Clinical trial NCT02972034
Conditions: Neoplasms Colorectal Cancer
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-01-13; Completion date: 2022-12-02
Enrollment: 111 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will evaluate the safety, tolerability and preliminary efficacy of MK-8353 when administered in combination with pembrolizumab (MK-3475). There are two parts in this study: Part 1 will be dose escalation and confirmation, and Part 2 will be a cohort expansion. In Part 1, the recommended phase II dose (RP2D) of MK-8353 in combination with a fixed dose of pembrolizumab in participants with advanced malignancies will be identified and confirmed. Participants will be initially enrolled to receive MK-8353 at 350 mg twice a day (BID) in combination with pembrolizumab at a fixed dose of 200 mg on Day 1 of each 3-week cycle (Q3W) for up to 24 months of treatment. In Part 2, participants with advanced colorectal cancer (CRC) that is microsatellite stable (i.e., non-microsatellite instability-high/deficient mismatch repair \[non-MSI-H/dMMR\]) who received at least one and up to five prior lines of therapy will be enrolled at the RP2D in the expansion cohort to further evaluate safety and efficacy.

Detailed description:

Arms: arm 1: Participants receive MK-8353 orally (PO) two times each day (BID) on Days 1 through 21 of each 21-day cycle PLUS pembrolizumab (pembro) 200 mg intravenously (IV) on Day 1 of each 21-day cycle for up to 35 cycles. arm 2: Participants receive MK-8353 PO once each day (QD) on Days 1 through 21 of each 21-day cycle PLUS pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 35 cycles. arm 3: Optional Arm: Participants receive MK-8353 PO QD on Days 1 to 7, Days 15 to 21 and Days 29 to 35 PLUS pembrolizumab 200 mg IV on Day 1 and Day 22 of each 42-day period (based on 2 cycles of 21 days) for up to 35 cycles. arm 4: Optional Arm: Participants undergo an MK-8353 PO QD run-in period from Day -14 to Day -1 prior to Cycle 1 during which they receive MK-8353 PO QD. After the run-in period, participants receive MK-8353 PO QD on Days 1 through 21 of each 21-day cycle PLUS pembrolizumab 200 mg IV on Day 1 of each 21-day cycle for up to 36 cycles.
Interventions: intervention 1: MK-8353 intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: PO capsule intervention 2: IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1b Study to Evaluate the Safety and
Tolerability of MK-8353 in combination with
Pembrolizumab in Patients with Advanced
Malignancies
NCT02972034
28-Jun-2021


