Clinical trial NCT03745989
Conditions: Solid Tumors
Keywords: advanced/metastatic solid tumors Selumetinib
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-02-22; Completion date: 2021-03-19
Enrollment: 30 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
This is a multicenter, worldwide, open-label study of MK-8353 in combination with selumetinib in participants with histologically or cytologically confirmed diagnosis of advanced solid tumor. This study will evaluate the safety, tolerability, and exploratory efficacy of MK-8353 in combination with selumetinib.

Detailed description:
As specified by Phase 1 protocol-flexible language, modifications to the dose or dosing regimen can be made to achieve the scientific goals of the trial objectives and/or ensure appropriate safety of the trial participants. The proposed doses may be adjusted based on evaluation of safety, tolerability, and pharmacokinetic data.

Arms: arm 1: Participants will receive a combination MK-8353 and selumetinib for 4 days on and 3 days off until disease progression or discontinuation. MK-8353 will be escalated sequentially from 50 mg to 250 mg based on pharmacokinetic and safety data. Selumetinib will be escalated sequentially from 25 mg to 75 mg based on pharmacokinetic and safety data. Doses may be adjusted downward sequentially based on tolerability
Interventions: intervention 1: MK-8353 intervention 2: Selumetinib
Intervention descriptions: intervention 1: Participants will receive MK-8353 orally twice daily (BID), escalated sequentially from 50 mg to 250 mg. intervention 2: Participants will receive selumetinib orally BID, escalated sequentially from 25 mg to 75 mg.

Protocol documents:
Prot_SAP_000.pdf: 
PRODUCT: MK-8353 
1
PROTOCOL/AMENDMENT NO.: 014-01
MK-8353-014-01 FINAL PROTOCOL
19-DEC-2018
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: Phase 1b Open-label Study of MK-8353 in Combination with Selumetinib 
(MK-5618) in Participants with Advanced/Metastatic Solid Tumors
Protocol Number: 014-01
Compound Number: MK-8353
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND
140238
Approval Date: 19-December-2018
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 01
19-DEC-2018
Amendment 01 was issued to address Agency feedback.
Original protocol
05-OCT-2018
Original protocol.
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 01
Overall Rationale for the Amendments:
This amendment was issued to address Agency feedback.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1. Protocol Summary
Intervention Groups
DL5: Reduced the maximum MK-8353 dose from 
300 mg to 250 mg, which is a 25% increment 
from the previous dose.
Edited the text in the description of Intervention 
Groups.
This modification was applied throughout 
the protocol to address an Agency request 
to decrease the increment between Dose 
Levels 4 and 5.
The text was edited to improve consistency 
within the protocol.
1.2.
Schema
Figure 1 and associated footnotes
Reduced the maximum MK-8353 dose from 300 
mg to 250 mg.
Revised Figure 1 to add Figure 1A:
Schema to Potential Diagonal MTD①
Added Figure 1B: Schema to Potential MTD②
and MTD③
Added Table 1: Starting Doses for ERKi and 
MEKi Escalation to Potential MTD②and 
MTD③
This modification was applied throughout 
the protocol to address an Agency request 
as provided in Section 1.0.
The figures were revised to incorporate 
single agent escalation above DL3 in 
accordance with the Agency request, and 
to provide clarity regarding the steps for 
dose escalation. 
 
 
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Section # and Name
Description of Change 
Brief Rationale 
1.3 Schedule of Activities
1.3.1
Dose Escalation Phase: 
Screening and Treatment Cycles
Added visits to treatment Cycles 1 through 4 for 
additional safety monitoring via chemistry panel 
assessments; 5 visits were added. 
The SoA was separated into 2 tables as reflected 
in subsections 1.3.1 and 1.3.2.
Additional modifications were made to the ‘Notes’ 
column to align with the differentiation between 
the 2 tables.
Visits were added to address an Agency 
request to increase safety monitoring.
The SoA was separated into 2 tables to 
accommodate the increased size of the 
table and maintain legibility.
Additional modifications were made to the 
'Notes' column to align with the 
differentiation between the 2 tables.
1.3 Schedule of Activities
1.3.2
Dose Escalation Phase: 
End of Treatment and Post-
Treatment
The SoA was separated into 2 separate tables as 
reflected in subsections 1.3.2 and 1.3.2.
Additional modifications were made to the ‘Notes’ 
column to align with the differentiation between 
the 2 tables.
Additional modifications were made to the 
'Notes' column to align with the 
differentiation between the 2 tables.
2.2.3.1 MK-8353 and Selumetinib 
Preclinical Studies
Inserted a paragraph at end of the section to 
highlight data provided in the IB regarding the 
elevation of serum creatinine and the assessment 
of cystatin C.
This modification was applied to address 
an Agency request to provide guidelines 
for triggering an assessment of cystatin C.
4.1 Overall Design
Reduced the maximum MK-8353 dose from 300 
mg to 250 mg. Revised text to align with new 
Schema depicted in Figures 1A and 1B; added 
Table 1 with starting doses for off-diagonal 
sequences.
This modification was applied to address 
an Agency request as provided in section 
1.0.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
4.3.2
Maximum Dose/Exposure 
for This Study
Reduced the maximum MK-8353 dose from 300 
mg to 250 mg.
This modification was applied to address 
an Agency request as provided in section 
1.0.
4.3.3
Rational for Dose Interval 
and Study Design
Reduced the maximum MK-8353 dose from 300 
mg to 250 mg.
This modification was applied to address 
an Agency request as provided in section 
1.0.
5.2 Exclusion Criteria
#13: Added text to include “other cognitive 
disorders.”
This modification was applied to address 
an Agency recommendation to ensure 
enrolled participants can meet the 
requirements of the study.
6.1 Study Intervention(s) 
Administered
Applied a modification to ‘Dosage Level(s)’ for 
MK-8353: Reduced the maximum MK-8353 dose 
from 300 mg to 250 mg.
This modification was applied to address 
an Agency request as provided in section 
1.0.
6.5.2
Prohibited Concomitant 
Medications
Table 5 (former Table 4): Removed an incorrect 
header from the 2nd page of the table. 
The incorrect header was removed thus 
providing clarity to the table.
6.5.3.1
MK-8352 Supportive Care
Diarrhea:
Revised text in the last sentence to indicate that 
supportive care should be based in institutional 
guidelines as permitted while maintaining 
compliance with guidance for prohibited 
medications.
Revised the text for clarity and alignment 
with other sections in the protocol.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
6.6.2
Definition of Dose 
Limiting Toxicity
#3: Incorporated a time limit of <72 hours.
These modifications were applied to 
address an Agency request to modify the 
definition of Dose Limiting Toxicities.
#4: Reduced the time interval to ≥72 hours
#6: Inserted new criterion to provide clarity 
regarding AST and ALT laboratory values.
#13: Eye Disorders
Retinal: Revised the Grade of the event
Other: Deleted the Grade ≥3 criteria
6.6.4.1 Dose Modification for 
MK-8353 and Selumetinib
Figure 4:
Revised figure to reflect reduction in the
maximum MK-8353 dose from 300 mg to 250 mg
This modification was applied to address 
an Agency request as provided in section 
1.0.
Table 6 (former Table 5):
Revised figure to reflect reduction in the 
maximum MK-8353 dose from 300 mg to 250 mg
This modification was applied to address 
an Agency request as provided in section 
1.0.
Table 7 (former Table 6):
Eye disorders, Grade 3: Revised to indicate that 
study treatment may be restarted at a reduced dose 
level.
This modification was applied to address 
an Agency request.
Rash, Grade 3: Revised to indicate that study 
treatment may be restarted at a reduced dose level.
This modification was applied to address 
an Agency request.
 
 
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Section # and Name
Description of Change 
Brief Rationale 
9.9 Sample Size and Power 
Calculations
Reduced the maximum MK-8353 dose from 300 
mg to 250 mg.
Edited other existing text to align with revisions to 
the study design.
This modification was applied to address 
an Agency request as provided in section 
1.0.
10.2
Appendix 2: Clinical 
Laboratory Tests
Comprehensive Chemistry Panel:
Added creatine kinase
Revised to address required safety 
monitoring.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................17
1.1
Synopsis.................................................................................................................17
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities (SoA) ................................................................................23
1.3.1
Dose Escalation: Screening and Treatment Phase .......................................23
1.3.2
Dose Escalation: End of Treatment and Post-Treatment.............................29
2
INTRODUCTION..........................................................................................................31
2.1
Study Rationale....................................................................................................31
2.1.1
Rationale for the Study and Selection Participant Population .....................31
2.1.2
Rationale for Combination of MK-8353 and Selumetinib ..........................31
2.2
Background ..........................................................................................................32
2.2.1
Pharmaceutical and Therapeutic Background .............................................32
2.2.1.1
MK-8353 Pharmaceutical and Therapeutic Background...................32
2.2.1.2
Selumetinib Pharmaceutical and Therapeutic Background ...............33
2.2.2
Mechanism of Action...................................................................................33
2.2.3
Preclinical and Clinical Trials......................................................................34
2.2.3.1
MK-8353 and Selumetinib Preclinical Studies..................................34
2.2.3.2
MK-8353 Clinical Studies .................................................................35
2.2.3.3
Selumetinib Clinical Studies..............................................................35
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................36
4
STUDY DESIGN............................................................................................................37
4.1
Overall Design ......................................................................................................37
4.2
Scientific Rationale for Study Design.................................................................40
4.2.1
Rationale for Dose Combination Sequences................................................40
4.2.2
Rationale for Endpoints ...............................................................................40
4.2.2.1
Efficacy Endpoints.............................................................................40
4.2.2.1.1
Response Rate Assessed by RECIST 1.1 ................................40
4.2.2.2
Safety Endpoints ................................................................................40
4.2.2.3
Pharmacokinetic Endpoints ...............................................................41
4.2.2.4
Planned Exploratory Biomarker Research.........................................41
4.2.2.4.1
Biospecimens ...........................................................................41
4.2.2.4.2
Imaging ....................................................................................42
 
 
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4.2.2.5
Future Biomedical Research..............................................................42
4.3
Justification for Dose ...........................................................................................43
4.3.1
Starting Dose for This Study........................................................................43
4.3.2
Maximum Dose/Exposure for This Study ...................................................43
4.3.3
Rationale for Dose Interval and Study Design ............................................44
4.3.4
Dose Finding Using a Modified Toxicity Probability Interval Design........44
4.4
Beginning and End of Study Definition .............................................................46
4.4.1
Clinical Criteria for Early Study Termination .............................................46
5
STUDY POPULATION ................................................................................................47
5.1
Inclusion Criteria.................................................................................................47
5.2
Exclusion Criteria................................................................................................49
5.3
Special Considerations for Subjects of Asian Ethnicity ...................................52
5.4
Lifestyle Considerations ......................................................................................52
5.4.1
Meals and Dietary Restrictions....................................................................52
5.4.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................53
5.4.3
Activity Restrictions ....................................................................................53
5.5
Screen Failures.....................................................................................................53
5.6
Participant Replacement Strategy......................................................................53
6
STUDY INTERVENTION............................................................................................54
6.1
Study Intervention(s) Administered...................................................................55
6.2
Preparation/Handling/Storage/Accountability .................................................56
6.2.1
Dose Preparation..........................................................................................56
6.2.2
Handling, Storage, and Accountability........................................................56
6.3
Measures to Minimize Bias: Randomization and Blinding..............................56
6.3.1
Intervention Assignment..............................................................................56
6.3.2
Stratification.................................................................................................57
6.3.3
Blinding........................................................................................................57
6.4
Study Intervention Compliance..........................................................................57
6.5
Concomitant Therapy..........................................................................................57
6.5.1
Acceptable Concomitant Medication...........................................................57
6.5.2
Prohibited Concomitant Medications ..........................................................57
6.5.3
Supportive Care ...........................................................................................61
6.5.3.1
MK-8353 Supportive Care.................................................................61
6.5.3.2
Selumetinib Supportive Care .............................................................64
6.6
Dose Modification (Escalation/Titration/Other)...............................................67
6.6.1
Dose Administration/Escalation ..................................................................67
6.6.1.1
Dose Administration (Preparation) ....................................................67
6.6.2
Definition of Dose limiting Toxicity ...........................................................68
 
 
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6.6.3
Timing of Dose Administration...................................................................70
6.6.3.1
Timing of Administration for MK-8353 and Selumetinib.................70
6.6.4
Guidelines for Dose Modification Due to Adverse Events .........................71
6.6.4.1
Dose Modification for MK-8353 and Selumetinib............................71
6.7
Intervention After the End of the Study............................................................78
6.8
Clinical Supplies Disclosure................................................................................78
6.9
Standard Policies..................................................................................................78
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................79
7.1
Discontinuation of Study Intervention...............................................................79
7.2
Participant Withdrawal From the Study...........................................................80
7.3
Lost to Follow-up .................................................................................................80
8
STUDY ASSESSMENTS AND PROCEDURES ........................................................81
8.1
Administrative and General Procedures ...........................................................81
8.1.1
Informed Consent.........................................................................................81
8.1.1.1
General Informed Consent.................................................................82
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................82
8.1.2
Inclusion/Exclusion Criteria ........................................................................82
8.1.3
Participant Identification Card.....................................................................82
8.1.4
Medical History ...........................................................................................83
8.1.5
Prior and Concomitant Medications Review ...............................................83
8.1.5.1
Prior Medications...............................................................................83
8.1.5.2
Concomitant Medications ..................................................................83
8.1.6
Assignment of Screening Number...............................................................83
8.1.7
Assignment of Treatment/Randomization Number .....................................84
8.1.8
Study Intervention Administration ..............................................................84
8.1.8.1
Timing of Dose Administration.........................................................84
8.1.8.1.1
MK-8353 Administration.........................................................84
8.1.8.1.2
Selumetinib Administration.....................................................84
8.1.9
Discontinuation and Withdrawal .................................................................84
8.1.9.1
Withdrawal From Future Biomedical Research ................................85
8.1.10
Participant Blinding/Unblinding..................................................................85
8.1.11
Calibration of Equipment.............................................................................85
8.2
Efficacy Assessments ...........................................................................................85
8.2.1
Tumor Imaging and Assessment of Disease................................................85
8.2.1.1
Initial Tumor Imaging........................................................................86
8.2.1.2
Tumor Imaging During the Study......................................................86
 
 
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8.2.1.3
End of Treatment and Follow-up Imaging.........................................87
8.2.2
RECIST 1.1 Assessment of Disease ............................................................87
8.2.3
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...........88
8.3
Safety Assessments...............................................................................................88
8.3.1
Physical Examinations.................................................................................88
8.3.1.1
Full Physical Examination .................................................................89
8.3.1.2
Directed Physical Examination..........................................................89
8.3.2
Full Ophthalmic Examination......................................................................89
8.3.3
Additional Testing .......................................................................................89
8.3.4
Vital Signs....................................................................................................90
8.3.5
Electrocardiograms ......................................................................................90
8.3.6
Echocardiogram/Multigated Acquisition Scan............................................90
8.3.7
Clinical Safety Laboratory Assessments .....................................................91
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................91
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................92
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......94
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...94
8.4.4
Regulatory Reporting Requirements for SAE .............................................94
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................94
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................95
8.4.7
Events of Clinical Interest (ECIs) ................................................................95
8.5
Treatment of Overdose........................................................................................95
8.6
Pharmacokinetics.................................................................................................95
8.6.1
Blood Collection for Plasma........................................................................95
8.6.1.1
MK-8353 Blood Collection for Plasma .............................................96
8.6.1.2
Selumetinib Blood Collection for Plasma..........................................96
8.7
Pharmacodynamics..............................................................................................96
8.8
Future Biomedical Research Sample Collection...............................................96
8.9
Planned Genetic Analysis Sample Collection ....................................................97
8.10
Biomarkers ...........................................................................................................97
8.11
Visit Requirements...............................................................................................97
8.11.1
Screening......................................................................................................98
8.11.2
Treatment Period..........................................................................................98
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........98
8.11.4
Post-treatment ..............................................................................................98
 
 
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9
STATISTICAL ANALYSIS PLAN .............................................................................99
9.1
Statistical Analysis Plan Summary.....................................................................99
9.2
Responsibility for Analyses/In-house Blinding ...............................................101
9.3
Hypotheses/Estimation ......................................................................................101
9.4
Analysis Endpoints.............................................................................................101
9.4.1
Efficacy/Pharmacokinetics Endpoints .......................................................101
9.4.2
Safety Endpoints ........................................................................................101
9.5
Analysis Populations..........................................................................................101
9.5.1
Safety Analysis Populations ......................................................................101
9.5.2
Pharmacokinetic Analysis Populations......................................................102
9.5.3
Efficacy Analysis Populations ...................................................................102
9.6
Statistical Methods.............................................................................................102
9.6.1
Statistical Methods for Efficacy Analysis..................................................102
9.6.2
Statistical Methods for Safety Analysis .....................................................102
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analysis......................................................................................................103
9.6.3.1
Demographic and Baseline Characteristics .....................................103
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........103
9.7
Interim Analyses ................................................................................................103
9.8
Multiplicity .........................................................................................................103
9.9
Sample Size and Power Calculations ...............................................................103
9.10
Subgroup Analyses.............................................................................................103
9.11
Compliance (Medication Adherence)...............................................................103
9.12
Extent of Exposure.............................................................................................103
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS ...................................................................................................104
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ......104
10.1.1
Code of Conduct for Clinical Trials...........................................................104
10.1.2
Financial Disclosure...................................................................................106
10.1.3
Data Protection...........................................................................................106
10.1.3.1
Confidentiality of Data ....................................................................107
10.1.3.2
Confidentiality of Participant Records.............................................107
10.1.3.3
Confidentiality of IRB/IEC Information..........................................107
10.1.4
Publication Policy......................................................................................107
10.1.5
Compliance with Study Registration and Results Posting Requirements .108
10.1.6
Compliance with Law, Audit, and Debarment ..........................................108
10.1.7
Data Quality Assurance .............................................................................109
10.1.8
Source Documents .....................................................................................109
 
