will be likely to show 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 participants or data values excluded from the analyses will be 
identified, along with the reasons for exclusion, in the CSR. At the end of the study, all 
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participants who were compliant with the study procedures and have available data from at 
least 1 treatment will be included in the per-protocol analysis dataset.
9.5.3
Efficacy Analysis Populations
The FAS population will be used for the analyses of efficacy data in this study. It consists of 
all participants with a screening/baseline scan that showed measurable disease by the 
investigator’s assessment, and who were administered at least 1 dose of study intervention.
Participants who receive the incorrect study intervention will be summarized according to the 
actual study intervention they receive. 
Efficacy data from participants who experienced disease progression in the monotherapy arm 
and crossed over into the combination arm will be summarized in their initial monotherapy 
dose group until the time of cross over and will be summarized separately thereafter.
9.6
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.
9.6.1
Statistical Methods for Efficacy Analysis
The statistical methods for efficacy analyses will be documented in the sSAP.
ORR will be estimated using an exact method based on the binomial distribution (Clopper-
Pearson interval).
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
AEs will be summarized by counts and frequencies for each dose level. Laboratory tests, 
vital signs, and other safety endpoints will be summarized as appropriate.
DLTs 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 nondecreasing with 
increasing dose levels and pools adjacent violators for weighted estimates by sample size, 
will be used to estimate the DLT rates across doses in each treatment arm. The estimate of 
the DLT rate among participants treated at the RP2D and the 90% Bayesian credible interval 
based on a prior distribution of Beta (1,1) for the estimate will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
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9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
PK parameters of study interventions will be summarized by planned visit and time for each 
dose separately.
PK and pharmacodynamics modeling analyses will be documented in the sSAP.
9.7
Interim Analyses
No interim analyses are planned. Data will be examined on a continuous basis to allow for 
dose-finding decisions.
9.8
Multiplicity
There will be no multiplicity adjustment since no hypothesis testing will be conducted.
9.9
Sample Size and Power Calculations
With a maximum sample size of 14 at each dose level, the overall sample size for this 
Phase 1/Phase 2 study is expected to be approximately 80. The actual sample size depends on 
the safety profiles and number of doses studied.
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide their 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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
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information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their 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.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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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 participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•   The tests detailed in Table 12 will be performed by the local laboratory.
•   Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•   Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 12
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test 
Hemoglobin
Alkaline phosphatase
Glucose
(serum or urine)a
Platelet count
ALT
Protein
Total T3 (or Free T3 [FT3]),
WBC (total and
AST
Specific gravity
Total T4 (or Free T4 [FT4]), 
and TSHb,c
differential)d
Bicarbonate
Microscopic
RBC
Calcium
examination or,
Anti-HCVe
Absolute
lymphocyte 
countd
Chloride
other standard 
diagnostic 
evaluation
HCV viral loadc,e
Creatinine
(if blood or
HCV genotypec,e
Glucose
protein is 
anti-HBsc, e
Absolute 
Phosphorus
abnormal)
HBsAge
neutrophil 
Potassium
Anti-HBc (total and IgM)c,e
countd
Sodium
HBeAgc, e
PT/INR
Total bilirubin
anti-HBec,e
aPTT or PTT
Direct bilirubin
HBV viral loadc,e
Total protein
GGTf
Blood urea nitrogen
PSA
(or Urea)
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; GGT=gamma-glutamyl transpeptidase; HBc= hepatitis B core; HBe= hepatitis Be; 
HBeAg=hepatitis B e-antigen; HBs=hepatitis B surface; HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; 
IgM=immunoglobulin M; PT/INR=prothrombin time/international normalized ratio; PTT=partial thromboplastin time; 
RBC=red blood cell; T3=triiodothyronine; T4=thyroxine; TSH=thryroid stimulating hormone; WBC=white blood cell.
a
Perform on women of childbearing potential only 72 hours before Day 1 of Cycle 1. Pregnancy tests must be 
repeated before every cycle if required or as specified per local regulatory guidance.
b T3 is preferred; if not available, Free T3 may be tested.
c
If the local laboratory is unable to perform these tests, the site may send the samples to another laboratory certified 
to perform the test. Details are provided in the Procedure Manual.
d Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
e
Tests are required for participants with known history or if local regulation mandates the testing.
f
GGT is required as clinically indicated.
Investigators must document their review of each laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.  
10.3.2
Definition of AE
AE definition
•   An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•   Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•   Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), 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, considered clinically significant in the medical 
and scientific judgment of the investigator.
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•   Exacerbation of a chronic or intermittent preexisting condition including either an increase 
in frequency and/or intensity of the condition.
•   New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.
•   Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•   Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•   For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose without 
any associated clinical symptoms or abnormal laboratory results is reported using the 
terminology “accidental or intentional overdose without adverse effect.”