Product:  MK-8353 (SCH 900353)
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase 1b Study to Evaluate the Safety and Tolerability of MK-8353 in combination with 
Pembrolizumab in Patients with Advanced Malignancies
IND NUMBER:  111,626
EudraCT NUMBER:  2016-003478-42
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1
TRIAL SUMMARY.................................................................................................. 14
2
TRIAL DESIGN........................................................................................................ 15
2.1
Trial Design ........................................................................................................... 15
2.2
Trial Diagram........................................................................................................ 18
3
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 19
3.1
Primary Objective(s) & Hypothesis(es).............................................................. 19
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 19
3.3
Exploratory Objectives......................................................................................... 20
4
BACKGROUND & RATIONALE.......................................................................... 20
4.1
Background ........................................................................................................... 20
Pharmaceutical and Therapeutic Background .................................................... 20
4.1.1.1
MK-8353...................................................................................................... 20
4.1.1.2
Pembrolizumab ............................................................................................ 22
4.1.1.3
Rationale for MK-8353 in Combination with Pembrolizumab ................... 23
Preclinical and Clinical Trials............................................................................. 24
4.1.2.1
MK-8353...................................................................................................... 24
4.1.2.2
Pembrolizumab ............................................................................................ 26
Ongoing Clinical Trials....................................................................................... 27
4.1.3.1
MK-8353...................................................................................................... 27
4.1.3.2
Pembrolizumab ............................................................................................ 28
4.2
Rationale................................................................................................................ 28
Rationale for the Trial and Selected Subject Population .................................... 28
Rationale for Dose Selection/Regimen............................................................... 29
4.2.2.1
Starting Dose for This Trial......................................................................... 31
4.2.2.2
Maximum Dose/Exposure for This Trial..................................................... 32
4.2.2.3
Rationale for Dose Interval and Trial Design.............................................. 32
Rationale for Endpoints ...................................................................................... 33
4.2.3.1
Efficacy Endpoints....................................................................................... 33
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4.2.3.2
Safety Endpoints.......................................................................................... 33
4.2.3.3
Pharmacokinetic Endpoints ......................................................................... 34
4.2.3.4
Antidrug Antibody Assay ............................................................................ 34
4.2.3.5
Tumor Markers ............................................................................................ 34
4.2.3.6
RAS/RAF Mutations and pMMR/dMMR (MSI) Status.............................. 34
4.2.3.7
Planned Exploratory Biomarker Research................................................... 35
4.2.3.8
Future Biomedical Research........................................................................ 36
4.3
Benefit/Risk ........................................................................................................... 37
5
METHODOLOGY ................................................................................................... 37
5.1
Entry Criteria........................................................................................................ 37
Diagnosis/Condition for Entry into the Trial...................................................... 37
Subject Inclusion Criteria.................................................................................... 37
Subject Exclusion Criteria .................................................................................. 39
5.2
Trial Treatment(s) ................................................................................................ 42
Dose Selection .................................................................................................... 44
5.2.1.1
Dose Selection (Preparation) ....................................................................... 44
5.2.1.2
Dose Escalation and Confirmation .............................................................. 44
5.2.1.3
Cohort Expansion......................................................................................... 47
5.2.1.4
Tolerability Evaluation Rules and Dose Escalation..................................... 47
5.2.1.5
Definition of Dose-limiting Toxicities......................................................... 49
5.2.1.6
Replacement of Subjects in Dose-limiting Toxicity Period ........................ 50
Dose Modification (Escalation/Titration/Other)................................................. 51
5.2.2.1
MK-8353 Dose Modifications..................................................................... 51
5.2.2.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 52
Timing of Dose Administration.......................................................................... 57
Trial Blinding...................................................................................................... 59
5.3
Randomization or Treatment Allocation............................................................ 59
5.4
Stratification.......................................................................................................... 59
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 59
Acceptable Concomitant Medications ................................................................ 60
Prohibited Concomitant Medications.................................................................. 60
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5.5.2.1
Prohibited Concomitant Medications for MK-8353.................................... 61
5.5.2.2
Prohibited Concomitant Medications for Pembrolizumab .......................... 63
5.6
Rescue Medications & Supportive Care............................................................. 63
Supportive Care Guidelines ................................................................................ 63
5.6.1.1
Supportive Care Guidelines for MK-8353................................................... 63
Supportive Care Guidelines for Pembrolizumab ................................................ 65
5.7
Diet/Activity/Other Considerations..................................................................... 65
Diet...................................................................................................................... 65
Contraception...................................................................................................... 66
Use in Pregnancy ................................................................................................ 67
Use in Nursing Women....................................................................................... 67
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 68
Discontinuation of Treatment ............................................................................. 68
5.8.1.1
Discontinuation of Trial Treatment After Disease Response ...................... 69
Withdrawal from the Trial .................................................................................. 70
5.9
Subject Replacement Strategy............................................................................. 70
5.10
Beginning and End of the Trial ........................................................................... 70
5.11
Clinical Criteria for Early Trial Termination ................................................... 70
6
TRIAL FLOW CHART ........................................................................................... 71
7
TRIAL PROCEDURES ........................................................................................... 82
7.1
Trial Procedures ................................................................................................... 82
Administrative Procedures.................................................................................. 82
7.1.1.1
Informed Consent......................................................................................... 82
7.1.1.1.1
General Informed Consent.................................................................... 82
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 83
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 83
7.1.1.3
Subject Identification Card .......................................................................... 83
7.1.1.4
Medical History ........................................................................................... 83
7.1.1.5
Prior and Concomitant Medications Review............................................... 83
7.1.1.5.1
Prior Medications.................................................................................. 83
7.1.1.5.2
Concomitant Medications..................................................................... 83
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7.1.1.6
Disease Details and Treatments................................................................... 84
7.1.1.6.1
Oncology Disease Details..................................................................... 84
7.1.1.6.2
Prior Oncology Treatment History ....................................................... 84
7.1.1.7
Assignment of Screening Number............................................................... 84
7.1.1.8
Assignment of Treatment/Randomization Number..................................... 84
7.1.1.9
Trial Compliance ......................................................................................... 84
Clinical Procedures/Assessments........................................................................ 85
7.1.2.1
Full Physical Examination........................................................................... 85
7.1.2.2
Vital Signs.................................................................................................... 85
7.1.2.3
Eastern Cooperative Oncology Group Performance Status......................... 85
7.1.2.4
Electrocardiogram........................................................................................ 85
7.1.2.5
Administration of MK-8353 and Pembrolizumab ....................................... 85
7.1.2.6
Disease Assessments.................................................................................... 86
7.1.2.7
Adverse Event Monitoring........................................................................... 86
Laboratory Procedures/Assessments .................................................................. 87
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 87
7.1.3.2
Other Laboratory Evaluations...................................................................... 88
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 88
7.1.3.3.1
Blood Collection for PK Assessment for MK-8353............................. 88
7.1.3.3.2
Blood Collection for PK Assessment for Pembrolizumab ................... 88
7.1.3.3.3
Blood Collection for RNA, Plasma, and Serum ................................... 89
7.1.3.4
Tumor Tissue Collection.............................................................................. 89
7.1.3.5
Planned Genetic Analysis Sample Collection.............................................. 89
7.1.3.6
Future Biomedical Research Samples ......................................................... 89
Other Procedures................................................................................................. 89
7.1.4.1
Withdrawal/Discontinuation........................................................................ 89
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 90
7.1.4.1.2
Lost to Follow up.................................................................................. 90
7.1.4.2
Subject Blinding/Unblinding ....................................................................... 90
7.1.4.3
Domiciling ................................................................................................... 90
7.1.4.4
Calibration of Equipment............................................................................. 91
Visit Requirements.............................................................................................. 91
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7.1.5.1
Screening Period .......................................................................................... 91
7.1.5.2
Treatment Period Visits ............................................................................... 91
7.1.5.3
Discontinued Subjects Continuing to be Monitored in the Trial................. 92
7.1.5.4
Posttreatment Period.................................................................................... 92
7.1.5.5
Survival Status ............................................................................................. 92
7.2
Assessing and Recording Adverse Events .......................................................... 92
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 93
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 94
Immediate Reporting of Adverse Events to the Sponsor.................................... 95
7.2.3.1
Serious Adverse Events ............................................................................... 95
7.2.3.2
Events of Clinical Interest............................................................................ 96
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 96
Evaluating Adverse Events................................................................................. 97
Sponsor Responsibility for Reporting Adverse Events .................................... 100
8
STATISTICAL ANALYSIS PLAN ...................................................................... 100
8.1
Statistical Analysis Plan Summary ................................................................... 100
8.2
Responsibility for Analyses/In-House Blinding ............................................... 101
8.3
Hypotheses/Estimation....................................................................................... 101
8.4
Analysis Endpoints ............................................................................................. 101
Efficacy/Immunogenicity/Pharmacokinetic Endpoints .................................... 101
Safety Endpoints ............................................................................................... 102
8.5
Analysis Populations........................................................................................... 102
Safety Analysis Population............................................................................... 102
Efficacy Analysis Populations .......................................................................... 102
8.6
Statistical Methods.............................................................................................. 102
Statistical Methods for Efficacy Analyses........................................................ 102
Statistical Methods for Safety Analyses ........................................................... 103
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 103
8.7
Interim Analyses ................................................................................................. 103
8.8
Multiplicity .......................................................................................................... 103
8.9
Sample Size and Power Calculations ................................................................ 103
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8.10
Subgroup Analyses and Effect of Baseline Factors ......................................... 104
8.11
Compliance (Medication Adherence)................................................................ 104
8.12
Extent of Exposure.............................................................................................. 104
9
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 105
9.1
Investigational Product ...................................................................................... 105
9.2
Packaging and Labeling Information ............................................................... 105
9.3
Clinical Supplies Disclosure............................................................................... 105
9.4
Storage and Handling Requirements................................................................ 105
9.5
Discard/Destruction/Returns and Reconciliation ............................................ 106
9.6
Standard Policies................................................................................................. 106
10
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 106
10.1
Confidentiality..................................................................................................... 106
Confidentiality of Data ..................................................................................... 106
Confidentiality of Subject Records................................................................... 106
Confidentiality of Investigator Information...................................................... 107
Confidentiality of IRB/IEC Information........................................................... 107
10.2
Compliance with Financial Disclosure Requirements..................................... 107
10.3
Compliance with Law, Audit and Debarment ................................................. 108
10.4
Compliance with Trial Registration and Results Posting Requirements...... 109
10.5
Quality Management System............................................................................. 110
10.6
Data Management............................................................................................... 110
10.7
Publications ......................................................................................................... 110
11
LIST OF REFERENCES....................................................................................... 111
12
APPENDICES......................................................................................................... 117
12.1
Merck Code of Conduct for Clinical Trials...................................................... 117
12.2
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 119
12.3
Cockcroft-Gault Formula .................................................................................. 123
12.4
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 124
12.5
irRECIST............................................................................................................. 125
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12.6
ECOG Performance Status................................................................................ 127
12.7
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 128
12.8
List of Abbreviations .......................................................................................... 129
13
SIGNATURES......................................................................................................... 132
13.1
Sponsor's Representative ................................................................................... 132
13.2
Investigator.......................................................................................................... 132
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LIST OF TABLES
Table 1
Inclusion Criteria Laboratory Parameters............................................................. 38
Table 2
Part 1 Trial Treatment (21-day cycles)................................................................. 42
Table 3
Dose Escalation and Confirmation Rules Based on the Modified Toxicity 
Probability Interval Design................................................................................... 47
Table 4
Dose Levels for MK-8353 + Pembrolizumab in Part 1........................................ 48
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse 
Events 
Associated 
with 
Pembrolizumab 
Monotherapy, 
Coformulations or IO Combinations .................................................................... 53
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ............................................................................................................. 56
Table 7
Treatment Schedule for MK-8353 + Pembrolizumab for Each Treatment 
Cycle ..................................................................................................................... 58
Table 8
Medications, Supplements, and Other Substances Prohibited During the Trial... 62
Table 9
Laboratory Tests ................................................................................................... 87
Table 10
Evaluating Adverse Events................................................................................... 98
Table 11
Estimate and 95% CI of ORR Under Various Scenarios.................................... 104
Table 12
Product Descriptions........................................................................................... 105
Table 13
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease for Subjects Receiving Pembrolizumab (MK-3475) (management per 
irRECIST)........................................................................................................... 126
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LIST OF FIGURES
Figure 1
Phase 1b Trial of MK-8353 in Combination with Pembrolizumab: Part 1 
Dose Escalation and Confirmation, and Part 2 Cohort Expansion....................... 18
Figure 2
Part 1: Dose Escalation and Confirmation of MK-8353 in Combination with 
Pembrolizumab in Arm A,  Arm B, and Optional Arms C and D Using the 
mTPI Design......................................................................................................... 19
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 07
28-JUN-2021
To update the dose modification and toxicity management 
guidelines for irAEs.
Amendment 06
24-AUG-2020
Added 2 dose levels to Arm B to further evaluate MTD.
Amendment 05
08-NOV-2018
The primary reasons for this amendment were to, 1) update the 
participant population to include microsatellite-stable CRC 
disease rather than an unselected CRC, 2) provide an additional 
MK-8353 dose level in Arms B, C, and D, and 3) incorporate 
new language to support flexible dosing.
Amendment 04
22-FEB-2018
The primary reasons for this amendment were to, 1) provide 
clarification regarding Arm D DLT evaluation period, 2) 
provide clarification regarding Arm D run-in period and 
subsequent cycles, and 3) expanded the dose modification 
guidelines to include supportive care, monitoring, and follow-
up.
Amendment 03
29-AUG-2017
The primary reasons for this amendment were to, 1) align 
multiple sections within the protocol with modifications 
applied to treatment Arms, 2) provide informative 
immunological assay information based on results observed in 
animal studies, 3) update specific inclusion and exclusion 
criteria, 4) update Table 8 and Table 12, and 3) provide a Flow 
Chart specific to Arm D.
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Document
Date of Issue
Overall Rationale
Amendment 02
11-AUG-2017
The primary reasons for this amendment were to modify text, 
tables, and figures in support of adding treatment arms and 
dose levels in all arms for MK-8353 dose escalation, also 
adding doses and schedules for potential exploration in Part 2.
Amendment 01
17-APR-2017
The primary reasons for this amendment were to, 1) modify 
text, tables, and figures in support of adding 2 additional 
optional treatment arms, additional doses in Arm A, also added 
doses and schedules for potential exploration in Part 2, 2) 
provide updated language in various sections and table to 
remove redundancy and provide clarity, and 3) provide updates 
to the Study Flow Chart to reflect modification to study design 
and to also provide clarification
Original Protocol
26-SEP-2016
Not applicable
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change
Rationale
5.2.2.2
Immune-Related 
Events 
and 
Dose 
Modification 
(Withhold, 
Treat, 
Discontinue)
The dose modification and 
toxicity 
management 
guidelines for irAEs and table 
were updated.
The dose modification and toxicity management 
guidelines for irAEs and table were updated as requested 
by the U.S. FDA in an effort to harmonize the 
presentation of safety information across all FDA-
approved PD-1/L1 antibody prescribing information.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
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1
TRIAL SUMMARY
Abbreviated Title
Phase 1b Study of MK-8353 + Pembrolizumab in Subjects with Advanced 
Malignancies 
Sponsor Product Identifiers
MK-8353 and pembrolizumab
Trial Phase
Phase 1b
Clinical Indication
Treatment of Advanced Solid Tumors with a Focus on non-MSI-H/dMMR
Colorectal Cancer ≥Second Line
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Oral (MK-8353) and intravenous (Pembrolizumab)
Trial Blinding
Unblinded Open-label
Treatment Groups
Part 1: Dose escalation and confirmation (modified toxicity probability 
interval design)
Arm A (MK-8353: twice daily [bid] continuous):
Dose level (DL)1:  MK-8353 350 mg bid + Pembrolizumab 200 mg once 
every 3 weeks (q3w)
DL1A: MK-8353 50 mg bid + Pembrolizumab 200 mg q3w
DL2A: MK-8353 50 mg + 100 mg + Pembrolizumab 200 mg q3w    
(total daily dose of 150 mg MK-8353)
DL3A: MK-8353 100 mg bid + Pembrolizumab 200 mg q3w
DL4A: MK-8353 150 mg bid + Pembrolizumab 200 mg q3w
DL5A: MK-8353 200 mg bid + Pembrolizumab 200 mg q3w
DL6A: MK-8353 300 mg bid + Pembrolizumab 200 mg q3w
Arm B (MK-8353: once daily [qd] continuous):
DL1B: MK-8353 50 mg qd + Pembrolizumab 200 mg q3w
DL2B: MK-8353 100 mg qd + Pembrolizumab 200 mg q3w
DL3B: MK-8353 150 mg qd + Pembrolizumab 200 mg q3w
DL4B: MK-8353 200 mg qd + Pembrolizumab 200 mg q3w
DL5B: MK-8353 300 mg qd + Pembrolizumab 200 mg q3w
DL6B: MK-8353 400 mg qd + Pembrolizumab 200 mg q3w
DL7B: MK-8353 600 mg qd + Pembrolizumab 200 mg q3w
DL8B: MK-8353 900 mg qd + Pembrolizumab 200 mg q3w
DL9B: MK-8353 1200 mg qd + Pembrolizumab 200 mg q3w
Optional Arm C (MK-8353: qd 1 week on/1 week off)
DL1C: MK-8353 50 mg qd + Pembrolizumab 200 mg q3w
DL2C: MK-8353 100 mg qd + Pembrolizumab 200 mg q3w
DL3C: MK-8353 150 mg qd + Pembrolizumab 200 mg q3w
DL4C: MK-8353 200 mg qd + Pembrolizumab 200 mg q3w
DL5C: MK-8353 300 mg qd + Pembrolizumab 200 mg q3w
DL6C: MK-8353 400 mg qd + Pembrolizumab 200 mg q3w
DL7C: MK-8353 600 mg qd + Pembrolizumab 200 mg q3w
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Optional Arm D (MK-8353:  qd
monotherapy run-in then 
continuous)
DL1D: MK-8353 50 mg qd + Pembrolizumab 200 mg q3w
DL2D: MK-8353 100 mg qd + Pembrolizumab 200 mg q3w
DL3D: MK-8353 150 mg qd + Pembrolizumab 200 mg q3w
DL4D: MK-8353 200 mg qd + Pembrolizumab 200 mg q3w
DL5D: MK-8353 300 mg qd + Pembrolizumab 200 mg q3w
DL6D: MK-8353 400 mg qd + Pembrolizumab 200 mg q3w
DL7D: MK-8353 600 mg qd + Pembrolizumab 200 mg q3w
Note: Doses of MK-8353 at 10 and 30 mg might be explored in Arms A, 
B, C, and/or D, based on the safety profile and pharmacokinetic (PK) data 
observed at the higher doses.
Part 2: Cohort expansion
MK-8353 at Recommended Phase 2 Dose(s) + Pembrolizumab 200 mg
q3w (several schedules and doses could be explored)
Number of trial subjects
Approximately 182 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 42 months
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial for approximately 28 months, from 
the time the subject signs the informed consent form through the final 
contact.  After a screening phase of up to 28 days, each subject will receive
assigned treatment for up to approximately 24 months. After the end of 
treatment, each subject will be followed for a minimum of 30 days (serious 
adverse events will be collected for 90 days), or until initiation of a new 
anticancer treatment, whichever occurs first.  Subjects will be treated until 
disease progression, unacceptable toxicity, or the withdrawal of consent, or 
for approximately 24 months, and will be treated thereafter at the 
discretion of the physician.
A list of abbreviations used in this document can be found in Section 12.8.
Pembrolizumab will be used throughout the protocol to refer to KEYTRUDA™ or MK-3475 
as supplied by the Sponsor.
2
TRIAL DESIGN
2.1
Trial Design
This is a multicenter, worldwide, open-label, nonrandomized, Phase 1b study of MK-8353 in 
combination with pembrolizumab in subjects with advanced solid tumors with a focus on 
subjects with ≥second line advanced non-MSI-H/dMMR colorectal cancer (CRC).
This study will evaluate the safety, tolerability, and preliminary efficacy of MK-8353 when 
administered in combination with pembrolizumab.  There are 2 parts in this study, dose 
escalation and confirmation (Part 1) and cohort expansion (Part 2).
Randomization Ratio
N/A
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For each subject, RAS/RAF mutations and proficient versus deficient mismatch repair 
(pMMR vs. dMMR) status will be required for enrolling in the study.  Archived tumor 
samples or newly obtained biopsies will be obtained during the screening period for 
assessment of these mutations and for biomarker evaluation.
In Part 1, the modified toxicity probability interval (mTPI) design [1] will be used to identify
and confirm the recommended Phase 2 dose(s) (RP2D[s]) of MK-8353 in combination with a 
fixed dose of pembrolizumab in subjects with advanced malignancies. Subjects will be 
enrolled in 1 of 2 arms to receive MK-8353 in combination with pembrolizumab at a fixed 
dose of 200 mg, during 21-day cycles for approximately 24 months of treatment. In Arm A
and Arm B, MK-8353 will be administered continuously at a starting dose of 50 mg twice 
daily (bid), or 50 mg once daily (qd), respectively (refer to Section 4.2.2).  Enrollment will 
alternate between arms.
Initially, the protocol started at a dose of 350 mg bid of MK-8353 in combination with 
pembrolizumab and several dose levels for escalation from this initial dose were planned;
however, 3 of the 4 subjects who received MK-8353 at 350 mg bid developed a Grade 3 rash 
and MK-8353 was discontinued at this dose for these 4 subjects (refer to Section 4.1.3.1).
The protocol was then amended (Amendment 1) to restart at a lower dose (100 mg bid) of 
MK-8353 in combination with pembrolizumab (Arm A) with a potential de-escalation dose 
of 50 mg bid; several dose levels for escalation were planned.  The subject enrolled at 
100 mg bid of MK-8353 in combination with pembrolizumab developed several Grade 3 
toxicities, including Grade 3 rash, and the next subjects were enrolled at 50 mg bid of 
MK-8353 in combination with pembrolizumab (refer to Section 4.1.3.1.).
Under Amendment 3, Arm A is to start at 50 mg bid of MK-8353 and Arm B was added and 
is to be enrolled in parallel to Arm A. In addition, 2 optional arms, Arm C (in which 
MK-8353 is to be administered 1 week on/1 week off at a starting dose of 50 mg qd in 
combination with pembrolizumab), and Arm D (in which MK-8353 is to be administered
first as monotherapy during a 2-week run-in at a starting dose of 50 mg qd, and then followed 
by continuous administration in combination with pembrolizumab at a dose of 50 mg qd).  
Lower doses of MK-8353 could be implemented in the event of unacceptable toxicities or 
based on PK measurements in Arm A or Arm B.  Doses of MK-8353 at 10 mg and 30 mg 
could also be explored in Arms C or D (refer to Section 5.2).  Additional doses between all 
described doses may be added based on reported toxicities upon agreement between the 
investigators and the Sponsor.
Barring dose-limiting toxicities (DLTs), additional subjects are to be enrolled and 
dose-finding is to proceed, according to an algorithm based on the mTPI method, targeting a 
dose with a 30% DLT rate for the combination therapy to determine the RP2D. Up to 
approximately 142 subjects evaluable for safety and tolerability are to be enrolled according 
to the mTPI method.  The final number of subjects enrolled in Part 1 will depend on the 
empirical safety observations (ie, DLTs), and the dose and schedule ultimately identified as 
the RP2D using the mTPI design.
In Part 2, up to approximately 40 subjects with advanced non-MSI-H/dMMR CRC, who 
received at least 1 and up to 5 prior lines of therapy, will be enrolled at the RP2D(s) of the 
combination treatment in the expansion cohort to further evaluate safety and efficacy.  
Several doses and schedules of MK-8353 in combination with pembrolizumab may be 
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explored in separate cohorts in Part 2. Based on previous studies, approximately 50% of 
enrolled subjects are expected to present with a KRAS mutant MMR proficient CRC.  
Preliminary efficacy will be evaluated using overall response rate (ORR) assessed by the 
investigator based on the Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1) as a secondary objective.  The duration of response (DOR), disease control 
rate (DCR), and progression-free survival (PFS) based on RECIST 1.1 as assessed by the 
investigator, as well as overall survival (OS) will be also evaluated as exploratory objectives.
Although there will not be any formal hypothesis testing in this study, an interim look at the 
data may be conducted to enable future trial planning and dosing decisions.
In Part 2, a 
futility check will be performed after the first ~18 evaluable subjects in each cohort are 
enrolled.  If no responses are observed, the trial may be stopped early.
Subjects will be monitored carefully for the development of adverse events (AEs), and for
clinical and/or radiographic evidence of disease progression according to RECIST 1.1;
however immune-related RECIST (irRECIST) could be used by the investigator for 
treatment decision.  In subjects who have initial evidence of radiological progressive disease 
by RECIST 1.1, it will be at the discretion of the investigator whether or not to continue a 
subject on study treatment until repeat imaging is obtained.  This clinical judgment decision 
should be based on the subject’s overall clinical condition, including performance status, 
clinical symptoms, and laboratory data.  Subjects may continue to receive study treatment 
until tumor assessment is repeated ≥4 weeks later in order to confirm progressive disease by 
irRECIST per site assessment.
Adverse events will be evaluated by the investigator, according to criteria outlined in the 
National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0, to establish the safety and tolerability of MK-8353 when administered in 
combination with pembrolizumab as per the primary objective of this study.
There will be no intrasubject dose escalation for subjects enrolled in this study.  The 
definition of DLTs and criteria for dose modification of MK-8353 are outlined in 
Sections 5.2.1.5 and 5.2.2.  Pembrolizumab will be administered at a fixed dose of 200 mg
once every 3 weeks (q3w), which will not be modified.
Subjects may receive study treatment (MK-8353 and pembrolizumab) for up to 35 cycles in 
Arms A, B, and C (approximately 24 months) and for up to 36 cycles in Arm D.  Subjects 
will be treated until disease progression, unacceptable toxicity, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to discontinue treatment, 
subject withdrawal of consent, pregnancy of the subject, subject completes treatment, or 
administrative reasons requiring cessation of treatment, at which point they will be 
discontinued from the study.  Subjects will be treated thereafter at the discretion of the
physician.
All subjects will be followed for at least 30 days after the last dose of MK-8353 or 
combination therapy for AE monitoring.  Serious adverse events (SAE) will be collected for 
90 days after discontinuation, 30 days if the subject initiates new anticancer therapy less than 
30 days after study treatment discontinuation, or until the day new anticancer therapy is 
initiated if between 30 days and 90 days after study treatment discontinuation.  Subjects with 
an ongoing AE of Grade >1 at the time of treatment discontinuation will be followed until 
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resolution of the AE to Grade 0 or 1, until considered stable by the treating physician, or until 
beginning a new anticancer therapy, whichever occurs first.
Subjects who discontinue treatment for reasons other than confirmed disease progression will 
have posttreatment follow-up for disease status (including imaging) until disease progression, 
initiating a new anticancer therapy, withdrawing consent for study participation, or becoming 
lost to follow up.
After confirmed disease progression, each subject will be contacted by telephone 
approximately every 12 weeks (84 ± 7 days) for survival until withdrawal of consent to 
participate in the trial, becoming lost to follow up, death, or end of the trial, whichever occurs 
first.
The trial will be conducted in conformance with Good Clinical Practices (GCP).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0
Trial Procedures.
2.2
Trial Diagram
The trial design is presented in Figure 1 and Figure 2.
Figure 1
Phase 1b Trial of MK-8353 in Combination with Pembrolizumab: Part 1 Dose 
Escalation and Confirmation, and Part 2 Cohort Expansion
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Figure 2
Part 1: Dose Escalation and Confirmation of MK-8353 in Combination with 
Pembrolizumab in Arm A, Arm B, and Optional Arms C and D Using the mTPI Design
3
OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
(1) Objective: To evaluate the safety and tolerability of MK-8353 when administered in 
combination with pembrolizumab in subjects with advanced solid tumors and in 
subjects with ≥second line advanced non-MSI-H/dMMR CRC.
3.2
Secondary Objective(s) & Hypothesis(es)
(1) Objective: To determine 1 or more RP2D of MK-8353 when given in combination 
with pembrolizumab in subjects with advanced solid tumors.
(2) Objective: 
To evaluate the antitumor activity (ORR based on RECIST 1.1 as 
assessed by the investigator) of MK-8353 in combination with pembrolizumab in 
subjects with advanced solid tumors who received MK-8353 at RP2D in Part 1 and in 
Part 2.
(3) Objective: 
To evaluate serum levels of protein biomarkers,
such as 
carcinoembryonic antigen (CEA), CA-125,
or CA19-9, before and after 
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administration of MK-8353 in combination with pembrolizumab in subjects with 
advanced solid tumors.
3.3
Exploratory Objectives
(1) Objective: To assess the PK profile of MK-8353 when given in combination with 
pembrolizumab in subjects with advanced solid tumors and in subjects with ≥second
line advanced non-MSI-H/dMMR CRC.
(2) Objective: To evaluate the DOR, DCR, and PFS based on RECIST 1.1 as assessed 
by the investigator, and OS, in subjects with advanced solid tumors, and in subjects
with ≥second line advanced non-MSI-H/dMMR CRC who received MK-8353 at 
RP2D in combination with pembrolizumab in Part 1 and in Part 2.
(3) Objective:  To evaluate the correlation between programmed cell death-ligand 
1 (PD-L1) expression levels and tumor response when MK-8353 is given in 
combination with pembrolizumab in subjects with advanced solid tumors or ≥second
line advanced non-MSI-H/dMMR CRC.
(4) Objective: To evaluate the ORR, DOR, DCR, and PFS based on RECIST 1.1 as 
assessed by the investigator, and OS in 1) subjects with RAS/RAF mutant versus
RAS/RAF wild-type with advanced solid tumors or ≥second line advanced
non-MSI-H/dMMR CRC; 2) subjects with pMMR versus dMMR advanced solid 
tumors or ≥second line advanced non-MSI-H/dMMR CRC; and 3) subjects with left 
versus
right advanced
non-MSI-H/dMMR CRC
who received MK-8353 in 
combination with pembrolizumab.
(5) Objective: To identify molecular (genomic, metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic 
activity, and/or the mechanism of action of MK-8353, pembrolizumab, and/or the 
combination therapy.
4
BACKGROUND & RATIONALE
4.1
Background
Refer to the respective Investigator’s Brochures (IBs) for detailed background information on 
MK-8353 and pembrolizumab.
Pharmaceutical and Therapeutic Background
4.1.1.1
MK-8353
MK-8353 is a highly selective, orally available, adenosine triphosphate competitive small 
molecule inhibitor of extracellular signal-regulated kinase (ERK).  MK-8353 not only 
inhibits the kinase activity of ERK, but also induces a conformational change in ERK that 
prevents its phosphorylation and activation by mitogen-activated protein/extracellular 
signal-regulated kinase (MEK).
ERK1 and ERK2 are closely related serine-threonine protein kinases.  They are components 
of the RAS/mitogen-activated protein kinase (MAPK) pathway, a critical signal transduction 
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pathway that is activated in response to growth factor binding and regulates cellular growth, 
differentiation, and survival in a variety of cell types [2]. ERK lies downstream from the 
small guanosine triphosphatase RAS and the protein kinases RAF and MEK in this pathway.  
Following its activation by RAS, RAF phosphorylates MEK1 and MEK2, which in turn 
phosphorylate ERK.  Activated, phosphorylated ERK (pERK) phosphorylates other 
substrates that govern the transcriptional output of cells [2] [3]. Constitutive activation of 
this pathway is frequently observed in human cancers and is associated with high rates of 
cancer cell proliferation.  Commonly, pathway activation occurs as a consequence of gain-of-
function oncogenic mutations in RAS or in 1 of the RAF kinase family members 
(eg, BRAF).
The high frequency of RAS or BRAF mutations in many cancers makes targeting this 
pathway an attractive strategy for cancer therapy.  Activating mutations of RAS are reported 
in ~25% of all cancers [4], with some, such as pancreatic cancer and CRC, harboring KRAS 
mutation rates of ~90% and ~50%, respectively [4].  NRAS mutations have been identified in 
~10% to 25% of melanomas [4] [3] [5] and KRAS mutations have been identified in ~30% 
of non-small cell lung cancers (NSCLCs) [6].
BRAF somatic missense mutations have been identified in ~50% to 70% of malignant 
melanomas, in which all mutations are within the kinase domain and a single substitution 
(V600E, previously designated V599E) accounts for ~80% of mutations [7] [3] [8]. 
Activating BRAF mutations have also been documented in a variety of human cancers, 
including CRC (~10% to 12%) [9], NSCLC (2% to 3%) [9], and thyroid cancer (~50%) [5].
With very few exceptions, BRAF and RAS mutations are mutually exclusive [10].
Although the introduction of BRAF inhibitors represents a significant advance in the 
treatment of BRAF V600 mutation-positive metastatic melanoma subjects [11], limitations of 
this novel therapy have already been identified, as has been the pattern with other highly 
selective small molecule kinase inhibitors (eg, imatinib in bcr-abl chronic myelogenous 
leukemia; erlotinib and gefitinib in epidermal growth factor receptor-mutant NSCLC; and the 
rapid onset of drug resistance that restricts the efficacy of vemurafenib and limits the median 
duration of response to only 6.7 months [data from the vemurafenib Phase 3 study BRIM3])
[12]. Understanding the specific mechanisms of resistance to BRAF inhibitors is critical for 
the development of more effective strategies to inhibit the MAPK pathway in order to delay 
or prevent the onset of resistance in BRAF-mutant melanoma.
In a majority of cell models and melanoma samples, acquired resistance to BRAF inhibitors 
was associated with a reactivation of the MAPK pathway indicating that the ‘addiction’ to 
this pathway remains unchanged [13].  In these resistant BRAF-mutant melanomas, the 
MAPK pathway can be reactivated through secondary activating mutations of the upstream 
NRAS or the downstream MEK1 kinase or an overexpression of the RAF1 and COT kinase.  
In addition, activation of further upstream receptor tyrosine kinase most probably due to 
alterations in molecular feedback loops affecting in particular the insulin-like-growth factor 
receptor and the platelet-derived growth factor receptor have also been detected.  Although 
all of these molecular events enable the melanoma cell to circumvent BRAF inhibition in 
order to reactivate the MAPK pathway, this activation renders most of the BRAF inhibitor-
resistant tumors susceptible to an inhibition of the downstream MEK kinase.
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Experimental data generated with a BRAF and MEK inhibitor combination therapy in 
BRAF-mutant melanoma cell lines in vitro and xenografts in vivo support this concept by 
demonstrating activity of the combination therapy in models of acquired BRAF resistance.
More importantly, superior antitumor activity of the BRAF and MEK inhibitor combination 
as compared with each agent as monotherapy was also observed in BRAF-sensitive models.  
In addition, preclinical safety data obtained with this combination therapy in a rat model 
indicate that the potential for proliferative skin lesions and secondary cutaneous malignancies 
is reduced in comparison with treatment with a BRAF inhibitor alone [14].
Data from recent clinical trials evaluating the combination of BRAF and MEK inhibitors 
have confirmed the efficacy of the double MAPK pathway blockade in subjects with 
BRAF-mutant tumors.  Clinical trials combining BRAF and MEK inhibitors have 
demonstrated activity in subjects with tumors harboring BRAF mutations [15] [16] [17] [18] 
[19].
These data clearly indicate that a concomitant and more potent inhibition of the MAPK
pathway at the critical level of the BRAF and MEK kinases leads to a more pronounced 
tumor inhibition, thus significantly delaying the onset of resistance.  A similar effect might 
be achieved by downstream blockade of the MAPK pathway at the ERK level.
In contrast to all known ERK inhibitors, which bind to the active conformation (type I), only 
MK-8353 can bind to both the active as well as the inactive conformation of ERK kinases, 
and therefore can prevent their activating phosphorylation by MEK1 and MEK2 (“dual 
specificity”).  This unique property of MK-8353 enables the phosphorylation status of ERK 
to serve as one of the target engagement biomarkers for MK-8353 action.  To date, very few
ERK inhibitors are in clinical development [20].
MK-8353 potently inhibits both ERK1 and ERK2 in vitro with IC50 values of 23.0 nM and 
8.8 nM, respectively.  MK-8353 caused a dose-dependent decrease in pERK1, pERK2, and 
phosphorylated p90 ribosomal S6 kinase levels with complete suppression of pERK1 and 
pERK2 at 30 nM in BRAF-mutant A2058 cells.  Also, the antiproliferative effects of 
MK-8353 were characterized against a large panel of tumor cells.  MK-8353 potently 
inhibited the growth of BRAF-mutant melanoma cell lines, and also inhibited growth of 
BRAF-mutant CRC and thyroid cancer cell lines.  In addition, MK-8353 inhibited the growth 
of KRAS mutant colon, pancreatic, and NSCLC tumor cell lines and NRAS mutant 
melanoma cell lines.  Inhibition of pERK by MK-8353 correlated with inhibition of cell 
proliferation and induction of apoptosis in vitro.  The efficacy of the ERK inhibitor MK-8353 
as a single agent was tested in a panel of BRAF and K/NRAS mutant mouse xenograft 
models.  MK-8353 inhibited tumor growth and induced tumor regression in both 
BRAF-mutant and K/NRAS-mutant mouse xenograft models.  These results further confirm 
the in vitro studies showing that tumor cells harboring BRAF or K- or NRAS mutations are 
sensitive to MK-8353.  Furthermore, clinical data from PN001 confirmed that MK-8353 in 
monotherapy has partial clinical activity in subjects with BRAF-mutant tumors (refer to
Section 4.1.2.1).
4.1.1.2
Pembrolizumab
The programmed cell death-1 (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 
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surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions.  PD-1 (encoded by the gene 
Pdcd1) is an immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic 
T-lymphocyte-associated antigen-4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or programmed cell 
death-ligand 2 [PD-L2]) [21] [22].  The structure of murine PD-1 has been resolved [23].  
PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-
type domain responsible for ligand binding and a cytoplasmic tail, which is 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 (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM 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 [21] [24] [25] [26].
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and 
CD8+ T cells, B cells, T regs, and natural killer cells [27] [28].  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T cells as well as subsets 
of macrophages and dendritic cells [29].  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including 
nonhematopoietic tissues as well as in various tumors [30] [31] [32] [33].  Both ligands are 
type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various nonhematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectable on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues [30].  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  High expression of PD-L1 on tumor cells (and to a lesser 
extent of PD-L2) has been found to correlate with poor prognosis and survival in various 
cancer types.
Pembrolizumab (KEYTRUDA™) is a potent and highly selective humanized monoclonal 
antibody (mAb) of the IgG4/kappa isotype designed to directly block the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab has shown clinical activity and is 
indicated in multiple tumor types (refer to package circular for KEYTRUDA™).
4.1.1.3
Rationale for MK-8353 in Combination with Pembrolizumab
In preclinical studies, agents targeting the RAS/RAF/MEK/ERK pathway have been 
associated with checkpoint inhibitors, and demonstrated synergistic and durable tumor 
regression [34] [35].  MEK inhibition increased the number of effector CD8+ T-cell 
trafficking in tumor from animal models, and protected them from death driven by chronic 
T-cell receptor stimulation [35].  In biopsies from subjects with metastatic melanoma taken 
10 to 14 days after treatment with BRAF or BRAF + MEK inhibitors, an increased 
expression of melanoma antigens and an increase in CD8+ T-cell infiltrate was observed 
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compared with baseline, together with a decrease in immunosuppressive cytokines [36].  
Thus, preclinical data indicate a potential additive/synergistic effect between compounds 
targeting the MAPK-pathway and checkpoint inhibitors.
Recently, combinations of MAPK inhibitors with anti-CTLA-4, anti-PD-1 or anti-PDL-1
mAbs have been tested in the clinic in different type of tumors.  In a Phase 2 clinical study, 
cobimetinib, a MEK1/2 small molecule inhibitor, has been evaluated in combination with 
atezolizumab, a PD-L1-blocking antibody, in subjects with advanced CRC and has shown 
clinical activity [37].
It is expected that the combination of MK-8353 and pembrolizumab may bring more benefit 
in tumors that are driven by MAPK pathway by inhibiting tumor growth and inducing 
apoptosis, as well as releasing tumor antigen and activating T-cell-based immune 
surveillance against tumor.
Preclinical and Clinical Trials
4.1.2.1
MK-8353
MK-8353 Preclinical Studies
The primary toxicological risks associated with preclinical administration of MK-8353 
consisted of skin irritation/inflammation in rats, significant body weight loss in dogs with 
decreased food consumption, and small intestine (enterocyte necrosis) and liver (portal 
inflammation and necrosis) toxicity in dogs.  These findings generally showed complete 
recovery at the end of the 1-month postdose periods.  In early exploratory non-Good 
Laboratory Practice (GLP) rat and dog studies with an amorphous form of MK-8353, tissue 
mineralization was noted.  In the 1-month rat and dog GLP studies using the salt form, no 
tissue mineralization was observed but effects of MK-8353 on serum biomarkers 
(ie, osteocalcin, beta-C-terminal telopeptide, parathyroid hormone, and ionized calcium) 
were present.
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MK-8353 Phase 1 Study in Cancer Subjects (PN001)
The safety of MK-8353 as a single agent was also evaluated in a Phase 1, dose-escalation 
study previously completed in subjects with advanced solid tumor (refer to the MK-8353 IB). 
In Part 1a, MK-8353 doses were increased up to 800 mg bid in subjects with any type of 
advanced solid tumor.  In Part 1b, subjects with BRAF- or RAS-mutant metastatic melanoma 
or metastatic CRC were enrolled in the dose confirmation phase.
MK-8353 400 mg bid dose was identified in Part 1a as the preliminary maximum tolerated 
dose (MTD), based on safety, tolerability, PK exposure, and preliminary clinical activity.  
The 100 mg, 200 mg, and 400 mg bid dose levels were deemed generally safe.  However, at 
the 800 mg bid dose, 2 evaluable subjects experienced DLTs, which per protocol determined 
this dose as exceeding the MTD.  The DLTs were Grade 3 nausea, Grade 3 vomiting, and 
Grade 3 diarrhea in the first subject and an event of Grade 3 fatigue in the second subject.
In Part 1b of Protocol 001, MK-8353 was administered at doses of 400 mg bid in 4 subjects. 
Two evaluable subjects experienced DLTs due to missed doses (due to Grade 2 diarrhea in 
the first subject, and an event of elevated bilirubin in the second subject).  Two subsequent 
subjects, enrolled at a dose level of 200 mg bid (which was well tolerated), demonstrated 
disease progression.  Four additional subjects were enrolled at a dose level of 300 mg bid, 
which was also well tolerated. Two of those subjects (with BRAF-mutant melanoma)
exhibited some response to MK-8353 (stable disease [SD] and partial response [PR]) and 
stayed on therapy for 168 days and 211 days, respectively.  In the next cohorts, 3 subjects 
received 350 mg bid with 1 PR (BRAF-mutant melanoma) and 1 SD (NRAS-mutant 
melanoma) reported.  Three subjects were treated at 400 mg bid, with PR observed in 
1 subject with BRAF-mutant melanoma previously treated with single agent vemurafenib, 
and concomitant administration of dabrafenib and trametinib.  One subject at a dose of 
400 mg bid presented a DLT of Grade 3 rash in Cycle 1.
Pharmacokinetic data did not 
correlate with MK-8353 clinical activity.  Limited PD results from skin biopsies suggest that 
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partial suppression of phospho-ERK protein expression may occur at doses of 300 mg bid
and up.
In the overall study, the most frequently reported AEs (>20%) included diarrhea, fatigue, 
nausea, maculopapular rash, and vomiting, and were also the most frequent MK-8353-related 
AEs (>20%).  The most frequent Grade 3 or 4 MK-8353-related AEs (>5%) were diarrhea, 
increased serum bilirubin without other liver function changes, and maculopapular rash.
In summary, although the expansion cohort did not point to a strict RP2D, partial clinical 
activity for MK-8353 was observed starting at a dose of 350 mg bid.
4.1.2.2
Pembrolizumab
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Antimouse PD-1 or antimouse PD-L1 antibodies have demonstrated antitumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, and CRC.  Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of interferon gamma, granzyme B, and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo [38] [39] [40] [41] [42] [43].  Experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models (refer to the pembrolizumab IB).
Pembrolizumab (Humanized IgG4 Anti-PD-1 Monoclonal Antibody)
Pembrolizumab is a potent and highly selective, anti-PD-1, humanized mAb of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands,
PD-L1 and PD-L2.  The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or 
can be induced in various tumors [44] [45] [46] [47].  High expression of PD-L1 on tumor 
cells (and to a lesser extent of PD-L2) has been found to correlate with poor prognosis and 
survival in various cancer types, including renal cell carcinoma [48], pancreatic carcinoma
[49], hepatocellular carcinoma [50], ovarian carcinoma [43], and NSCLC [51].  Furthermore, 
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with 
malignant melanoma [27] [11].
Preclinical in vitro and in vivo experiments have shown that PD-1 and/or PD-L1 blockade 
using mAbs enhances tumor cell-specific T-cell activation, cytokine production, antitumor 
effector mechanisms, and clearance of tumor cells by the immune system [49] [52] [53] [54]. 
Pembrolizumab is a pure PD-1 antagonist, with higher affinity and receptor blocking activity 
compared with other anti PD-1 products in development.  Pembrolizumab has an acceptable 
preclinical safety profile, and is currently in clinical development as a potential treatment for 
subjects with advanced malignancies in Phase 1 single agent trial.
A Phase 1 study of pembrolizumab that explored safety, PK, PD, and anti-tumor activity of 
pembrolizumab demonstrated that pembrolizumab is well tolerated. No DLTs were observed 
across the 3 dose levels tested (1, 3, and 10 mg/kg).  Evaluation of the preliminary data 
demonstrated evidence of anti-tumor activity of pembrolizumab in subjects with NSCLC, 
CRC, melanoma, sarcoma, or carcinoid.  Drug-related AEs included Grade 1 fatigue, nausea, 
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diarrhea, dysgeusia, breast pain, and pruritus.  One drug-related Grade 2 AE of pruritus was 
also reported.  No drug-related AEs ≥Grade 3 were observed.
Ongoing Clinical Trials
4.1.3.1
MK-8353
Current Study: Phase 1b Study of MK-8353 in Combination with Pembrolizumab in 
Subjects with Advanced Malignancies (PN013)
In Protocol 013-00, 4 subjects were enrolled at the original starting dose of MK-8353 at 
350 mg bid in combination with a fixed dose of pembrolizumab at 200 mg q3w. Of these 
4 subjects, 3 developed an acneiform rash at ~Day 10 of Cycle 1, which worsened to an 
extensive Grade 3 maculopapular rash at Day 11, Day 12, and Day 12, respectively. The 
3 subjects stopped MK-8353, were hospitalized, and recovered with intravenous (IV) steroids 
and IV antibiotics in approximately 5 to 10 days. The fourth subject stopped MK-8353 on 
Day 9, based on the Grade 3 rashes occurring in the other subjects, and did not develop any 
rash or other AE in Cycle 1. These 3 DLTs triggered a de-escalation of MK-8353 as per the 
mTPI statistical method used in the study; however, the de-escalation dose of MK-8353 at 
300 mg bid in the initial protocol was deemed too close to the starting dose of 350 mg bid, 
and was not used by consensus between the investigators and the Sponsor. 
Amendment 1 was established to modify, in Part 1 of the study, the starting dose of 
MK-8353 for dose escalation in combination with pembrolizumab (Arm A: bid continuous; 
starting dose: 100 mg bid) with a de-escalation dose of 50 mg bid and to add 2 optional
schedules: bid with a drug holiday, and qd continuous (refer to Section 5.2).  
One subject with advanced CRC was enrolled at the 100 mg bid dose of MK-8353 in 
combination with pembrolizumab.  Similar to prior observations, the subject developed a 
Grade 1 rash on the evening of Day 8, which became a Grade 3 maculopapular rash on 
Day 11.  The subject was hospitalized, and recovered following administration of IV steroids 
and antibiotics. 
Following this DLT, the consensus among investigators and the Sponsor was to de-escalate 
the dose to 50 mg bid of MK-8353 in combination with pembrolizumab for the next subject.  
The next subject (advanced CRC) completed Cycle 1 and started Cycle 2 with MK-8353 at a 
dose of 50 mg bid in combination with pembrolizumab.  The subject did not develop any 
DLT during Cycle 1.  Based on this information, the protocol was further amended.
In Amendment 3, the schedule of administration of MK-8353 in combination with
pembrolizumab was modified in Part 1 as follows: 