 
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10.1.9
Study and Site Closure...............................................................................110
10.2
Appendix 2: Clinical Laboratory Tests............................................................111
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................112
10.3.1
Definition of AE ........................................................................................112
10.3.2
Definition of SAE ......................................................................................113
10.3.3
Additional Events Reported in the Same Manner as SAE.........................114
10.3.4
Recording AE and SAE .............................................................................115
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................118
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................120
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................121
10.5.1
Definitions..................................................................................................121
10.5.2
Contraception Requirements......................................................................122
10.5.3
Pregnancy Testing......................................................................................124
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................125
10.7
Appendix 7: Country-specific Requirements ..................................................130
10.8
Appendix 8: Abbreviations ...............................................................................131
11
REFERENCES.............................................................................................................133
 
 
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LIST OF TABLES
Table 1
Starting Doses for MK-8353 or Selumetinib Escalation to Potential MTD
②and MTD③.................................................................................................38
Table 2
Dose-finding Rules per mTPI Design..............................................................46
Table 3
Adequate Organ Function Laboratory Values .................................................48
Table 4
Study Interventions ..........................................................................................55
Table 5
Examples of CYP3A4 Inducers/Inhibitors and Narrow Therapeutic Index 
Substrates of CYP3A4, CYP2C8, OATP1B1/3 and OCT2 Prohibited 
During the Trial................................................................................................60
Table 6
Examples of Maximum Dose Reductions........................................................73
Table 7
MK-8353 and Selumetinib Dose Modification and Treatment 
Discontinuation Guidelines for Drug-Related Adverse Events .......................74
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease .............................................................................................................88
Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................93
Table 10
Protocol-required Safety Laboratory Assessments........................................111
 
 
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LIST OF FIGURES
Figure 1
Dual Dose Escalation of MK-8353 and Selumetinib; (1A) Schema to 
Potential Diagonal MTD①; and (1B) Schema to Potential MTD②and 
MTD③.............................................................................................................21
Figure 2
Study Flow Chart .............................................................................................22
Figure 3
Mitogen Activated Protein Kinase Pathway and the Targets ..........................33
Figure 4
Example of Sequential Dose Reduction Along the Off-Diagonal 
Sequences.........................................................................................................72
 
 
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: Phase 1b Open-label Study of MK-8353 in Combination with Selumetinib 
(MK-5618) in Participants with Advanced/Metastatic Solid Tumors
Short Title: A Phase 1b Study of MK-8353 + Selumetinib in Advanced/Metastatic Solid 
Tumors
Acronym:
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for the study.
This study is to be conducted in male and female participants with advanced/metastatic solid 
tumors.
Primary Objectives
Primary Endpoints
- To determine the safety and tolerability and 
to establish preliminary RP2D(s) for the MK-
8353 and selumetinib combination in 
participants with advanced/metastatic solid 
tumors 
- DLTs
- AEs
- Study drug discontinuations due to an AE
Secondary Objectives
Secondary Endpoints
- To evaluate the pharmacokinetics (PK) of 
MK-8353 and selumetinib 
- Pharmacokinetic parameters, including 
AUC, Cmin and Cmax
 
 
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Advanced/Metastatic Solid Tumors
Population
Participants with advanced solid tumors
Study Type
Interventional
Intervention Model
Sequential
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 48 months from the time the first 
participant signs the informed consent until the last 
participant’s last study-related telephone call or visit.
Number of Participants:
Approximately 80 participants will be enrolled in this dose escalation study, as described in 
Section 9; the overall sample size will be at most 140 participants. 
 
 
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Intervention Groups and Duration:
Intervention 
Groups
This is a dual dose escalation study using the modified toxicity probability 
interval (mTPI) design to evaluate the safety, tolerability, and efficacy of the 
combination of MK-8353 and selumetinib (MK-5618).  Up to five dose levels 
for each drug will be evaluated in combination:

MK-8353 (ERKi): 50, 100, 150, 200, and 250 mg

MK-5618 (selumetinib, MEKi): 25, 50, 75, 100, and 125 mg
Total 
Number
There is 1 intervention group (MK-8353 + selumetinib) in this dose escalation
study.
Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the informed consent form (ICF) through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will receive the 
assigned intervention until disease progression is radiographically 
documented and confirmed by the site per Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1); unacceptable AEs; intercurrent 
illness that prevents further administration of treatment; investigator’s 
decision to withdraw the participant; participant withdrawal of consent;
pregnancy of the subject; noncompliance with study treatment or procedure 
requirements, or administrative reasons requiring cessation of treatment. After 
the end of treatment, participants are to be followed up for safety for at least 
30 days following the last study dosing and until recovery or stabilization of 
all related toxicities. During the first year in the study, tumor measurements 
will continue to be made every 9 weeks until progressive disease is observed, 
and each participant will be followed for survival. After 12 months on study, 
imaging will be performed every 12 weeks from first dose or as clinically 
indicated.
Upon identification of the preliminary RP2D(s) for the MK-8353 and 
selumetinib combination, additional participants with solid tumors will be 
enrolled in a future dose expansion phase of this trial. Participants in the 
planned expansion phase of this study will receive MK-8353 in combination 
with selumetinib as dual therapy. 
 
 
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
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1.2
Schema
The dual dose escalation and conformation plan and schema are depicted in Figure 1 and the 
study design is shown in Figure 2.
ERK = extracellular signal-regulated kinase; MEK = mitogen activated protein kinase
Dose: 
•
MK-8353 (ERKi): 50, 100, 150, 200, and 250 mg
•
MK-5618 (selumetinib, MEKi): 25, 50, 75, 100, and 125 mg
This grid illustrates 25 possible dose combinations formed by 5 unique MK-8353 (ERKi) doses and 5 unique 
MK-5618 (selumetinib, MEKi) doses. Using the modified toxicity probability interval (mTPI) design, the dose 
escalation will start by identifying the maximum tolerated dose (MTD) in the sequence of dose combinations 
formed along the diagonal of the grid, denoted by ①s shown in Figure 1A. If following the mTPI design the 
dose escalation along the diagonal of the dose combination grid concludes at either the starting dose, (MK-8353 
50 mg + selumetinib 25 mg), or the last dose on the diagonal sequence, (MK-8353 250 mg + selumetinib 125 
mg), the study will end with 1 MTD only.
If the dose escalation in the diagonal sequence is concluded at either (DL2, MK-8353100 mg + selumetinib 50 
mg), (DL3, MK-8353 150 mg + selumetinib 75 mg), (DL4, MK-8353 200 mg + selumetinib 75 mg) or (DL5 
MK-8353 200 mg + selumetinib 100 mg), 2 separate dose de-escalations will be initiated simultaneously along 
2 off-diagonal dose combination sequences denoted by ②and ③, to identify additional potential MTDs as 
shown in Figure 1B.
If following the mTPI design decision rules, the initial dose escalation is concluded at DL6, only one additional 
sequence will be explored: MK-8353 150 mg/100 mg selumetinib and MK-8353 150 mg/125 mg selumetinib 
(See Table 1).
Figure 1
Dual Dose Escalation of MK-8353 and Selumetinib; (1A) Schema to Potential 
Diagonal MTD①; and (1B) Schema to Potential MTD②and MTD③
 
 
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Figure 2
Study Flow Chart
 
 
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1.3
Schedule of Activities (SoA)
1.3.1
Dose Escalation: Screening and Treatment Phase
Study Period: Study Period:
Screening 
Phase
Treatment Cycles (3-week Cycles)
Notes
Treatment Cycle (C) / Visit:
Screening 
(Visit)
C1
C2
C3
C4
C5
C6
C7
C8 and 
beyond
Collection Timepoint
(Study Day [D]):
D1
D
4
D
8
D
15
D1
D
4
D
15
D1
D
15
D1
D
15
D1
D
4
D1
D1
D1
Scheduling Window(Days):
-28 to -1
-1
±3
±3
±3
-1
±3
±3
±3
±3
±3
±3
-1
±3
±3
±3
Administrative Procedures
Informed Consent
X
Informed Consent for 
Optional On-treatment 
Tumor Biopsy
X
Informed Consent for FBR
X
Participating in FBR is optional for study 
participants.
Participant Identification 
Card
X
Inclusion/Exclusion 
Criteria
X
Demographics and Medical 
History
X
Cancer Disease Status and 
Prior Treatment History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
MK-8353
Administration
X
X
Administered BID 4 days on/3 days off. 
Escalation/dosing schedule (eg. direction of dose 
escalation, BID vs. QD, on/off intermittent dosing 
schedule) may be adjusted based on totality of data 
(PK, pharmacodynamic, and safety). 
Selumetinib 
Administration
X
X
Administered BID 4 days on/3 days off. 
Escalation/dosing schedule (eg. direction of dose 
escalation, BID vs. QD, on/off intermittent dosing 
schedule) may be adjusted based on totality of data 
(PK, pharmacodynamic, and safety).
 
 
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Study Period: Study Period:
Screening 
Phase
Treatment Cycles (3-week Cycles)
Notes
Treatment Cycle (C) / Visit:
Screening 
(Visit)
C1
C2
C3
C4
C5
C6
C7
C8 and 
beyond
Collection Timepoint
(Study Day [D]):
D1
D
4
D
8
D
15
D1
D
4
D
15
D1
D
15
D1
D
15
D1
D
4
D1
D1
D1
Scheduling Window(Days):
-28 to -1
-1
±3
±3
±3
-1
±3
±3
±3
±3
±3
±3
-1
±3
±3
±3
Efficacy Assessments
Tumor Imaging
X
X
X
Screening: Imaging must be performed within 28 
days prior to the date of Cycle 1 Day 1 (C1D1). 
For the first 12 months on study: Imaging will be 
performed Q9W (63 days ± 7 days) calculated from 
the date of the first dose.
After 12 months on study: Imaging will be 
performed Q12W (± 14 days) from first dose or as 
clinically indicated.
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
AEs that occur after the ICF is signed but before 
treatment allocation must be reported if:
Event causes participant to be excluded from the 
study, or
Event is the result of a protocol-specified
intervention, including but not limited to washout 
or discontinuation of usual therapy or a study 
procedure
Full Physical Examination
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Can be obtained within 3 days prior to C1D1.
Full Ophthalmic 
Examination 
X
X
X
Performed at the Screening Visit, C2D1 and then 
every 8 weeks ±7 days) from C2D1 and EoT.
Height, Weight, and Vital 
Signs
X
X
X
X
X
X
X
X
X
Height will be measured at the Screening Visit only. 
Vital signs: temperature, pulse, respiratory rate, and 
blood pressure
C1D1: Can be obtained within 3 days prior 
C1D1: It is not necessary to repeat C1D1 testing 
if the Screening Visit assessment was performed 
within 7 days prior to C1D1.
12-Lead Electrocardiogram
X
X
X
X
X
X
X
X
Screening: ECG will be performed in triplicate to 
confirm QTcF interval.
C2 and beyond: ECGs will be performed predose, 
every cycle.
 
 
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Study Period: Study Period:
Screening 
Phase
Treatment Cycles (3-week Cycles)
Notes
Treatment Cycle (C) / Visit:
Screening 
(Visit)
C1
C2
C3
C4
C5
C6
C7
C8 and 
beyond
Collection Timepoint
(Study Day [D]):
D1
D
4
D
8
D
15
D1
D
4
D
15
D1
D
15
D1
D
15
D1
D
4
D1
D1
D1
Scheduling Window(Days):
-28 to -1
-1
±3
±3
±3
-1
±3
±3
±3
±3
±3
±3
-1
±3
±3
±3
Echocardiogram/
MUGA scan (Q12W)
X
X
X
X
X
X
Obtain scans as follows:
• Screening Visit
• Treatment: C2D1 and C5D1, then every 12 weeks
ECOG Performance Scale
X
X
X
X
X
X
X
X
X
C1D1: 
Can be obtained within 3 days prior
It is not necessary to repeat C1D1 testing if the 
Screening Visit assessment was performed within 
7 days prior to C1D1.
Survival Status
X
X
All participants will be followed up for survival 
every 12 weeks (± 14 days) after discontinuation 
(unless consent is withdrawn). In addition, upon 
Sponsor request, participants may be contacted for 
survival status at any time during the study.
LOCAL Laboratory Assessments
Pregnancy Test – Urine or 
Serum β-hCG, if applicable
X
X
Pregnancy tests may be performed if clinically 
warranted, or as defined by local regulations.
Monthly pregnancy testing should be conducted as 
per local regulations where applicable.
PT/INR and aPTT/PTT
X
CBC with Differential
X
X
X
X
X
X
X
X
X
C1D1: Does not need to be obtained if Screening
Visit samples were obtained within 3 days prior to 
C1D1.
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Specific to creatinine: Cystatin C could be evaluated 
if creatinine is abnormal (≥10% increase from 
baseline). Cystatin C may be conducted by central 
vendor only if analysis was not available from local 
study site laboratory.
C1D1: Does not need to be obtained if Screening 
Visit samples were obtained within 3 days prior to 
C1D1.
Fasting Glucose
X
X
C2D4: Obtain pre-dose prior to FDG-PET scan; 
performed only in participants enrolled in the MTD
levels
Urinalysis
X
X
X
X
X
To be performed at the Screening Visit and every 
other cycle starting at C2.
Serum Tumor Markers
X
X
Collected Q3W starting at C1, as appropriate for 
tumor type.
 
 
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Study Period: Study Period:
Screening 
Phase
Treatment Cycles (3-week Cycles)
Notes
Treatment Cycle (C) / Visit:
Screening 
(Visit)
C1
C2
C3
C4
C5
C6
C7
C8 and 
beyond
Collection Timepoint
(Study Day [D]):
D1
D
4
D
8
D
15
D1
D
4
D
15
D1
D
15
D1
D
15
D1
D
4
D1
D1
D1
Scheduling Window(Days):
-28 to -1
-1
±3
±3
±3
-1
±3
±3
±3
±3
±3
±3
-1
±3
±3
±3
CENTRAL Laboratory Assessments
MK-8353 
Pharmacokinetics
X
X
X
X
X
X
C1D1: Pre-dose samples will be collected (within 
24 hours prior to pre-dose). Morning dose(s) 
should be withheld until sample has been drawn. 
Post-dose samples will be collected at hours 1
(± 10 minutes), 2 (± 10 minutes), 4
(± 10 minutes), 6 (± 10 minutes), and 1 sample 
any time between 8 and 12 hours (prior to PM 
dosing for BID regimen).
C1D4: Pre-dose/trough samples will be collected
at time 0 (within -10 minutes prior to pre-dose). 
Morning dose(s) should be withheld until sample 
has been drawn. Post-dose samples will be 
collected at hours 1 (± 10 minutes), 2
(± 10 minutes), 4 (± 10 minutes), 6
(± 10 minutes), and 1 sample any time between 8 
and 12 hours (prior to PM dosing for BID 
regimen).
Additional samples will be collected at C2D1, 
C2D4, C5D1 and C5D4: Pre-dose/trough: Collect 
at time 0 (within -10 minutes prior to pre-dose). 
Morning dose(s) should be withheld until sample 
has been drawn, and Post-dose: Hours 1 
(± 10 minutes) and 4 (± 10 minutes). 
The exact time of sample collection and time of 
administration of MK-8353 will be recorded.
 
 
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Study Period: Study Period:
Screening 
Phase
Treatment Cycles (3-week Cycles)
Notes
Treatment Cycle (C) / Visit:
Screening 
(Visit)
C1
C2
C3
C4
C5
C6
C7
C8 and 
beyond
Collection Timepoint
(Study Day [D]):
D1
D
4
D
8
D
15
D1
D
4
D
15
D1
D
15
D1
D
15
D1
D
4
D1
D1
D1
Scheduling Window(Days):
-28 to -1
-1
±3
±3
±3
-1
±3
±3
±3
±3
±3
±3
-1
±3
±3
±3
Selumetinib 
Pharmacokinetics
X
X
X
X
X
X
C1D1: Pre-dose samples will be collected (within 
24 hours prior to pre-dose). Morning dose(s) 
should be withheld until sample has been drawn. 
Post-dose samples will be collected at hours 1
(± 10 minutes), 2 (± 10 minutes), 4
(± 10 minutes), 6 (± 10 minutes), and 1 sample 
any time between 8 and 12 hours (prior to PM 
dosing for BID regimen).
C1D4: Pre-dose/trough samples will be collected
at time 0 (within -10 minutes prior to pre-dose). 
Morning dose(s) should be withheld until sample 
has been drawn. Post-dose samples will be 
collected at hours 1 (± 10 minutes), 2
(± 10 minutes), 4 (± 10 minutes), 6
(± 10 minutes), and 1 sample any time between 8 
and 12 hours (prior to PM dosing for BID 
regimen).
Additional samples will be collected at C2D1, 
C2D4, C5D1 and C5D4: Pre-dose/trough: Collect 
at time 0 (within -10 minutes prior to pre-dose). 
Morning dose(s) should be withheld until sample 
has been drawn, and Post-dose: Hours 1 
(± 10 minutes) and 4 (± 10 minutes). 
The exact time of sample collection and time of 
administration of selumetinib will be recorded.
Blood for Genetic Analysis
X
Collect pre-dose.
Blood for RNA Analysis
X
X
X
X
Samples will be collected:
• Pre-dose: C1D1, C1D4, C2D4, and C5D4
Blood for Plasma 
Biomarker Analysis
X
X
X
X
Samples will be collected:
• Pre-dose: C1D1, C1D4, C2D4, and C5D4
Blood for Serum 
Biomarker Analysis
X
X
X
X
Samples will be collected:
• Pre-dose: C1D1, C1D4, C2D4, and C5D4
Blood For ctDNA
X
X
X
X
Samples will be collected:
• Pre-dose: C1D1, C1D4, C2D4, and C5D4
 
 
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Study Period: Study Period:
Screening 
Phase
Treatment Cycles (3-week Cycles)
Notes
Treatment Cycle (C) / Visit:
Screening 
(Visit)
C1
C2
C3
C4
C5
C6
C7
C8 and 
beyond
Collection Timepoint
(Study Day [D]):
D1
D
4
D
8
D
15
D1
D
4
D
15
D1
D
15
D1
D
15
D1
D
4
D1
D1
D1
Scheduling Window(Days):
-28 to -1
-1
±3
±3
±3
-1
±3
±3
±3
±3
±3
±3
-1
±3
±3
±3
Blood for pERK
X
X
X
X
X
X
Samples will be collected C1D1:
Pre-dose: Collect at time 0, within 24 hours prior 
to pre-dose); morning dose(s) should be withheld 
until sample has been drawn, and
Samples will be collected C1D4, C2D1, C2D4, 
C5D1, C5D4:
Pre-dose: Collect at time 0 (within 10 minutes 
prior to pre-dose); morning dose(s) should be 
withheld until sample has been drawn, and 
Post-dose: Hours 1 (± 10 minutes) and 4 
(± 10 minutes)
Exploratory Imaging
FDG-PET Scan
X
X
Obtain in participants enrolled in the MTD levels. 
Screening Visit: The baseline scan will be performed 
between -14 to -1 days prior to C1D1.
C2D4: Scan will be performed predose
Tumor Tissue Collection
Archival or Newly 
Obtained Tumor Tissue 
Collection
X
On-treatment Tumor 
Biopsy (Optional)
X
Abbreviations: aPTT/PTT= activated prothrombin time/partial thromboplastin time; β-hCG=human chorionic gonadotropin; BID=twice daily; CBC=complete blood count; 
ctDNA=circulating tumor DNA; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; EoT=end of 
treatment; ERK=extracellular signal-regulated kinase; FBR=future biomedical research; FDG-PET=18F-flourodeoxyglucose-positron emissions tomography;FT3=free 
triiodothyronine; FT4=free thyroxine; hr = hour; ICF = informed consent form; IHC= immunohistochemistry; IV=intravenous; MSI/MMR= microsatellite instability/mismatch 
repair; MUGA= multigated acquisition; PD = progressive disease; pERK= phosphorylation of ERK; PK= pharmacokinetic; PT/INR = prothrombin time/International Normalized 
Ratio; PT/PTT=prothrombin time/partial thromboplastin time;Q3W=every 3 weeks; Q9W=every 9 weeks; Q12W= every 12 weeks; QD = once daily; QTcF = Fridericia’s Q-T 
interval corrected formula; RNA=ribonucleic acid.
 