•   Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
Events NOT meeting the AE definition
•   Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•   Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•   Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•   Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•   Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.   Results in death
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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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d.   Results in persistent or significant disability/incapacity
•    The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•    This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.   Is a congenital anomaly/birth defect
•    In offspring of participant taking the product regardless of time to diagnosis.
f.   Other important medical events
•    Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
•    Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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10.3.4
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame 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
10.3.5
Recording AE and SAE
AE and SAE recording
•   When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•   The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets 
at each examination.
•   It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•   There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•   The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity /toxicity
•   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 CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade recorded 
on the AE CRFs/worksheets.
-   Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
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-   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 AE?
•   The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•   The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-   Exposure: Is there evidence that the participant was actually exposed to the Sponsor’s 
product such as: reliable history, acceptable compliance assessment (pill count, diary, 
etc), expected pharmacologic effect, or measurement of drug/metabolite in bodily 
specimen?
-   Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with IMP)?
-   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.
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(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-   Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦   If yes, did the AE recur or worsen?
◦   If yes, this is a positive rechallenge.
◦   If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•   Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•   The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•   Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-   Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦   There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-   No, there is not a reasonable possibility of Sponsor’s product relationship:
◦   Participant did not receive the Sponsor’s product OR temporal sequence of the AE 
onset relative to administration of the Sponsor’s product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a participant with overdose without an associated AE.)
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•   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 their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•   The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•   For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to 
support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•   The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•   New or updated information will be recorded in the CRF.
•   The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, 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 EDC tool.
-   Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-   If the electronic system is unavailable for more than 24 hours, then the site will use the 
paper AE Reporting form.
•   Reference Section 8.4.1 for reporting time requirements.
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•   The site will enter the SAE data into the electronic system as soon as it becomes available.
•   After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•   If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•   Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•   If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•   In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service.
•   Initial notification via telephone does not replace the need for the investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames.
•   Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
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
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•   Postmenopausal female
•   A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
-   A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or 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.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This 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. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    Male condoms must be used in addition to female participant hormonal contraception.
d    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
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 Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
a.   The biology of how drugs/vaccines work
b.   Biomarkers responsible for how a drug/vaccine enters and is removed by the body
c.   Other pathways with which drugs/vaccines may interact
d.   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 Research3, 4
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.   Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5.   Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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 future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6.   Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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 before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7.   Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8.   Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9.   Reporting of Future Biomedical Research Data to Participants3, 4
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 Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11.  Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12.  Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13.  References
1.   National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.   International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.   Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.   Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Not applicable
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
ART
anti-retroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
BID
twice daily
CD
cluster of differentiation
CD3ζ
CD3 zeta
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CR
complete response
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
trough (minimum) concentration
CYP
cytochrome P450
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid 
DOR
duration of response
DU
current dose is unacceptably toxic
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
electronic Data Monitoring Committee 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
FAS
Full Analysis Set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIH
first-in-human
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Abbreviation
Expanded Term
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GI
gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
IC
Informed Consent
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug 
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
LAM
lactational amenorrhea method
LLOQ
lower limit of quantification
LPLV
last participant last visit
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NIMP
noninvestigational medicinal product
NSCLC
non–small cell lung cancer
NYHA
New York Health Association
OR
objective response
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Abbreviation
Expanded Term
ORR
objective response rate
OS
overall survival
PBPK
physiologically based PK
PCWG
Prostate Cancer Working Group
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PN
protocol number
po
orally
PP
Per-Protocol
PPI
proton-pump inhibitors
PQC
product quality complaint
PR
partial response
PSA
prostate-specific antigen
Q2W
every 2 weeks
Q3W
every 3 weeks
QD
once daily
QTcF
corrected QT interval by Fridericia
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SIM
Site Imaging Manual
SLAB
Supplemental laboratory test(s)
SoA
schedule of activities
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
t1/2
half life
TE
target engagement
Tmax
time to maximum plasma concentration
TME
tumor microenvironment
ULN
upper limit of normal
US(A)
United States (of America)
WOCBP
woman/women of childbearing potential
ZAP70
zeta-chain-associated protein kinase
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10.9
Appendix 9: Prostate Cancer Working Group Criteria
1.  Description of the Prostate Cancer Working Group (PCWG) Process for Assessment 
of Bone Lesions 
The rules for evaluation of response and progression based on bone lesions were created by 
the Prostate Cancer Working Group, and published as part of both PCWG2 and 
PCWG3[Scher, H. I., et al 2016]. All bone lesions are evaluated according to these rules, 
including assessment at screening and evaluation of response.
2.  Imaging Methods 
The PCWG rules were designed based on the radionuclide (Tc-99m) bone scintigraphy. 
Other modalities, including FDG-PET, sodium fluoride PET, bone MRI, etc. may have 
individual advantages, but the PCWG rules were not created with the performance 
characteristics of these methods in mind and should not be used instead of radionuclide bone 
scan. 
