Clinical trial NCT03833427
Conditions: Advanced/Metastatic Solid Tumors
Keywords: programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-03-18; Completion date: 2022-06-28
Enrollment: 32 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study will examine the safety, pharmacokinetics, and efficacy of escalating doses of selumetinib (MK-5618) in combination with intravenous (IV) pembrolizumab (MK-3475) for participants with advanced / metastatic solid tumors.

Detailed description:

Arms: arm 1: Participants receive 200 mg pembrolizumab (IV infusion; every three weeks \[Q3W\]) in combination with selumetinib at dose level 1 (dosed orally; twice daily \[BID\]) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks. arm 2: Participants receive 200 mg pembrolizumab (IV infusion; Q3W) in combination with selumetinib at dose level 2 (dosed orally; BID) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks. arm 3: Participants receive 200 mg pembrolizumab (IV infusion; Q3W) in combination with selumetinib at dose level 3 (dosed orally; BID) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks. arm 4: Participants receive 200 mg pembrolizumab (IV infusion; Q3W) in combination with selumetinib at dose level 4 (dosed orally; BID) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks. arm 5: Participants receive 200 mg pembrolizumab (IV infusion; Q3W) in combination with selumetinib at dose level 5 (dosed orally; BID) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks. arm 6: Participants receive 200 mg pembrolizumab (IV infusion; Q3W) in combination with selumetinib at dose level 6 (dosed orally; BID) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks. arm 7: Participants receive 200 mg pembrolizumab (IV infusion; Q3W) in combination with selumetinib at dose level 7 (dosed orally; BID) for up to 35 treatment cycles (cycle length: 3 weeks). During each 3-week cycle, selumetinib will be administered only for the first two weeks.
Interventions: intervention 1: Selumetinib intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Selumetinib oral capsules administered BID at escalating dose levels. Selumetinib administered only in weeks 1\&2 of each 3-week treatment cycle. intervention 2: Pembrolizumab administered by IV infusion at 200 mg Q3W, given on cycle day 1 of each 3-week treatment cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1b Multi-center Clinical Study of 
Selumetinib (MK-5618) in Combination with 
Pembrolizumab (MK-3475) in Participants with 
Advanced/Metastatic Solid Tumors.
NCT03833427
28-APR-2021


PRODUCT: MK-5618 
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 1b Multi-center Clinical Study of Selumetinib (MK-5618) in 
Combination with Pembrolizumab (MK-3475) in Participants with Advanced/Metastatic 
Solid Tumors.
Protocol Number: 001-04
Compound Number: MK-5618
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
139596
Approval Date: 28 April 2021
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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 04
28-APR-2021
This amendment was issued to update the dose modification and toxicity management 
guidelines for irAEs.
Amendment 03
09-JAN-2019
This is a Canada-specific amendment to address Agency feedback.
Amendment 02
20-DEC-2018
This amendment was issued to address Agency feedback.
Amendment 01
19-OCT-2018
This amendment incorporates the approved Study Design (Figure 1).
Original protocol
12-OCT-2018
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
This amendment was issued to update the dose modification and toxicity management guidelines for irAEs.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
6.6.1.2.1
Immune-Related 
Events and Dose 
Modification (Withhold, 
Treat, Discontinue)
The dose modification and toxicity 
management guidelines for irAEs and 
table were updated.