 
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1.3.2
Dose Escalation: End of Treatment and Post-Treatment
Study Period:
End of Treatment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / Visit:
Discontinuation
Safety Follow-up
Follow-up Visits
Survival Follow-up
Collection Timepoint: (Study Day [D])
At time of 
Treatment 
Discontinuation
30 days
Post-last dose
Every
9 or 12 weeks 
Post-discontinuation
Every 12 weeks
Post-last dose
Scheduling Window (Days):
+7
+14
±7
±14
Administrative Procedures
Prior and Concomitant Medication 
Review
X
X
Efficacy Assessments
Tumor Imaging
X
X
In participants who discontinue study therapy without documented PD, 
tumor imaging should continue in Post-treatment Follow-up Visits, 
following the same imaging schedule from the treatment phase; and as 
clinically indicated. 
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
Follow-up Visits: AEs will be collected when participant is in the clinic for 
tumor imaging assessment.
Full Physical Examination
X
Full Ophthalmic Examination 
X
X
Performed at the EoT.
An ophthalmic examination at the Safety Follow-up Visit is only required 
if there was a clinically significant abnormality noted at EoT
Weight and Vital Signs
X
Vital signs: temperature, pulse, respiratory rate, and blood pressure
12-Lead Electrocardiogram
X
X
Echocardiogram/
MUGA scan (Q12W)
X
ECOG Performance Scale
X
X
Post-study Anticancer Therapy Status
X
X
Survival Status
X
X
X
X
All participants will be followed up for survival every 12 weeks 
(± 14 days) after discontinuation (unless consent is withdrawn). In 
addition, upon Sponsor request, participants may be contacted for survival 
status at any time during the study.
 
 
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Study Period:
End of Treatment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / Visit:
Discontinuation
Safety Follow-up
Follow-up Visits
Survival Follow-up
Collection Timepoint: (Study Day [D])
At time of 
Treatment 
Discontinuation
30 days
Post-last dose
Every
9 or 12 weeks 
Post-discontinuation
Every 12 weeks
Post-last dose
Scheduling Window (Days):
+7
+14
±7
±14
LOCAL Laboratory Assessments
CBC with Differential
X
X
Chemistry Panel
X
X
Specific to creatinine: Cystatin C could be evaluated if creatinine is 
abnormal. Cystatin C may be conducted by central vendor only if analysis 
was not available from local study site laboratory.
Urinalysis
X
X
Serum Tumor Marker
X
X
Collected as appropriate for tumor type.
CENTRAL Laboratory Assessments
Blood for RNA Analyses
X
Blood for Plasma Biomarker Analyses
X
Blood for Serum Biomarker Analyses
X
Blood for ctDNA
X
Abbreviations: ctDNA=circulating tumor DNA; DNA=deoxyribonucleic acid; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EoT=end of treatment; hr 
= hour; MUGA= multigated acquisition; PD = progressive disease; Q12W= every 12 weeks; QTcF = Fridericia’s Q-T interval corrected formula; RNA=ribonucleic acid.
 
 
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2
INTRODUCTION
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 induces a conformational change in ERK that prevents its 
phosphorylation and activation by mitogen-activated protein/extracellular signal-regulated 
kinase (MEK). Selumetinib (also known as MK-5618, AZD6244, or ARRY-142886) is a 
potent, selective, adenosine triphosphate non-competitive, allosteric inhibitor of MEK, 
thereby inhibiting the phosphorylation of ERK by MEK. MK-8353 is under study for the 
treatment of solid tumors in combination therapy with selumetinib. This is a Phase 1b dose-
escalation, and dose-finding trial to assess the safety and tolerability of MK-8353 in
combination therapy with selumetinib. Refer to the MK-8353 and selumetinib Investigator’s 
Brochure (IB) for further information.
2.1
Study Rationale
2.1.1
Rationale for the Study and Selection Participant Population
MK-8353 is a potent ERK inhibitor that has demonstrated antitumor activity in preclinical 
cancer cell lines and in xenograft and syngeneic animal tumor models, both as a single agent 
and in combination with other therapeutic agents, including anti PD-1 therapy. 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, and a Phase 1b study of MK-8353 is 
ongoing as of 25-SEP-2018 to evaluate its safety and preliminary efficacy in combination 
with pembrolizumab. Selumetinib is a MEK inhibitor, under clinical evaluation in multiple 
indications, and has been shown to inhibit growth and/or the survival of selected tumor cell 
lines in vitro and xenograft growth in vivo either as monotherapy or in combination with 
established chemotherapies. Emerging data suggests that the combining ERK and MEK 
inhibitors reduces resistance, and may result in deeper and more durable suppression of the 
mitogen activated protein kinase (MAPK) signaling pathway compared with single agent 
targeting of the pathway [Xue, Y., et al 2017] [Merchant, M., et al 2017] (Section 2.1.2
Rationale for Combination of MK-8353 and Selumetinib).
The combination of MK-8353 and selumetinib will be evaluated in participants with any 
advanced solid tumor for which no curative therapy is available, and thus, suitable for an 
investigational treatment. Approximately 80 participants will be enrolled (see Section 9.9 for 
additional details).
2.1.2
Rationale for Combination of MK-8353 and Selumetinib
Emerging data suggest that inhibition of either MEK or ERK alone only transiently inhibits 
the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and 
ERK results in deeper and more durable suppression of MAPK signaling that is not 
achievable with any dose of the single agents, in tumors where feedback reactivation occurs. 
Combined MEK and ERK inhibition is synergistic in RAS mutant models but, where the 
RAF complex is dissociated from RAS and thus feedback productivity is disabled. Pathway
reactivation in RAS mutant models occurs at the level of CRAF with combination treatment
 
 
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resulting in a markedly more active pool of CRAF. However, distinct from single node 
targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream 
signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these
data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback 
reactivation can be rescued with sufficient inhibition by using a combination of MEK and 
ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway 
output and tumor growth in vivo to a greater extent than the maximum tolerated doses of 
single agents, and results in improved anti-tumor activity in multiple xenografts as well as in 
two KRAS mutant genetically engineered mouse (GEM) models. Collectively, these data 
demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater 
than additive anti-tumor effects and elucidates a highly effective combination strategy in 
MAPK-dependent cancer, such as KRAS mutant tumors [Merchant, M., et al 2017].
A recent study described that parallel evolutionary tracts enabled the selection and 
propagation of distinct BRAF-amplified subclones, occurring in the same tumor shortly after 
drug treatment, allowing the tumor to adapt while maintaining its intratumoral heterogeneity. 
In this study, a fitness threshold model was derived, where fitness threshold refers to the 
barrier that subclonal populations need to overcome to regain fitness in the presence of drug 
treatment. Drugs targeting different nodes of the same pathway have distinct mechanisms of 
actions and, as a consequence, they exert a different evolutionary selective pressure. As such, 
the level of BRAFamp that was required to overcome the effect of the drug differed between 
RAF, MEK, and ERK inhibitors, with tumors treated with the latter able to tolerate higher 
levels of BRAFamp. This model predicts that sequential treatment is ineffective, demonstrated 
by findings that treatment with a RAFi followed by treatment with an ERKi led to a progres-
sive increase in BRAF CN and that patients who were pre-treated with ERK signaling 
inhibitors did not respond well to subsequent treatment with another inhibitor of the pathway.
The model also predicts that at a sufficiently high fitness threshold, a broader range of 
BRAFamp subclones, including those with high-level amplification, is at a fitness 
disadvantage and prevented from propagation. One way to achieve this is with concurrent 
targeting of the RAF, MEK, and ERK kinases, which imposed a sufficiently high fitness 
threshold to prevent the propagation of subclones with high-level BRAFamp. When 
administered on an intermittent schedule, this treatment inhibited tumor growth in 11/11 
PDXs of lung cancer or melanoma without apparent toxicity in mice [Xue, Y., et al 2017].
Based on these emerging data, this study will use a dual inhibition approach, combining 
MEK (selumetinib) and ERK (MK-8353) inhibitors for concurrent targeting of the MAPK 
pathway.
2.2
Background
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
MK-8353 Pharmaceutical and Therapeutic Background
MK-8353 is a potent and selective ERK inhibitor, under clinical evaluation in multiple 
indications, both as a single agent and in combination with other therapeutic agents. For more 
details, refer to the MK-8353 IB.
 
 
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2.2.1.2
Selumetinib Pharmaceutical and Therapeutic Background
Selumetinib is a MEK inhibitor, under clinical evaluation in multiple indications, both as a 
single agent and in in combination with established chemotherapies, novel targeted agents, 
and immunotherapy. For more details, refer to the selumetinib IB.
2.2.2
Mechanism of Action
Activation of the MAPK pathway is implicated in contributing to the aberrant growth of 
~30% of human cancers particularly those tumors that have activating mutations in RAS and 
BRAF. While BRAF and MEK inhibitors have shown clinical success in BRAF-mutant 
melanoma and BRAF-mutant non-small cell lung cancer, they have shown limited activity in 
RAS-mutant tumors. Emerging preclinical data is showing that this limited activity is due to 
insufficient pathway suppression and likely pathway reactivation. In preclinical models, 
simultaneous targeting of both MEK and ERK results in deeper and more durable 
suppression of MAPK signaling that is not achievable with any dose of either single agent
(Figure 3). These encouraging preclinical data lend support to the hypothesis that dual MEK 
and ERK inhibition may enable stronger sustained anti-tumor activity in MAPK-addicted 
tumors.
ERK = extracellular signal-regulated kinase; ERKi = extracellular signal-regulated kinase inhibitor; 
MEK = mitogen activated protein kinase; MEKi = mitogen activated protein kinase inhibitor
Figure 3
Mitogen Activated Protein Kinase Pathway and the Targets
 
 
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2.2.3
Preclinical and Clinical Trials
2.2.3.1
MK-8353 and Selumetinib Preclinical Studies
In vitro MK-8353 inhibits the growth of cancer cell lines that are mutant for BRAF, KRAS, 
or NRAS but has limited activity on cell lines wild-type for BRAF and RAS. The 
antiproliferative effects of MK-8353 on BRAF-mutant cell lines are associated with 
increased levels of apoptosis. In vivo MK-8353 was shown to inhibit the growth of human 
tumor xenografts mutant for BRAF, NRAS, and KRAS. In a number of the mutant models 
MK-8353 induced marked tumor regressions indicative of significant anti-tumor activity.
Preclinically, selumetinib also inhibited the proliferation of human cancer cell lines mutant 
for BRAF and RAS. Selumetinib also preferentially inhibited the human xenograft models 
mutant for BRAF and RAS and had limited anti-tumor activity on wild-type models.
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.
Human absorption, distribution, metabolism, and excretion (ADME) data show that 
selumetinib is cleared through oxidative metabolism and glucuronidation. Metabolism is 
mediated primarily by CYP3A4, CYP2C19, UGT1A1 and 1A3. Clinical drug-drug 
interaction (DDI) data with itraconazole, fluconazole and rifampicin are consistent with these 
findings. Selumetinib is reported to be a weak inducer of CYPs 3A, 1A and 2C9.
For MK-8353, clearance occurs mostly through oxidative metabolism by CYP3A4, and to a 
minor extent through glucuronidation by UGT1A3 and 1A4 as determined by enzyme 
phenotyping. In vitro studies have shown that MK-8353 is a time-dependent inhibitor and 
competitive inhibitor CYP3A4. RIS data suggested no induction at clinically relevant 
exposures. Whereas for MK-8353 no clinical DDI data are currently available, based upon 
the ADME profiles and interaction properties of MK-8353 and selumetinib, a 
pharmacokinetic (PK) interaction between the two molecules appears possible. Predictions of 
DDI were conducted using a static model as well as using physiologically-based 
pharmacokinetic (PBPK) simulations. Simulation results suggest weak DDI upon co-dosing 
of selumetinib with MK-8353 at 300 mg BID (selumetinib AUC is predicted to increase up 
to 1.6-fold). 
Preclinical data show that MK-8353 is an inhibitor of transporters MATE1 and OCT2 (see IB 
section 4.2.4.4). These transporters, which are involved in the active tubular secretion 
component of creatinine, have been shown to contribute to approximately 10-40% of 
 
 
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creatinine clearance [Levey, A. S., et al 1988] [Chu, X., et al 2016]. Therefore, inhibition of 
these transporters may lead to a rise in serum creatinine that may not be indicative of renal 
dysfunction. When creatinine increases from baseline ≥10%, monitoring of cystatin C may 
be used as an alternative marker to evaluate renal function.
2.2.3.2
MK-8353 Clinical Studies
MK-8353 is currently under development evaluation in multiple indications. The initial 
clinical evaluations of MK-8353 include a single-rising-dose study in healthy volunteers and 
a multiple-rising-dose study in subjects with advanced cancer [Moschos, S. J., et al 2018]. In 
the MK-8353 monotherapy dose escalation, the MTD was determined to be 350 mg BID 
with continuous dosing. Currently, a dose escalation study to evaluate safety and preliminary 
efficacy of MK-8353 in combination with pembrolizumab is ongoing. Refer to the IB for 
detailed information on preclinical and clinical experience with MK-8353.
2.2.3.3
Selumetinib Clinical Studies
Selumetinib is under clinical evaluation in multiple indications. More than 3900 participants 
have been exposed to selumetinib in Phase 1 through Phase 3 studies, including 3 Phase 3
trials (2 completed and 1 ongoing), where a total of 598 participants have been treated. The 
PK, pharmacodynamics, and safety of selumetinib have been well characterized. Refer to the
IB for detailed information on preclinical and clinical experience with selumetinib.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Given the unmet medical need that exists for patients with advanced malignancies, described 
in Section 2.1, the objective of the current study is to assess the safety and tolerability of the 
combination study medication. The combination regimen being examined in the current 
study has a potential to provide improvement of efficacy without increase of toxicity.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
 
 
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3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for the study.
This study is to be conducted in male and female participants with advanced/metastatic solid 
tumors.
Objectives
Endpoints
Primary
•
To determine the safety and tolerability 
and to establish preliminary RP2D(s) for 
the MK-8353 and selumetinib 
combination in participants with 
advanced/metastatic solid tumors 
•
DLTs
•
AEs
•
Study drug discontinuations due to an AE
Secondary
•
To evaluate the pharmacokinetics (PK) of 
MK-8353 and selumetinib
•
Pharmacokinetic parameters, including 
AUC, Cmin and Cmax
Tertiary/Exploratory
•
To evaluate the overall response rate 
(ORR) and progression-free survival 
(PFS) based on RECIST 1.1 as assessed 
by the investigator for each dose level,
and overall survival (OS).
•
OR (overall response): participants who 
have a confirmed complete response 
(CR) or partial response (PR)
•
PFS: time from the first dose of study 
medication to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
OS: time from the first dose of study 
medication to death due to any cause.
•
To evaluate the serum levels of protein 
biomarkers (eg, carcinoembryonic 
antigen) before and after administration 
of MK-8353 in combination with
selumetinib
•
Determination of molecular/proteomic 
markers indicative of clinical response, 
safety or mechanism of action of 
MK-8353 and selumetinib
•
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 in 
combination with selumetinib
•
Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood RNA variation, proteomics and 
immunohistochemistry (IHC), and other 
biomarkers (18F-fluoro-deoxy-glucose 
positron emission tomography [FDG-
PET])
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 1b, multicenter, worldwide, open-label study of MK-8353 in combination 
with selumetinib in participants with histologically or cytologically confirmed diagnosis of 
advanced solid tumor. This study will evaluate the safety, tolerability, and preliminary 
efficacy of MK-8353 in combination with selumetinib.
The dose escalation will start in the sequence of dose combinations formed along the 
diagonal of the dose combination grid denoted by ①in Figure 1A): (DL1, MK-8353 50 mg
+ selumetinib 25 mg), (DL2, MK-8353 100 mg + selumetinib 50 mg), (DL3, MK-8353
150 mg + selumetinib 75 mg), (DL4, MK-8353 200 mg + selumetinib 75 mg), (DL5, 
MK-8353 200 mg + selumetinib 100 mg), (DL6, MK-8353 250 mg + selumetinib 100 mg),
and (DL7, MK-8353 250 mg + selumetinib 125 mg). The mTPI design with a target dose-
limiting toxicity (DLT) rate of approximately 30% will be applied to identify a potential
MTD in this sequence of dose combinations. If following the mTPI design the dose 
escalation along the diagonal of the dose combination grid concludes at either the starting 
dose, (DL1, MK-8353 50 mg + selumetinib 25 mg), or the last dose on the diagonal 
sequence, (DL7, MK-8353 250 mg + selumetinib 125 mg), the study will end with one MTD 
only. Otherwise, the study will simultaneously initiate additional off-diagonal dose 
combination sequences to identify additional potential MTDs as detailed in Table 1 and 
Figure 1B (Table 1). Following Table 1 and Figure 1B, if the dose escalation along the 
diagonal is concluded at either DL2, DL3, DL4, or DL5, two simultaneous off-diagonal dose 
combination sequences will be initiated with the respective starting doses specified in 
Table 1. The complete sequence for each possible scenario is found in Figure 1B. Thus, to 
identify MTD②, MK-8353 will be escalated while keeping selumetinib fixed. To identify 
MTD③, selumetinib will be escalated while keeping MK-8353 fixed.  If the dose escalation 
along the diagonal is concluded at DL6, only one additional sequence will be explored using 
the mTPI decision rules by keeping MK-8353 fixed at 150 and escalating selumetinib: MK-
8353 150 mg/100 mg selumetinib and MK-8353 150 mg/125 mg selumetinib.
 