Two arms, Arm A and new Arm B, are to run in parallel with alternate 
nonrandomized enrollment.  The starting dose of MK-8353 for dose escalation in 
combination with pembrolizumab in these 2 arms is 50 mg bid and 50 mg qd, 
respectively, based on a continuous schedule (refer to Section 5.2).

Additionally, the 2 new optional arms, Arm C and Arm D, will both have a starting 
dose of 50 mg qd.  Arm C will follow a drug-holiday, 1 week on/1 week off schedule;
whereas Arm D will include a run-in period of MK-8353 as monotherapy, from 
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Cycle 1 Day 1 to Day 14, prior to the continuous administration of the combination 
starting in Cycle 2 Day 1 (refer to Section 5.2).
4.1.3.2
Pembrolizumab
A Phase 2 clinical study has been conducted to evaluate the clinical efficacy of 
pembrolizumab in subjects with progressive metastatic carcinoma with or without MMR 
deficiency [55].  This study (KEYNOTE 016) enrolled 41 subjects: 11 subjects with dMMR
CRC, 21 subjects with pMMR CRC, and 9 subjects with dMMR noncolorectal tumors
(ie, 4 ampullary or cholangiocarcinomas, 2 endometrial
carcinomas, 2 small bowel 
carcinomas, and 1 gastric carcinoma).  Subjects had Stage IV disease and had failed multiple 
other chemotherapies.  Microsatellite instability (MSI) was a significant predictor of an 
increased immune-related objective response rate (irORR) (40% in dMMR CRC, 71% in 
dMMR non-CRC, 0% in pMMR CRC) and of an improved immune-related progression-free 
survival (irPFS) rate (78%, 67%, and 11%, respectively).  Whole-exome sequencing revealed 
a mean of 1,782 somatic mutations per tumor in dMMR cancers versus 73 somatic mutations 
per tumor in pMMR cancers.  The study is ongoing, with median PFS and OS not yet 
reported in the cohort with dMMR CRC.
Clinical trials investigating pembrolizumab are ongoing in advanced melanoma, NSCLC, 
bladder cancer, hematologic malignancies, and in a number of other advanced solid tumor 
indications.  For study details, and safety and efficacy summaries, please refer to the IB.
4.2
Rationale
Rationale for the Trial and Selected Subject Population
MK-8353 is a potent ERK inhibitor that has demonstrated antitumor activity in preclinical 
cancer cell lines and xenograft animal models, both as a single agent and in combination with 
other therapeutic agents.  A Phase 1 study of MK-8353 was conducted in subjects with 
advanced solid tumors to evaluate its safety and preliminary efficacy as a single agent.  The 
current study is a follow up to the monotherapy study to evaluate the effects of MK-8353 in 
combination with pembrolizumab in subjects with advanced solid tumors and in subjects 
with ≥second line advanced non-MSI-H/dMMR CRC.
In Part 1 of this study, the combination of MK-8353 and pembrolizumab will be evaluated in 
subjects with any advanced solid tumors for which no curative therapy is available, and thus,
suitable for an investigational treatment.  Up to approximately 142 subjects will be enrolled 
in Part 1.
Part 2 will enroll until a total of 40 additional subjects are treated at the RP2D (several doses 
and schedules may be explored) defined in Part 1.
Colorectal tumorigenesis develops mainly via 2 pathways: chromosomal instability and 
MSI, which is a consequence of dMMR.  Deficient MMR can result from a germline 
mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2), which is causing the Lynch 
Syndrome, or is more frequently sporadic (epigenetic activation of MLH1).  Sporadic dMMR 
tumors frequently carry the activating somatic V600E mutation in exon 15 of the BRAF 
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oncogene.  BRAFV600E mutations occur downstream from and are mutually exclusive of 
KRAS codon 12 and 13 mutations.
This population has a high unmet medical need.  Subjects with metastatic CRC whose tumors 
harbor BRAFV600E mutations generally respond poorly to standard therapies.  A lower 
proportion of subjects with pMMR tumors with mutant BRAF or mutant KRAS survived at 
5 years compared with subjects with pMMR tumors without these mutations [19] [56].  
Single agent vemurafenib (BRAF inhibitor) did not show meaningful clinical activity in this 
population [57].  Combined BRAF and MEK inhibition with dabrafenib and trametinib in 
combination elicited some clinical activity in this population [19].
This contrasts with subjects with CRC tumors with dMMR (MSI-H), for which high somatic 
mutation loads were associated with an irORR of 40% and prolonged irPFS of 78% at 
20 weeks when they received pembrolizumab in monotherapy [55].  In comparison, in 
subjects with tumors pMMR, the irORR was 0% and the irPFS at 20 weeks was 11%.
Therefore, in Part 2 of this study, the population of interest for the combination of MK-8353, 
a potent ERK inhibitor targeting the most downstream step of the MAPK pathway, and 
pembrolizumab, a checkpoint inhibitor, are subjects with pMMR, RAS/RAF-mutated 
advanced non-MSI-H/dMMR CRC.
Subjects in Part 1 or Part 2 may not need to be selected based on the presence of BRAF and 
KRAS/NRAS mutations in their tumors, as activating KRAS mutations have been identified 
in 30% to 40% of CRC, whereas BRAF mutations are found in ~5% to 15% of CRC [56] [7].  
Similarly, subjects in Part 1 will not be selected based on MSI status, as MSI occurs in <5% 
of subjects with advanced CRC; however, subjects in Part 2 will have advanced 
non-MSI-H/dMMR CRC. At screening, the subject must provide a tumor sample (archival 
or newly obtained) evaluation of RAS and RAF mutations, pMMR and dMMR status, and 
PD-1, PD-L1, and PD-L2 expression, as well as left or right side location of the tumor as 
assessed by the investigator, for efficacy exploratory analyses.  
Subjects may also agree to provide an optional on-treatment biopsy, for biomarker analysis 
as outlined in the Trial Flow Chart (Section 6.0).
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and informed consent documents.
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Rationale for Dose Selection/Regimen
Starting Dose and Dose Escalation of MK-8353 in Combination with Pembrolizumab
Based on data from Protocol 001 and emerging safety information from Protocol 013 (refer 
to Section 4.1.2.1), the doses of MK-8353 for the dose escalation in Part 1 were modified in 
Amendment 3 to continue Arm A at the de-escalation dose of 50 mg bid (continuous dosing),
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and to start in parallel at 50 mg qd in the new Arm B (qd continuous dosing).  Additionally, 
the 2 optional arms were modified to be new Arm C (1 week on/1week off) and new Arm D 
(monotherapy run-in followed by continuous dosing) (refer to Section 4.1.3.1). The drug 
holiday schedule in optional Arm C is to provide a release from the potential constant 
inhibition of ERK phosphorylation.  A run-in schedule, such as the one proposed for 
MK-8353 in Arm D, has been used to improve the tolerability of combining 2 drugs.  In Arm 
A, MK-8353 is administered on a continuous schedule bid, at doses based on PK data 
collected in earlier studies and preclinical efficacy studies in murine models (refer to the IB 
for MK-8353).
At a dose of 100 mg bid and 200 mg bid, MK-8353 in monotherapy was shown to be well 
tolerated in subjects with advanced solid tumors with no DLTs observed (PN001).  At 
800 mg bid, the DLTs observed in this study were nausea, vomiting, diarrhea, and fatigue (all 
Grade 3).  The MTD was determined to be 400 mg bid.  Of note, the restarting dose of 
MK-8353 in combination with pembrolizumab for this amendment is now more than 80% 
below the MTD in Protocol 001.
The dose level of MK-8353 will be escalated during this study until the RP2D(s) and 
schedule(s) of the combination regimen can be determined.
In Arm A, the initial dose of 50 mg bid for MK-8353 may be escalated to a daily dose of 
150 mg (50 mg + 100 mg qd), 100 mg bid, 150 mg bid, 200 mg bid, and potentially 300 mg 
bid, based on the occurrence of DLTs during Cycle 1 and according to the mTPI method 
(refer to Section 5.2.1.2.).  
Similarly, in Arm B, the initial dose of 50 mg qd for MK-8353 may be escalated to 
100 mg qd, 150 mg qd, 200 mg qd, 300 mg qd, 400 mg qd, 600 mg qd, 900 mg qd, and 
potentially 1200 mg  qd, based on the occurrence of DLTs during Cycle 1 and according to 
the mTPI method.  Enrollment will alternate between arms, and will also be guided by the 
occurrence of toxicities.
Furthermore, additional optional arms (Arms C and D) may be implemented based on 
toxicities occurring at any dose level in Arm A and/or Arm B (the decision to start optional 
Arm C and/or Arm D will be made in conjunction with the investigators and the Sponsor). If 
Arm C and/or Arm D are implemented, MK-8353 will be administered qd at a starting dose 
of 50 mg, and this dose may be escalated to 100 mg, 150 mg, 200 mg, 300 mg, 400 mg, or 
600 mg either 1 week on/1 week off (Arm C), or with a monotherapy run-in of 2 weeks 
followed by continuous administration (Arm D) (refer to Section 5.2.1.2).
Also, in each of these 4 arms, doses of 30 mg and 10 mg may be explored in the respective 
schedules, as well as additional intermediate doses, depending on the occurrence of toxicities 
and PK results at the higher doses, when the 10 mg capsules become available.
Modifications to the dose or dosing regimen of MK-8353 may be required to achieve the 
scientific goals of the trial objectives and/or to ensure appropriate safety monitoring of the 
trial subjects. Details of allowed modifications are provided in Section 5.2.2.1.
Fixed Dose of Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (q3w).  Based on 
the totality of data generated in the KEYTRUDA development program, 200 mg q3w is the 
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appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type.  As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose-
and 
exposure-efficacy relationships from 2 mg/kg q3w to 10 mg/kg every 2 weeks (q2w), 