The dose modification and toxicity management 
guidelines for irAEs and table were updated as requested 
by the U.S. FDA in an effort to harmonize the 
presentation of safety information across all FDA-
approved PD-1/L1 antibody prescribing information.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities (SoA)................................................................................18
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................30
2.2
Background ..........................................................................................................31
2.2.1
Pharmaceutical and Therapeutic Background .............................................31
2.2.1.1
Selumetinib Pharmaceutical and Therapeutic Background ...............31
2.2.1.2
Pembrolizumab Pharmaceutical and Therapeutic Background .........31
2.3
Benefit/Risk Assessment......................................................................................31
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................32
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................35
4.2.1.1
Efficacy Endpoints.............................................................................35
4.2.1.1.1
Response Rate Assessed by RECIST Version 1.1...................35
4.2.1.1.2
Response Rate Assessed by Modified Response Evaluation 
Criteria in Solid Tumors 1.1 for Immune-based 
Therapeutics (iRECIST) ..........................................................35
4.2.1.2
Safety Endpoints................................................................................36
4.2.1.3
Pharmacokinetic Endpoints ...............................................................36
4.2.1.5
Future Biomedical Research..............................................................38
4.2.2
Rationale for the Use of Comparator/Placebo .............................................38
4.3
Justification for Dose...........................................................................................38
4.3.1
Starting Dose for This Study........................................................................38
4.3.1.1
Rationale for Starting and Maximum Dose of Selumetinib...............38
4.3.1.2
Rationale for Dose Interval and Escalation Increments.....................39
4.3.1.3
Rationale for Fixed Dose Pembrolizumab.........................................39
4.3.1.4
Dose Finding Using a Modified Toxicity Probability Interval 
Design ................................................................................................40
CCI
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4.4
Beginning and End of Study Definition .............................................................42
4.4.1
Clinical Criteria for Early Study Termination .............................................43
5
STUDY POPULATION ................................................................................................43
5.1
Inclusion Criteria.................................................................................................43
5.2
Exclusion Criteria................................................................................................45
5.3
Special Consideration for Participants of Asian Ethnicity ..............................48
5.4
Lifestyle Considerations......................................................................................49
5.4.1
Meals and Dietary Restrictions....................................................................49
5.4.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................49
5.4.3
Activity Restrictions ....................................................................................49
5.5
Screen Failures.....................................................................................................49
5.6
Participant Replacement Strategy......................................................................49
6
STUDY INTERVENTION............................................................................................50
6.1
Study Intervention(s) Administered...................................................................50
6.2
Preparation/Handling/Storage/Accountability .................................................52
6.2.1
Dose Preparation..........................................................................................52
6.2.2
Handling, Storage, and Accountability........................................................52
6.3
Measures to Minimize Bias: Randomization and Blinding..............................53
6.3.1
Intervention Assignment..............................................................................53
6.3.2
Stratification.................................................................................................53
6.3.3
Blinding........................................................................................................53
6.4
Study Intervention Compliance..........................................................................53
6.5
Concomitant Therapy..........................................................................................53
6.5.1
Acceptable Concomitant Medication...........................................................53
6.5.2
Prohibited Concomitant Medications ..........................................................54
6.5.3
Supportive Care ...........................................................................................55
6.5.3.1
Selumetinib Supportive Care Guidelines...........................................55
6.5.3.2
Pembrolizumab Supportive Care Guidelines.....................................57
6.6
Dose Modification (Escalation/Titration/Other)...............................................58
6.6.1
Dose Modifications Due to Adverse Events................................................58
6.6.1.1
Selumetinib Dose Modification Due to Adverse Events...................58
6.6.1.2
Pembrolizumab Dose Modification Due to Adverse Events.............64
6.6.1.2.1
Immune-Related Events and Dose Modification (Withhold, 
Treat, Discontinue) ..................................................................64
6.6.1.2.2
Dose Modification and Toxicity Management of Infusion-
Reactions Related to Pembrolizumab......................................69
6.6.1.2.3
Other Allowed Dose Interruption for Pembrolizumab ............70
6.6.2
Dose Administration/Escalation ..................................................................70
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6.6.2.1
Dose Administration (Preparation)....................................................70
6.6.2.2
Definition of Dose-limiting Toxicity.................................................71
6.7
Intervention After the End of the Study............................................................73
6.8
Clinical Supplies Disclosure................................................................................73
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................73
7.1
Discontinuation of Study Intervention...............................................................73
7.2
Participant Withdrawal From the Study...........................................................75
7.3
Lost to Follow-up .................................................................................................75
8
STUDY ASSESSMENTS AND PROCEDURES........................................................75