 
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Table 1
Starting Doses for MK-8353 or Selumetinib Escalation to Potential MTD②and 
MTD③
MTD① 
per 
mTPI
Starting dose for MK-8353 
escalation to potential MTD② 
(see Figure 1B)
Starting dose for Selumetinib 
escalation to potential MTD③  
(see Figure 1B)
DL1
No additional escalation
No additional escalation
DL2
100 mg MK-8353/25 mg selumetinib
50 mg MK-8353/50 mg selumetinib
DL3
150 mg MK-8353/50 mg selumetinib
100 mg MK-8353/75 mg selumetinib
DL4
150 mg MK-8353/50 mg selumetinib
100 mg MK-8353/75 mg selumetinib
DL5
200 mg MK-8353/75 mg selumetinib
150 mg MK-8353/100 mg selumetinib
DL6
No additional escalation
a
150 mg MK-8353/100 mg selumetinib
DL7
No additional escalation
No additional escalation
a ERKi escalation per Figure 1B is not required because highest dose of ERKi is tolerable at 
DL6.
The rationale for conducting the dose escalation along these sequences is given in 
Section 4.2.1.
In each of the off-diagonal sequences, the mTPI design with a target DLT rate of 
approximately 30% will be applied to identify a potential MTD. Based on the emerging 
safety and/or efficacy signals, other dose levels may also be explored in consultation and 
agreement with the investigators and Sponsor.
The DLT rates across different dose combinations, in each dose combination sequence, will 
be estimated using isotonic regression under the assumption of monotonicity between the 
DLT rates and dose levels in each row and in each column of the dose combination grid
[Dykstra, R. L. 1982]. This dose escalation study may yield multiple MTDs. The totality of 
the data will be considered before deciding on the dose combinations(s) to carry forward to 
further development (ie, preliminary RP2D).
Upon identification of the preliminary RP2D(s) for the MK-8353 and selumetinib 
combination, additional participants with solid tumors will be enrolled in the dose expansion 
 
 
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phase of this trial. Participants in the expansion phase of this study will receive MK-8353 in 
combination with selumetinib as dual therapy. 
Preliminary efficacy will be evaluated using objective response rate (ORR) and progression-
free survival (PFS) assessed by the investigator based on the RECIST Version 1.1 as 
exploratory objectives. Overall survival (OS) will also be evaluated as an exploratory 
objective. 
Participants will be monitored carefully for the development of AEs and for clinical and/or 
radiographic evidence of disease progression according to RECIST 1.1. In participants who 
have initial evidence of radiological progressive disease (PD) by RECIST 1.1, it will be at 
the discretion of the investigator whether to continue a participant on study 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.
Adverse events will be evaluated by the investigator, according to criteria outlined in the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.0, to establish the safety and tolerability of MK-8353 in combination with 
selumetinib as per the primary objective of this study. The definition of DLTs and criteria for 
dose modification are outlined in Section 6.6.2 and Section 6.6.3.
Participants may receive study treatment until disease progression is radiographically 
documented and confirmed by the site per RECIST 1.1, unacceptable toxicity (AEs), 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw treatment, participant withdrawal of consent, pregnancy of the subject, 
noncompliance with study treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment, at which point they will be discontinued from the study.
After the end of treatment (EoT), participants are to be followed up for safety for at least 30 
days following the last study dosing and until recovery or stabilization of all related 
toxicities. Tumor measurements will continue to be made every 9 weeks until PD is
observed, and each participant will be followed for survival. Imaging will not be collected 
during the Survival Follow-up Visit(s).
Participants may also agree to provide an optional on-treatment biopsy for biomarker 
analysis as outlined in the Scheduled of Activities (SoA; Section 1.3).
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
 
 
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4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Dose Combination Sequences
Because this is a dual dose escalation study, more than one dose combination level may 
satisfy the target DLT rate. Therefore, dose escalation along multiple dose combination 
sequences may need to be conducted. Initiating the dose escalation along the diagonal of the 
dose combination grid of Figure 1A (DL1, DL2 and DL3) is motivated by the potential for a 
more efficient study; beyond DL3 to DL7 each drug is escalated individually to mitigate the 
potential for overlapping toxicities (Figure 1A). 
Consistent with the mTPI design, this study assumes nondecreasing toxicity with increasing 
dose levels. This assumption is made in each row and in each column of the dose 
combination grid, which implies the same relationship holds along the diagonal as well. Due 
to this assumption and the dose escalation decisions under the mTPI design, the simultaneous 
off-diagonal sequences outlined in Figure 1B will not start at the dose combinations 
immediately above and immediately to the right of the dose combination that concludes the 
dose escalation along the diagonal sequence. Instead, these sequences will start at the dose 
combinations immediately to the left and below this dose combination in the case of DL2, 
DL3 and DL5 (Figure 1B).  If the dose combinations that conclude the escalation along the 
diagonal sequence are DL4 or DL6, the starting doses in the off-diagonal sequence(s) may be
even more conservative (Figure 1B). 
4.2.2
Rationale for Endpoints
4.2.2.1
Efficacy Endpoints
Exploratory Efficacy endpoints in this study include ORR and PFS, which are based on 
RECIST 1.1 as assessed by investigator. RECIST 1.1 is a validated tool in assessing anti-
cancer activity of an investigational agent. Overall survival is also an exploratory endpoint.
An imaging contract research organization will be used to collect, clean, and hold tumor 
imaging. Images will be collected for possible analysis by blinded, independent central 
review (BICR).
4.2.2.1.1
Response Rate Assessed by RECIST 1.1
RECIST 1.1 will be used by the principal investigator to determine the objective response. 
4.2.2.2
Safety Endpoints
The primary safety endpoint is the incidence of DLTs and number of discontinuations of 
study treatment due to an AE. Safety and tolerability will be assessed by clinical review 
throughout the trial. The toxicities and grades experienced by participants who have received 
study treatment, including AEs, serious AEs (SAEs) and events of clinical interest (ECIs)
will be summarized. Other safety measures evaluated in study include laboratory tests, 
 
 
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electrocardiograms (ECGs), echocardiogram/multigated acquisition), vital signs, physical
examinations, and eye examination.
4.2.2.3
Pharmacokinetic Endpoints
A secondary objective of this trial is to characterize the PK profile of MK-8353 and 
selumetinib (and their metabolites). The PK concentrations of MK-8353 and selumetinib 
(and its metabolites) will be used to derive PK parameters of the agents. Furthermore, the 
results of these analyses will be potentially used in conjunction with the pharmacodynamics, 
safety, and exploratory endpoint data to help assess future dosing strategies for MK-8353 and 
selumetinib.
4.2.2.4
Planned Exploratory Biomarker Research
4.2.2.4.1
Biospecimens
It is important to investigate the determinants of response or resistance to cancer treatments 
administered, as well as determinants of AEs in the course of our clinical studies. These 
efforts may identify novel predictive/PD biomarkers and generate information that may 
better guide single-agent and combination therapy. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.      
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). 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. 
Circulating tumor DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
 
 
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correlate to clinical response to treatment. Specific MEK signaling-related gene sets may be 
evaluated and new signatures may be identified. Individual genes related to the immune 
system may also be evaluated. MicroRNA profiling may also be pursued as well as exosomal 
profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses. Tumor or blood-
derived proteins may correlate with response to treatments. Therefore, tumor tissue may be 
subjected to proteomic analyses using a variety of platforms that could include but are not 
limited to immunoassays detecting pERK and liquid chromatography/mass spectrometry. 
This approach could identify novel protein biomarkers that could aid in patient selection for 
treatments.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, tumor derived proteins can be shed from tumor 
and released into the blood. Assays such as enzyme-linked immunoassay (ELISA) measure 
such proteins in serum. Correlation of expression with response to treatment 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.
4.2.2.4.2
Imaging
For MEK inhibitors, it has been observed that decrease in FDG uptake is primarily related to 
decrease in GLUT1 mediated by drug-induced changes in MAPK signaling pathways 
[Baudy, A. R., et al 2012]. In clinical studies with MEK inhibitors, FDG was able to identify 
early nonresponding patients with a high negative predictive value [Kraeber-Bodere, F., et al
2012] [Zimmer, L., et al 2014] [Rosen, L. S., et al 2016]. Early changes in FDG PET 
parameters in the tumor may be indicative of biological and pharmacodynamic activities 
related to mode of action and thus contribute towards selection of optimum dosing regimen 
of MK-5618 and MK-8353. This study will evaluate FDG-PET as an exploratory biomarker 
of pharmacodynamic changes related to mechanism of action of the study drugs at the MTD 
levels.
4.2.2.5
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
 
 
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future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 6.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
In the absence of a reliable pharmacodynamic marker for both ERKi and MEKi, variability 
in PK alone was also used to guide starting dose.
MK-8353 starting dose will be 50 mg BID with 4 days on/3 days off intermittent dosing 
schedule. This was selected based on PK simulations of MK-8353 indicated that 50 mg BID 
would be the highest dose where there is no overlap in the interquartile range of exposure 
from the 350 mg BID dose could be expected (MTD of MK-8353 monotherapy was 350 mg 
BID with continuous dosing [PN001]).
The starting dose for selumetinib is planned to be 25 mg BID with 4 days on/3 days off 
intermittent dosing schedule. PK simulations indicated that the interquartile range of 
exposures at 25 mg BID would have a separation from exposures at 75 mg BID dose 
(monotherapy selumetinib MTD = 75 mg BID continuous dosing).
In addition, in the clinical evidence of cobimetinib (MEKi) + GDC-0994 (ERKi) trial, 
[Weekes, C. D., et al 2017] started at 2/3 cobimetinib and 1/2 of GDC-0994 of the RP2D 
with 21 days on and 7 days off dosing schedule, and had 1 DLT observed [Weekes, C. D., et 
al 2017]. Therefore, a more conservative approach is to have a starting dose at 1/5 of the 
MTD of MK-8353 and 1/3 of the MTD of selumetinib with an intermittent dosing of 4 days 
on/3 days off. 
4.3.2
Maximum Dose/Exposure for This Study
The maximum dose of MK-8353 for this study will be 250 mg administered orally BID, on a 
4 days on followed by 3 days off schedule (maximum 500 mg total per day). The Phase 2 
dose for MK-8353 monotherapy is 350 mg BID administered continuously. This will provide 
a total dose of 6000 mg per 3-week cycle which is less than monotherapy dose per 3-week 
cycle (14700 mg).
The maximum dose of selumetinib for this study will be 125 mg administered orally BID, on 
a 4 days on followed by 3 days off schedule (maximum 250 mg total per day). The Phase 2 
dose for selumetinib monotherapy is 75 mg BID administered continuously. This will 
provide a total dose of 3000 mg per 3-week cycle which is less than monotherapy dose per 
3-week cycle (3150 mg).
Inhibition of both MEK and ERK may exacerbate toxicity of either inhibitor alone. However, 
intermittent dosing schedules of both MK-8353 and selumetinib (4 days on followed by 3 
 
 
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days off schedule) is likely to be better tolerated than continuous dosing and short half-lives
(approximately 8 hours) would reduce concerns over toxicity while maintain anti-tumor 
activity [Xue, Y., et al 2017].
4.3.3
Rationale for Dose Interval and Study Design
MK-8353 will have 50 mg incremental dose levels up to 250 mg (50, 100, 150, 200, 250 mg 
BID). Selumetinib will have 25 mg incremental dose levels up to 125 mg (25, 50, 75, 100,
and 125 mg BID). These follow incremental increases of 100%, 50%, 33% and 25%.  The 
smaller increases at higher doses take into consideration the risk for greater overlapping 
toxicity.
An alternate dose level, frequency drug administration and dosing schedule may be explored,
and an optimal dose will be selected based on totality of data (PK, pharmacodynamic, and 
safety) emerging throughout the trial. The protocol will be amended as required.
The 4 days on/3 days off schedule was selected based on 1) a preclinical evidence that 4 days 
on/3 days off with vemurafenib (RAFi), trametinib (MEKi), SCH984 (ERKi) which was 
shown to ameliorate toxicity and sustain efficacy [Xue, Y., et al 2017]. In this study, 
continuous MEK/ERK/BRAFi administration was toxic and sequential ERK/MEK inhibition 
fosters resistance and was less effective, 2) the most common safety signal we see for MAPK 
pathway is skin rash, usually start seeing early time like from approximately 7 days after the 
treatment and within 3 month [Wang, D., et al 2007], 3) the short half-life of selumetinib and 
MK-8353 (approximately 8 hours) suggests that selumetinib and MK-8353 would be 
eliminated in as long as 2 days after stopping treatment, therefore, have the potential 
advantage to exploit intermittent schedules that have (preclinically) been shown to ameliorate 
toxicity but maintain anti-tumor activity [Xue, Y., et al 2017].
4.3.4
Dose Finding Using a Modified Toxicity Probability Interval Design
The modified toxicity probability interval (mTPI) design [Ji Y, Li Y, Bekele BN 2007] with
a target DLT rate of approximately 30% will be applied to identify the MTD in each of the 
studied dose combination sequences described above.
In each dose combination sequence separately, dose escalation and de-escalation decisions 
will be based on the mTPI design and will depend on the number of participants enrolled and 
number of DLTs observed at the current dose combination level. The number of DLTs will 
be based on the DLT evaluable population which consists of participants who finished 
Cycle 1. See Section 5.6 and Section 9.5.1 for details.
A minimum of 3 participants will be required at each dose combination level. However, 
depending on the accrual rate, 3, 4, 5, or 6 participants may be enrolled at each new dose 
combination level. In Table 2, the columns indicate the numbers of participants treated at the 
current dose combination level, and the rows indicate the numbers of participants 
experiencing DLT. The entries of the table are the dose-finding decisions: E, S, D, and DU 
represent escalating the dose, staying at the same dose, de-escalating the dose, and excluding 
the dose from the trial due to unacceptable toxicity, respectively. For example, if 0 out of 
 
 
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3 participants at a given dose combination level develop a DLT, then the dose can escalate to 
the next level. If 2 participants out of 3 develop a DLT, the dose will be de-escalated to the 
next lower dose level. If 3 out of 3 participants develop a DLT, this indicates an unacceptable 
toxicity at this dose combination. The dose combination should be de-escalated, and the 
current dose combination will not be explored further. If 1 out of 3 participants at a given 
dose combination level develops a DLT, then additional participants should be enrolled at 
that dose combination level following the rules below.
When adding participants to a dose combination level in response to a “stay” decision, the 
number of additional participants to be enrolled is capped to minimize the exposure to a dose 
combination that may be unacceptably toxic (denoted as DU in Table 2). Secondly, to 
determine how many more participants can be enrolled at the dose combination level, one 
can count steps in diagonal direction (down and to the right) from the current cell to the first 
cell marked DU. For example, if 1 of 3 participants have experienced a DLT at a given dose 
combination level, no more than an additional 3 participants should be enrolled at this dose 
combination level until additional DLT data are available. This is because this dose 
combination level would be considered unacceptably toxic if all 3 of the additional 
participants experience a DLT (ie, 4/6 participants with DLT in Table 2). The same 
principles will be applied whether 3, 4, 5, or 6 participants are initially enrolled at that dose 
combination level.
A D or DU decision at the lowest dose combination level will stop the trial. An E decision at 
the highest dose combination level will result in staying at that level. During dose finding, it 
may be acceptable to deescalate to an intermediate dose combination that was not predefined 
and not previously-studied if evaluation of toxicity at such a dose combination is desired. If 
this approach is taken, 3 to 6 new participants may be enrolled at the new intermediate dose
combination, and the rules should be used to determine further enrollment at this dose 
combination level.
Dose finding will end after 14 participants have been enrolled at any of the tested dose
combinations, in each sequence separately, regardless of subsequent dose escalation decision.
The DLT rates across dose combination levels will be estimated under the assumption of a 
monotonic relationship between toxicity and dose in each column, in each row and along the 
main diagonal of the dose combination grid. In each dose combination sequence, the dose 
combination with an estimated DLT rate closest to 30% will be treated as a preliminary 
MTD. However, the totality of the data will be considered before deciding on the dose(s) to 
carry forward into the planned expansion phase, and the escalation schedule may be adjusted 
based on PK, pharmacodynamic, and safety data emerging throughout the trial.
Note that although 30% was the target toxicity rate used to generate the guidelines in
Table 2, the observed rates of participants with DLTs at the MTD(s) may be slightly above or 
below 30%.
Dose escalation decisions will be made upon ongoing review of available PK, 
pharmacodynamic, and safety data at the current dose level.
 
 
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Based on the emerging safety and/or efficacy signals, lower, intermediate or higher dose 
combination levels may also be explored in consultation and agreement with the investigators 
and Sponsor. The exact additional dose combinations in each sequence during dose 
escalation is not predetermined, which will allow for flexibility in dose escalation based on 
emerging safety data in the clinical trial. The protocol will be amended as necessary.
Table 2
Dose-finding Rules per mTPI Design
Number of Participants Evaluable for DLT at Current Dose
Number of 
participants with at 
least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
D = De-escalate to the next lower dose; DU = The current dose is unacceptably toxic; E = Escalate 
to the next higher dose; S = Stay at the current dose 
Target toxicity rate = 30%.
Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.03[Ji Y, Li Y, Bekele BN 
2007], [Ji, Y. and Wang, S.-J. 2013]
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study, or at (a) particular study site(s), may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems, or the number of discontinuations for administrative reasons is 
too high. 
 