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 physiologically based PK [PBPK] 
analysis) at 200 mg q3w.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy).  Five studies compared 2 mg/kg q3w versus 10 mg/kg 
q3w (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg q3w versus 10 mg/kg q2w (KN001 Cohort B3, KN001 Cohort F2, and 
KN006).  All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5 fold difference in exposure.  
The 2 mg/kg q3w (or 200 mg fixed-dose) provided similar responses to the highest doses 
studied.  Subsequently, flat dose-exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer, and classical 
Hodgkin Lymphoma, confirming 200 mg q3w as the appropriate dose independent of the 
tumor type.  These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg q3w.  First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 
200 mg q3w.  Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over 
a wide range of tumor penetration and PD-1 expression.  This evaluation concluded that 
pembrolizumab at 200 mg q3w achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg q3w fixed dose and 2 mg/kg q3w dose.
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg q3w fixed dose was 
selected for evaluation across all pembrolizumab protocols.
Therefore, pembrolizumab will be evaluated in combination with MK-8353 at the fixed dose 
of 200 mg q3w.  Modifications to the dose or dosing regimen of pembrolizumab will not be 
allowed in this study.  Details are provided in Section 5.2.2.2.
4.2.2.1
Starting Dose for This Trial
The starting dose for MK-8353 in combination with pembrolizumab is 50 mg bid continuous 
in Arm A, and 50 mg qd in Arm B (continuous), optional Arm C (1 week on/1 week off),
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and optional Arm D (MK-8353 monotherapy run-in) (refer to Section 4.1.2.1).  Doses in 
Arms A and B and optional Arms C and D may be adjusted depending on PK and emerging
toxicity data.
Pembrolizumab will be administered as a fixed dose of 200 mg q3w for every study subject 
(refer to Section 4.1.2.2).
4.2.2.2
Maximum Dose/Exposure for This Trial
The maximum dose of oral MK-8353 for this trial is as follows:
Arm A: 350 mg bid; maximum 700 mg total per day
Arm B: 1200 mg qd; maximum 1200 mg total per day
Arms C and D: 600 mg qd; maximum 600 mg total per day
The maximum dose of pembrolizumab will be 200 mg administered intravenously q3w.
The maximum dose of MK-8353 is based on the single agent doses tested in the healthy 
volunteer study and in Protocol 001 (refer to Section 4.1.2.1). Also, preliminary data from 
Protocol 013 at the 350 mg bid dose of MK-8353 in combination with pembrolizumab have 
suggested intolerable skin toxicity (refer to Section 4.1.3.1).
The maximum dose of pembrolizumab is based on single agent doses tested in KN-001, as 
well as the highest doses tested in combination in Phase 1 to 2 trials (refer to Section 4.1.2.2 
and package circular for KEYTRUDA).
4.2.2.3
Rationale for Dose Interval and Trial Design
In MK-8353 Protocol 001, doses from 100 mg bid to 800 mg bid were evaluated.
The 
highest dose level (800 mg bid) was found to be not tolerable (refer to Section 4.1.2.1 and the 
MK-8353 IB).  
Although a dose of 350 mg bid was well tolerated in monotherapy and showed signs of 
clinical activity in Protocol 001, preliminary data from Protocol 013 have suggested that 
MK-8353 at 350 mg bid in combination with pembrolizumab leads to unacceptable toxicity 
(Grade 3 rash reported in 3 of the 4 subjects treated at this dose; refer to Section 4.1.3.1).
In the current amendment, dose escalation of MK-8353 (in combination with 
pembrolizumab) will start at 50 mg bid and 50 mg qd in Arm A and Arm B, respectively 
(continuous schedule). In spite of the high inter-individual variability observed in PK data 
from MK-8353, these doses are expected to produce meaningfully lower exposure from the 
previously tested 350 mg bid dose. The 2 optional Arms C and D will explore a drug holiday 
schedule (1 week on/1 week off; Arm C), and a 2-week run-in with MK-8353 as a single 
agent prior to the continuous administration of the combination (Arm D).  The 2 optional 
arms could be triggered if unacceptable toxicities occur in Arm A and/or Arm B. In Arm B, 
once daily doses that achieve the same average exposure at steady state compared with bid
doses (with lower trough levels, but higher Cmax) will be explored in parallel to Arm A.
Pembrolizumab will be evaluated in the combination therapy at its full single-agent dose 
(200 mg intravenously q3w), and will not be escalated or de-escalated during this trial (refer 
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to Section 5.2.1).  This dose was shown to be efficacious as a single agent and in 
combination, with an acceptable AE profile.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
The efficacy of MK-8353 in combination with pembrolizumab will be evaluated in subjects 
with 
advanced 
solid 
tumors, 
and 
in 
subjects 
with 
≥second 
line
advanced 
non-MSI-H/dMMR CRC, by measuring ORR, DCR, DOR, PFS, and OS.
Overall response rate will be used as a secondary endpoint as assessed by the investigator 
based on RECIST 1.1, to evaluate efficacy of MK-8353 in combination with pembrolizumab 
in subjects with advanced solid tumors, and in subjects with ≥second line advanced 
non-MSI-H/dMMR CRC.
Radiological images (eg, computed tomography [CT], magnetic resonance imaging [MRI]) 
will be collected for possible analysis by blinded, independent central review.
The Site 
Imaging Manual (SIM) contains specific instructions for the acquisition and submission of 
radiologic images to the central imaging vendor for this study.
Exploratory endpoints include OS, DCR, DOR, and PFS as assessed by the investigator
based on RECIST 1.1 (refer to Appendix 12.4).
Secondary and exploratory efficacy endpoints will also be summarized according to 
RAS/RAF mutant status, pMMR status, and colon side of the tumors (in subjects with 
non-MSI-H/dMMR CRC).
Immune-related RECIST could be used by the investigator for treatment decision as outlined 
in Section 7.1.2.6 and Appendix 12.5.
4.2.3.2
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of 
MK-8353 in combination with pembrolizumab in subjects with advanced solid tumors, and 
in subjects with ≥second line advanced non-MSI-H/dMMR CRC.
The primary safety analysis will be based on subjects who experience toxicities as defined by 
NCI CTCAE version 4.0 criteria for the duration of the study.  Dose-limiting toxicities will 
be evaluated during Cycle 1 for the purpose of dose escalation and de-escalation decisions.
Safety will be assessed by quantifying the toxicities experienced by subjects who have 
received MK-8353 and pembrolizumab and their grades, including SAEs and events of 
clinical interest (ECIs).
Safety will be assessed by reported AEs using NCI CTCAE, version 4.0. The attribution to 
drug, time-of-onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded.  Safety parameters that will be analyzed include, but are not 
limited to, overall AEs, specific SAEs, SAEs, fatal AEs, and laboratory changes.
Other safety endpoints include laboratory safety assessments, Eastern Cooperative Oncology 
Group (ECOG) performance status, vital signs, and physical examinations.
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4.2.3.3
Pharmacokinetic Endpoints
Serum samples will be obtained to measure PK of MK-8353 when given in combination with
pembrolizumab.  MK-8353 (Parts 1 and 2) and pembrolizumab (Part 1 only) serum peak and 
trough concentrations at planned visits and times will be summarized.  Pharmacokinetic data 
of MK-8353 and pembrolizumab will be compared with the previously validated population 
PK model and potentially used to update the model.
4.2.3.4
Antidrug Antibody Assay
Formation of antidrug antibodies can potentially confound drug exposures at therapeutic 
doses, and prime for subsequent infusion-related toxicity.  Antidrug antibody response to 
pembrolizumab at the beginning of each cycle will be determined to understand drug 
metabolism, exposure, and safety.  Blood samples collected for antidrug antibody may only 
be stored at this time.  Further analyses may be performed if required. If ongoing antidrug 
antibody sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
4.2.3.5
Tumor Markers
Serum samples will be obtained prior to study start and on Day 1 of each cycle to evaluate 
the kinetics of tumor markers such as CEA, CA-125, and CA 19-9, as appropriate. In a 
previous study, CEA decrease was predictive of PFS and ORR and occurred well in advance 
of radiographic confirmation of disease control [55]. Subjects with disease progression had 
rapid tumor marker elevation within 30 days after the initiation of therapy that significantly 
preceded radiographic changes [55].
4.2.3.6
RAS/RAF Mutations and pMMR/dMMR (MSI) Status
Testing for BRAF mutation (methodology detecting both V600E and/or V600K mutations),
KRAS codon 12 and 13 mutations, and NRAS mutations (for non-CRC solid tumors) will be 
indicated according to tumor type as judged by the investigator, and performed by local 
laboratory testing.
Microsatellite instability, a form of genomic instability, occurs through the insertion or 
deletion of repeating nucleotides during deoxyribonucleic acid (DNA) replication and failure 
of the MMR system to correct errors in nucleotide repeat markers.  Testing for 
pMMR/dMMR (MSI) status is already standardized and performed in Clinical Laboratory 
Improvement Amendments (CLIA)-certified laboratories without need for assay 
development.  Mismatch repair proteins, or MSI loci testing for CRC is already clinically 
indicated as per National Comprehensive Cancer Network, European Society for Medical 
Oncology, and American Society of Clinical Oncology (ASCO) guidelines [58] [59] [60]. 
All means of testing for MSI status (eg, immunohistochemistry [IHC], polymerase chain 
reaction [PCR], next generation sequencing [NGS]) performed locally will be accepted.  For 
other non-CRCs for which MSI testing is not currently clinically indicated, MSI status will 
be performed locally by CLIA-certified IHC or PCR-based tests for eligibility, or by a central 
laboratory if local laboratory testing is not available.
For central laboratory testing for MSI status, archived tumor samples or newly obtained 
biopsies will be used.
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4.2.3.7
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Additional biomarker research to identify factors important for MK-8353 and 
pembrolizumab combination therapy will be pursued.
Pretreatment and on-treatment tumor (when obtained) and blood samples collected in this 
study may undergo proteomic, genomic, and transcriptional analyses (both DNA and 
ribonucleic acid [RNA] analyses).  Additional research may evaluate factors important for
predicting responsiveness or resistance to MK-8353 and pembrolizumab combination 
therapy and other immunologic targets. Expression of candidate biomarkers in tumor tissue 
will be evaluated both at baseline and at least 10 to 14 days after initiation of combination 
therapy with MK-8353 and pembrolizumab (optional on-treatment biopsy in Cycle 2), 
including immune-signaling markers on the surface of tumor cells, phenotypic and functional 
immune cell markers on tumor-infiltrating lymphocytes (which may include PD-1, PD-L1, 
CD8 T cells), inhibition of ERK phosphorylation, and possible other biomarkers, as well as 
DNA/RNA changes. These and other additional biomarker or genomic research to identify 
factors important for MK-8353 and pembrolizumab combination therapy (eg, human 
leukocyte antigen genotype) may also be pursued.
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 subjects. 
Thus, to aid future subjects, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy as well as determinants of 
AEs in the course of clinical trials.  These efforts will identify novel predictive/PD 
biomarkers and generate information that will better guide single-agent and combination 
therapy with immuno-oncology drugs.  To identify novel biomarkers, we will collect 
biospecimens (eg, blood components, tumor material) 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, single nucleotide polymorphism analyses, 
whole exome sequencing, whole genome sequencing):
this research will evaluate
whether genetic variation within a clinical trial population correlates with response to 
the treatment(s) under evaluation.  If genetic variation is found to predict efficacy or 
AEs, the data might inform optimal use of therapies in the subject population.  
Furthermore, it is important to evaluate germline DNA variation across the genome in 
order to interpret tumor-specific DNA mutations.  Finally, MSI will be evaluated as 
this is an important biomarker for some cancers (ie, CRC).

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 (eg, mutations, methylation status, MSI).  Key 
molecular changes of interest to immuno-oncology drug development include the 
mutational burden of tumors and the clonality of T-cells in the tumor 
microenvironment.  Increased mutational burden (sometimes referred to as a 
‘hyper-mutated’ state) may generate neo-antigen presentation in the tumor 
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microenvironment.  To conduct this type of research, it is important to identify 
tumor-specific mutations that occur across all genes in the tumor genome.  Thus, 
genome-wide approaches may be used for this effort.  Note that in order to 
understand tumor-specific mutations; it is necessary to compare the tumor genome 
with the germline genome.  Microsatellite instability will also be evaluated as this is 
an important biomarker for some cancers (ie, CRC).

Tumor and blood RNA analyses: both genome-wide and targeted messenger RNA 
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 (such as those capturing interferon-gamma transcriptional pathways) may 
be evaluated and new signatures may be identified.  Individual genes related to the 
immune system may also be evaluated (eg, interleukin-10).  MicroRNA profiling may 
also be pursued.

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 subjects with NSCLC, and an in vitro diagnostic device has been 
developed for use with pembrolizumab in NSCLC.  Preliminary data indicate that this 
association may also be true in additional cancer types (ie, triple-negative breast 
cancer, head and neck cancer, and gastric cancer).  Additional tumor or blood-derived 
proteins may also correlate with response to pembrolizumab.  Tumor tissue may, 
therefore, 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 subject selection for pembrolizumab therapy.

Other blood-derived biomarkers: in addition to expression on tumor tissue, PD-L1 
and other tumor-derived proteins can be shed from tumors and released into the 
blood.  Assays such as enzyme-linked immunoassay measure these 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.
4.2.3.8
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research (FBR) on specimens consented for 
FBR during this clinical trial. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects.  The objective of collecting specimens for FBR is to 
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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 subjects receive the correct dose of 
the correct drug/vaccine at the correct time.  The details of FBR are presented in Section 
12.2.  Additional informational material for institutional review boards/ethics review 
committees (IRBs/ERCs) and investigational site staff is provided in Section 12.1.
4.3
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying MK-8353 and pembrolizumab IB and 
informed consent documents.
5
METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with advanced or metastatic solid tumors in Part 1 and Male/Female 
subjects with ≥second line advanced or metastatic non-MSI-H/dMMR CRC in Part 2 will be 
enrolled in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Part 1:
have a histologically or cytologically documented, locally advanced or 
metastatic solid malignancy.  Each subject must have received at least 1 and up to 
5 prior lines of cancer treatment regimen, excluding neo-adjuvant, adjuvant, 
maintenance treatment and surgery.
Note: a repeat line of treatment does not count in the total number if the subject
did not progress the first time; a 2-week or more duration of treatment counts in 
the total number of prior line of treatment if the subject progressed.
2. Part 2: have a histologically confirmed adenocarcinoma originating from the colon or 
rectum (Stage 4 American Joint Committee on Cancer 7th edition).
Must be 
non-MSI-H/dMMR CRC.  Appendiceal cancer is included.
AND
Experienced disease progression or was intolerant to at least 1 and up to 5 systemic 
chemotherapy regimen for metastatic non-MSI-H/dMMR CRC that must have 
included fluoropyrimidines and irinotecan, or oxaliplatin, ± anti-vascular endothelial 
growth factor or anti-epidermal growth factor receptor (if indicated by RAS 
mutational status); disease progression must have occurred within 3 months of the last 
systemic therapy administration.  Subjects who were not deemed appropriate 
candidate for any of these agents due to medical history and/or contraindications may 
be eligible upon consultation with the Sponsor.
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3. Provide an archival or newly obtained tumor tissue sample and blood samples for 
assessment of RAS/RAF mutation and pMMR/dMMR status and for biomarker 
analysis.
4. Have at least 1 measurable lesion as defined by RECIST 1.1 on imaging studies (CT 
or MRI) as assessed by the investigator/local radiology review.  Cutaneous lesions 
and other superficial lesions that are detectable only by physical examination and 
subcutaneous lesions detectable by CT are not considered measurable lesions for the 
purposes of this protocol, but may be considered as nontarget lesions.
5. Be willing and able to provide written informed consent for the trial.  The subject 
may also provide consent for FBR.  However, the subject may participate in the main 
trial without participating in FBR.
6. Be ≥18 years of age on day of signing the informed consent.
7. Have a performance status of 0 or 1 on the ECOG Performance Scale.
8. Have an anticipated life expectancy of at least 3 months.
9. Be able to swallow and retain oral medication and must not have any clinically 
significant gastrointestinal abnormalities that may alter absorption.
10. Have adequate organ function as defined in Table 1:
Table 1
Inclusion Criteria Laboratory Parameters
System
Laboratory Value
Hematological
ANC
≥1,500/mcL
Platelets
≥100,000/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L
Renal
Serum creatinine
OR Measured or calculateda CrCl
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 × ULN OR
60 mL/min for subject with creatinine levels >1.5 ×
institutional ULN
Hepatic
Serum total bilirubin
≤1.5 × ULN OR
Direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN OR
≤5 × ULN for subjects with liver metastases
Coagulation
INR or PT
aPTT
≤1.5 × ULN unless the subject is receiving anticoagulant 
therapy as long as PT or aPTT is within therapeutic range 
of intended use of anticoagulants 
a Calculate CrCl using standard Cockcroft-Gault formula (Appendix 12.3). 
ALT (SGOT)=alanine aminotransferase; ANC=absolute neutrophil count; aPTT=activated partial 
thromboplastin time; AST (SGPT)=aspartate aminotransferase; CrCl=creatinine clearance; GFR=glomerular 
filtration rate; INR=International Normalized Ratio; PT=prothrombin time; ULN=upper limit of normal.
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11. Female subject of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  The serum pregnancy test must be negative for the subject to be 
eligible.
12. Female subjects may be enrolled in the trial if they are:
-
Of nonchildbearing potential, which is defined as:

A female subject ≥45 years of age and has not had menses for greater than 
1 year,

A female who is amenorrheic for >2 years without a hysterectomy and 
oophorectomy and a follicle-stimulating hormone (FSH) value in the 
postmenopausal range upon pretrial (screening) evaluation,
and/or

A female who is status post hysterectomy, oophorectomy, or tubal ligation.  
Documented hysterectomy or oophorectomy must be confirmed with medical 
records of the actual procedure or confirmed by an ultrasound.  Tubal ligation 
must be confirmed with medical records of the actual procedure; otherwise,
the subject will be excluded.  Information must be captured appropriately 
within the site's source documents.
-
Of childbearing potential who are willing to use either 2 adequate barrier 
methods, or to abstain from heterosexual activity throughout the trial, starting 
with the screening visit (Visit 1) through 120 days after the last dose of trial 
treatment.  Please refer to Section 5.7.2 for a list of acceptable birth control 
methods.
13. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2, starting with the first dose of study 
medication through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has disease that is suitable for local treatment administered with curative intent.
2. Part 1: has received prior therapy with cancer vaccines, or compounds targeting PD-1
(including pembrolizumab), PD-L1, PD-L2, CTLA-4, or MEK.
Note:  Examples of MEK inhibitors include, but are not limited to, trametinib and 
cobimetinib.
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3. Part 2: has received prior therapy with cancer vaccines, or compounds targeting PD-1
(including pembrolizumab), PD-L1, PD-L2, CTLA-4, LAG-3, CD-137, OX-40, 
CD-40, GITR, BRAF, MEK or other molecules in the MAPK pathway.
Note:  Examples of BRAF inhibitors include, but are not limited to, dabrafenib and 
vemurafenib.
4. Is currently participating in or has participated in a study of an investigational agent 
or using an investigational device within 4 weeks prior to the first dose of trial 
treatment.
5. Has taken during the 14 days prior to enrollment, or is currently taking medication 
that interferes with CYP3A4 or CYP2C8 as listed in Table 8.
6. Has Gilbert’s Syndrome.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.  
The use of physiologic doses of corticosteroids may be approved after consultation 
with the Sponsor.
8. Has had a prior anticancer mAb within 4 weeks prior to study Day 1 or who has not 
recovered (ie, ≤Grade 1 or at baseline) from AEs due to agents administered more 
than 4 weeks earlier.
9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 14 days prior to study Day 1 or who has not recovered (ie, ≤Grade 1 or at 
baseline) from AEs due to a previously administered agent.
Note: Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to 
this criterion and may qualify for the study upon consultation with the Sponsor.
Note: If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.
10. Has received transfusion of blood products (including platelets or red blood cells) or 
administration of colony stimulating factors (including granulocyte-colony 
stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor 
[GM-CSF] or recombinant erythropoietin) within 4 weeks prior to study Day 1.
11. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin that has undergone potentially curative therapy, or in situ cervical cancer.
12. Has known active central nervous
system
metastases and/or carcinomatous 
meningitis.
Note:  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging, using the identical 
imaging modality for each assessment, either MRI or CT scan) for at least 4 weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
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baseline, have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 14 days prior to trial treatment.  This exception does not include 
carcinomatous meningitis which is excluded regardless of clinical stability.
13. Active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive 
drugs).  Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
14. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
15. Has a history of interstitial lung disease.
16. Has an active infection requiring systemic therapy.
17. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
18. Has a known psychiatric or substance abuse disorder that would interfere with the 
subject's ability to cooperate with the requirements of the trial.
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
20. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
21. Has known active hepatitis B (eg, hepatitis B surface antigen reactive) or hepatitis C 
(eg, hepatitis C virus RNA [qualitative] is detected).
22. Has received a live-virus vaccination within 30 days of planned treatment start.  
Seasonal flu vaccines that do not contain live virus are permitted.
23. Is expected to require any other form of systemic or localized antineoplastic therapy 
while in study.
24. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its 
excipients.
25. Has had an allogeneic tissue/solid organ transplant.
26. Part 2: Have a histologically confirmed adenocarcinoma originating from the colon 
or rectum that is microsatellite instable (ie, MSI-H).
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5.2
Trial Treatment(s)
Part 1: the treatments to be used in this trial are outlined below in Table 2.  A cycle of 
treatment in this study is defined as 21 days (Day 1 to Day 21), except for the MK-8353 
monotherapy run-in of 14 days in Arm D.  In Arm A, 6 dose levels of MK-8353 are planned 
in Part 1 on a continuous schedule starting at 50 mg bid, (Table 2).  In Arm B (continuous) 
and optional Arms C (1 week on/1 week off) and D (run-in), 7 dose levels of MK-8353 are 
planned, starting at 50 mg qd (Table 2). Concomitant administration of pembrolizumab will 
be at the fixed dose of 200 mg q3w in all arms.
Table 2
Part 1 Trial Treatment (21-day cycles)
Drug
Dose Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment
Use
Arm A (bid continuous)
MK-8353
DL1  350 mg
bid
Oral
Days 1 to 21 of each 
cycle
Experimental
DL1A* 50 mg
bid
DL2A 50 mg  
+ 100 mg *
bid
DL3A  100 mg
bid
DL4A 150 mg
bid
DL5A  200 mg
bid
DL6A 300 mg
bid
Pembrolizumab
200 mg
q3w
Intravenous 
infusion
Day 1 of each cycle
Experimental
Arm B (qd continuous)
MK-8353
DL1B  50 mg
qd
Oral
Days 1 to 21 of each 
cycle
Experimental
DL2B 100 mg
qd
DL3B 150 mg
qd
DL4B 200 mg
qd
DL5B 300 mg
qd
DL6B 400 mg
qd
DL7B 600 mg
DL8B 900 mg
DL9B 1200 mg
qd
qd
qd
Pembrolizumab
200 mg
q3w
Intravenous 
infusion
Day 1 of each cycle
Experimental
Optional Arm C (qd 1 week on/1 week off)
MK-8353
DL1C  50 mg
qd
Oral
Days 1 to 7, Days 
15 to 21, and Days 
29 to 35 of each 42-
day cycle (based on 
2 cycles of 21 days)
Experimental
DL2C  100 mg
qd
DL3C  150 mg
qd
DL4C  200 mg
qd
DL5C  300 mg
qd
DL6C  400 mg
qd
DL7C  600 mg
qd
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Drug
Dose Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment
Use
Pembrolizumab
200 mg
q3w
Intravenous 
infusion
Days 1 and 22 of 
each 42-day period 
(based on 2 cycles 
of 21 days)
Experimental
Optional Arm D (MK-8353 monotherapy run-in then qd continuous)
MK-8353
DL1D 50 mg
qd
Oral
Run-in from 
Cycle 1, Day 1 to 
Day 14 prior to 
Cycle 2, then 
continuous from 
Days 1 to 21 of each 
cycle
Experimental
DL2D  100 mg
qd
DL3D 150 mg
qd
DL4D 200 mg
qd
DL5D 300 mg
qd
DL6D 400 mg
qd
DL7D 600 mg
qd
Pembrolizumab
200 mg
q3w
Intravenous 
infusion
Day 1 of each cycle
starting with Cycle 2
Experimental
* If 50 mg bid/qd doses are not tolerable, dose of 10 mg and 30 mg may be explored.
** DL2A (150 mg daily) will be administered as a morning dose of 50 mg and an evening dose of 100 mg 
MK-8353.
bid=twice daily, DL=dose level, q3w=once every 3 weeks, qd=once daily.
Part 2: MK-8353 will be administered at the RP2D(s) identified for MK-8353 in Part 1 of 
the study (several doses and schedules could be explored), in combination with 
pembrolizumab at a fixed dose of 200 mg (same fixed dose as in Part 1).  The decision to 
bring specific schedule(s) or dose(s) into the expansion cohorts in Part 2 will be based on 
exposure parameters, as well as the safety profile and potential preliminary efficacy 
observed, and will be made jointly by the investigators and the Sponsor.
Throughout the study (Part 1 and Part 2) in Arms A and B, the first dose of MK-8353 will 
occur at the trial site on Day 1 of each cycle, shortly before the pembrolizumab infusion.  
Pembrolizumab will be then administered through an IV infusion as described in the 
Pharmacy Manual.  For optional Arm C, administration will follow the schedule described in 
Table 2.  For optional Arm D, after the screening visit, the subject will receive MK-8353
monotherapy unsupervised at his/her home from Cycle 1, Day 1 to Day 14, prior to Cycle 2
Day 1.  
1. Arm A (bid continuous):
-
For the cohorts in Arm A (bid schedule), subsequent dosing of MK-8353 will be 
performed in the evening of the same day (Day 1), and then twice a day by the 
subject (ie, unsupervised at his/her home) at approximately the same time each 
day, until Day 1 of the next cycle.
2. Arm B (qd continuous):
-
In Arm B (qd schedule), subsequent dosing of MK-8353 will be performed the 
next day (Day 2), and then once a day by the subject (ie, unsupervised at his/her 
home) at approximately the same time each day, until Day 1 of the next cycle.
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3. Optional Arm C (1 week on/1 week off):
-
In optional Arm C (1 week on/1 week off qd schedule), subsequent dosing of 
MK-8353 will be performed the next day by the subject (ie, unsupervised at 
his/her home) at approximately the same time each day, on Days 1 to 7, 
Days 15 to 21, and Days 29 to 35 of a 42-day period (corresponding to 2 cycles of 
21 days) until Day 1 of Cycle 3.
4. Optional Arm D (monotherapy run-in then continuous):
-
In optional Arm D (monotherapy run-in then qd continuous), MK-8353 will be 
administered qd from Cycle 1, Day 1 to Day 14 (ie, unsupervised at his/her 
home), prior to Cycle 2 Day 1.  Cycle 2 Day 1 will be performed at the clinical 
site.  Subsequent dosing of MK-8353 will be performed the next day (Cycle 2 
Day 2), and then once a day by the subject (ie, unsupervised at his/her home) at 
approximately the same time each day, until Day 1 of the next cycle.
Enrollment will be accomplished by nonrandom assignment to each combination treatment 
dose level in Part 1, using an interactive voice response system/integrated web response 
system (IVRS/IWRS). In Part 2, if several schedules and/or doses at RP2D are explored for 
the combination therapy, assignment will be randomized. Enrollment will be 
semi-competitive between sites.
All supplies indicated in Table 2 above will be provided centrally by the Sponsor or locally 
by the trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
5.2.1.2
Dose Escalation and Confirmation
In Part 1 of the study, an mTPI design [1] with a target DLT rate of approximately 30% will 
be applied for dose escalation and confirmation to determine a RP2D for MK-8353 in 
combination with pembrolizumab.
In Arms A (bid continuous) and B (qd continuous), predetermined dose levels of MK-8353 
(in combination with a fixed dose of pembrolizumab) will be explored independently. In 
Arm A, a de-escalation dose of 50 mg is available if the starting dose of 100 mg is deemed 
not tolerable. All dose escalation and de-escalation decisions will be based on the occurrence 
of DLTs at a given dose during the DLT evaluation period and will be made jointly by the 
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investigators and the Sponsor. In Arm B, additional intermediate dose levels between 600 
and 1200 mgs may be explored.
Additionally, the investigators and the Sponsor can decide jointly to open the 2 optional 
schedules (Arm C and/or Arm D) based on safety information and PK data obtained from 
Arms A and B. All dose escalation and de-escalation decisions in these 2 arms will be also 
based on the occurrence of DLTs at a given dose during the DLT evaluation period (Cycle 1
for Arm C [21 days], and Cycles 1 and 2 for Arm D [35 days]) and will be made jointly by 
the investigators and the Sponsor.
Additional doses of 10 mg and 30 mg could be explored in any of the 4 arms based on safety 
information and exposure data obtained at the higher doses.  The decision to explore these 
lower doses will be made jointly by the investigators and the Sponsor.
The dose of pembrolizumab will remain constant at 200 mg q3w for each dose level of
MK-8353 and in each arm.
In Table 3, the number of subjects treated is indicated in the columns and the number of 
subjects who experienced a DLT is indicated in the rows.  Dosing decisions include escalate 
to the next higher dose (E), stay at the current dose (S), de-escalate to the next lower dose 
(D), and de-escalate to a lower dose and never test this dose again (ie, unacceptably toxic 
dose; DU).
During dose escalation, a minimum of 3 subjects is required at each dose. At the starting 
dose in Arm A (DL1A), 1 subject will be enrolled, and subsequent subjects will be enrolled 
once the first subject has reached Cycle 1 Day 15. 
Additionally, previously enrolled 
subjects, continuing on the study, will be able to restart MK-8353 at 100 mg bid in 
combination with pembrolizumab once the first subject has reached Cycle 1 Day 15. In 
subsequent doses for each arm, staggering enrollment is optional.
Depending on accrual rate, 3, 4, 5, or 6 subjects may be enrolled at each new dose until the 
last of those subjects completes the DLT assessment period.
For example, the dose 
escalation rules will proceed as follows if 3 subjects are enrolled: if 0 out of the first 
3 subjects at a given dose level develops a DLT, then the dose can be escalated to the next 
level without further expansion. If 1 out of the first 3 subjects at a given dose level develops 
a DLT, no more than an additional 3 subjects should be enrolled at this dose level until 
additional DLT data are available since this dose would be considered unacceptably toxic if 
all 3 of the additional subjects experience a DLT (ie, 4 out of 6 subjects). If 2 out of the first 
3 subjects at a given dose level develop a DLT, the dose will be de-escalated to the next 
lower level. If 3 out of the first 3 subjects at a given dose level develop a DLT, this dose will 
be considered unacceptably toxic (ie, the dose will be de-escalated and never re-escalated to 
that dose again).
The same principle will be applied whether 3, 4, 5, or 6 subjects are 
enrolled in the same dose cohort according to Table 3.
Based on the mTPI design, the number of subjects who are enrolled at a dose, but are not yet 
fully evaluable for DLT assessment, may not exceed the number of remaining subjects who 
are at risk of developing a DLT before the dose would be considered unacceptably toxic
(denoted as DU in Table 3). To determine how many more subjects can be enrolled at a dose 
level, one can count steps in a diagonal direction (down and to the right) from the current cell 
to the first cell marked DU.  In total, 3 to 14 subjects may be enrolled at a given dose level.
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For example, if 1/3 subjects have experienced a DLT at a given dose level, no more than an 
additional 3 subjects 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 subjects experience a DLT (ie, 4/6 subjects with DLTs as in Table 3).
This is a Phase 1b assessment of MK-8353 in humans, and the PK, PD, and safety profiles of
the compound are still being elucidated. This protocol is written with some flexibility to
accommodate the inherent dynamic nature of Phase 1 clinical studies. Modifications to the
dose, dosing regimen and/or clinical or laboratory procedures currently outlined above may
be required to achieve the scientific goals of the study objectives and/or to ensure appropriate
safety monitoring of the study participants. As such, some alterations from the currently 
outlined dose and/or dosing regimen may be permitted based on newly available data, but the 
maximum daily dose may not exceed those currently outlined in the protocol, including 
repeat of or decrease in the dose of the study intervention administered in any given arm.
Dose escalation and confirmation will end after 14 subjects have been treated at any one of 
the selected doses. The pool-adjacent-violators-algorithm [1] will be used to estimate the 
DLT rates across doses. The dose with an estimated DLT rate closest to 30% may be treated 
as a preliminary MTD. The totality of the data will be considered before a dose is selected to 
carry forward to Part 2 and the escalation schedule may be adjusted based on PK and safety 
data emerging throughout the study to determine the RP2D.
Note that although 30% was the target toxicity rate used to generate the guidelines in
Table 3, the observed rates of subjects with DLTs at the MTD may be slightly above or 
below 30%.
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Table 3
Dose Escalation and Confirmation Rules Based on the Modified Toxicity 
Probability Interval Design
Number of subjects treated at current dose
Number of toxicities
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
Target toxicity rate = 30%
Flat non-informative prior Beta (1,1) is used as a prior and ε1=ε2=0.05[1].
D=de-escalate to the next lower dose; DU=the current dose is unacceptably toxic, E=escalate to the next 
higher dose, S=stay at the current dose.
5.2.1.3
Cohort Expansion
Up to approximately 40 additional subjects will be treated at the RP2D(s) identified in Part 1
for MK-8353, in combination with the fixed dose of pembrolizumab (200 mg IV q3w), to 
collect more safety and efficacy data at that dose. The population to be enrolled into the 
cohort expansion (Part 2) is defined in Inclusion Criterion #2 (Section 5.1.2). Several doses 
and schedules may be explored in Part 2.
5.2.1.4
Tolerability Evaluation Rules and Dose Escalation
The different dose levels of MK-8353 in Arms A and B and optional Arms C and D planned 
in Part 1 are presented in Table 4.
In Amendment 3 of Protocol 013, the starting dose of MK-8353 is 50 mg bid in Arm A and 
50 mg qd in Arm B and optional Arms C and D.  Dose escalation will continue as outlined 
above (Section 5.2.1.2) according to mTPI dose-finding rules.  Additionally, doses of 
MK-8353 at 10 mg and 30 mg could be explored in each arm (Section 5.2.1.2).  Concomitant 
administration of pembrolizumab will be at the fixed dose of 200 mg q3w in all arms and at 
all dose levels of MK-8353.
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The occurrence of any of the following toxicities during the DLT window will be considered 
a DLT, if assessed by the investigator to be possibly, probably, or definitely related to study 
drug administration:
1. Grade 4 nonhematologic toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia associated with bleeding
3. Grade 3 nonhematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care.
4. Any Grade 3 or Grade 4 nonhematologic laboratory value if:

Medical intervention is required to treat the subject, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week.

Exceptions:
o
Clinically nonsignificant, treatable, or reversible laboratory abnormalities 
(eg, liver function tests, uric acid)
5. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour

Grade 4 is defined as ANC <1000/mm3 with a single temperature of 
>38.3 degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour, with life-threatening consequences 
and urgent intervention indicated
6. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
7. Any treatment-related toxicity that causes the subject to discontinue treatment during 
Cycle 1.
8. Missing >25% of MK-8353 doses as a result of drug-related AE(s) during the first 
cycle.
9. Grade 5 toxicity.
5.2.1.6
Replacement of Subjects in Dose-limiting Toxicity Period
In order to fully evaluate the safety of the combination therapy in this study, all subjects 
enrolled must meet the criteria for evaluability for Cycle 1. 
Subjects are considered 
nonevaluable and will be replaced if:

They are enrolled but not treated.
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
They discontinue from the trial prior to completing all safety evaluations due to 
reasons other than drug-related AEs.

They received <90% of the total pembrolizumab infusion in Cycle 1 (eg, because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a 
drug-related event.

They received ≤75% of MK-8353 doses intended for the trial during Cycle 1 and did 
not experience a drug-related event.

They must take a prohibited concomitant medication during Cycle 1, unless this 
medication is used to treat a study drug-related AE.

They must undergo medical / surgical procedures or have logistical issues not related 
to study therapy (eg, elective surgery, unrelated medical events) during Cycle 1.
Subjects discontinuing within 21 days (or 35 days for Arm D) of the first dose due to reasons 
unrelated to study treatment will not be considered evaluable for DLTs and may be replaced. 
Subjects with a DLT within 21 days (or 35 days for Arm D) of the first dose should not be 
replaced.
Nonevaluable subjects will not be counted toward the (Part 1 or Part 2) total for DLT 
evaluation.
Subjects who experience a DLT in the DLT window should be discontinued from the trial.  
However, if in the opinion of the investigator, the subject is deriving clinical benefit from the 
study treatment, the subject may be allowed to continue on the trial after discussion with the 
Sponsor.
Dose Modification (Escalation/Titration/Other)
For individual subjects, dose delays and modifications of trial treatment will be based on 
treatment-related toxicity, laboratory test results prior to treatment administration, and 
clinical assessments during the previous cycle and on the day of treatment.  Guidelines for 
dose delay and dose modification are described below and are applicable to the start of each 
cycle as well as during the cycle if treatment-related toxicities occur.
5.2.2.1
MK-8353 Dose Modifications
Criteria for Dose Delay
Except in Cycle 1 in which dosing can be delayed up to 2 weeks, dosing of MK-8353 should 
be delayed for up to 3 weeks, until the AE is resolved to baseline status or ≤Grade 1 in case 
of:
-
Any treatment-related hematological or nonhematological AE ≥Grade 3
OR
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-
Any abnormal nonhematological laboratory value ≥Grade 3 that requires medical 
intervention, hospitalization, or persists for ≥1 week, except for a clinically 
nonsignificant, treatable, or reversible laboratory abnormalities
Any ≥Grade 3 AE of nausea and/or vomiting, or anorexia if left untreated without medical 
intervention will not require a dose delay.
A reoccurring Grade 2 hematological or nonhematological AE, which in the opinion of the 
investigator is treatment-related and significant despite medical intervention, should be 
discussed with the Sponsor prior to any dose delay.
Subjects should be assessed weekly until the AE has resolved to baseline status or ≤Grade 1 
and dosing resumes or the subject is discontinued from the study.
If treatment is delayed by more than 3 weeks (or by more than 2 weeks in Cycle 1) because 
of treatment-related toxicity, study treatment should be discontinued.  However, subjects 
with evidence of clinical benefit may be allowed to continue treatment despite a treatment 
delay (for any reason) of more than 3 weeks, after discussion with the Sponsor.
Criteria for Dose Modification
Once a dose delay occurs, upon resolution of any treatment-related AE to baseline status or 
≤Grade 1, the dose level of MK-8353 for the subsequent doses must be reduced 1 dose level.
Any dose level reduction will be permanent (ie, dose re-escalation is NOT allowed).  No 
more than 2 dose level reductions will be allowed.  Subjects who require further dose 
reductions or dose reductions below DL -1 should be discontinued from the study treatment.
Dose reductions are not permitted during the DLT evaluation period.
5.2.2.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab 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 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, 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. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reaction are provided in Table 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject 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 hrs
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 subject 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/hr to 50 
mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment.
Subject may be premedicated 
1.5h (±30 minutes) prior to 
infusion of pembrolizumab
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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Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:

Epinephrine**

IV fluids

Antihistamines

NSAIDs

Acetaminophen

Narcotics

Oxygen

Pressors

Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during 
the period of drug administration.
For further information, please refer to the NCI CTCAE, version 4.0 at http://ctep.cancer.gov
CTCAE=Common Toxicity Criteria for Adverse Events; IV=intravenous; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs; po=per os (by mouth).
Dosing interruptions are permitted after Cycle 1 in the case of medical/surgical events or 
logistical reasons not related to study therapy (eg, elective surgery, unrelated medical events, 
subject vacation, and/or holidays).  Subjects should be placed back on study therapy within 
3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor.  The 
reason for interruption should be documented in the subject’s study record.
Timing of Dose Administration
All trial treatments will be administered on an outpatient basis.
Trial treatment should be administered after all procedures/assessments have been completed 
as detailed on the Trial Flow Chart (Section 6.0) and Table 7.
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Table 7
Treatment Schedule for MK-8353 + Pembrolizumab for Each Treatment Cycle 
Treatment
Day 1
Days 2 – 21
am
pm
am
pm
Arm A (bid continuous)
MK-8353
X
X
X
X
Pembrolizumab
X
Arm B (qd continuous) 
Day 1
Days 2 – 21
am
am 
MK-8353
X
X
Pembrolizumab
X
Optional Arm C (qd 1 week on/ 1 week off)
Day 1 
Days 2 to 7,
15 to 21, and 
29 to 35
Day 22
Days 8-14,
23-28,
and 36-42
am
am
am
am
MK-8353
X
X
Pembrolizumab
X
X
Optional Arm D (monotherapy run-in then qd continuous)
Cycle 1, Day 1
to Day 14
Day 1 of 
subsequent 
cycles
Days 2 – 21 of subsequent cycles
am
am
am
MK-8353
X
X
X
Pembrolizumab
X
bid=twice daily; qd=once daily.
In Arm A, starting on Day 1 of Cycle 1, MK-8353 will be administered orally approximately 
every 12 hours on each day (bid) of a 21-day treatment cycle.  MK-8353 may be 
administered up to 4 hours before or after the scheduled time for MK-8353 oral intake.
In Arm B, starting on Day 1 of Cycle 1, MK-8353 will be administered orally qd
approximately every 24 hours on each day of a 21-day treatment cycle.  MK-8353 may be 
administered up to 4 hours before or after the scheduled time for MK-8353 oral intake. 
In optional Arm C, starting on Day 1 of Cycle 1, MK-8353 will be administered orally qd
approximately every 24 hours for Days 1 to 7, Days 15 to 21, and Days 29 to 35 of a 42-day 
period (corresponding to 2 cycles of 21 days) until Day 1 of Cycle 3, when this 42-day period 
will start again.
In optional Arm D, starting on Cycle 1, Day 1 and until Day 14 (day prior to Day 1 of 
Cycle 2), and then continuously starting on Day 1 of Cycle 2, MK-8353 will be administered 
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orally qd approximately every 24 hours on each day of a 14- or 21-day treatment cycle.  
MK-8353 may be administered up to 4 hours before or after the scheduled time for MK-8353 
oral intake. 
All capsules comprising a dose should be taken within approximately 15 minutes.
On Day 1 of each 21-day cycle, after potential MK-8353 administration in the morning (for 
Arms A and B, and optional Arm D), pembrolizumab will be administered at a fixed dose of 
200 mg as a 30-minute IV infusion.  For optional Arm C, refer to Table 7.
Sites should make every effort to target the pembrolizumab infusion timing to be as close to 
30 minutes as possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes: -5 min/+10 min).
Except for Cycle 2 of Arms A, B, and C, and Cycle 3 of Arm D (to respect the duration of 
evaluation for DLTs), trial treatment of pembrolizumab may be administered up to 3 days
before or after the scheduled Day 1 of each cycle due to administrative reasons (up to 3 days
after treatment allocation is permitted).
The Pharmacy Manual
contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
In Part 1, treatment allocation will occur centrally using IVRS/IWRS. Subjects enrolled in 
the trial will be allocated to treatment by nonrandom assignment using the IVRS/IWRS. In 
Part 2, treatment allocation will occur by random assignment using IVRS/IWRS if more than 
1 schedule is being evaluated.
Enrollment will alternate between arms, and will also be guided by the occurrence of 
toxicities, following dose escalation and confirmation rules based on the mTPI design.
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy rests with the investigator 
and/or the subject's primary physician.  However, the decision to continue the subject on 
trial therapy or vaccination schedule requires the mutual agreement of the investigator, the 
Sponsor and the subject.
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Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’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 case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids. 
If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.
All concomitant medications taken by the subject from the date of first dose of trial treatment 
through 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
Bisphosphonate or denosumab therapy is allowed as long as it is begun at least 2 weeks prior 
to randomization.  If started after randomization, it will be determined to be consistent with 
symptomatic progression or disease and clinical progression will be declared at that time 
followed by discontinuation of study treatment.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol (with the exception of denosumab as 
noted above in Section 5.5.1)

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab and MK-8353

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case by case basis after consultation with Sponsor.  
The subject must have clear measurable disease outside the radiated field.  
Administration of palliative radiation therapy will be considered clinical 
progression for the purposes of determining PFS.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, rabies, Bacille 
Calmette-Guerin, and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed.  However intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
o
Note:  Inhaled steroids are allowed for management of asthma.
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Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.  Section 5.1.3 describes other medications that are prohibited in this trial.
There are no prohibited therapies during the Posttreatment Follow-up Phase.
5.5.2.1
Prohibited Concomitant Medications for MK-8353
Inhibitors/inducers/substrates of the cytochrome P450 enzymes
CYP3A4 inhibitors/inducers/substrates are listed below.  The subject must not take the 
treatments listed in Table 8 during the trial after the start of the study treatment.  Because this 
list is not comprehensive, the investigator should use his/her medical judgment when a 
subject presents with a medication not on the list or call the Sponsor Clinical Director for 
clarification.
Subjects who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
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Table 8
Medications, Supplements, and Other Substances Prohibited During the Trial
Strong 3A4
Inducersa,d
Strong CYP3A4
Inhibitorsb,d
Moderate CYP3A4 
Inhibitorsb,d
CYP3A4 or CYP2C8
Substrates With 
Narrow Therapeutic 
Rangec,d
Other
carbamazepine
phenobarbital
phenytoin
rifabutin
rifampin
troglitazone
indinavir
nelfinavir
ritonavir
clarithromycin
itraconazole
ketoconazole
nefazodone
atazanavir
saquinavir
telithromycin
alprazolam
cannabis (oral; IV)
amprenavir
aprepitant
diltiazem
erythromycin
fluconazole
fosamprenavir
verapamil
grapefruit juice
star fruit juice
alfentanilc
ergotaminec
diergotaminec
cyclosporine c
fentanylc
pimozidec
quinidinec
sirolimusc
tacrolimusc
astemizolec,e
terfenadinec,e
cisapridec,e
paclitaxelc
repaglinidec
lurasidonec
Any chemotherapy
Any biologic therapy
Any hormonal therapy
Investigational drugs
Radiation therapy 
(except palliative 
radiation to isolated 
lesions after 
discussion with the 
Sponsor)
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% to 80% decrease in 
clearance of sensitive CYP3A substrates when the inhibitors were given at the highest approved dose and the shortest 
dosing interval in clinical evaluations.  Strong inhibitors are defined as causing a >5 fold increase in the plasma AUC 
values or more than 80% decrease in clearance.
c CYP3A4 and CYP2C8 substrates with narrow therapeutic range refers to drugs whose exposure response indicates that 
increases in their exposure levels by the concomitant use of CYP3A4 or CYP2C8 inhibitors may lead to serious safety 
concerns. 
 
For 
specific 
information, 
refer 
to
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/.aspx.
e Not available in the United States, and limited availability in the European Union.
CYP
cytochrome P450; IV
intravenously.
MK-8353 is a competitive and irreversible metabolism-dependent inhibitor of cytochrome 
P450 (CYP) 3A4, a substrate of CYP3A4, and a direct competitive inhibitor of CYP2C8.  As 
such, concomitant use of other drugs that are identified in Table 8 as strong inducers, strong 
or moderate inhibitors, or substrates (characterized with a narrow therapeutic range) of 
CYP3A4 or CYP2C8, is prohibited while the subject is enrolled in this study.
If the use of a CYP3A4 or CYP2C8 medication listed in Table 8 is medically necessary, and 
an alternate therapeutic agent is not available, then the subject must discontinue treatment 
with MK-8353.
MK-8353 may potentially inhibit the activity of other CYP3A4 or CYP2C8 substrates that 
are not identified as prohibited in Table 8.  Caution and close drug monitoring is strongly 
advised when MK-8353 is administered concomitantly with other CYP3A4 or CYP2C8 
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substrates.  Refer to Table 8 for more detailed information regarding adverse effects of 
CYP3A4 substrates with a narrow therapeutic range.
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.
5.5.2.2
Prohibited Concomitant Medications for Pembrolizumab
Glucocorticoids (inhaled steroids as part of a stable regimen for the treatment of 
asthma/chronic obstructive pulmonary disease) are permitted for any purpose other than to 
modulate symptoms from an AE.  The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor.  Additionally, a short limited course of steroids 
may be used to treat medical conditions and/or AEs during the study after Sponsor
notification and consultation.
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contrast dye) is 
permitted.
Section 5.1.3 describes other medications that are prohibited in this trial.
There are no prohibited therapies during the Posttreatment Follow-up Phase.
5.6
Rescue Medications & Supportive Care
Supportive Care Guidelines
5.6.1.1
Supportive Care Guidelines for MK-8353
Medications required to treat AEs or concurrent illnesses other than those prohibited in 
Table 8 are allowed during the study.  These include antiemetics, growth factors, and other 
supportive care medications.  Contraceptive medications as described in Section 5.1 are 
allowed.
Bisphosphonates are allowed for subjects with lytic bone metastases.  Antiemetics, including 
serotonin-receptor antagonists, metoclopramide, prochlorperazine, or thiethylperazine are 
allowed.  Aprepitant is a CYP3A4 inhibitor and should not be used in the study.
Skin rash has been observed in subjects treated with inhibitors of the MAPK pathway and is 
expected in the current study.  It may be representative of an on-target effect of the study 
medication.  Appropriate clinical management of skin rash may be utilized as clinically 
indicated.  An algorithm based on dermatology best practices for other contemporary 
targeted agents that cause skin toxicity is offered below as guidance to manage skin toxicities 
seen in subjects being treated on this protocol.  The algorithm suggests a step-wise approach 
to rash management.