8.1
Administrative and General Procedures ...........................................................76
8.1.1
Informed Consent.........................................................................................76
8.1.1.1
General Informed Consent.................................................................76
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................77
8.1.2
Inclusion/Exclusion Criteria ........................................................................77
8.1.3
Participant Identification Card.....................................................................77
8.1.4
Medical History ...........................................................................................77
8.1.5
Prior and Concomitant Medications Review...............................................77
8.1.5.1
Prior Medications...............................................................................77
8.1.5.2
Concomitant Medications..................................................................78
8.1.6
Assignment of Screening Number...............................................................78
8.1.7
Assignment of Treatment/Randomization Number.....................................78
8.1.8
Study Intervention Administration ..............................................................78
8.1.8.1
Oral medication: Selumetinib ............................................................78
8.1.8.2
Infusion: Pembrolizumab...................................................................79
8.1.8.3
Timing of Dose Administration.........................................................79
8.1.8.3.1
Timing for Administration of Selumetinib (MK-5618)...........79
8.1.8.3.2
Timing for Administration of Pembrolizumab (MK-3475).....79
8.1.9
Discontinuation and Withdrawal .................................................................80
8.1.9.1
Withdrawal From Future Biomedical Research ................................80
8.1.10
Participant Blinding/Unblinding..................................................................81
8.1.11
Domiciling ...................................................................................................81
8.1.12
Calibration of Equipment.............................................................................81
8.2
Efficacy Assessments ...........................................................................................81
8.2.1
Tumor Imaging and Assessment of Disease................................................81
8.2.1.1
Initial Tumor Imaging........................................................................81
8.2.1.2
Tumor Imaging During the Study......................................................82
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8.2.1.3
End of Treatment and Follow-up Tumor Imaging.............................83
8.2.2
RECIST 1.1 Assessment of Disease............................................................83
8.2.3
iRECIST Assessment of Disease.................................................................83
8.2.4
Eastern Cooperative Oncology Group Performance Scale..........................88
8.3
Safety Assessments...............................................................................................89
8.3.1
Physical Examinations.................................................................................89
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 .......................................................................................90
8.3.4
Vital Signs....................................................................................................90
8.3.5
Electrocardiograms ......................................................................................90
8.3.6
Echocardiogram/Multigated Acquisition Scan............................................91
8.3.7
Clinical Safety Laboratory Assessments .....................................................91
8.3.7.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................92
8.3.7.2
Pregnancy Testing..............................................................................92
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................92
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................93
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 .............................................95
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................95
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)................................................................96
8.5
Treatment of Overdose........................................................................................96
8.5.1
Treatment of Overdose for Selumetinib ......................................................96
8.5.2
Treatment of Overdose for Pembrolizumab ................................................96
8.6
Pharmacokinetics.................................................................................................96
8.6.1
Blood Collection for Plasma Selumetinib and Serum Pembrolizumab.......96
8.7
Pharmacodynamics..............................................................................................97
8.8
Future Biomedical Research Sample Collection...............................................97
8.9
Planned Genetic Analysis Sample Collection....................................................97
8.10
Biomarkers ...........................................................................................................98
8.10.1
Screening......................................................................................................98
8.10.2
Treatment Period..........................................................................................99
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8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........99
8.10.4
Safety Follow-up Visit.................................................................................99
8.10.5
Imaging Follow-up Visit..............................................................................99
8.10.6
Survival Follow-up Visit............................................................................100
8.10.7
Poststudy....................................................................................................100
9
STATISTICAL ANALYSIS PLAN ...........................................................................100
9.1
Statistical Analysis Plan Summary...................................................................100
9.2
Responsibility for Analyses/In-house Blinding ...............................................101
9.3
Hypotheses/Estimation ......................................................................................101
9.4
Analysis Endpoints.............................................................................................102
9.4.1
Pharmacokinetics/Efficacy Endpoints .......................................................102
9.4.2
Safety Endpoints........................................................................................102
9.5
Analysis Populations..........................................................................................102
9.5.1
Safety Analysis Populations ......................................................................102
9.5.2
Pharmacokinetic Analysis Populations......................................................102