 
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Early study termination will be the result of the following specified criteria:
1. Incidence or severity of adverse drug reactions in this or other studies suggest a 
potential health hazard to participants
2. Plans to modify or discontinue the development of the study drug
3. Quality or quantity of data recording is inaccurate or incomplete
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-8353 or selumetinib.
5
STUDY POPULATION
Male/female participants at least 18 years of age with advanced/metastatic solid tumor(s) will 
be enrolled in the study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Have a histologically- or cytologically-documented, locally-advanced or metastatic solid 
tumor by pathology report and have received, or been intolerant to, all treatment known 
to confer clinical benefit.
2. Provide an archival or newly obtained tumor tissue sample and blood samples for 
assessment of RAS/RAF mutation and for biomarker analysis.
3. Have at least 1 measurable lesion as defined by RECIST 1.1 on imaging studies 
(computed tomography [CT] or magnetic resonance imaging [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.
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale. (Obtain within 7 days prior to first dose of study treatment.)
5. Have the ability to swallow and retain oral medication.
6. Demonstrate adequate organ function as defined in Table 3
Note: All screening evaluations should be performed within the Screening period, and 
labs are to be obtained within 7 days of initiation of treatment.
 
 
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL (>1,000/mcL)
Platelets
>100,000/mcL 
Hemoglobin
>9 g/dL or >5.6 mmol/La
Renal
Serum creatinine or 
creatinine clearance (CrCl) 
(measured or calculated)b or
Glomerular Filtration Rate (GFR) 
in place of CrCl
≤1.5 X ULN or 
≥60 mL/min for participant with creatinine 
levels >1.5 X ULN 
Hepatic
Total bilirubin (serum) 
≤1.5 X ULN or 
Direct bilirubin <ULN for participants with 
total bilirubin levels >1.5 X ULN
AST (SGOT) and ALT (SGPT)
<2.5 X ULN or ≤5 X ULN for participants 
with liver metastases
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin 
Time (aPTT)
< 1.5 X ULN unless participant is receiving 
anticoagulant therapy 
< 1.5 X ULN unless participant is receiving 
anticoagulant therapy 
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate aminotransferase (serum 
glutamic oxaloacetic transaminase); ULN = upper limit of normal
a
Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable 
dose of erythropoietin (≥ approximately 3 months).
b
Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be 
adapted according to local regulations and guidelines.
Demographics
7. Is Male or Female and a minimum of 18 years of age inclusive, at the time of signing the 
informed consent.
Male Participants
8. Must agree to use a contraception as detailed in Appendix 5 of this protocol during the 
treatment period and for at least 120 days after the last dose of study intervention and 
refrain from donating sperm during this period.
 
 
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Female Participants
9. Eligible to participate if she is not pregnant, not breastfeeding, and at least 1 of the 
following conditions applies:
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least 120 days, after the last dose of study intervention. 
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study. The participant may also provide consent/assent 
for future biomedical research. However, the participant may participate in the main 
study without participating in future biomedical research.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Have had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks 
(2 weeks for palliative radiation) prior to the first dose of study treatment, or has not 
recovered to CTCAE Grade 1 or better from any AEs that were due to cancer 
therapeutics administered more than 4 weeks earlier (this includes participants with 
previous immunomodulatory therapy with residual immune-related AEs). Participants 
receiving ongoing replacement hormone therapy for endocrine immune-related AEs will 
not be excluded from participation in this study.
2. Have a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or 
in situ cervical cancer, or other in-situ cancers.
3. Have clinically active central nervous system metastases and/or carcinomatous 
meningitis. Participants with previously-treated brain or meningeal metastases may 
participate and be eligible for treatment provided they are stable and asymptomatic 
(without evidence of progression by MRI scan of the brain separated by at least 4 weeks 
after treatment), have no evidence of new or enlarging brain metastases, are evaluated 
within 4 weeks prior to first study treatment administration, and are off 
immunosuppressive doses of systemic steroids at least 2 weeks prior to enrollment
 
 
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4. Have an active infection requiring therapy.
Note: Rescreening is possible after the infection resolves.
5. Have known human immunodeficiency virus (HIV) and/or Hepatitis B or C infections, or 
known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B virus (HBV) DNA or 
Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a known positive Hep C 
Ab result and known quantitative hepatitis C virus RNA results greater than the lower 
limits of detection of the assay.
6. Have undergone major surgery and has not fully recovered from any effects of major 
surgery without significant detectable infection and/or toxicity. 
Note: Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study intervention administration. 
Note: Surgery requiring regional/epidural anesthesia must be completed at least 72 
hours before first study intervention administration and participants should be 
recovered.
7. Have clinically significant cardiovascular disease as defined by the following:
a) Uncontrolled hypertension (at screening/baseline: systolic BP ≥150 mmHg or 
diastolic BP ≥95 mmHg, despite optimal therapy)
b) LVEF <55% measured by echocardiography (or multigated acquisition scan)
c) Symptomatic heart failure (New York Heart Association grade II-IV), prior or current 
cardiomyopathy, or severe valvular heart disease
d) Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical 
therapy)
e) Clinically significant cardiac arrhythmia and/or conduction abnormality ≤6 months
prior to start of study treatment
f)
Myocardial infarction (MI) or acute coronary syndrome (ACS) ≤6 months prior to 
start of study treatment
g) Mean QTcF interval >470 ms (based on mean of 3 measurements corrected for heart 
rate based on Fridericia’s formula)
8. Have a history of thromboembolic or cerebrovascular events within 6 months prior to 
treatment start, including transient ischemic attacks (TIAs), cerebrovascular accidents 
(CVAs), deep vein thrombosis, or pulmonary embolism.
 
 
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9. Have neuromuscular disorders associated with an elevated creatine kinase (eg, 
inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy.
10. Have one or more of the following ophthalmological findings/conditions:
a) Intraocular pressure >21 mmHg, or uncontrolled glaucoma (irrespective of intraocular 
pressure)
b) Current or past history of central serous retinopathy or retinal vein occlusion
c) Retinal degenerative disease
11. Have a known history of Gilbert’s Syndrome.
12. Have a history or current evidence of a gastrointestinal (GI) condition (eg, inflammatory 
bowel disease, Crohn’s disease, ulcerative colitis) or impaired liver function or diseases 
that in the opinion of the investigator may significantly alter the absorption or 
metabolism of oral medications.
13. Have a known psychiatric or substance abuse disorder, or any other cognitive disorder 
per the opinion of the investigator, that would interfere with the participant’s ability to 
cooperate with the requirements of the study.
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
the last dose of study treatment.
Prior/Concomitant Therapy
15. Received prior therapy with a MEK inhibitor (eg, cobimetinib, trametinib), or an ERK 
inhibitor (eg, MK-8353, GCD-0994, ulixertinib), or a BRAF inhibitor (eg, dabrafenib, 
vemurafenib).
16. Received any herbal medications/supplements or any medications or foods that are strong
or moderate inhibitors or inducers of CYP2C19 and CYP3A4 enzymes within 14 days
prior to the start of study treatment (Table 5).
Prior/Concurrent Clinical Study Experience
17. Is currently participating and receiving study treatment in a study of an investigational 
agent or has participated and received study treatment in a study of an investigational 
agent or has used an investigational device within 28 days of administration of 
selumetinib.
Note: Participants who have entered the Post-treatment Follow-up Phase of an 
investigational study may participate as long as it has been 4 weeks since the last 
dose of the previous investigational agent.
 
 
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Diagnostic Assessments
Other Exclusions 
18. Have a history of allergic reactions attributed to compounds of similar chemical or 
biologic composition to agents and/or excipients used in the study.
Pregnancy Exclusion
19. A WOCBP who has a positive urine pregnancy test within 24 hours before the first dose 
of study treatment (see Appendix 5). If the urine test cannot be confirmed as negative, a 
serum pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
5.3
Special Considerations for Subjects of Asian Ethnicity
Plasma exposure of selumetinib (Cmax and AUC) is higher, at a population level, in subjects
of Asian ethnicity by approximately 1.5- to 2-fold, compared with Western subjects. 
However, the PK of selumetinib show considerable variation and there is overlap in the range 
of exposure experienced by Asian and Western subjects (some individual Asian subjects 
have similar plasma levels to those in Western subjects). The higher average plasma 
exposure was not associated with a change in the tolerability profile of single dose 
selumetinib.
Patients of Asian ethnicity are not excluded from studies evaluating selumetinib. However,
when considering enrolling an individual of Asian ethnicity to a selumetinib clinical study,
investigators should make a clinical judgment as to whether the potential risk of experiencing
higher selumetinib plasma levels outweighs the potential benefit of treatment with
selumetinib. Investigators should be aware of the potentially higher risk of adverse events 
when monitoring patients of Asian ethnicity receiving treatment in clinical studies of 
selumetinib.
Additional details are available in the selumetinib IB.
5.4
Lifestyle Considerations
5.4.1
Meals and Dietary Restrictions
Selumetinib should be taken on an empty stomach; no food or drink other than water for 
approximately 2 hours prior to dosing and approximately 1 hour after dosing. The participant 
must be fasting for the glucose (finger stick) obtained pre-dose on C2D4 visit.
Foods that contain CYP3A inhibitors must not be consumed during the study. Grapefruit 
juice and other fruit juices 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 inhibitors, such as grapefruit juice, may significantly increase the 
levels of MK-8353 and cause increased toxicity. 
 
 
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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.
5.4.2
Caffeine, Alcohol, and Tobacco Restrictions
There are no study specific restrictions.
5.4.3
Activity Restrictions
There are no study specific restrictions.
5.5
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.6
Participant Replacement Strategy
In order to adequately evaluate the safety of the doses administered in this study, all 
participants enrolled must meet the criteria for evaluability for Cycle 1. Participants are 
considered nonevaluable and will be replaced if:

They are allocated but not treated.

They discontinue from the trial prior to completing all the safety evaluations for 
reasons other than treatment-related AEs.

They receive less than 75% of the total selumetinib or MK-8353 study treatment in 
Cycle 1 and did not experience a DLT.
Participants who are not evaluable will be replaced unless accrual to the dose level has 
stopped. Nonevaluable participants will not be counted toward the total number of 
participants in the dose level for DLT evaluation.
If a participant experiences a DLT in Cycle 1, study intervention may be discontinued 
following discussion between the Sponsor and investigator. However, if the participant is 
deriving clinical benefit from the study intervention, the participant may be allowed to 
continue after discussion between the Sponsor and the investigator.
 
 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Study interventions provided by the Sponsor will be packaged to support enrollment and 
replacement participants as required. When a replacement participant is required, the Sponsor 
or designee needs to be contacted prior to dosing the replacement supplies. Clinical supplies 
will be labeled with guidance to administer as directed.
 
 
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
Table 4
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
MK-8353 + 
MK-5618
Experimental
MK-8353
Drug
Capsule
50 mg,
100 mg
50 mg,
100 mg,
150 mg,
200 mg,
250 mg
Oral
BID
4 days on 
and 3 days 
off
Experimental
IMP
Provided 
centrally 
by 
Sponsor
MK-8353 + 
MK-5618
Experimental
MK-5618 
(Selumetinib)
Drug
Capsule
25 mg
25 mg,
50 mg,
75 mg,
100 mg,
125 mg
Oral
BID
4 days on 
and 3 days 
off
Experimental
IMP
Provided 
centrally 
by 
Sponsor
BID = Twice daily; IMP = Investigational Medicinal Products; NIMP = Non-investigational Medicinal Product
Alternate dose levels, drug administration frequency and dosing schedule (eg, BID vs. once daily [QD], on/off intermittent dosing schedule) may be explored.
All supplies indicated in Table 4 will be provided per the "Sourcing" row depending upon local country operational requirements. 
Every attempt should be made to source these supplies from a single lot/batch number. The study site is responsible for recording the 
lot number, manufacturer, and expiry date for any locally purchased product per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
 
 
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6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation will occur centrally using an interactive response system / integrated 
web response system (IRS/IWRS). Participants will first be assigned in a nonrandom fashion
to the diagonal dose combination sequence. Once this sequence is closed and in case two 
additional off-diagonal dose combination sequences are initiated, participants will be 
allocated by alternate assignment to either off-diagonal sequence. In each sequence, a new 
dose combination will open for enrollment without delay once the 21-day DLT observation 
 
 
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period of the previous dose combination level is completed. Dose escalation decisions within 
each sequence will be made independently.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol specified treatment plan or procedures 12 weeks will be 
considered noncompliant. Further, any interruptions of MK-8353 and selumetinib doses for
non-drug related or administrative reasons require consultation between the investigator and 
the Sponsor and written documentation of the collaborative decision on participant 
management.
6.5
Concomitant Therapy
6.5.1
Acceptable Concomitant Medication
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care except for those that are prohibited as described in Section 6.5.2. All
concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the study period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF.
All concomitant medications received within 30 days before the first dose of study 
intervention and 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered after 30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs as defined in Section 8.4.
6.5.2
Prohibited Concomitant Medications
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during time periods specified by this protocol for that medication or vaccination. If there is a 
clinical indication for any medications or vaccinations specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor Clinical Director. The final decision on any
supportive therapy or vaccination rests with the investigator and/or the participant’s primary 
physician. However, the decision to continue the participant on study intervention requires 
the mutual agreement of the investigator, the Sponsor, and the participant.
 
 
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Participants are prohibited from receiving the following therapies during the Screening and 
study intervention phase(s):
1.
Antineoplastic systemic chemotherapy or biological therapy 
2.
Immunotherapy not specified in this protocol
3.
Chemotherapy not specified in this protocol
4.
Investigational agents other than MK-8353 and selumetinib
5.
Any supplemental vitamin E. High doses of vitamin E have been reported to cause 
bleeding and interrupt blood coagulation processes.

Selumetinib capsules contain vitamin E in the form of D-a-tocopheryl 
polyethylene glycol 1000 succinate (TPGS), a water-soluble form of vitamin E, 
which acts as a formulation excipient. 

Selumetinib should be administered with caution in participants who are receiving 
concomitant coumarin anticoagulant medications, eg, warfarin. These participants 
should have their INR monitored, anticoagulant assessments conducted more 
frequently, and the dose of the anticoagulant therapy adjusted accordingly.
6.
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion after the DLT observation period in order 
for the participant to be considered evaluable for DLT.
7.
Agents that may affect the metabolism of MK-8353 or selumetinib (eg, 
strong/moderate inhibitors or inducers of CYP3A4 and CYP2C19), unless considered 
clinically indicated (Table 5)
Note: If the PI determines the use of such agent is clinically indicated, caution 
must be taken when co-administering these agents with MK-8353 and 
selumetinib. 
 
 
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8.
Compounds with a narrow therapeutic index that are substrates for CYP3A4, -2C8, 
OATP1B1/3, and OCT2 should be avoided (Table 5). Once study treatment is 
initiated, the participant must not take medications listed in Table 5 during the course 
of the study.

Table 5 is not a comprehensive listing. The investigator must use his/her medical 
judgment when a participant presents with a medication not on the list or call the 
Sponsor for clarification as needed. The investigator should consult an actively 
updated list of drugs that are clinically relevant inducers, or inhibitors of CYP450, 
including CYP2C19 and CYP3A4, and a narrow therapeutic index that are 
substrates for CYP3A4, -2C8, OATP1B1/3, and OCT2, as well as the product 
labeling of these compounds for reference.
 
 
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Table 5
Examples of CYP3A4 Inducers/Inhibitors and Narrow Therapeutic Index 
Substrates of CYP3A4, CYP2C8, OATP1B1/3 and OCT2 Prohibited During the Trial 
Strong CYP3A4 
Inhibitorsa,g
Strong CYP3A4 
Inducersb,g
Moderate CYP3A4 
Inhibitorsc,g
Moderate CYP3A4 
Inducersd,g
Atazanavir
Cannabis (oral, IV)
Clarithromycin
Cobicistat
Conivaptan
Danoprevir and ritonavir
Dasabuvir
Elvitegravir and ritonavir
Grapefruit juice and other 
juicesf
Idelalisib
Indinavir and ritonavir
Itraconazole
Ketoconazole
Lopinavir and ritonavir
Paritaprevir and ritonavir
(ombitasvir and/or dasabuvir)
Posaconazole
Nefazodone
Nelfinavir
Ritonavir
Saquinavir and ritonavir
Telithromycin
Tipranavir and ritonavir
Troleandomycin
Voriconazole
Carbamazepine
Enzalutamide
Mitotane
Phenobarbital
Phenytoin
Rifabutin
Rifampin
St John’s worte
Amprenavir
Aprepitant
Cimetidine
Ciprofloxacin
Clotrimazole
Crizotinib
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Fluconazole
Fluvoxamine
Fosamprenavir
Imatinib
Tofisopam
Verapamil
Grapefruit juice and 
other juicesf
Bosentan
Efavirenz
Etravirine
Modafinil
CYP3A4 Substrates with 
Narrow Therapeutic Indexh
CYP2C8 Substrates with 
Narrow Therapeutic 
Indexh
OATP1B1/1B3 
Substrates with Narrow 
Therapeutic Indexi
OCT2 Substrates 
with Narrow 
Therapeutic Indexi
Alfentanil
Alprazolam
Astemizole
Cisapride
Ergotamine
Diergotamine
Cyclosporine
Fentanyl (including 
Duragesic)
Hydrocodone
Lovastatin
Lurasidone
Paclitaxel
Pimozide
Quinidine
Rivaroxaban
Sirolimus
Tacrolimus
Cisapride
Repaglinide
Paclitaxel
Asunaprevir
Atorvastatin
Bosentan
Danoprevir
Docetaxel
Glyburide
Nateglinide
Paclitaxel
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
Dofetilide
Metformin
 
 
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Strong CYP3A4 
Inhibitorsa,g
Strong CYP3A4 
Inducersb,g
Moderate CYP3A4 
Inhibitorsc,g
Moderate CYP3A4 
Inducersd,g
CYP = cytochrome P450; OATP = Organic Anion Transporting Polypeptide; OCT = Organic Cation Transporter
a
Strong inhibitors are drugs that increase the plasma AUC of sensitive CYP index substrates by 5-fold.
b
Strong inducers are drugs that decrease the plasma AUC of sensitive CYP index substrates by 80%. 
c
Moderate inhibitors are defined as causing a ≥2- but <5-fold increase in the AUC values of sensitive CYP index 
substrates when the inhibitors were given at the highest approved dose and the shortest dosing interval in clinical 
evaluations.
d
A moderate inducer decreases the AUC of a sensitive index CYP substrate by ≥50% to 80%.
e
The effect of St John’s wort varies widely and is preparation-dependent.
f
The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used 
(eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (eg, low 
dose, single strength).
g
Compiled from the table of substrates, inhibitors and inducers available at: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0
93664.htm (“Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers”).
h
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, accessible at the 
following link: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm09366
4.htm (In subsection “CYP Enzymes”, select “Clinical substrates”).
i
OATP1B1/1B3 and OCT2 substrates with narrow therapeutic range refers to drugs whose exposure-response 
indicates that increases in their exposure levels by the concomitant use of OATP1B1/1B3 or OCT2 inhibitors may 
lead to serious safety concerns. For specific information, refer to the Classification of Substrates tables, accessible 
at the following link: 
https://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm09366
4.htm (In subsection “Transporters”, select “Clinical substrates”).
Based on investigator assessment, participants who require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
intervention and continue in the Post-treatment Follow-up Phase as outlined in the SoA
(Section 1.3). Participants may receive other medications that the investigator deems to be 
medically necessary.
6.5.3
Supportive Care
6.5.3.1
MK-8353 Supportive Care
Medications required to treat AEs or concurrent illnesses other than those prohibited in 
Section 6.5.2 are allowed during the study. These include antiemetics, growth factors, and 
other supportive care medications. Contraceptive medications as described in Appendix 5 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.
 