If the rash is NCI CTCAE Grade 1, consider starting with topical steroids 
(eg, betamethasone), topical antibiotics such as clindamycin gel, or no treatment if the 
subject is asymptomatic.  Use of topical steroid cream with higher potency may be 
considered early in subjects with moderate rash on the face.
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
If the rash is NCI CTCAE Grade 2, continue topical steroid or pimecrolimus cream 
and consider adding an oral tetracycline or a similar agent.

If the rash reaches NCI CTCAE Grade 3 or above, dose interruption and/or dose 
reduction, coupled with the addition of topical steroids is recommended.

Pruritus of any grade may be treated with an antihistamine, such as diphenhydramine 
or hydroxyzine hydrochloride.

Xerosis can be treated with classical emollients.

Secondary infection may complicate or worsen skin toxicity.  To reduce the 
likelihood of nasal infection, intranasal mupirocin may be considered.  Infected rash 
may be treated with a short course of an oral tetracycline, such as doxycycline.  Sun 
exposure should be avoided in subjects receiving doxycycline or other tetracycline 
antibiotics.

If there is a clinical diagnosis of impetigo, or an infection with Staphylococcus aureus 
is confirmed, topical mupirocin may be used.  Infected lesions suspected to be 
treatment-resistant should be cultured.  If there is no improvement after 2 weeks of 
treatment, therapy for the rash should be considered ineffective and discontinued.

Additionally, oral antihistamines (nonsedative) may also be considered for the 
treatment of Grade 1 to 3 rashes.  Oral steroids may be considered for Grade 3 rash.
Every medication taken by the subject during the trial and the reason for use must be 
recorded in the electronic case report form (eCRF).  Note that the use of any concomitant 
medication must relate to the documented medical history, prophylaxis, or an AE of the 
subject.
Subjects will be permitted to receive appropriate supportive care measures as deemed 
necessary by the treating physician including but not limited to the items outlined below:

Diarrhea: diarrhea should be treated promptly with appropriate supportive care, 
including loperamide.  Subjects should be instructed to begin taking loperamide at the 
first sign of: 
1) poorly formed or loose stool, 2) occurrence of more bowel 
movements than usual in one day, or 3) unusually high volume of stool.  Loperamide 
should be taken in the following manner: 4 mg at first onset of diarrhea, then 2 mg
after each unformed stool.  The daily dose of loperamide should not exceed 
16 mg/day.  Loperamide should be deferred if blood or mucus is present in the stool 
or if diarrhea is accompanied by fever.  In this setting, appropriate diagnostic 
microbiologic specimens should be obtained to exclude an infectious etiology.  
Subjects should be also advised to drink liberal quantities of clear fluids to help 
prevent dehydration.  Supportive care with steroids (as described in Section 5.6.2) or 
other CYP3A4 inhibitor/inducer /substrate according to institutional guidelines in the 
context of standard of care for diarrhea are permitted.

Nausea/vomiting:
nausea and vomiting should be treated aggressively.  After an 
initial occurrence of Grade 2 or higher nausea or vomiting, strong consideration 
should be given to the administration of prophylactic antiemetic therapy according to 
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standard institutional practice.  Subjects should be strongly encouraged to maintain 
liberal oral fluid intake.

Anemia: transfusions and/or erythropoietin may be utilized as clinically indicated 
per ASCO/American Society of Hematology (ASH) guidelines after the first cycle of 
combination therapy for the treatment of anemia, but should be clearly noted as 
concurrent medications.

Neutropenia:
colony stimulating factors including G-CSF, pegylated G-CSF or 
GM-CSF according to ASCO/ASH guidelines after the first cycle of combination 
therapy.
Colony stimulating factors can be administered for the management of 
neutropenia toxicities after Cycle 1.

Thrombocytopenia: transfusion of platelets may be used per ASCO/ASH guidelines 
if clinically indicated.

Anti-infectives: subjects with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents as considered appropriate by the 
treating investigator for a given infectious condition, according to standard 
institutional practice.
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined along with the dose modification 
guidelines in Section 5.2.2.2, Table 5.  Where appropriate, these guidelines include the use of 
oral or IV treatment with corticosteroids, as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased.  For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care.  The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.
Note:  If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the investigator does not need to follow the treatment guidance.  Refer to 
Table 5 in Section 5.2.2.2 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
5.7
Diet/Activity/Other Considerations
Diet
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-8353 and for the entire duration of the study.  Consumption of CYP3A4 
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inhibitors, such as grapefruit juice, may significantly increase the levels of MK-8353 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-8353. A 
partial list of CYP3A inhibitors is provided in Section 5.5.2.1.
Contraception
MK-8353 and/or pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, 
it is not known if MK-8353 and/or pembrolizumab have transient adverse effects on the 
composition of sperm.
For this trial, male subjects will be considered to be of nonreproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of nonreproductive potential if they are either:
(1) Postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high FSH level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy.  In the absence of 12 months of 
amenorrhea, a single FSH measurement is insufficient.);
OR
(2) Have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy, or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
OR
(3) Has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving MK-8353 and/or pembrolizumab and 
for 120 days after the last dose.  Subjects must comply with one of the following:
(1) Practice abstinence† from heterosexual activity;
OR
(2) Use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

Intrauterine device

Vasectomy of a female subject’s male partner

Contraceptive rod implanted into the skin
Combination method (requires use of 2 of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)
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
Cervical cap with spermicide (nulliparous women only)

Contraceptive sponge (nulliparous women only)

Male condom or female condom (cannot be used together)

Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. 
Periodic abstinence (eg, calendar, ovulation, sympto-thermal, postovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study, subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up through 
120 days.  If there is any question that a subject of childbearing potential will not reliably 
comply with the requirements for contraception, that subject should not be entered into the 
study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-8353 and/or 
pembrolizumab, the subject will be immediately discontinued from treatment. The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 7.2.
Use in Nursing Women
It is unknown whether MK-8353 and/or pembrolizumab are excreted in human milk.  
Because many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, subjects who are breastfeeding are not eligible for 
enrollment.
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5.8
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 and Section 7.1.5.4.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue
treatment.
o
The subject interrupts trial medication administration due to treatment-related toxicity for 
more than 14 consecutive days in Cycle 1, or 21 days in ≥Cycle 2.
o
The subject has a medical condition or personal circumstance that, in the opinion of the 
investigator and/or Sponsor, places the subject at unnecessary risk from continued 
administration of study drug.
o
The subject has a confirmed positive serum pregnancy test.
o
The subject presents clinical progression or has confirmed radiological disease 
progression per RECIST 1.1 criteria as assessed by the investigator (exception if the 
Sponsor approves treatment continuation).
o
The subjects present unacceptable adverse experiences as described in Section 5.2.1.5.
o
The subject is noncompliant with trial treatment or procedure requirements.
o
The investigator decides to withdraw the subject from treatment.
o
The subject has completed 35 treatments (approximately 2 years) with pembrolizumab.
After treatment discontinuation, each subject will be followed for 30 days for AE monitoring.  
Subjects will be monitored for SAEs for 90 days after treatment discontinuation, 30 days if 
the subject initiates new anticancer therapy less than 30 days after study treatment 
discontinuation, or the day new anticancer therapy is initiated if between 30 days and 90 days
after study treatment discontinuation.  Subjects with an ongoing AE of Grade >1 at the time 
of treatment discontinuation will be followed until resolution of the AE to Grade 0 to 1, until 
considered stable by the treating physician, or until beginning a new anticancer therapy, 
whichever occurs first.
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Subjects who discontinue treatment for reasons other than confirmed disease progression will 
have posttreatment follow up for disease status until disease progression, initiating a new 
anticancer therapy, withdrawing consent for study participation, or becoming lost to 
follow up.
After confirmed disease progression each subject will be contacted by telephone 
approximately 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.
5.8.1.1
Discontinuation of Trial Treatment After Disease Response
Subjects who attain an investigator-determined confirmed disease response of complete 
response (CR) may discontinue study treatment (MK-8353 and pembrolizumab) after 
receiving at least 2 additional cycles of MK-8353 and pembrolizumab, as applicable, beyond 
the date when the initial response was declared and after a total of at least 8 cycles of 
MK-8353 and pembrolizumab, as applicable. The decision to continue or discontinue study 
treatment after confirmed disease response is at the investigator’s discretion.
After treatment discontinuation, each subject will be followed for 30 days for AE monitoring.  
Subjects will be monitored for SAEs for 90 days after treatment discontinuation, 30 days if 
the subject initiates new anticancer therapy less than 30 days after study treatment 
discontinuation, or the day new anticancer therapy is initiated if between 30 days and 90 days
after study treatment discontinuation.  Subjects with an ongoing AE of Grade >1 at the time 
of treatment discontinuation will be followed until resolution of the AE to Grade 0 to 1, until 
considered stable by the treating physician, or until beginning a new anticancer therapy, 
whichever occurs first.
Subjects will have posttreatment follow up for disease status until disease progression, 
initiating a new anticancer therapy, withdrawing consent for study participation, or becoming 
lost to follow up.
After confirmed disease progression each subject will be contacted by telephone 
approximately 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.
Subjects who discontinue study treatment after confirmed CR may be eligible to be re-treated 
with study treatment at the discretion of the investigator, if all of the following conditions are 
met:

The subject experiences investigator-determined confirmed disease progression;

No other anticancer therapy was administered since the last dose of study treatment;

The subject meets the safety parameters listed in the Inclusion/Exclusion criteria; and