Only bone lesions seen by bone scan may be followed for assessment of tumor treatment 
response. Bone disease seen by CT only (not visible on bone scan) is presumed not to 
represent active disease and should not be documented as a bone lesion (sclerotic lesions 
seen on CT may represent healed disease or nonmalignant confounders such as bone infarcts 
or other benign findings).
3.  Documentation of Bone Lesions at Baseline
At screening, individual bone lesions may be recorded as non-target lesions only, and the 
number of bone lesions should be noted.
4.  Assessment of Bone Response at Subsequent Imaging Time Points
At all follow-up time points, bone disease will be classified as PD, PDu, Non-PD, NED, or 
NE. The definitions are summarized in Table 13, and described in more detail below.
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Table 13
Bone Response Abbreviations and Associated Definitions
Bone Response
Definition
PD
Progressive disease: 
2 new lesions, not flare, persistent
PDu
Progressive disease unconfirmed: 
Temporary marker of possible PD, to be updated to PD or non-PD once 
a subsequent scan is available. 
If this is the final visit, the visit response will remain PDu, but is 
updated to PD during analysis by the Sponsor.
Non-PD
Non-progressive disease: 
At least one bone lesion present, but not enough to trigger PD
NE
Non-evaluable: 
Status of bone lesions cannot be determined (scan quality, scan 
missing, etc.)
NED
No evidence of disease: 
No lesions seen on bone scan
Abbreviations: NE=non-evaluable; NED=no evidence of disease; Non-PD=non-progressive disease; PD=progressive 
disease; PDu=progressive disease unconfirmed
5.  Descriptions of Bone Response Categories
5.1  No Evidence of Disease
No lesions seen on bone scan at this visit. Either none were seen at screening, or all 
completely resolved on subsequent imaging. 
5.2  Non-progression (Non-PD)
At least one bone lesion is present on the scan at this visit, but the conditions for progression 
have not been met, because there are not at least 2 new lesions present.
5.3  Unconfirmed Progressive Disease (PDu)
At least 2 new bone lesions are present, but an additional scan is required for confirmation. 
This response category is meant as a placeholder that reflects temporary uncertainty, and is 
updated to PD or non-PD once a subsequent bone scan is available.
5.4  Progressive Disease (PD)
At least 2 new bone lesions are present, which have been confirmed to not represent flare or 
any other confounder (see below), and which are persistent for at least 6 weeks. The new 
bone lesions do not all have to appear at the same time. Thus if one new lesion appears at 
visit N, and another new lesion at visit N+1, visit N+1 is considered to represent PD.
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5.5 Confirmation of Progression
Radiographic progression of bone lesions is defined as the appearance of ≥ 2 new bone 
lesions on radionuclide bone scan. When ≥ 2 new bone lesions are first observed, this is 
classified as PD-U, which marks the possibility of progression that will be resolved by the 
next scan.
5.5.1
For new lesions within the flare window (<12 weeks)
After a scan classified as PDu within the first 12 weeks of treatment, if the next bone scan 
outside the flare window shows at least 2 additional new bone lesions (in addition to the new 
lesions seen on the prior scan), the initial progression is considered confirmed, and the bone 
scan response updated to PD. Because this requires at least 2 new lesions, followed by 
another 2 new lesions, this is known as the “2+2 rule”.
If the next bone scan outside the flare window does not show at least 2 additional new bone 
lesions, the lesions seen on the prior scan within the flare window are considered to be 
preexisting lesions that became more visible because of the tumor flare phenomenon.

The bone response at the prior visit is updated to non-PD.

The bone lesions seen within the flare window are ignored for the purposes of 
counting new lesions at later timepoints, since they were not new. This may be 
referred to as “re-baselining”.
5.5.2
For new lesions outside the flare window (> 12 weeks) 
After a scan classified as PDu after the first 12 weeks of treatment, if at least 2 of the new 
lesions seen on that scan persist on the next bone scan performed at least 6 weeks later, this 
confirms the initial progression. The prior response is then updated to PD. If the new lesions 
have disappeared on this later scan, the prior response is updated to non-PD because these 
lesions are presumed to be nonmalignant in nature. No rebaselining of lesions will occur in 
this scenario.
5.6  Superscan
A “superscan” occurs when there is diffuse skeletal involvement by tumor, such that 
individual bone lesions are not distinguishable. The bone scan may initially appear normal, 
because the increase bone uptake may be uniform, but can be distinguished by the faint or 
absent activity in the kidneys and urinary tract.
If there is a true superscan at screening, identifying individual new bone lesions, and 
determining progression based on bone lesions, may be impossible. 
If a superscan occurs after screening, the participant’s bone response will be recorded as PD. 
No subsequent imaging will be required for confirmation, because a superscan is extremely 
unlikely to be caused by benign conditions or tumor flare. 
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5.7  Management Following Confirmed Progressive Disease
If repeat imaging does confirm PD, participants will be discontinued from study treatment.
Note: If a participant has confirmed radiographic progression as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered after consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue (reference the efficacy section of the 
protocol).
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