 
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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.

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.
 
 
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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 according to institutional guidelines in the 
context of standard of care for diarrhea are permitted (except prohibited medications; 
see Section 6.5.2).

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 
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 
American Society of Clinical Oncology (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.
 
 
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6.5.3.2
Selumetinib Supportive Care

Hypertension: It is recommended that additional blood pressure monitoring occur for 
participants who may be at risk (participants with hypertension at baseline) or those 
with antecedents of hypertension or those treated with antihypertensive medication. 
Early initiation of treatment is recommended after diagnosis, with aggressive 
management of emergent hypertension.

Nausea and/or vomiting: Because nausea and vomiting have been reported for 
selumetinib, it is recommended that participants are educated on the possibility of 
occurrence of these side effects prior to starting study treatment. Participant education 
as well as proper management of nausea and/or vomiting at the first sign is important. 
Clinical judgment and experience of the treating physician should guide the 
management plan of each participant. Participants experiencing nausea and/or 
vomiting CTCAE Grade ≥1 should receive antiemetics at the discretion of the treating 
physician (as per local guideline). It is recommended that participants be provided a 
prescription for antiemetics, and are instructed on the use of antiemetics on the first 
day of study drug treatment. Prophylactic antiemetics such as dexamethasone 8 mg, 
prochlorperazine, or metoclopramide may be administered to participants on an "as 
needed" basis. Medication use should be recorded accordingly.
Dose interruption/reduction decisions for nausea and/or vomiting should be based on 
the CTCAE grade of the toxicity and the guidelines provided in Section 6.6.4.
As guidance for recommendations on supportive measures for the prevention and/or 
management of nausea and/or vomiting, the published recommendation from ASCO
[Sepulveda, A. R., et al 2017], European Society for Medical Oncology (ESMO)
[Van Cutsem, E., et al 2016], and Multinational Association of Supportive Care 
(MASCC) can be used [Basch, E., et al 2011] [Roila, F., et al 2010].

Diarrhea: Management of diarrhea should be instituted at the first sign of abdominal 
cramping, loose stools or overt diarrhea. All concomitant therapies used for treatment 
of diarrhea must be recorded on the Concomitant Medications section of the 
participant record. It is recommended that participants be provided loperamide tablets 
and are instructed on the use of loperamide on the first day of selumetinib treatment. 
In addition to the selumetinib -induced diarrhea dosing guidelines, these instructions 
should be provided at each visit and the site should ensure that the participant 
understands the instructions. 
For uncomplicated Grade 1/2 diarrhea 

Stop all lactose-containing products, alcohol and eat frequent small meals that 
include bananas, rice, applesauce, or toast) 

Stop laxatives, bulk fiber (ie, Metamucil®) and stool softeners (eg, docusate 
sodium; Colace®) 
 
 
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
Stop high-osmolar food supplements such as Ensure® Plus and Jevity® Plus 
(with fiber) 

Drink 8 to 10 large glasses of clear liquids per day (eg, water, Pedialyte®, 
Gatorade® or broth) 

Consider administration of standard dose of loperamide: initial administration 4 
mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after each unformed 
stool

Discontinue loperamide after 12-hours diarrhea-free (Grade 0) interval

If uncomplicated Grade 1 to 2 diarrhea persists for more than 24 hours, escalate to 
high dose loperamide: 2 mg every 2 hours (max. of 16 mg/day) or after each 
unformed stool. 
Note: Oral antibiotics may be started as prophylaxis for infections under the 
discretion of the physician. 

If uncomplicated Grade 1 to 2 diarrhea persists after 48 hours of treatment with 
loperamide, discontinue loperamide and begin a second-line agent which can be 
an opiate (opium tincture or paregoric), octreotide acetate or steroid (budesonide).
For complicated Grade 1/2 diarrhea or any Grade 3 to 4 diarrhea 

The participant must call the investigator immediately 

If loperamide has not been initiated, initiate loperamide immediately. Initial 
administration 4 mg, then 2 mg every 4 hours (maximum of 16 mg/day) or after 
each unformed stool. 

Administer IV fluids and electrolytes as needed. In case of severe dehydration, 
replace loperamide by octreotide. 

Monitor/continue IV fluids and antibiotics as needed. Intervention should be 
continued until the participant is diarrhea free for at least 24 hours. 

Hospitalization may need to be considered. 
Skin Toxicity: Clinical judgment and experience of the treating physician should guide 
the management plan of each participant. In general, the following interventions are in 
addition to the rash dosing adjustment guidelines in Table 6.

Prophylaxis of skin toxicity to be initiated 24 hours prior to the first treatment 
with study drug or later as needed. 
 
 
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
Application of topical agents to the most commonly affected skin areas such as 
face, scalp, neck, upper chest and upper back.
Topical agents include non-oily sunscreen (para-aminobenzoic acid [PABA] free, 
SPF ≥30, ultraviolet A [UVA]/ultraviolet B [UVB] protection), topical steroids 
(preferably mometasone cream ie, Elocon®) and topical erythromycin (ie, 
Eryaknen® or topical pimecrolimus). 
Note: Topical agents should be applied on a daily basis starting on Day 1 of study 
treatment or 24 hours prior to the first dose, and more often as needed. 

Possibly oral doxycycline (100 mg daily) for the first 2-3 weeks of study drug 
administration.
Other effective medications are antihistamines, other topical corticosteroids, other
topical antibiotics and low-dose systemic corticosteroids. 
The treatment algorithm based on CTCAE grade is as follows:
Mild rash (CTCAE Grade 1) 

Consider prophylactic rash treatment if not already started. 

Topical or other topical corticosteroid (ie, mometasone cream) and/or topical 
antibiotic (ie, erythromycin 2%) are recommended. 

The participant should be reassessed within a maximum of 2 weeks or as per 
investigator opinion. 
Moderate rash (CTCAE Grade 2)

Use of topical erythromycin or clindamycin (1%) plus topical mometasone or 
pimecrolimus cream (1%) plus oral antibiotics such as: lymecycline (408 mg 
QD), doxycycline (100 mg BID) or minocycline (50 to 100 mg QD).

Although there has been no evidence of phototoxicity or photosensitivity in 
participants being treated with selumetinib, doxycycline (or minocycline as 
second-line) should be used with thorough UV protection (ie, avoidance of direct 
exposure to sunlight, use of sunscreen and sunglasses).

Use of acitretin is not recommended
 
 
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Severe rash (CTCAE Grade 3-4)
CTCAE Grade 3

In addition to the interventions recommended for moderate rash, consider oral 
prednisolone at a dose of 0.5 mg/kg. Upon improvement, taper the dose in a 
stepwise manner (25 mg for 7 days, subsequently decreasing the dose by 
5 mg/day every day). 

Alternatively, in addition to the interventions recommended for moderate rash, 
consider oral isotretinoin (low doses, ie, 0.3 to 0.5 mg/kg) [Lacouture, M. E., et al 
2011]. 

Use of acitretin is not recommended. 
CTCAE Grade 4

Immediately discontinue the participant from study drug and treat the participant 
with oral and topical medications (see recommendation CTCAE Grade 3).
Symptomatic Treatment:

It is strongly recommended that participants who develop rash/skin toxicities 
receive symptomatic treatment:
o
For pruritic lesions, use cool compresses and oral antihistaminic agents
o
For fissuring, use Monsel’s solution, silver nitrate, or zinc oxide cream. If not 
sufficient use mild steroid ointments or combinations of steroids and 
antibiotics such as Fucicort®
o
For desquamation, use emollients with mild pH 5/neutral (best containing urea 
10%)
o
For paronychia, antiseptic bath and local potent corticosteroids, use oral 
antibiotics and if no improvement is seen, refer to a dermatologist or surgeon
o
For infected lesions, obtain bacterial and fungal cultures and treat with topical 
or systemic antibiotics based on sensitivity of culture
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Administration/Escalation
6.6.1.1
Dose Administration (Preparation)
Details on preparation and administration of MK-8353 and selumetinib are provided in the 
appropriate Pharmacy/Procedures Manual.
 
 
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6.6.2
Definition of Dose limiting Toxicity
All toxicities will be graded using NCI CTCAE v4.0 based on the investigator assessment.
The DLT window of observation will be during Cycle 1. The observation window can be 
modified to encompass Cycle 1 and 2 (and/or additional cycles).
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to study treatment 
administration.
1. Grade 4 nonhematologic toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:

Grade 4 thrombocytopenia of any duration

Grade 3 thrombocytopenia associated with clinically significant bleeding 
3. Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per SOC lasting <72 hours; 
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per SOC.
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if:

Clinically significant medical intervention is required to treat the subject, or

The abnormality leads to hospitalization, or

The abnormality persists for ≥72 hours.

The abnormality is consistent with drug-induced liver injury and meeting the 
protocol Events of Clinical Interest criteria (see Section 8.4.7)
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc.
 
 
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5. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as 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. An elevated AST or ALT laboratory value that is ≥3X the ULN and an elevated total 
bilirubin laboratory value that is ≥2X the ULN and, at the same time, an alkaline 
phosphate laboratory value that is <2X the ULN, as determined by the way of
protocol-specified laboratory testing or unscheduled laboratory testing.
7. Prolonged delay (>2 weeks) in initiating Cycle 2 due to treatment-related toxicity.
8. Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1.
9. Missing >25% of MK-8353 and/or selumetinib doses as a result of drug-related AE(s) 
during the first cycle.
10. Grade 5 toxicity.
11. Cardiac disorders

Absolute decrease in LVEF >10% compared with baseline and the LVEF is 
below the institution’s lower limit of normal

Left ventricular systolic dysfunction Grade ≥3

Other cardiac disorders Grade ≥3
12. Vascular disorders

Hypertension CTCAE Grade ≥3 requiring more than 1 drug or more intensive 
therapy

Grade 4 hypertension
 
 
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13. Eye disorders
Retinal:

Retinopathy or retinal detachment Grade ≥2, confirmed by ophthalmic 
examination

Retinal vein disorder including retinal vein occlusion, confirmed by 
ophthalmic examination
Visual disturbances without ocular (retinal) changes:

Blurred vision, flashing lights, floaters: Grade ≥3
Other specify:

Grade 4 confirmed by ophthalmic examination
6.6.3
Timing of Dose Administration
6.6.3.1
Timing of Administration for MK-8353 and Selumetinib
Participants should be instructed to take MK-8353 and selumetinib capsules 12 ± 2 hours 
apart for BID dosing schedule with a large glass of water (~250 mL) in the morning and in 
the evening at approximately the same time every day. (If dosing is changed to QD, 
participants should be instructed to take MK-8353 and selumetinib capsules every 24 ± 2 
hours in the morning). Starting on Day 1 of Cycle 1, MK-8353 and selumetinib will be 
administered 4 days on/3 days off concomitantly at the same time. On clinic days when PK 
samples are scheduled, dosing should be delayed until arrival at the clinic and until the pre-
dose PK sample has been taken.
The reason for any variability in administration of MK-8353 and selumetinib outside of the 
protocol specified window should be documented in the subject’s chart and recorded on the 
electronic Case Report Forms (eCRFs).
Every effort should be made to begin the first dose of study intervention on the day of 
treatment assignment, but if this is not achieved, study intervention should be initiated no 
later than 3 days from the date of treatment assignment. All subsequent cycles of study 
intervention may be administered up to 3 days before or 3 days after the scheduled Day 1 of 
each cycle due to administrative reasons per the investigator’s judgment. All study 
interventions will begin on Day 1 of each cycle after all predose study procedures and 
assessments have been completed as detailed in Section 2, Summary of Activities.
The Pharmacy Manual contains specific instructions for administration of MK-8353 and 
selumetinib and additional guidance (for example, missed doses).
 
 
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6.6.4
Guidelines for Dose Modification Due to Adverse Events
6.6.4.1
Dose Modification for MK-8353 and Selumetinib
Adverse events (both nonserious and serious) associated with MK-8353 and selumetinib
exposure may occur shortly after the first dose or several months after the last dose of 
treatment. 
The CTCAE v4.0 must be used to grade the severity of AEs for individual participants. The 
investigator may attribute each toxicity event to MK-8353 alone, to selumetinib alone, or to 
the combination, but modification of the doses of both drugs must be followed according to 
Table 7. Examples of dose reduction are as follows:
Example 1:
If a participant is receiving a dose along the MTD①diagonal of the dose combination grid 
(eg, Dose Level 5, which is MK-8353 200 mg and selumetinib 100 mg) and per Table 7 a 
dose reduction is indicated, both MK-8353 and selumetinib will have doses reduced to the 
next lower dose level along the diagonal (eg, to Dose Level 3, which is MK-8353 150 mg
and selumetinib 75 mg).
 
 
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Example 2:
If a participant is receiving a dose along one of the off-diagonal dose sequences and per 
Table 7 a dose reduction is indicated, both MK-8353 and selumetinib will have doses 
reduced along the diagonal of the dose combination grid to the next lower dose level
sequentially, as shown in Figure 4.
Figure 4
Example of Sequential Dose Reduction Along the Off-Diagonal Sequences
ERK = extracellular signal-regulated kinase; 
MEK = mitogen-activated protein/extracellular signal regulated kinase
 
 
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Example 3:
If a participant is receiving a dose combination where one of the drugs (MK-8353 or 
selumetinib) is already at their lowest dose level (eg, MK-8353 50 mg or selumetinib 25 mg) 
and per Table 7 a dose reduction is indicated, then participants should be 
discontinued.Table 6 provides some examples of what the dose reductions would be for 
various dose levels.
Table 6
Examples of Maximum Dose Reductions
Selumetinib/MK-8353
Selumetinib/MK-8353
1st dose reduction
Selumetinib/MK-8353
2nd dose reduction
75 mg /250 mg
50 mg/200 mg
25 mg/150 mg
50 mg /250 mg
25 mg/200 mg
off study
75 mg /200 mg
50 mg/150 mg
25 mg/100 mg
50 mg /200 mg
25 mg/150 mg
off study
50 mg /150 mg
25 mg/100 mg
off study
125 mg /150 mg
100 mg/100 mg
75 mg/50 mg
100 mg /150 mg
75 mg/100 mg
50 mg/50 mg
125 mg /100 mg
100 mg/50 mg
off study
100 mg /100 mg
75 mg/50 mg
off study
75 mg /100 mg
50 mg/50 mg
off study
If a dose modification for toxicity occurs with MK-8353 or selumetinib, the dose may not be 
re-escalated to the dose that preceded the dose modification. Dose modifications will be
based on the previous cycle.
Participants may have up to 2 dose modifications of MK-8353 and selumetinib throughout 
the course of the study, as described in Table 7. If further toxicity occurs or the criteria for 
resuming treatment are not met, the participant must be discontinued from the study 
treatment. If a participant experiences several toxicities and there are conflicting 
recommendations, follow the most conservative dose adjustment recommended (dose 
reduction appropriate to the most severe toxicity).
Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
 
 
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Table 7
MK-8353 and Selumetinib Dose Modification and Treatment Discontinuation 
Guidelines for Drug-Related Adverse Events
Eye disorders – Retinal Events (including serous detachment of the retina)
Grade 1
Maintain dose level of MK-8353 and selumetinib and repeat ophthalmic 
monitoring including visual acuity assessment and ocular coherence tomography 
(OCT) within 10 days.
Grade 2
Interrupt MK-8353 and selumetinib dosing and refer the participant to 
ophthalmologist within 1 week and obtain OCT within 10 days:
If resolved to baseline or Grade ≤1 within 10 days, resume treatment at current 
dose level and continue schedule of visual assessments established per protocol.
If not resolved to baseline or Grade ≤1 within 10 days, resume treatment at 
reduced dose level and continue the schedule of events of visual assessments 
established per protocol.
Grade 3
Interrupt MK-8353 and selumetinib and refer the participant to ophthalmologist 
within 1 week and obtain OCT:
If resolved to baseline or Grade ≤1 within 7 days, resume treatment at a reduced
dose level and continue schedule of visual assessments established per protocol.
If not resolved to baseline or Grade ≤1 within 7 days, continue to hold the MK-
8353 and selumetinib dose and repeat ophthalmic assessment in 10 days.
If resolved to baseline or Grade ≤ 1, resume treatment at reduced dose level and 
continue schedule of visual assessments established per protocol.
If remains Grade 3, permanently discontinue MK-8353 and selumetinib.
Grade 4
Permanently discontinue MK-8353 and selumetinib and immediately follow up 
with ophthalmic monitoring.
Eye disorder – Retinal Vein Occlusion (RVO)
Any Grade
Permanently discontinue MK-8353 and selumetinib.
Other Eye Disorders (ie, Non-retinal Events)
Grade 1-2
Maintain dose level of MK-8353 and selumetinib and increase frequency of 
ophthalmic monitoring to at least 14 days until stabilization or resolution.
Grade 3
Interrupt MK-8353 and selumetinib and refer participant to ophthalmologist 
within 1 week:
If resolved to Grade ≤1 in ≤21 days, reduce 1 dose level of MK-8353 and
selumetinib.
If not resolved to Grade ≤1 in ≤21 days, permanently discontinue MK-8353 and
selumetinib.
Grade 4
Permanently discontinue MK-8353 and selumetinib.
 