The study is ongoing.
Subjects will resume study treatment in the same Part of the study and at the same dose of 
MK-8353 to which they were initially allocated and at the 200 mg fixed dose of 
pembrolizumab.  The criteria for withdrawal and discontinuation after re-treatment are as 
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outlined in Section 5.8.  Response or progression after re-treatment will not be counted 
toward the secondary and exploratory efficacy endpoints, ORR, or PFS of this study.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 and Section 7.1.5.4 for those procedures to be completed at each specified 
visit.
Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
Other Procedures.
5.9
Subject Replacement Strategy
A subject who discontinues from trial treatment or withdraws from the trial during or after 
Cycle 2 (refer to Section 5.2.1.6 for subject replacement during Cycle 1) will not be replaced.
5.10
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, withdraws 
from the trial or is lost to follow-up (ie, the subject is unable to be contacted by the 
investigator).
5.11
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects
4. Plans to modify or discontinue the development of the study drug
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided to the sites so that appropriate adjustments to subject treatment can be made.
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Grade >1 at the time of treatment discontinuation will be followed until resolution of the AE to Grade 0 to 1, until considered stable by the treating physician, or until 
beginning a new anticancer therapy, whichever occurs first.
11. Baseline radiology scans of chest, abdomen, and pelvis, and all known tumor sites (if evaluable by imaging) must be obtained within 28 days prior to C1D1 and must be 
repeated every 9 weeks (±7 days) from C1D1.  Confirmatory scans to confirm progressive disease should be obtained at least 4 to 5 weeks after the documented response.  
Imaging must be obtained at the End of Treatment Visit at discontinuation unless done within the previous 4 weeks.  Imaging is to be continued if subject discontinues study 
for reason other than progressive disease.
12. After confirmed disease progression, subjects will be contacted by telephone approximately every 12 weeks 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.  Updated survival status may be requested by the Sponsor at any time during the course 
of the study.  Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be 
contacted for their survival status (excluding participants that have a death event previously recorded).
13. Tumor tissue (archival or newly obtained biopsy) will be required at Screening upon signing the informed consent for the study.  This sample will be assessed to collect 
information on the RAS/RAF and pMMR/dMMR (MSI) tumor mutation status and exploratory biomarkers for all subjects enrolled in the study.  Sample can be evaluated 
for mutation by local laboratory testing, or sent to central laboratory for analysis (if cannot be performed by local laboratory).  Tissue will be also sent to central laboratory 
for biomarker analysis and leftover tissue may be saved for FBR if the subject signs the FBR consent.
14. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response.  This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes.  If the sample is collected, 
leftover extracted DNA will be stored for FBR if the subject signs the FBR consent.  If the planned genetic analyses are not approved, but FBR is approved and consent is 
given, this sample will be collected for the purpose of FBR.
15. Whole blood samples should be collected predose at Cycle 1, Cycle 2, Cycle 5, and again at discontinuation.  Leftover specimens will be stored for FBR if the subject 
consents to FBR.
16. Hematology tests include complete blood count with 5 part differential and platelets.  Hematology does not need to be repeated on C1D1 if Screening samples were obtained 
within 3 days of C1D1.
17. Urine dipstick or microscopic urinalysis may be performed according to site SOP.  Urine dipstick includes pH, protein, glucose, leukocyte, esterase, ketones, and nitrite.  
Mandatory microscopic urinalysis will be performed if the dipstick results are abnormal.  Microscopic analysis includes white blood cell count, red blood cell count, 
epithelial cells and casts.
18. Serum Chemistry tests include sodium, potassium, calcium, phosphate, chloride, bicarbonate/CO2 (if performed in region), BUN, creatinine (cystatin C could be evaluated if 
creatinine is abnormal), SGOT (AST), SGPT (ALT), total proteins, total bilirubin (direct bilirubin if abnormal), albumin, alkaline phosphatase, glucose, uric acid, amylase, 
lipase, lactate dehydrogenase (LDH), and γ glutamyltransferase (GGT).  Serum chemistry does not need to be repeated on C1D1 if screening samples were obtained within 
3 days of C1D1. Cystatin C may be conducted by central vendor only if analysis was not available from local study site laboratory.
19. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Furthermore, any subject receiving anticoagulant therapy 
should have coagulation factors monitored closely throughout the trial.
20. For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours prior to the first dose of study treatment.  If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required and must be negative.  Monthly pregnancy testing should be conducted as per local 
regulations where applicable.
21. HIV testing should include HIV Type 1 and Type 2 (eg, HIV 1/ 2 antibody screening test and evaluation of HIV viral load as needed).  Hepatitis testing should include 
HCV, RNA (qualitative), or Hepatitis C antibody, and HBsAg.
22. Samples for thyroid function testing should be collected on Day 1 of Cycle 1 and on Day 1 of Cycle 2.  Following Cycle 2, testing will be performed every other cycle 
(ie, Cycles 1, 2, 4, 6, etc., with a window of +/ 3 days) and at the Posttreatment Safety Follow up Visit.  Analysis of T3 or FT3, T4 or FT4, and TSH will be performed by 
the local study site laboratory (conducted by central vendor only if analysis was not available from local study site laboratory).
23. In Part 1 only, blood for pembrolizumab antidrug antibodies should be collected prior to dosing on Day 1 of Cycles 1, 2, 4, and 8, and every 4 cycles thereafter, and at the 
30 day Posttreatment Safety Follow up Visit.  Please refer to the procedure manual for detailed sampling time points.
24. Optional on treatment tumor biopsy will be performed on Day 15 of Cycle 2 if the informed consent for optional on treatment biopsy sample has been obtained.  Leftover 
tissue may also be saved for FBR if the subject signs the FBR consent.
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25. Procedures for collection of PK samples and precise time points are described in the Procedures Manual.  Cycle 1 Day 1 (Arms A, B, and C) and Cycle 2 Day 1 (Arms A and 
B only) samples for MK 8353 PK testing should be collected prior to dosing, and 1 hour, 2 hours, 4 hours, and 8 hours after drug administration of MK 8353 (+/ 10 
minutes); prior to dosing on Cycle 1 Day 8 (Arms A, B and C); prior to dosing on Cycle 1 Day 15 (Arms A, B, and C); prior to dosing on Cycle 4 Day 1 (Arms A and B); 
and prior to dosing on Cycle 8 Day 1 (Arms A and B).  If the sample day falls on a weekend or a holiday, please consult the Sponsor for alternate sample collection times.
26. Procedures for collection of PK samples and precise time points are described in the Procedures Manual.  Predose (trough) PK samples for pembrolizumab will be collected 
within 24 hours before infusion in Cycles 1, 2, 4, and 8 and every 4 cycles thereafter, 30 days after discontinuation of study drug (or until the subject starts new anticancer 
therapy).  Postdose (peak) PK samples will be drawn within 30 minutes after end of pembrolizumab infusion in Cycles 1 and 8.
AE adverse event; ALT alanine aminotransferase; AST aspartate aminotransferase; BUN blood urea nitrogen; C1D1 Cycle 1 Day 1; CR complete response; CT computed 
tomography; ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; FBR future biomedical research; min minute; PD progressive disease; 
pERK phosphorylated extracellular regulated kinase; PGt pharmacogenetic; PK pharmacokinetic; PR interval between the P wave and the QRS wave; QRS interval from 
onset of the Q wave to end of  the S wave; QT interval from onset of the QRS complex to end of the T wave; QTcF QT interval corrected for heart rate; SAE serious adverse 
event; SGOT serum glutamic oxaloacetic transaminase; SGPT serum glutamic pyruvic transaminase.
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1.
Visits should occur within the prespecified days window (eg, +/ 3 days), except Cycle 3 Day 1, which should occur with a window of +3 days.
2.
Screening procedures to be performed within 28 days prior C1D1, unless otherwise noted.  Informed consent may be obtained more than 28 days prior to C1D1 to allow for 
tumor tissue collection.
3.
Subject Identification Card must be given to subject at the start of study and must be collected when the subject is no longer participating in any portion of the study.
4.
Record medications taken 4 weeks prior to C1D1 and all medications taken up to and including 30 days after the last dose of study drug or the End of Treatment (whichever 
is later).  Refer to inclusion/exclusion criteria for prohibited medications and washout periods.
5.
Must be performed within 3 days prior to Day 1 of each cycle.  Physical examination, ECOG Performance Status, ECG, vital signs must be performed within 3 days prior to 
C1D1.  It is not necessary to repeat C1D1 testing if the Screening testing was performed within 7 days prior to C1D1.  Full physical examination will be performed at the 
Screening Visit and at the Treatment Discontinuation Visit. Directed physical examination will be done as indicated at all other visits.
6.
Perform standard 12 lead ECG reporting ventricular rate, PR and QRS duration, and QT/QTcF intervals prior to any blood collections or other study procedures.
7.
Vital signs include blood pressure, pulse rate, and respiratory rate while sitting; temperature, height (at screening only), and weight.
8.
After Cycle 2, MK 8353 may be dispensed up to 3 days prior to the cycle start to coincide with the physical exam.  In Arm D, MK 8353 will be administered continuously, 
once a day starting on Cycle 1 Day 1 to Day 14, prior to Cycle 2 Day 1.  Study drug may only be dispensed after the treating physician has confirmed the subject will 
continue on to the next cycle.  Each subsequent cycle is 21 days.  Subjects may receive treatment for up to 36 cycles in optional Arm D.
9.
Pembrolizumab will be administered via IV infusion beginning with Cycle 2 Day 1.  Refer to Figure 2 for dosing instructions.  Each cycle is 21 days (except for Cycle 1 of 
optional Arm D, which is a 14 day MK 8353 monotherapy run in cycle).  Subjects may receive treatment for up to 36 cycles in optional Arm D.
10. AEs and SAEs will be recorded from the time of treatment allocation.  All AEs and SAEs that occur after the consent form is signed but before treatment allocation must be 
reported by the investigator if they cause the subject to be excluded from the trial, or are the result of a protocol specified intervention, including but not limited to washout 
or discontinuation of usual therapy or a study procedure.  After treatment discontinuation, each subject will be followed for 30 days for AE monitoring.  Subjects will be 
monitored for SAEs for 90 days after treatment discontinuation, 30 days if the subject initiates new anticancer therapy less than 30 days after study treatment 
discontinuation, or until the day new anticancer therapy is initiated if between 30 days and 90 days after study treatment discontinuation.  Subjects with an ongoing AE of 
Grade >1 at the time of treatment discontinuation will be followed until resolution of the AE to Grade 0 to 1, until considered stable by the treating physician, or until 
beginning a new anticancer therapy, whichever occurs first.
11. Baseline radiology scans of chest, abdomen, and pelvis, and all known tumor sites (if evaluable by imaging) must be obtained within 28 days prior to C1D1 and must be 
repeated every 9 weeks (±7 days) from C1D1.  Confirmatory scans to confirm PD should be obtained at least 4 to 5 weeks after the documented response.  Imaging must be 
obtained at the End of Treatment visit at discontinuation unless done within the previous 4 weeks.  Imaging is to be continued if subject discontinues study for reason other 
than PD.
12. After confirmed disease progression each subject will be contacted by telephone approximately every 12 weeks 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.  Updated survival status may be requested by the Sponsor at any time during the course 
of the study.  Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be 
contacted for their survival status (excluding participants that have a death event previously recorded).
13. Tumor tissue (archival or newly obtained biopsy) will be required at Screening upon signing the informed consent for the study.  This sample will be assessed to collect 
information on the RAS/RAF and pMMR/dMMR (MSI) tumor mutation status and exploratory biomarkers for all subjects enrolled in the study.  Sample can be evaluated 
for mutation by local laboratory testing, or sent to central laboratory for analysis (if cannot be performed by local laboratory). Tissue will be also sent to central laboratory 
for biomarker analysis and leftover tissue may be saved for FBR if the subject signs the FBR consent.
14. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response.  This sample will not be collected at that site if 
there is either a local law or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes.  If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent.  If the planned genetic analyses are not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
15. Whole blood samples should be collected predose at Cycle 2, Cycle 3, Cycle 5, and again at discontinuation.  Leftover specimens will be stored for FBR if the subject 
consents to FBR.
16. Hematology tests include complete blood count with 5 part differential and platelets.  
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17. Urine dipstick or microscopic urinalysis may be performed according to site SOP.  Urine dipstick includes pH, protein, glucose, leukocyte, esterase, ketones, and nitrite.  
Mandatory microscopic urinalysis will be performed if the dipstick results are abnormal.  Microscopic analysis includes white blood cell count, red blood cell count, 
epithelial cells and casts.
18. Serum Chemistry tests include sodium, potassium, calcium, phosphate, chloride, bicarbonate/CO2 (if performed in region), BUN, creatinine (cystatin C could be evaluated if 
creatinine is abnormal), SGOT (AST), SGPT (ALT), total proteins, total bilirubin (direct bilirubin if abnormal), albumin, alkaline phosphatase, glucose, uric acid, amylase, 
lipase, lactate dehydrogenase (LDH), and γ glutamyltransferase (GGT).  . Cystatin C may be conducted by central vendor only if analysis was not available from local study 
site laboratory.
19. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Furthermore, any subject receiving anticoagulant therapy 
should have coagulation factors monitored closely throughout the trial.
20. For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 72 hours prior to the first dose of study treatment.  If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required and must be negative.  Monthly pregnancy testing should be conducted as per local 
regulations where applicable.
21. HIV testing should include HIV Type 1 and Type 2 (eg, HIV 1/ 2 antibody screening test and evaluation of HIV viral load as needed).  Hepatitis testing should include 
HCV, RNA (qualitative), or Hepatitis C antibody, and HBsAg.
22. Samples for thyroid function testing should be collected on Day 1 of Cycle 2 and on Day 1 of Cycle 3.  Following Cycle 3, testing will be performed every other cycle 
(ie, Cycles 2, 3, 5, 7, etc., +/ 3 day window) and at the Posttreatment Safety Follow up Visit.  Analysis of T3 or FT3, T4 or FT4, and TSH will be performed by the local 
study site laboratory (conducted by central vendor only if analysis was not available from local study site laboratory).
23. In Part 1 only, blood for pembrolizumab antidrug antibodies should be collected prior to dosing on Day 1 of Cycles 2, 4, and 8, and every 4 cycles thereafter, and at the 30
day Post treatment Safety Follow up Visit.  Please refer to the procedure manual for detailed sampling time points.
24. Optional on treatment tumor biopsy will be performed on Day 15 of Cycle 3 if the informed consent for optional on treatment biopsy sample has been obtained.  Leftover 
tissue may also be saved for future biomedical research if the subject signs the FBR consent.
25. Procedures for collection of PK samples and precise time points are described in the Procedures Manual.  Cycle 2 Day 1 and Cycle 3 Day 1 samples for MK 8353 PK testing 
should be collected prior to dosing, and 1 hour, 2 hours, 4 hours, and 8 hours after drug administration of MK 8353 (+/ 10 minutes); prior to dosing on Cycle 2 Day 8; prior 
to dosing on Cycle 2 Day 15; prior to dosing on Cycle 5 Day 1; and prior to dosing on Cycle 9 Day 1.  If the sample day falls on a weekend or a holiday, please consult the 
Sponsor for alternate sample collection times.
26. Procedures for collection of PK samples and precise time points are described in the Procedures Manual.  For Part 1 only, predose (trough) PK samples for pembrolizumab 
will be collected within 24 hours before infusion in Cycles 2, 5, and 9 and every 4 cycles thereafter, 30 days after discontinuation of study drug (or until the subject starts 
new anticancer therapy).  Postdose (peak) PK samples will be drawn within 30 minutes after end of pembrolizumab infusion in Cycles 2 and 9.
AE adverse event; ALT alanine aminotransferase; AST aspartate aminotransferase; BUN blood urea nitrogen; C1D1 Cycle 1 Day 1; C 
complete response; 
CT computed tomography; ECG electrocardiogram; ECOG Eastern Cooperative Oncology Group; FBR future biomedical research; min minute; PD progressive 
disease; pERK phosphorylated extracellular regulated kinase; PGt pharmacogenetic; PK pharmacokinetic; PR interval between the P wave and the QRS wave; 
QRS interval from onset of the Q wave to end of  the S wave; QT interval from onset of the QRS complex to end of the T wave; QTcF QT interval corrected for heart rate; 
SAE serious adverse event; SGOT serum glutamic oxaloacetic transaminase; SGPT serum glutamic pyruvic transaminase.
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7
TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research. If there are changes to the subject’s status during the 
trial (eg, health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
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7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial as per Sections 5.1.2 and 5.1.3.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
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 previous 10 years
that are considered to be clinically significant by the Investigator.  Details regarding the 
disease for which the subject has enrolled in the trial will be recorded separately and should 
not be listed in medical history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1
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 subject 
within 4 weeks days before Day 1, Cycle 1 of the study.
7.1.1.5.2
Concomitant Medications
The investigator or qualified designee will record medications, if any, taken by the subject 
during the trial from start of study treatment through the Safety Follow-up Visit, 30 days
after the last dose of study drug.  After the Safety Follow-up Visit, record all medications 
related to reportable SAEs and ECIs as defined in Section 7.2.
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7.1.1.6
Disease Details and Treatments
7.1.1.6.1
Oncology Disease Details
Prior and current details regarding the disease for which the subject has been enrolled in the 
trial will be obtained by the investigator or qualified designee.
7.1.1.6.2
Prior Oncology Treatment History
The investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, radiation, radiosurgeries, and surgeries regardless of time prior to first 
dose of study treatment.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
7.1.1.8
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.  Although subjects are 
being allocated, and not randomized, to treatment in Part 1, this unique number is termed a 
randomization number throughout the protocol for operational purposes.  Allocation of 
subjects will be managed by the Sponsor through an IVRS/IWRS. If more than 1 schedule is
to be evaluated in Part 2, treatment allocation will occur by random assignment using 
IVRS/IWRS. Once a treatment/randomization number is assigned to a subject, it can never 
be re-assigned to another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.9
Trial Compliance
Interruptions from the protocol specified treatment(s) for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
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Clinical Procedures/Assessments
7.1.2.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period.  Clinically significant findings from the screening exam should be 
recorded as medical history.
Height will be measured at Screening only.
Weight will be measured at the time of full physical examination as outlined in the Trial 
Flow Chart (Section 6.0).
Full physical examination will be performed at the Screening Visit and at the Treatment 
Discontinuation Visit. Directed physical examination will be done as indicated at all other 
visits as outlined in the Trial Flow Chart (Section 6.0).
After the first dose of study treatment, new clinically significant abnormal findings should be 
recorded as AEs.
7.1.2.2
Vital Signs
The investigator or qualified designee will measure vital signs at the time points outlined in 
the Trial Flow Chart (Section 6.0).  Vital signs should include body temperature, pulse, 
respiratory rate, and blood pressure.
7.1.2.3
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess the ECOG performance status of the 
subject (Appendix 12.6) at the time points outlined in the Trial Flow Chart (Section 6.0).
7.1.2.4
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be performed by the investigator or qualified 
designee at screening as outlined in the Trial Flow Chart (Section 6.0).
7.1.2.5
Administration of MK-8353 and Pembrolizumab
MK-8353 will be taken orally by the subject at the dose and schedule allocated through an 
IVRS/IWRS for the currently enrolling cohort(s).
Pembrolizumab will be administered at the fixed dose of 200 mg by IV infusion on Day 1 of 
each 21-day cycle (beginning with Cycle 2 for optional Arm D).  The Pharmacy Manual
contains specific instructions for the preparation and administration of the infusion solution.
Designated site personnel will be responsible for preparing and administering 
pembrolizumab.  They will also be required to record limited information during each 
infusion (eg, infusion date/time, lot number and expiry date for product administered, total 
dose/volume administered, etc.).  Refer to Pharmacy Manual for further details.
Subjects may receive study treatment (MK-8353 and pembrolizumab) for up to 35 cycles in 
Arms A, B, and C, and up to 36 cycles in Arm D.
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7.1.2.6
Disease Assessments
Response will be based on RECIST 1.1 (Appendix 12.4) as assessed by investigator/local 
radiology review. Images used for tumor measurements will be sent to a central imaging 
vendor for potential blinded, central review.
The process for image collection and 
transmission to the central imaging vendor can be found in the SIM.
Immunotherapeutic agents, such as pembrolizumab, may produce antitumor effects by 
potentiating an endogenous cancer-specific immune response.  The response patterns seen 
with such an approach may extend beyond the usual time course of responses seen with 
typical cytotoxic agents, and can manifest a clinical response after an initial increase in tumor
burden or even the appearance of new lesions.  Subjects could, at the discretion of the 
investigator, continue in the trial until the initial assessment of progressive disease is 
confirmed at least 4 weeks later (refer to Section 4.2.3.1).
The details on the irRECIST 
assessment can be found in Appendix 12.5.
Initial imaging (eg, CT scan, MRI, positron emission tomography) should be performed 
within 28 days prior to the first dose of study treatment, and should be repeated 9 weeks after 
the first dose and every 9 weeks until confirmed progressive disease, initiating a new 
anticancer therapy, withdrawing consent for study participation, or becoming lost to 
follow up, whichever occurs first.
The same imaging technique should be used at each time point and the schedule of disease 
assessment should not be adjusted for delays, if any, in cycle starts.
7.1.2.7
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as outlined in the Trial Flow Chart (Section 6.0), and more frequently, if 
clinically indicated.  Adverse events will be graded according to the NCI CTCAE,
version 4.0 or later (Appendix 12.7).  Toxicities will be characterized in terms of seriousness, 
causality, toxicity grade, and action taken with regard to study treatment(s).
Because this is a dose escalation trial to establish the RP2D of MK-8353 when used in 
combination with pembrolizumab, each dose escalation will be based on the safety and 
tolerability experienced by subjects at each dose level.  The safety and tolerability for the 
DLT evaluation period in each cohort will be reviewed prior to the start of the next cohort in 
each treatment arm.  The Sponsor and the Principal Investigators will review the safety and 
tolerability in each treatment arm independently and the appropriateness of dose escalation, 
when each cohort is completed and the next cohort is opened for enrollment.  The frequency 
of these communications will depend on enrollment at each dose level, as well as any 
potential new information regarding a safety concern in this trial or other relevant trials.
As this is a Phase 1 trial, there is no plan for an external safety reviewer.  Data from 
individual subjects will be closely followed on an ongoing basis by the applicable Principal 
Investigator and the Sponsor.
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Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below in Table 9. The total amount of blood/tissue to be drawn/collected over the 
course of the trial (from pretrial and posttrial cycles), including approximate blood/tissue 
volumes drawn/collected by cycle and by sample type per subject can be found in the 
Procedures Manual and for the FBR samples, in Section 12.2.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 9.
Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Red blood cell 
(RBC) count
Total protein
Blood
Prothrombin time 
(PT)/International 
normalized ratio (INR)4
Hemoglobin
Albumin
Glucose
Activated partial 
thromboplastin time (aPTT)4
Hematocrit
Alanine aminotransferase (ALT)
Protein
Thyroid function testing (T4, 
T3, TSH)5
White blood cell 
(WBC) count 
(total and 
differential)
Aspartate aminotransferase (AST)
Specific gravity
Serum β-human chorionic 
gonadotropin (β-hCG)3
Absolute 
neutrophil count 
(ANC)
Alkaline phosphatase
Microscopic exam, if 
abnormal results are 
noted
Follicle stimulating hormone 
(FSH)6
Platelet count
Lactate dehydrogenase (LDH)
Urine pregnancy test3
Human immunodeficiency 
virus (HIV; HIV Type 1 and 
Type 2)
Gamma glutamyl transferase 
(GGT)
Hepatitis (HCV, RNA 
[qualitative], or Hepatitis C 
antibody, and HBsAg)
Total bilirubin
Direct bilirubin, if total bilirubin is 
above the upper limit of normal
Bicarbonate/Carbon dioxide 
(CO2)1
Calcium
Chloride
Phosphorus
Potassium
Sodium
Glucose
Creatinine
Cystatin C
Blood urea nitrogen (BUN)/Urea2
Uric acid
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Hematology
Chemistry
Urinalysis
Other
Amylase
Lipase
1. If bicarbonate/CO2 testing is not done as part of standard of care in your region then these tests do not need to 
be performed.
2. Blood urea nitrogen is preferred; if not available urea may be tested.
3. Women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is positive or cannot 
be confirmed as negative, a serum pregnancy test is required.
4. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the 
trial.
5. Total T3 is preferred; if not available free T3 may be tested.  Total T4 is preferred; if not available free T4 may 
be tested.
6. In women <45 years of age, a high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormone replacement therapy.  In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
ALT alanine aminotransferase; ANC absolute neutrophil count; aPTT activated partial thromboplastin time; AST aspartate 
aminotransferase; β hCG serum β human chorionic gonadotropin; BUN blood urea nitrogen; CO2 carbon dioxide; 
FSH follicle stimulating hormone; GGT gamma glutamyl transferase; HBsAg hepatitis B surface antigen; HCV hepatitis C 
virus; HIV human immunodeficiency virus; INR International Normalized Ratio; LDH lactate dehydrogenase; 
PD progressive disease; pERK phosphorylated extracellular regulated kinase; PGt pharmacogenetic; PT prothrombin time; 
RBC red blood cell; RNA ribonucleic acid; T3 triiodothyronine; T4 thyroxine; TSH thyroid stimulating hormone.
Laboratory tests will be performed at the time points outlined in the Trial Flow Chart 
(Section 6.0).  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of MK-8353.
7.1.3.2
Other Laboratory Evaluations
Samples for antidrug antibody testing (pembrolizumab) and blood for biomarker analyses 
will be collected at the time points outlined in the Trial Flow Chart (Section 6.0).  Collection, 
storage and shipment instructions will be provided in the Procedures Manual.  Blood samples 
collected for antidrug antibody may only be stored at this time.  Further analyses may be 
performed if required. If ongoing antidrug antibody sampling is deemed to be unnecessary 
by the Sponsor, it may be reduced or discontinued.
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.3.1
Blood Collection for PK Assessment for MK-8353
Samples for PK evaluations for MK-8353 will be collected at the time points outlined in 
Section 6.0
Trial Flow Chart.  Sample collection, storage and shipment instructions for 
blood samples will be provided in the Procedures Manual. Blood samples collected for PK 
may only be stored at this time. Further analyses may be performed if required. If ongoing 
PK sampling is deemed to be unnecessary by the Sponsor, it may be reduced or discontinued.
7.1.3.3.2
Blood Collection for PK Assessment for Pembrolizumab
Samples for PK evaluations for pembrolizumab will be collected in Part 1 only at the 
timepoints outlined in Section 6.0 
Trial Flow Chart.  Sample collection, storage and 
shipment instructions for blood samples will be provided in the Procedures Manual. Blood 
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samples collected for PK may only be stored at this time. 
Further analyses may be 
performed if required. If ongoing PK sampling is deemed to be unnecessary by the Sponsor, 
it may be reduced or discontinued.
7.1.3.3.3
Blood Collection for RNA, Plasma, and Serum
Blood samples will be collected at the time points outlined in Section 6.0
Trial Flow Chart.
Sample collection, storage, and shipment instructions for blood samples will be provided in 
the Procedures Manual.  Any leftover samples will be stored for FBR if the subject signs the 
FBR consent.
7.1.3.4
Tumor Tissue Collection
At screening subjects must provide a tumor sample (archival or newly obtained) for 
biomarker analysis. Analysis will include tumor’s RAS/RAF mutation and pMMR status.
Subjects may also agree to provide an optional on-treatment biopsy, for biomarker analysis 
as outlined in the Trial Flow Chart (Section 6.0).
Sample collection, storage, and shipment instructions for tumor samples will be provided in 
the Procedures Manual.  Archival samples are not required to be submitted within the 
screening period but must be obtained by the site at the earliest convenient time.
Any leftover samples will be stored for FBR if the subject signs the FBR consent.
7.1.3.5
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.
7.1.3.6
Future Biomedical Research Samples
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover RNA from blood for RNA analysis