 
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Liver-related Adverse Events
Grade 1 AST or 
ALT (> ULN - 3 
× ULN)
Maintain dose level of MK-8353 and selumetinib.
Grade 2 AST or 
ALT (>3 - 5.0 ×
ULN) or 3 ×
baseline value (if 
liver metastasis) 
AND blood 
bilirubin ≤2.0 ×
ULN
Interrupt dose of MK-8353 and selumetinib until resolved to Grade ≤1 (or Grade 
≤2 in case of liver metastasis), then:

If resolved in ≤14 days, maintain dose level of MK-8353 and selumetinib.

If resolved in >14 days, reduce dose level of MK-8353 and selumetinib.
Recurrence: 

Interrupt dosing of MK-8353 and selumetinib until resolved to Grade ≤1 (or 
Grade ≤2 in case of liver metastasis), then resume treatment at a reduced dose.
Grade 2 AST or 
ALT (> 3 - 5.0 ×
ULN) or 3 ×
baseline value (if 
liver metastasis) 
AND blood 
bilirubin > 2.0 ×
ULN
Interrupt dose of MK-8353 and selumetinib until resolved to Grade ≤1 (or Grade 
≤2 in case of liver metastasis), then:

If resolved in ≤7 days, resume treatment at a reduced dose of MK-8353 and
selumetinib.

If not resolved in ≤7 days, permanently discontinue MK-8353 and
selumetinib.
Grade 3 AST or 
ALT (>5.0 - 8.0 
× ULN) AND 
blood bilirubin 
≤2.0 × ULN
Interrupt dose of MK-8353 and selumetinib until resolved to Grade ≤1 (or Grade 
≤2 in case of liver metastasis), then:

If resolved in ≤14 days, maintain dose level of MK-8353 and selumetinib.

If resolved in >14 days, reduce dose level of MK-8353 and selumetinib.
Recurrence: 

Interrupt dosing of MK-8353 and selumetinib until resolved to Grade ≤1 (or 
Grade ≤2 in case of liver metastasis), then resume treatment at a reduced 
dose.
AST or ALT (>8 
x ULN) AND 
blood bilirubin* 
≤ 2.0 × ULN
Permanently discontinue MK-8353 and selumetinib.
AST or ALT 
(>5.0 × ULN) 
AND blood 
bilirubin* >2.0 ×
ULN
Permanently discontinue MK-8353 and selumetinib.
AST or ALT 
Grade 4 (>20.0 ×
ULN)
Permanently discontinue MK-8353 and selumetinib.
 
 
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Cardiac Disorders
Left ventricular 
systolic 
dysfunction 
Asymptomatic 
decrease of 
>10% in LVEF 
compared to 
baseline and the 
LVEF is below 
the institution’s 
lower limit of 
normal
Interrupt dose of MK-8353 and selumetinib and repeat evaluation of LVEF within 
2 weeks. 

If the LVEF recovers (defined as LVEF ≥50% or ≥LLN and absolute decrease 
≤10% compared to baseline) ≤3 weeks, reduce 1 dose level after approval of 
the Sponsor Medical Monitor. Monitor LVEF 2 weeks after restarting on MK-
8353 and selumetinib, every 4 weeks for 12 weeks and subsequently as per 
protocol. 

If the LVEF does not recover within 3 weeks, permanently discontinue 
participant from study treatment. Closely monitor LVEF until resolution (or 
16 weeks).
Grade 3-4
Permanently discontinue participant from MK-8353 and selumetinib. Closely 
monitor LVEF until resolution (or 16 weeks).
CK Elevation
Grade 1-2
Continue treatment on same dose level. Ensure patient is adequately hydrated. 
Monitor closely CK and serum creatinine levels.
(If total CK ≥3 X ULN, measure isoenzymes and myoglobin in blood and urine).
Grade 3 (>5.0 -
10.0 × ULN) 
without renal 
impairment (ie, 
serum creatinine 
< 1.5 × ULN or 
1.5 × baseline)
If asymptomatic, maintain dose of MK-8353 and selumetinib. Monitor closely and 
measure isoenzymes and myoglobin in blood and urine.
If symptomatic (muscle pain/spasms or muscle weakness), interrupt dose of MK-
8353 and selumetinib until resolved to CTCAE Grade ≤1 and monitor closely, 
then:

If resolved in ≤21 days, reduce 1 dose level of MK-8353 and selumetinib.

If resolved in >21 days, permanently discontinue MK-8353 and selumetinib.
Grade 4
without renal 
impairment (ie, 
serum creatinine 
<1.5 × ULN or 
1.5 × baseline)
If asymptomatic, interrupt dose of MK-8353 and selumetinib and monitor 
closely. Ensure patient is adequately hydrated and monitor and measure 
isoenzymes and myoglobin in blood or urine, and serum creatinine.

If resolved in ≤21 days, reduce 1 dose level of MK-8353 and selumetinib.

If resolved in >21 days, permanently discontinue MK-8353 and selumetinib.

If symptomatic, permanently discontinue MK-8353 and selumetinib.
If symptomatic (muscle pain/spasms), permanently discontinue MK-8353 and
selumetinib.
Grade 3 or 4 
with renal 
impairment (ie, 
serum creatinine 
≥1.5 × ULN or 
1.5 × baseline)
Interrupt MK-8353 and selumetinib dose until resolved to Grade <1 or baseline 
level. Ensure patient is adequately hydrated. Monitor isoenzymes and myoglobin 
in blood or urine, and serum creatinine, then:

If resolved in ≤21 days, reduce 1 dose level of MK-8353 and selumetinib.

If resolved in >21 days, permanently discontinue MK-8353 and selumetinib.
Recurrence:

Permanently discontinue MK-8353 and selumetinib
 
 
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Rash
Grade 1
Treatment with MK-8353 and selumetinib should be maintained at the current 
dose. 
Initiate prophylactic regimen if it was not already and monitor closely.
Grade 2
First occurrence: Treatment with MK-8353 and selumetinib should be maintained 
at the current dose and rash should be closely monitored. Initiate prophylactic 
regimen if it was not already started. 
Reassess within a maximum of two weeks. If rash worsens or does not improve, 
interrupt dosing until improvement to Grade ≤1. Resume treatment at the same 
dose level.
Second occurrence: Reassess within a maximum of 2 weeks. If rash worsens or 
does not improve, interrupt dosing until improvement to Grade ≤1. Resume 
treatment at a reduced dose level.
Only one dose reduction is permitted.
Grade 3
First occurrence: Treatment with MK-8353 and selumetinib should be interrupted.
Reassess the participant weekly. Consider referral to dermatologist and manage 
rash per dermatologist’s recommendation.
Interrupt treatment until improvement to Grade ≤1. Resume treatment with 
MK-8353 and selumetinib at a reduced dose level.
Second occurrence: Interrupt treatment until improvement to Grade ≤1. Resume 
treatment with MK-8353 and selumetinib at a reduced dose level. If participant is 
at the lowest dose, participant should be discontinued.
Consider referral to dermatologist and manage rash per dermatologist’s 
recommendation.
Grade 4
Permanently discontinue MK-8353 and selumetinib.
Diarrhea
Uncomplicated 
Grade 1-2
Consider temporary interruption of MK-8353 and selumetinib until resolved to 
Grade ≤1. Treatment with MK-8353 and selumetinib may then be resumed at the 
same dose level.
Complicated 
Grade 1-2
Temporarily interrupt MK-8353 and selumetinib treatment until resolved to Grade 
≤1. Restart MK-8353 and selumetinib at one reduced dose level. If participant is at 
the lowest dose, participant should be discontinued.
Grade 3-4
Temporarily interrupt MK-8353 and selumetinib treatment until resolved to Grade 
≤1. Restart MK-8353 and selumetinib at a reduced dose level. If participant is at 
the lowest dose, participant should be discontinued.
Nausea/Vomiting
Grade 1-2
Treatment with MK-8353 and selumetinib should be maintained at the current 
dose. Promptly institute antiemetic measure.
Grade 3
Temporarily interrupt MK-8353 and selumetinib treatment until resolved to Grade 
≤1. Resume treatment with MK-8353 and selumetinib at the same dose if, in the 
judgment of the investigator, the toxicity is considered to be unrelated to 
selumetinib, or at one reduced dose level. 
Note: Interrupt dose for ≥Grade 3 vomiting or Grade 3 nausea only if the 
vomiting or nausea cannot be controlled with optimal antiemetics (as per local 
practice).
Grade 4
Permanently discontinue MK-8353 and selumetinib treatment
 
 
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Interstitial Lung Disease/Pneumonitis
Grade 1
Maintain dose level of MK-8353 and selumetinib. Monitor weekly.
Grade 2
Withhold MK-8353 and selumetinib for up to 3 weeks.

If improved to Grade 0 or 1, resume treatment at 1 reduced dose level of 
MK-8353 and selumetinib

If not resolved within 3 weeks, permanently discontinue MK-8353 and
selumetinib.
Grade 3-4
Permanently discontinue MK-8353 and selumetinib.
Venous Thromboembolism
Uncomplicated 
DVT or PE
Withhold MK-8353 and selumetinib for up to 3 weeks.

If improved to Grade 0 or 1, resume at reduced dose.

If not improved, permanently discontinue.
Life threatening 
PE
Permanently discontinue MK-8353 and selumetinib.
All other Adverse Events (suspected to be related)
Grade 1-2
If the event is a persistent Grade 2 AE not responsive to a specific therapy, 
consider MK-8353 and selumetinib interruption or reduction.
Grade 3
For other AEs, interrupt MK-8353 and selumetinib until resolution to Grade ≤1 or 
to pre-treatment/baseline level. If the event resolves within 21 days, then 
MK-8353 and selumetinib may be restarted at a lower dose (one level below that 
previously received) based upon the Investigator’s discretion.
Grade 4
Permanently discontinue study drug (MK-8353 and selumetinib).
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; 
CTCAE = Common Terminology Criteria for Adverse Events; LLN = lower limit of normal; LVEF = left 
ventricular ejection fraction; ULN = upper limit of normal
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention, MK-8353 50 mg (or 100 mg) or 
selumetinib 25 mg, are included in the label text; random code/disclosure envelopes or lists 
are not provided.
6.9
Standard Policies
This section is not applicable.
 
 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant interrupts study intervention administration due to treatment-related 
toxicity for more than 14 consecutive days in cycle 1 or has >25% cumulative missed 
doses.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Confirmed radiographic disease progression outlined in Section 8.2 (exception if the 
Sponsor approves treatment continuation).
•
Unacceptable adverse experiences as described in Section 8.4.
•
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
 
 
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•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue treatment.
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
 
 
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The total amount of blood/tissue to be drawn/collected over the course of the trial, including 
approximate blood/tissue volumes drawn/collected by cycle and by sample type per subject 
can be found in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or future biomedical 
research .If there are changes to the participant’s status during the study (eg, health or age of 
 
 
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majority requirements), the investigator or medically qualified designee must ensure the 
appropriate consent is in place.
8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
 
 
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The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the participant has enrolled in the study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study treatment(s), the 
study treatment(s) should be discontinued and the participant will move into the Post-
treatment Follow-up Phase; if a participant initiates a new anticancer therapy within 30 days 
after the last dose of the study treatment, the 30 day Safety Follow-up Visit should occur 
before the first dose of the new therapy.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation.Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
 
 
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will receive an allocation number (AN). The AN identifies the 
participant for all procedures occurring after randomization. Once an is assigned to a 
participant, it can never be re-assigned to another participant.
A single participant cannot be assigned more than 1 AN.
8.1.8
Study Intervention Administration
During on-site visits, administration of study medication will be witnessed by the 
investigator and/or trial staff. The administration, the dose, the time of administration, as well 
as any immediate reactions at the time of intake will be documented in the eCRF.
For non-visit days, MK-8353 and selumetinib will be taken at home. 
When a participant attends a study visit, he/she will bring any unused capsules.
8.1.8.1
Timing of Dose Administration
8.1.8.1.1
MK-8353 Administration
MK-8353 is an oral medication, and is supplied as hard-shell capsules in strength of 50 mg or 
100 mg. Participants should be instructed to take MK-8353 capsule(s) in the morning and in 
the evening at approximately the same times every day.
MK-8353 will be taken BID for the repeated schedule of 4 days on followed by 3 days off.
The Pharmacy Manual contains specific instructions for MK-8353 storage and 
administration.
8.1.8.1.2
Selumetinib Administration
Selumetinib is an oral medication, and is supplied as hard-shell capsules in strength of 
25 mg. Participants should be instructed to take selumetinib capsules in the morning and in 
the evening at approximately the same times every day. Selumetinib should be taken on an 
empty stomach; no food or drink other than water for approximately 2 hours prior to dosing 
and approximately 1 hour after dosing.
Selumetinib will be taken BID in a repeating cycle of 4 days on followed by 3 days off.
The Pharmacy Manual contains specific instructions for MK-5618 (selumetinib) storage and 
administration.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
 
 
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4 .
8.1.9.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the imaging contract research 
organization can be found in the Site Imaging Manual (SIM). Tumor imaging is strongly 
preferred to be acquired by CT. For the abdomen and pelvis, contrast-enhanced MRI may be 
used when CT with iodinated contrast is contraindicated, or when mandated by local 
practice. MRI is the strongly preferred modality for imaging the brain. The same imaging 
technique regarding modality, ideally the same scanner, and the use of contrast should be 
 
 
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used in a participant throughout the study to optimize the reproducibility of the assessment of 
existing and new tumor burden and improve the accuracy of the assessment of response or 
progression based on imaging.
Note: for the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer located at the site or at an offsite 
facility.
Imaging of chest, abdomen, and pelvis is typical. The SIM will include detailed instructions 
for specific tumor types and clinical scenarios.
Although RECIST 1.1 references to a maximum of 5 target lesions in total and 2 per organ, 
Merck allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to 
enable a broader sampling of tumor burden.
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at the Screening Visit must be performed within 28 days prior to the 
date of allocation.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 28 days prior 
to the date of allocation.
Participants with previously treated brain metastases may participate provided they have 
stable brain metastases (ie, without evidence of progression by imaging confirmed by MRI if 
MRI was used at prior imaging, or confirmed by CT imaging if CT used at prior imaging) for 
at least 4 weeks prior to the first dose of study intervention. Any neurologic symptoms must 
have returned to baseline and participants must have no evidence of new or enlarging brain 
metastases, and have not used steroids for brain metastases for at least 28 days prior to study 
initiation as per local site assessment. This exception does not include carcinomatous 
meningitis, as participants with carcinomatous meningitis are excluded regardless of clinical 
stability.
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±7 days) for the first 12 months on treatment, or more frequently if clinically 
indicated. After 12 months on treatment, subsequent tumor imaging should be performed 
every 12 weeks (84 days ±14 days), or more frequently if clinically indicated. Imaging 
timing should follow calendar days and should not be adjusted for delays in cycle starts. 
Imaging should continue to be performed until disease progression is identified by the 
 
 
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investigator, the start of new anticancer treatment, withdrawal of consent, or death, 
whichever occurs first.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging every 
9 weeks, starting with the next scheduled imaging time point. Participants who receive 
additional imaging confirmation do not need to undergo the next scheduled tumor imaging if 
it is less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging 
time point. Note that the response does not typically need to be verified in real time by BICR.
8.2.1.3
End of Treatment and Follow-up Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of intervention discontinuation (±4 week window). If previous imaging was 
obtained within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study treatment due to 
documented disease progression, this is the final required tumor imaging.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by radiologic tumor until 
the start of a new anticancer treatment, documented disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first. The timing for these 
assessments should continue the same imaging schedule from the treatment phase (9 weeks 
± 7 days in the first 12 months, or 12 weeks ± 14 days beyond 12 months – see Section 
8.2.1.2); Imaging should occur at any time where there is clinical suspicion of PD.
8.2.2
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by the investigator as the primary measure for assessment of tumor 
response, date of disease progression, and as a basis for all protocol guidelines related to 
disease status (eg, discontinuation of study treatment). Although RECIST 1.1 references a 
maximum of 5 target lesions in total and 2 per organ, this protocol allows a maximum of 
10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling 
of tumor burden.
Participants who show evidence of radiological PD by RECIST 1.1, as determined by the 
investigator, will be discontinued from the study (see Table 8). 
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status 
 
 
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
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from trial treatment at 
site-assessed first radiologic evidence of PD.
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1 
Repeat imaging 
at 4 to 8 weeks 
to confirm PD
May continue study 
treatment at the local 
site investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site.
NA
Discontinue treatment
NA = not applicable; PD = progressive disease; PFS = progression-free survival
8.2.3
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at the Screening Visit, prior 
to the administration of each dose of study intervention and during the Post-treatment 
Follow-up Phase as specified in the SoA (Section 1.3).
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Study 
Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) as per institutional standard. Height and weight 
will also be measured and recorded.
A brief directed physical examination will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) per institutional standard.
 
 
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Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
Screening phase. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in the SoA (Section 1.3). After 
the first dose of study intervention, new clinically significant abnormal findings should be 
recorded as AEs.
8.3.1.2
Directed Physical Examination
The investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to trial treatment administration at the time points indicated in the SoA 
(Section 1.3). New clinically significant abnormal findings should be recorded as AEs.
8.3.2
Full Ophthalmic Examination
Full ophthalmic examination, including best corrected visual acuity for distance testing, 
automated visual field testing, slit lamp examination, intraocular pressure and dilated 
fundoscopy with attention to retinal abnormalities, especially retinal pigment epithelial 
detachment (RPED), serous detachment of the retina and RVO, will be performed by an 
ophthalmologist at the Screening Visit, C2D1 and then every 8 weeks from C2D1 and EoT. 
An ophthalmic examination at the Safety Follow-up Visit is only required if there was a 
clinically significant abnormality noted at EoT. For all participants, ophthalmic assessments 
may be performed more frequently per SOC or if clinically indicated for evaluation of any 
visual signs or symptoms.
8.3.3
Additional Testing
Participants with clinical suspicion of retinal abnormalities (ie, RPED, serous detachment of 
the retina, RVO, photopsia, metamorphopsia, impairment of visual acuity), must complete at 
least one of the following additional assessments: 

For non-vascular abnormalities: optical coherence tomography (OCT) of the macula 
(spectral domain OCT recommended) 

For vascular abnormalities: fluorescein angiography of the central 30 degrees. 

Images/results of the ophthalmic examinations (at a minimum, OCT and/or 
fluorescein angiography) should be sent to the study site and be maintained in the 
participant’s source document file. These images/results may be requested to be sent 
to the Sponsor or designee.
 