Leftover plasma from blood for plasma biomarker analysis

Leftover serum from blood for serum biomarker analysis

Leftover main study tumor
See Appendix 12.2 regarding collection and management of specimens.
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
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adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
7.1.4.1.1
Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research.  Subjects may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com).  Subsequently, 
the subject's consent for Future Biomedical Research will be withdrawn.  A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the subject of completion of withdrawal.  Any analyses in progress at 
the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research trial data and results.  
No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
7.1.4.1.2
Lost to Follow up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject 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 
subject at each missed visit (eg, phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.
Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the prespecified data handling and analysis guidelines.
7.1.4.2
Subject Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Domiciling
Subjects will report to the clinical research unit prior to dosing on Day 1 of each 21-day 
cycle to allow for completion of all pretreatment procedures as outlined in the Trial Flow 
Chart (Section 6.0). On Day 1 of Cycles 1 and 2 (for Arm D, on Day 1 of Cycles 2 and 3), 
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the subject will remain in the unit for at least 8 hours after the start of the MK-8353 
administration and pembrolizumab infusion for PK blood sampling.
7.1.4.4
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening Period
During the screening period, potential subjects will be evaluated to determine whether or not 
they fulfill the entry requirements as detailed in Section 5.1.
Written informed consent must be obtained prior to performing any protocol-specific 
procedures.  Results of tests performed prior to the subject 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, including tumor imaging, are to be completed within 28 days prior to 
the first dose of study treatment except for screening laboratory tests which are to be 
performed within 3 days prior to the first dose of study treatment.
Screening procedures may be repeated after consultation with the Sponsor.
7.1.5.2
Treatment Period Visits
Subjects who are eligible for study participation will be allocated by nonrandom assignment 
to a dose cohort and assigned to receive a specified dose of MK-8353 on a specific schedule 
by the Sponsor.  Subjects will receive a 200 mg fixed dose of pembrolizumab in addition to 
their assigned dose of MK-8353.  MK-8353 and pembrolizumab treatment will be 
administered on Day 1 of each 21-day cycle (except in optional Arm C and Cycle 1 of
optional Arm D), as outlined in Section 5.2.
During Cycle 1 (Cycle 2 for optional Arm D), study visits will occur on Days 1, 8, and 15.  
From Cycles 2 to 4 inclusively (Cycles 3 to 5 inclusively for optional Arm D), study visits 
will occur on Days 1 and 15.  Starting at Cycle 5 (Cycle 6ˆfor optional Arm D), subjects will 
be required to attend study visits on Day 1.  The investigator may require more frequent 
visits from subjects, if clinically indicated.  Tumor imaging and response assessment will 
occur every 9 weeks after the first dose of study treatment (first dose of pembrolizumab in 
optional Arm D).
Study treatment (MK-8353 and pembrolizumab) may be administered for up to 35 cycles (up 
to 36 cycles for optional Arm D).
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7.1.5.3
Discontinued Subjects Continuing to be Monitored in the Trial
When a subject discontinues trial treatment in treatment period and/or retreatment period,
procedures for discontinuation will be conducted.
7.1.5.4
Posttreatment Period
When subjects discontinue study treatment, the assessments at the End-of-Treatment Visit 
should be completed.
Furthermore, subjects will be required to return to the clinic approximately 30 days after the 
last dose of study treatment for the Posttreatment Safety Follow-up Visit.  If a subject 
initiates a new anticancer therapy within 30 days after the last dose of study treatment, the 
Posttreatment Safety Follow-up Visit should occur before the first dose of the new therapy.
After treatment discontinuation, each subject will be followed for 30 days for AE monitoring.  
Subjects will be monitored for SAEs for 90 days after treatment discontinuation, 30 days if 
the subject initiates new anticancer therapy less than 30 days after study treatment 
discontinuation, or until the day new anticancer therapy is initiated if between 30 days and 
90 days after study treatment discontinuation.  Subjects with an ongoing AE of Grade >1 at 
the time of treatment discontinuation will be followed until resolution of the AE to Grade 0
to 1, until considered stable by the treating physician, or until beginning a new anticancer 
therapy, whichever occurs first.
Subjects who discontinue treatment for reasons other than confirmed disease progression will 
have posttreatment follow up for disease status until disease progression, initiating a new 
anticancer therapy, withdrawing consent for study participation, or becoming lost to 
follow up.
After confirmed disease progression, each subject will be contacted by telephone 
approximately 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 as shown in Section 6.0
Trial Flow Chart.
7.1.5.5
Survival Status
To ensure current and complete survival data are available, updated survival status may be 
requested during the course of the study by the Sponsor. Upon Sponsor notification, all 
subjects who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding subjects 
who have a previously recorded death event in the collection tool).
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (ie, any clinically significant adverse change in 
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frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For this trial, an overdose of MK-8353 will be defined as any dose above what is indicated 
for the specific treatment arms:
Arm A: 350 mg twice a day
Arm B: 1200 mg once a day
Optional Arms C and D: 600 mg once a day
An 800 mg bid dose has been administered every day in MK-8353 Protocol 001 in 6 subjects 
as a single agent (refer to Section 4.1.2.1). 
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An overdose of pembrolizumab will be defined as any dose of 1000 mg or greater (≥5 times 
the indicated dose).
No specific information is available on the treatment of overdose of MK-8353 or 
pembrolizumab. In the event of overdose, the subject should be observed closely for signs of 
toxicity. Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of trial treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator.  All reported pregnancies must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 
24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause other than progression 
of the cancer under study (reference Section 7.2.3.3 for additional details), whether or not 
related to the Sponsor's product, must be reported within 24 hours to the Sponsor either by 
electronic media or paper. Electronic reporting procedures can be found in the EDC data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
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7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described
in Section 7.2.3 to the Sponsor, unless there is evidence suggesting a causal relationship 
between the drug and the event.  Any such event will be submitted to the Sponsor within 
24 hours either by electronic or paper media.  Specifically, the suspected/actual events 
covered in this exception include any event that is disease progression of the cancer under 
study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is
not progression of the cancer under study will be forwarded to global safety as a SAE within
24 hours of determination that the event is not progression of the cancer under study.
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Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (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 adverse experience to the single agent.
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Table 10
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre existing condition that has not 
worsened is not a serious adverse event.  A pre existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product?
Is the time of onset of the AE compatible with a drug induced effect (applies to trials with investigational medicinal product)?
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
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor’s product; or (3) the trial is a single dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject 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 trial is a single dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED 
BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology or 
toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
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
Subject 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 subject with overdose without an 
associated AE.)
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, ie, per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and key 
secondary analyses of the study.  Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
If, after the study has begun, changes are made to primary and/or key 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 prior to the conduct of any analyses, 
will be documented in the sSAP and referenced in the clinical study report (CSR) for the 
study.  Post hoc exploratory analyses will be clearly identified in the CSR.
8.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial.  Full details are 
in the Statistical Analysis Plan, Section 8.2 to Section 8.12.
Study Design Overview
Phase 1b Study of MK-8353 + Pembrolizumab in Subjects with Advanced 
Malignancies.  The study applies an mTPI design for dose escalation and 
confirmation of the MTD, followed by a cohort expansion.
Analysis Populations
Safety: All-Subjects-as-Treated (ASaT)
Efficacy: Full Analysis Set (FAS)
Primary Endpoint(s)
Proportion of subjects experiencing at least one DLT in Cycle 1 (Day 1 to 
21) for Arms A, B, and C, or Cycles 1 and 2 (35 days) for optional Arm D
Key Secondary Endpoints
ORR based on RECIST 1.1 as assessed by the investigator
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
ORR will be estimated using an exact method based on the binomial
distribution (Clopper-Pearson interval).
Treatment Assignment
Subjects will be allocated by nonrandom assignment to different dose 
levels of MK-8353 coadministered with pembrolizumab centrally through 
IVRS/IWRS; the study is open-label.
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentages, means, standard deviations, etc.) 
will be provided for the safety endpoints as appropriate.  The 
pool-adjacent-violators-algorithm [61] will be used to estimate the DLT 
rates across doses.  The estimates of the DLT rates among subjects treated 
at the MTD of MK-8353 and the 80% Bayesian credible intervals for the 
estimates will be provided.
Interim Analyses
There is no formal hypothesis testing at the interim analyses. An interim 
futility check will be performed for Part 2.
Multiplicity
No multiplicity adjustment is planned in this Phase 1b trial.
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Sample Size and Power
The study is designed to assess the safety and tolerability of MK-8353 
when administered in combination with pembrolizumab in subjects with 
advanced solid tumors with an expansion to subjects with ≥second line
advanced non-MSI-H/dMMR CRC.  The study is not powered to address a 
statistical hypothesis.
For Part 1, up to approximately 142 evaluable subjects (up to 14 per dose 
level) will be included.  The final sample size for Part 1 will depend on the 
number of subjects experiencing DLTs at each dose level and may be 
increased if the RP2D is not reached and additional dose levels are 
required.
For Part 2, the planned sample size is up to approximately 40 subjects.
8.2
Responsibility for Analyses/In-House Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label (ie, subjects, investigators, and Sponsor personnel will be aware of 
subject treatment assignment after each subject is enrolled and treatment is assigned).  
Allocation to treatment will not be randomized.
8.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.0.
8.4
Analysis Endpoints
Efficacy/Immunogenicity/Pharmacokinetic Endpoints
Efficacy endpoints are secondary and exploratory endpoints in this study (refer to
Sections 3.2 and 3.3).
The following efficacy endpoints are derived from the RECIST 1.1 criteria:
Objective Response Rate:  defined as the proportion of subjects who have achieved 
confirmed CR or PR.
Duration of Response: defined for subjects who achieved a tumor response (CR or PR) as 
the time between the date of the first documented tumor response and the subsequent date of 
the objectively documented disease progression or death, whichever occurs first.  Response 
duration for subjects who have not progressed or died at the time of analysis will be censored 
at the date of their last tumor assessment.
Disease Control Rate: defined as the proportion of subjects who have achieved CR, PR, or 
SD.
Progression-free Survival: defined as the time from the first dose of study medication to the 
first objective documentation of tumor progression or death due to any cause.  Detailed 
censoring rules will be described in the sSAP.
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Overall survival: defined as the time from the first dose of study medication to death due to 
any cause.  Subjects who did not die will be censored on the date of their last study 
assessment or contact.
PK endpoints include serum concentrations of MK-8353 and pembrolizumab and derived PK 
parameters.
Safety Endpoints
The primary safety endpoint is the rate of DLTs.  Safety will be monitored by cumulative 
data reviews throughout the trial.  The toxicities experienced by subjects who have received 
study treatment, including AEs and SAEs and their grades will be summarized.  Other safety 
measures evaluated in all parts of the study include laboratory safety assessments, ECGs, 
vital signs, and physical examinations.
A description of safety measures is provided in Section 7.
8.5
Analysis Populations
Safety Analysis Population
The ASaT population will be used for the analysis of safety data in this study.  The ASaT 
population consists of all subjects who received at least 1 dose of study treatment.  In case of 
treatment administration errors, subjects will be analyzed according to the treatment they 
actually received.  For DLT evaluation, ASaT subjects that were observed for safety for 
21 days after the first dose of assigned treatment (or 35 days for subjects in optional Arm D) 
or experienced a DLT prior to 21 days after the first dose of assigned treatment (or prior to 
35 days for subjects in optional Arm D) will be included. The replacement subjects will also 
be considered evaluable if the above specified criteria are met.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Efficacy Analysis Populations
The FAS population will be used for the analysis of efficacy data in this study.  It consists of 
all subjects with a baseline scan with measurable disease by investigator assessment who 
were administered a dose of the study medicine.
8.6
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.
PK will be analyzed and reported separately.
Statistical Methods for Efficacy Analyses
Objective response rate will be estimated using an exact method based on the binomial 
distribution (Clopper-Pearson interval).
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Statistical Methods for Safety Analyses
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.
Adverse events will be summarized as counts and frequencies for each dose level.  
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
Dose-limiting toxicities will be listed, and further summarized by dose level.  The pool
adjacent-violators-algorithm [1], which forces the DLT rate estimates to be non-decreasing 
with increasing dose levels and pools adjacent violators for weighted estimates by sample 
size, will be used to estimate the DLT rates across doses.  The estimates of the DLT rates 
among subjects treated at the MTD and the 80% Bayesian credible intervals based on a prior 
distribution of Beta (1,1) for the estimates will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior
and concomitant therapies will be summarized.
8.7
Interim Analyses
In this study there will be no formal hypothesis testing, although an interim analysis may be 
conducted to enable future trial planning at the Sponsor’s discretion and data will be 
examined on a continuous basis to allow for dose escalation and confirmation decisions.
An interim futility check will be performed for Part 2.  If there are no responders among 
approximately the first 18 evaluable subjects that have at least 1 postbaseline scan 
assessment, the trial may be stopped early for futility.  If the true response rate is 10%, there 
is an 85% chance to observe at least one responder among 18 subjects.
8.8
Multiplicity
There will be no multiplicity control in this study.
8.9
Sample Size and Power Calculations
Part 1 dose escalation and confirmation is expected to enroll up to approximately 
142 subjects (up to 14 subjects per dose level).  The final sample size for Part 1 will depend 
on the number of subjects experiencing DLTs at each dose level, and may be increased if the 
RP2D is not reached and additional dose levels are required.
For Part 2, the planned sample size is up to approximately 40 subjects.  The primary efficacy 
endpoint will be the ORR based on the investigator assessment per RECIST 1.1.  Table 11
shows the ORR estimate and 95% CI under various scenarios.  Of note, any ≥second line
advanced non-MSI-H/dMMR CRC subjects enrolled in Part 1 and treated at the dose level
that is selected for Part 2 will also be included for this efficacy analysis.
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Table 11
Estimate and 95% CI of ORR Under Various Scenarios
Sample Size
Number of Responses 
(PR/CR)
Observed ORR
95% Confidence Interval
of ORR
40
4
10%
(2.8%,  23.7%)
5
12.5%
(4.2%,  26.8%)
6
15%
(5.7%,  29.8%)
7
17.5%
(7.3%,  32.8%)
8
20%
(9.1%,  35.7%)
9
22.5%
(10.8%,  38.4%)
10
25%
(12.7%,  41.2%)
54
4
7.4%
(2.1%,   17.9%)
5
9.3%
(3.1%,     20.3%)
6
11.1%
(4.2%,   22.6%)
7
13.0%
(5.4%,   24.9%)
8
14.8%
(6.6%,    27.1%)
9
16.7%
(7.9%,    29.3%)
10
18.5%
(9.3%,   31.4%)
It is assumed that: 1) 40 ≥second line advanced non-MSI-H/dMMR CRC subjects are enrolled in Part 2
(expansion) and are also evaluable for efficacy analysis; 2) the number of ≥second line advanced 
non-MSI-H/dMMR CRC subjects enrolled in Part 1 and treated at the dose level that is selected for Part 2 could 
be between 0 and 14. 
CR=complete response; CRC=colorectal; ORR=overall response rate; PR=partial response.
8.10
Subgroup Analyses and Effect of Baseline Factors
Subgroup analyses of efficacy endpoints will be conducted as needed (eg, RAS/RAF 
mutation status [mutant versus wild-type], Mismatch Repair status [pMMR versus dMMR]
and tumor location [left versus right]).
8.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial.  Any deviation 
from protocol-directed administration will be reported.
8.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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9
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 12. Clinical 
supplies will be packaged to support enrollment and replacement subjects as required.  When 
a replacement subject is required, the Sponsor or designee needs to be contacted prior to 
dosing the replacement supplies.
Table 12
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional Information
Pembrolizumab (100 mg/4 mL)
Injection
Provided centrally by the Sponsor
MK-8353
Capsules
Provided centrally by the Sponsor
All supplies indicated in Table 12 will be provided centrally by the Sponsor.
Any commercially available product not included in Table 12 will be provided by the trial 
site, subsidiary or designee.  Every attempt should be made to source these supplies from a 
single lot/batch number.  The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Sites will receive open-label bottles of MK-8353 and open-label kits of pembrolizumab.
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
CCI
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Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.  Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
9.6
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10
ADMINISTRATIVE AND REGULATORY DETAILS
10.1
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
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Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.2
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 
21 CFR Part 54, to provide his/her financial interests in and/or arrangements with the 
Sponsor to allow for the submission of complete and accurate certification and disclosure 
statements.  The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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10.3
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
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when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (eg, availability of the Protocol/CSR CI 
during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
10.4
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
10.5
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
10.6
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
10.7
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
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and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11
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Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic factors 
in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
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Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. 
Prognostic effect of epithelial and stromal lymphocyte infiltration in non-small cell 
lung cancer. Clin Cancer Res 2008;14(16):5220-7.
[24]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et 
al. Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal 
cancer patients. BMC Immunol 2010;11:19.
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Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18(1B):689-94.
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Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et 
al. Type, density, and location of immune cells within human colorectal tumors 
predict clinical outcome. Science 2006;313(5795):1960-4.
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Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.
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Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol. 
2009 Sep;10(9):840-1.
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Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol 
Immunother 2008;57(1):97-106.
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[30]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
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Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, 
et al. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and 
metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 
2009;58(3):449-59.
[32]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[33]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. J Exp Med. 2000 Mar 
6;191(5):891-8.
[34]
Liu L, Mayes PA, Eastman S, Shi H, Yadavilli S, Zhang T, et al. The BRAF and 
MEK Inhibitors Dabrafenib and Trametinib: Effects on Immune Function and in 
Combination with Immunomodulatory Antibodies Targeting PD-1, PD-L1, and 
CTLA-4. Clin Cancer Res. 2015 Apr 1;21(7):1639-51.
[35]
Ebert PJ, Cheung J, Yang Y, McNamara E, Hong R, Moskalenko M, et al. MAP 
Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with 
PD-L1 Checkpoint Blockade. Immunity. 2016 Mar 15;44(3):609-21.
[36]
Frederick DT, Piris A, Cogdill AP, Cooper ZA, Lezcano C, Ferrone CR, et al. 
BRAF inhibition is associated with enhanced melanoma antigen expression and a 
more favorable tumor microenvironment in patients with metastatic melanoma. 
Clin Cancer Res. 2013 Mar 1;19(5):1225-31.
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Bendell JC, Kim TW, Goh BC, Wallin J, Oh DY, Han SW, et al. Clinical activity 
and safety of cobimetinib (cobi) and atezolizumab in colorectal cancer (CRC) 
[abstract]. J Clin Oncol. 2016; (34 suppl). Abstract no. 3502.
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Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic 
value of tumour-infiltrating lymphocytes (TILs) in colorectal cancer. J Pathol 
1997;182(3):318-24.
[39]
Dudley JC, Lin MT, Le DT, Eshleman JR. Microsatellite Instability as a Biomarker 
for PD-1 Blockade. Clin Cancer Res. 2016 Feb 15;22(4):813-20.
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Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-
1. N Engl J Med 2008;358(25):2698-703.
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Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
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Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are associated 
with outcome in neoadjuvant chemotherapy-treated ovarian carcinoma. Cancer 
Immunol Immunother 2010;59(6):909-19.
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Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell 
exhaustion: an update on implications for chronic infections and tumor evasion. 
Cancer Immunol Immunother. 2007 May;56(5):739-45.
[45]
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-
L1 on tumor cells in the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002;99(19):12293-
7.
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Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic significance of 
tumor infiltrating lymphocytes in human melanoma. Cancer Immun. 2009 Apr 
2;9:3.
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Korman A, Chen B, Wang C, Wu L, Cardarelli P, Selby M. Activity of anti-PD-1 
in murine tumor models: role of "host" PD-L1 and synergistic effect of anti-PD-1 
and anti-CTLA-4 [Abstract]. J Immunol 2007;178:48.37.
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Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes 
correlates with poor prognosis in renal cell carcinoma. BJU Int 2011;107(9):1500-
6.
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Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival in 
patients with colorectal cancer. Cancer Immunol Immunother 2010;59:653-61.
[50]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory tumor 
microenvironment is associated with superior survival in hepatocellular carcinoma 
patients. J Hepatol 2010;52:370-9.
[51]
Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. 
Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung 
Cancer. N Engl J Med. 2016 Oct 8. [Epub ahead of print].
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Immunology of gynecologic neoplasms: analysis of the prognostic significance of 
the immune status. Curr Cancer Drug Targets 2009;9(4):541-65.
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Ruffell B, DeNardo DG, Affara NI, Coussens LM. Lymphocytes in cancer 
development: polarization towards pro-tumor immunity. Cytokine Growth Factor 
Rev 2010;21:3-10.
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Shirabe K, Motomura T, Muto J, Toshima T, Matono R, Mano Y, et al. Tumor-
infiltrating lymphocytes and hepatocellular carcinoma: pathology and clinical 
management. Int J Clin Oncol 2010;15:552-8.
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Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 
Blockade in Tumors with Mismatch-Repair Deficiency. N Engl J Med. 2015 Jun 
25;372(26):2509-20.
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Sinicrope FA, Shi Q, Smyrk TC, Thibodeau SN, Dienstmann R, Guinney J, et al. 
Molecular markers identify subtypes of stage III colon cancer associated with 
patient outcomes. Gastroenterology. 2015 Jan;148(1):88-99.
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Kopetz S, Desai J, Chan E, Hecht JR, O'Dwyer PJ, Maru D, et al. Phase II Pilot 
Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal 
Cancer. J Clin Oncol. 2015 Dec 1;33(34):4032-8.
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Colon cancer, version 3.2014. J Natl Compr Canc Netw. 2014 Jul;12(7):1028-59.
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Practice Guidelines. Ann Oncol. 2010 May;21 Suppl 5:v78-81.
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Stoffel EM, Mangu PB, Gruber SB, Hamilton SR, Kalady MF, Lau MW, et al. 
Hereditary colorectal cancer syndromes: American Society of Clinical Oncology 
Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: 
European Society for Medical Oncology Clinical Practice Guidelines. J Clin Oncol. 
2015 Jan 10;33(2):209-17.
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probability intervals. Clin Trials 2007;4:235-44.
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12
APPENDICES
12.1
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP non Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time and labor intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
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12.2
Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 7.1.3.3 
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial site.  No personal identifiers will appear on 
the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in 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 Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
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Subsequently, the subject's specimens will be flagged in the biorepository and restricted 
to main study use only. If specimens were collected from study participants specifically 
for Future Biomedical Research, these specimens will be removed from the biorepository 
and destroyed. Documentation will be sent to the investigator confirming withdrawal 
and/or destruction, if applicable. It is the responsibility of the investigator to inform the 
subject of completion of the withdrawal and/or destruction, if applicable.  Any analyses 
in progress at the time of request for withdrawal/destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject 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 subjects.  Subjects will not be identified by 
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name in any published reports about this study or in any other scientific publication or 
presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (ie, only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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12.3
Cockcroft-Gault Formula
Calculated Creatinine Clearance  Sex × ((140 - Age) / (Serum Creatinine))
× (Weight / 72), where male  1 and female  0.85
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12.4
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response.  While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study. 
* New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). E.A. Eisenhauer, 
P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. 
Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij. Eur J Cancer. 2009 Jan;45(2):228-47.
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12.5
irRECIST
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs.
irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions while subjects are receiving pembrolizumab (MK-3475). Treatment 
efficacy based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively and is an exploratory objective for this study. Refer to Table 13 for 
management of subjects per irRECIST.  
This clinical judgment decision by the site should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data.  Clinical 
stability is defined as the following: 
1. Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values
2. No decline in ECOG performance status 
3. Absence of rapid progression of disease 
4. Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention  
In determining whether or not the tumor burden has increased or decreased per irRECIST,
the local site investigator should consider all target and non-target lesions as well as any 
incremental new lesion(s). Confirmation of progressive disease at repeat imaging is defined 
by occurrence of ANY of the following conditions: 

Tumor burden remains ≥20% and at least 5 mm absolute increase compared to nadir

Non-target disease resulting in initial progressive disease is qualitatively worse

New lesion resulting in initial progressive disease is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
ALL of the following conditions must be met in order for progressive disease NOT to be 
confirmed at repeat imaging: 

Tumor burden is < 20 % or < 5 mm absolute increase compared to nadir

Non-target disease resulting in initial progressive disease is stable or qualitatively 
improved

New lesion resulting in initial progressive disease is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target progression since last evaluation
Additional details about irRECIST are referenced in the Merck TIP Sheet for RECIST 1.1 
and irRECIST.
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  
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Table 13
Imaging and Treatment after First Radiologic Evidence of Progressive Disease for 
Subjects Receiving Pembrolizumab (MK-3475) (management per irRECIST)
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of 
PD by 
RECIST 
1.1(1)
Repeat imaging at >
4 weeks at site to 
confirm PD
May continue study 
treatment 
at 
the 
investigator’s 
discretion 
while 
awaiting 
confirmatory tumor 
imaging.
Repeat imaging at >
4 weeks to confirm 
PD per physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging 
confirms PD 
by irRECIST 
at the local 
site
No 
additional 
imaging required
Discontinue 
treatment (2)
No 
additional 
imaging required
N/A
Repeat tumor 
imaging 
shows SD, 
PR or CR by 
irRECIST by 
the local site
Continue 
regularly 
scheduled 
imaging 
assessments
Continue 
study 
treatment 
at 
the 
local 
site 
investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments
May 
restart 
study 
treatment if condition 
has improved and/or 
clinically 
stable 
per 
investigator’s 
discretion. Next tumor 
image 
should 
occur 
according to the regular 
imaging 
schedule 
outlined in the protocol
1)
Disease progression will be assessed by the local site/investigator for subjects participating in the study.  All images 
will be submitted to a central imaging vendor for potential analysis at the end of the study.
2)
If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks apart demonstrating progressive 
disease) per irRECIST, but the subject is achieving a clinically meaningful benefit, an exception to continue treatment 
may be considered following consultation with the Sponsor.  Follow up scans will then be performed Q9W (63 ± 7 
days) or earlier as clinically indicated.
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12.6
ECOG Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory.  Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(eg, light housework, office work).
2
In bed <50% of the time.  Ambulatory and capable of all self-care, but 
unable to carry out any work activities.  Up and about more than 50% of 
waking hours.
3
In bed >50% of the time.  Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  
Totally confined to bed or chair.
5
Dead.
Source: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P. Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group.  Am J Clin Oncol 5:649-655, 1982.  The Eastern Cooperative Oncology 
Group, Robert Comis M.D., Group Chair.
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12.7
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.  
(http://ctep.cancer.gov/reporting/ctc.html).  
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12.8
List of Abbreviations 
Abbreviation/Term 
Definition
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
AUC0-∞
area under the curve from time 0 extrapolated to infinite time
bid
twice daily
BUN
blood urea nitrogen
CEA
carcinoembryonic antigen
CFR
Code of Federal Regulations
CI
Coordinating Investigator
CLIA
Clinical Laboratory Improvement Amendments
Cmax
maximum concentration in blood
CR
complete response
CRC
colorectal cancer
CrCl
creatinine clearance
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
cytotoxic t-lymphocyte-associated antigen-4
DCR
drug control rate
DL
dose level
DLT
dose-limiting toxicity
dMMR
deficient mismatch repair
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EMA
European Medicines Agency
ERC
Ethics Review Committee
ERK
extracellular signal-regulated kinase
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone
FT3
free triiodothyronine
FT4
free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GLP
Good Laboratory Practice
G-CSF
granulocyte-colony stimulating factor
GM-CSF
granulocyte-macrophage colony-stimulating factor
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Abbreviation/Term 
Definition
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
IC50
half-maximal inhibitory concentration
ICH
International Conference on Harmonization
Ig
immunoglobulin
IHC
immunohistochemistry
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
irORR
immune-related overall response rate 
irPFS
immune-related progression-free survival
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
ITSM
immunoreceptor tyrosine-based switch motif
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
LDH
lactate dehydrogenase
mAB
monoclonal antibody
MAPK
mitogen-activated protein kinase
MEK
mitogen-activated protein/extracellular signal-regulated kinase
MMR
mismatch repair
MRI
magnetic resonance imaging
MSI
microsatellite instability
MTD
maximum tolerated dose
mTPI
modified toxicity probability interval
NCI
National Cancer Institute
non-MSI-H/dMMR
Non-microsatellite instability-high/deficient mismatch repair
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
OTC
over-the-counter
PD-1
programmed cell death-1
PD-L1
programmed cell death-ligand 1
PD-L2
programmed cell death-ligand 2
PD
pharmacodynamic
pERK
phosphorylated extracellular signal-regulated kinase
PFS
progression-free survival
PK
pharmacokinetic
pMMR
proficient mismatch repair
PR
partial response
PT
prothrombin time
q2w
once every 2 weeks
q3w
once every 3 weeks
qd
once daily
RECIST
Response Evaluation Criteria in Solid Tumors
RAF
rapidly accelerated fibrosarcoma
RAS
rat sarcoma
RNA
ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
serious adverse event
SD
stable disease
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Abbreviation/Term 
Definition
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SIM
Site Imaging Manual
sSAP
supplemental Statistical Analysis Plan
T3
triiodothyronine
Tmax
time to maximum concentration
T4
thyroxine
TSH
thyroid stimulating hormone
ULN
upper limit of normal
WBC
white blood cells
β-hCG
β-human chorionic gonadotropin
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13
SIGNATURES
13.1
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
13.2
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0
TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
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