 
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8.3.4
Vital Signs
The investigator or qualified designee will take vital signs at the Screening Visit, prior to the 
administration of each dose of study intervention and at the EoT Visit as specified in the SoA 
(Section 1.3). Vital signs include temperature, pulse, respiratory rate, and blood pressure. 
Height will be measured at the Screening Visit only.
Blood pressure and pulse measurements should be performed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. The 
participant should be in a semi-recumbent or supine position for at least 10 minutes prior to 
having the measurement performed. The correct size of the blood pressure cuff and correct 
positioning of the participant’s arm are essential to the accuracy of the blood pressure 
measurement.
8.3.5
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA (Section 1.3). Clinically significant abnormal findings should 
be recorded as medical history. Additional ECGs may be performed as clinically necessary.

A standard 12-lead ECG will be performed using local standard procedure.

The ECG measurement performed at the Screening Visit will be used to determine 
eligibility.

The ECG measurement at any time point should be used for AE grading and 
recommended dose modifications.

When an ECG is to be performed at the same time point as a blood collection, the 
ECG is to be performed first.

ECG will be performed predose at every visit starting at C2D1.
Screening: Triplicate 12-lead ECGs will be obtained at the Screening Visit only.
Three individual ECG tracings should be obtained as closely as possible in succession, but no 
more than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes. Refer to Section 5.2 (Exclusion Criterion 7 for QTcF withdrawal criteria).
8.3.6
Echocardiogram/Multigated Acquisition Scan
Cardiac ejection fraction will be assessed by transthoracic ECHO or MUGA scans at the time 
points specified in the SoA (Section 1.3). The same method should be used throughout the 
study. Participants who develop signs/symptoms of CHF at any point during the study are 
required to have an evaluation of LVEF measurement by ECHO or MUGA.
 
 
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8.3.7
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 4.
Progression of the cancer under study is not considered an AE unless it results in 
hospitalization or death as described in Section 8.4.6 and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
 
 
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
•
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
 
 
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Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
Specified Follow-
up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (ECI) 
(require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential Drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
ECI (Do not require 
regulatory reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
study participants for outcome. Further information on follow-up procedures is given in 
Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Progression of the cancer under study is not considered a reportable event unless it results in 
hospitalization or death.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 

An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.

An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-8353 and/or selumetinib by ≥20% of the indicated single dose. No specific 
information is available on the treatment of overdose of of MK-8353 and/or selumetinib. In 
the event of overdose, MK-8353 and selumetinib should be discontinued and the participant 
should be observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma
Sample collection, storage, and shipment instructions for PK samples will be provided in the 
operations/laboratory manual for both MK-8353 and selumetinib.
 
 
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Pharmacokinetic samples should be drawn according to the PK collection schedule for all 
participants. The exact time of sample collection and time of administration of MK-8353 and 
selumetinib will be recorded.
8.6.1.1
MK-8353 Blood Collection for Plasma
Blood samples for determination of plasma concentrations of MK-8353. Plasma samples for 
MK-8353 will be obtained from consenting participants. Serial plasma samples for PK 
analysis of MK-8353 will be collected C1D1 and C1D4 at time 0 (within 24 hours prior to 
pre-dose for C1D1 or within -10 minutes prior to pre-dose for C1D4 trough sample), post-
dose at 1(± 10 minutes), 2 (± 10 minutes), 4(± 10 minutes), 6 (± 10 minutes), and 1 sample 
any time between 8 and 12 hours (prior to PM dosing for BID regimen). Additional samples 
will be collected at pre-dose/trough (within -10 minutes prior to pre-dose), hours 1
(± 10 minutes), and hours 4 (± 10 minutes) at C2D1, C2D4, C5D1, C5D4. The exact time of 
sample collection and time of administration of MK-8353 will be recorded.
8.6.1.2
Selumetinib Blood Collection for Plasma
Blood samples for determination of plasma concentrations of selumetinib and N-desmethyl 
selumetinib. Other metabolites (eg, selumetinib amide) may also be determined. Plasma
samples for selumetinib and N-desmethyl selumetinib will be obtained from consenting 
participants. Serial plasma samples for PK analysis of selumetinib and N-desmethyl 
selumetinib will be collected C1D1 and C1D4 at time 0 (within 24 hours prior to pre-dose for 
C1D1 and within -10 minutes prior to pre-dose for C1D4 trough sample), post-dose at 
1(± 10 minutes), 2 (± 10 minutes), 4 (± 10 minutes), 6 (± 10 minutes), and 1 sample any time 
between 8 and 12 hours (prior to PM dosing for BID regimen). Additional samples will be 
collected at pre-dose/trough (within -10 minutes prior to pre-dose), hours 1 (± 10 minutes), 
and hours 4 (± 10 minutes) at C2D1, C2D4, C5D1, C5D4. The exact time of sample 
collection and time of administration of selumetinib will be recorded.
Based on observed toxicity and severity of toxicity, we may pause the study and analyze PK 
to assess if there is a need to modify the dose/dosing schedule (eg, lower the dose; change 
from BID to QD).
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
provided in operations/laboratory manual.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Leftover from specimens listed in Section 8.10, Biomarkers.
 
 
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8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis 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 the 
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 participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
8.10
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:
•
Blood for Genetic Analysis
•
Blood for ctDNA
•
Blood for RNA Analyses
•
Blood for Plasma Biomarker Analyses
•
Blood for Serum Biomarker Analyses
•
Blood for pERK
•
Archival or Newly Obtained Tumor Tissue collection
•
On-treatment Tumor Biopsy (Optional)
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be provided in the Procedures Manual.
Exploratory FDG-PET:
Exploratory imaging will be used as a biomarker of the study drugs. FDG-PET scans will be 
obtained from participants at the MTD levels only as specified in the SoA. Details for the 
collection and storage scans will be provided in the operations/laboratory manual.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
 
 
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8.11.1
Screening
Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of 
study intervention except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment. An exception is hepatitis testing, which may be done up to 28 days prior to 
the first dose of trial treatment.

Evaluation of ECOG is to be performed within 7 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of trial treatment. If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test will be required 
(performed by the local study site laboratory).

Archival tumor sample collection is not required to be obtained within 28 days prior 
to the first dose of trial treatment. Newly obtained tumor tissue may be obtained 
within 90 days of treatment initiation.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided above in Section 8 – Study Assessments and Procedures.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. For participants who 
discontinue study treatment without documented disease progression, every effort should be 
made to continue monitoring their disease status by radiologic imaging in post-treatment
follow up visits. Imaging will not be collected during Survival Follow-up Visit(s). Visit 
requirements are outlined in the SoA (Section 1.3). Additional details regarding participant 
withdrawal and discontinuation are presented in Section 8.1.9 –Discontinuation and 
Withdrawal. Additional details regarding Post-treatment Follow-up imaging visits are 
represented in Section 8.2.1.3 – End of Treatment and Follow-up Imaging.
8.11.4
Post-treatment
Participants will be required to return to clinic approximately 30 days after the last dose of 
study intervention for the post-treatment Safety Follow-up Visit. If a participant initiates a 
 
 
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new anticancer therapy within 30 days after the last dose of study treatment, the Post-
treatment Safety Follow-up Visit should occur before the first dose of the new therapy.
After treatment discontinuation, each participant will be followed for up 30 days for AE 
monitoring. Participants will be monitored for SAEs for 90 days after treatment 
discontinuation, 30 days if the participant 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. Participants with an 
ongoing AE of Grade >1 at the time of treatment discontinuation will be followed until 
resolution of the AE to Grade 0 to 1, until considered stable by the treating physician, or until 
beginning a new anticancer therapy, whichever occurs first.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by radiologic tumor until 
the start of a new anticancer treatment, documented disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first. The timing for these 
assessments should continue the same imaging schedule from the treatment phase (9 weeks 
± 7 days in the first 12 months, or 12 weeks ± 14 days beyond 12 months – see Section 
8.2.1.2 Tumor Imaging During the Study); Imaging should occur at any time where there is 
clinical suspicion of progression. 
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 the SoA (Section 1.3).
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
 
 
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If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report for the study. 
Post hoc exploratory analyses will be clearly identified in the Clinical Study Report.
Study Design Overview
This is a Phase 1b trial of MK-8353 in combination with 
selumetinib in participants with advanced/metastatic solid 
tumors. The study applies the mTPI design for dual-agent dose 
finding.
Treatment Assignment
Participants will be allocated centrally through interactive 
response technology to MK-8353 coadministered with 
selumetinib. Nonrandom assignment to dose levels will be used 
in the diagonal dose combination sequence. In case two 
additional off-diagonal dose combination sequences are 
initiated, participants will be allocated by alternate assignment 
to either off-diagonal sequence.
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT)
PK (Secondary): Per-Protocol (PP)
Efficacy (Exploratory): Full Analysis Set (FAS) 
Primary Endpoint(s)
DLTs
AEs
Study drug discontinuations due to an AE
Secondary Endpoints
PK parameters including AUC, Cmax and Cmin
Statistical Methods for 
Efficacy/ 
Pharmacokinetic 
Analyses
Efficacy analyses are documented in the sSAP.
PK parameters of study medicines will be summarized by 
planned visit and time for each dose separately.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints as 
appropriate. The DLT rates across different dose combinations, 
in each dose combination sequence, will be estimated using 
isotonic regression under the assumption of monotonicity 
between the DLT rates and dose levels in each row and in each 
column of the dose combination grid [Dykstra, R. L. 1982]. 
The estimate of the DLT rate among participants treated at the 
RP2D for the MK-8353 and selumetinib combination, and the
associated 80% Bayesian credible intervals will be provided.
Interim Analyses
No efficacy interim analysis will be performed.
Multiplicity
No multiplicity adjustment is planned in this Phase 1b trial.
 
 
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Sample Size and Power The overall sample size for this study depends on the observed 
DLT profiles of MK-8353 in combination with selumetinib. A 
target sample size of 80 participants will be used for study 
planning purposes. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, ie, participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned. 
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3 – Hypothesis, Objectives, 
and Endpoints.
9.4
Analysis Endpoints
9.4.1
Efficacy/Pharmacokinetics Endpoints
Efficacy endpoints (OR, PFS, OS) are exploratory endpoints in this study. Details of the 
analysis plan will be documented in the sSAP.
Pharmacokinetic endpoints include plasma concentrations of MK-8353 and selumetinib, as 
well as derived PK parameters.
9.4.2
Safety Endpoints
The primary safety endpoint is the incidence of DLTs. In addition, safety and tolerability will 
be assessed by clinical review of all relevant parameters including AEs, laboratory tests, and 
vital signs.
A description of safety measures is provided in Section 8.3 – Safety Assessments.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all subjects who received at least 1 dose of study treatment. 
The DLT evaluable population includes APaT participants who meet the criteria for DLT 
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 5.6 Participant Replacement Strategy for details. 
 
 
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At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.2
Pharmacokinetic Analysis Populations
The PP population will be used for the analysis of PK data in this study. The PP population 
consists of the subset of participants who complied with the protocol sufficiently to ensure 
that their data will be likely to exhibit the effects of treatment, according to the underlying 
scientific model. Compliance includes such considerations as exposure to treatment, 
availability of measurements, and the absence of major protocol violations. Any participants 
or data values excluded from the analyses will be identified, along with the reasons for 
exclusion, in the clinical study report (CSR). At the end of the study, all participants who 
were compliant with the study procedures and have available data from at least 1 treatment 
may be included in the PP analysis dataset.
9.5.3
Efficacy Analysis Populations
The FAS population will be used for the analyses of efficacy data in this study. It consists of 
all participants with a baseline scan that demonstrated measurable disease by the 
investigator’s assessment, and who were administered at least 1 dose of study medicine.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory endpoints will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analysis
The statistical methods for efficacy analyses will be documented in the sSAP.
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
Adverse events will be summarized by 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 summarized by dose level. The DLT rates across
different dose combinations, in each dose combination sequence, will be estimated using 
isotonic regression under the assumption of monotonicity between the DLT rates and dose 
levels in each row and in each column of the dose combination grid [Dykstra, R. L. 1982]. 
The estimate of the DLT rate among participants treated at the RP2D and the 80% Bayesian 
credible interval based on a prior distribution of Beta (1,1) for the estimate will be provided.
 
 
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analysis
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Pharmacokinetic parameters of study medicines will be summarized by planned visit and 
time for each dose separately. 
9.7
Interim Analyses
No efficacy interim analysis will be conducted.
9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
With a maximum sample size of 14 at each dose level, the overall sample size for this 
Phase 1b trial will be at most 140 (the scenario where dose escalation along the diagonal 
concludes at DL2 and extends to off-diagonal escalation in Figure 1B which has a total of 
10 dose combination levels and assumes 14 subjects per dose level). The actual sample size 
depends on the safety profiles and number of doses studied. For example, if dose escalation 
along the diagonal concludes at DL3 and then proceeds to the off-diagonal escalations, where 
there are three dose combination levels in each sequence, the sample size is expected to be 
approximately 80, assuming 6 subjects in the first two dose levels and 14 subjects at the final 
dose combination level in each sequence. Alternatively, if dose escalation along the diagonal 
of the dose combination grid concludes at the last dose on the diagonal sequence, (MK-8353
250 mg, selumetinib125 mg), the sample size is expected to be approximately 50, also 
assuming 6 subjects in the first six dose levels and 14 subjects at the final dose.
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial. Any deviation 
from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
 
 
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
 
 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutiona Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
 
 
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
 
 
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, 
rules and regulations relating to the conduct of the clinical study. The Code of Conduct, a 
collection of goals and considerations that govern the ethical and scientific conduct of 
clinical investigations sponsored by MSD, is provided in this appendix under the Code of 
Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
 
 
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10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
 
 
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10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 10 will be performed by the local laboratory.
•
If the local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Table 10
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
Hemoglobin
Alkaline phosphatase
Glucose
urine)a
Platelet count
Alanine aminotransferase
Protein
PT/INR
WBC (total and
Aspartate aminotransferase
Specific gravity 
aPTT or PTT
differential)b
Bicarbonate
Microscopic exam, if
Anti-HCV
RBC
Calcium
abnormal results are
HCV viral loadc
Absolute
Chloride
noted
HCV genotypec
lymphocyte countb
Creatinine
anti-HBsc
Absolute 
Cystatin Cd
HBsAg 
neutrophil countd
Glucose
Anti-HBc (total and IgM)c
Phosphorus
HBeAgc
Potassium
anti-HBec
Sodium
HBV viral loadc
Total bilirubin
Anti-HDV c
Creatine kinase
AFP
Direct bilirubin
CRP
Total protein
GGT
Blood urea nitrogen
a.
Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. Pregnancy tests must be 
repeated prior to every cycle if required or as specified per local regulatory guidance.
b.
Report % or absolute results per standard of practice. Report the results in the same manner throughout the 
study.
c.
If the local laboratory is unable to perform these tests, the site should submit the sample to the central 
laboratory for testing. Details are provided in the Procedure Manual.
d. 
Specific to creatinine: Cystatin C could be evaluated if creatinine is abnormal. Cystatin C may be conducted 
by central vendor only if analysis was not available from local study site laboratory.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent, or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
 
 
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•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not considered a reportable event unless it results in hospitalization or death.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.7 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
 
 
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d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
 
 
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10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
 
 
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Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite
in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
-
If yes, did the AE resolve or improve?
-
If yes, this is a positive dechallenge.
-
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
-
If yes, did the AE recur or worsen?
 
 
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-
If yes, this is a positive rechallenge.
-
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
 
 
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•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
 
 
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•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not applicable.
 
 
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
•
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
 
 
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10.5.2
Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea
method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
 
 
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Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc
•
Intrauterine hormone-releasing system (IUS)c
•
Intrauterine device (IUD)
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly 
effective method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.
1.
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
2.
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly).
a)
Male condoms must be used in addition to the hormonal contraception.
b)
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines,
acceptable contraceptive implants are limited to those which inhibit ovulation.
c)
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, sympothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method (LAM).
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
 
 
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10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Following initiation of treatment additional pregnancy testing will be performed if clinically 
warranted and at monthly intervals as defined by local regulations where applicable, during 
the treatment period plus 30 days (a menstruation cycle) after the last dose of study 
intervention, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
o
Definitions
9.
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. 
10.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
11.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
12.
DNA: Deoxyribonucleic acid.
13.
RNA: Ribonucleic acid.
o
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.10 will be 
used in various experiments to understand:
•
The biology of how drugs/vaccines work
•
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
•
Other pathways drugs/vaccines may interact with
•
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
 
 
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o
Summary of Procedures for Future Biomedical Research.

Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy

Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.

eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.

Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
o
Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
 
 
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At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
o
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
o
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.
o
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 
 
 
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answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
o
Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
o
Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
o
Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
o
Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
 
 
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o
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
o
References
1.
National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2.
International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3.
Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4.
Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADL
activities of daily living
AE
adverse event 
AN
allocation number
ANC
absolute neutrophil count
APaT
All Participants as Treated
ASCO 
American Society of Clinical Oncology
ASH 
American Society of Hematology
AUC
area under the curve
BID
administered twice daily
BP
Blood pressure
Cmax
maximum concentration
Cmin
minimum concentration
CR
complete response
CRAF
Cellular protein encoded by the raf1 gene
CRF
Case Report Form 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DDI
Drug-drug interaction
DILI
drug-induced liver injury
DL
dose level
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
EMA
European Medicines Agency
EoT
end of treatment
ERK
extracellular signal-regulated kinase
ERKi
extracellular signal-regulated kinase inhibitor
FDAAA
Food and Drug Administration Amendments Act
FDG-PET
fluorodeoxyglucose-positron emissions tomography
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
GLP
Good Laboratory Practice
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board 
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
MAPK
mitogen activated protein kinase
MEK
mitogen-activated protein kinase
MEKi
mitogen-activated protein kinase inhibitor
 
 
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Abbreviation
Expanded Term
MRI
magnetic resonance imaging
MTD
maximum tolerated dose 
mTPI
modified toxicity probability interval
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OR
overall response
ORR
objective response rate
OS
overall survival
PD
progressive disease
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic
PP
Per protocol
PR
partial response
QD
once daily
RAS
ras proto-oncogene family
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
RVO 
Retinal vein occlusion
SAE
serious adverse event 
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
WOCBP
woman/women of childbearing potential 
 
 
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11
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