9.5.3
Efficacy Analysis Populations...................................................................103
9.6
Statistical Methods.............................................................................................103
9.6.1
Statistical Methods for Efficacy Analysis..................................................103
9.6.2
Statistical Methods for Safety Analysis.....................................................103
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..........104
9.7
Interim Analyses ................................................................................................104
9.8
Multiplicity .........................................................................................................104
9.9
Sample Size and Power Calculations ...............................................................104
9.10
Subgroup Analyses.............................................................................................104
9.11
Compliance (Medication Adherence)...............................................................104
9.12
Extent of Exposure.............................................................................................104
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................105
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......105
10.1.1
Code of Conduct for Clinical Trials...........................................................105
10.1.2
Financial Disclosure...................................................................................107
10.1.3
Data Protection...........................................................................................107
10.1.3.1
Confidentiality of Data ....................................................................108
10.1.3.2
Confidentiality of Participant Records.............................................108
10.1.3.3
Confidentiality of IRB/IEC Information..........................................108
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10.1.4
Publication Policy......................................................................................108
10.1.5
Compliance with Study Registration and Results Posting Requirements .109
10.1.6
Compliance with Law, Audit, and Debarment ..........................................109
10.1.7
Data Quality Assurance .............................................................................110
10.1.8
Source Documents .....................................................................................110
10.1.9
Study and Site Closure...............................................................................111
10.2
Appendix 2: Clinical Laboratory Tests............................................................112
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................113
10.3.1
Definition of AE ........................................................................................113
10.3.2
Definition of SAE ......................................................................................114
10.3.3
Additional Events Reported in the Same Manner as SAE.........................115
10.3.4
Recording AE and SAE .............................................................................115
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................119
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................121
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................122
10.5.1
Definitions..................................................................................................122
10.5.2
Contraception Requirements......................................................................123
10.5.3
Pregnancy Testing......................................................................................125
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................126
10.7
Appendix 7: Country-specific Requirements..................................................131
10.8
Appendix 8: Abbreviations ...............................................................................132
11
REFERENCES.............................................................................................................134
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LIST OF TABLES
Table 1
Dose-finding Rules per mTPI Design..............................................................42
Table 2
Adequate Organ Function Laboratory Values .................................................44
Table 3
Study Interventions..........................................................................................51
Table 4
Dose Modification Guideline for Selumetinib.................................................59
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................66
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................69
Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease.............................................................................................................88
Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................94
Table 9
Protocol-required Safety Laboratory Assessments........................................112
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LIST OF FIGURES
Figure 1
Study Design: Dose Escalation of Selumetinib in Combination with 
Pembrolizumab ................................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1b Multi-center Clinical Study of Selumetinib (MK-5618) in 
Combination with Pembrolizumab (MK-3475) in Participants with Advanced/Metastatic
Solid Tumors.
Short Title: A Phase 1b Study of Selumetinib plus Pembrolizumab in Metastatic/Advanced 
Solid Tumors
Acronym:
Hypotheses, Objectives, and Endpoints:
There is no hypothesis testing in this study. 
The objectives and endpoints apply to the study population of male and female participants at 
least 18 years of age with metastatic/advanced solid tumors. Participants receiving 
selumetinib in combination with pembrolizumab will be evaluated as follows: 
Primary Objectives
Primary Endpoints
- To determine the safety and tolerability 
and to establish a preliminary 
recommended Phase 2 dose (RP2D) of 
selumetinib when used in combination 
with pembrolizumab
- Dose-limiting toxicities (DLTs)
- Adverse events (AEs)
- Study drug discontinuations due to an AE
Secondary Objectives
Secondary Endpoints
- To evaluate the pharmacokinetics (PK) of 
selumetinib
- Pharmacokinetic parameters including area 
under the curve (AUC), minimum 
concentration (Cmin) and maximum 
concentration (Cmax)
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Advanced Metastatic Solid Tumors
Population
Participants with advanced metastatic 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
40 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 50 participants will be enrolled in this dose escalation study, as described in 
Section 9; the overall sample size will be 84 participants maximum for this dose escalation 
study.
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Intervention Groups and Duration:
Intervention 
Groups
This is a multiple dose escalation study using the single agent, modified 
toxicity probability interval (mTPI) design and will evaluate safety, 
tolerability, and efficacy in the following treatment interventions:
Intervention 
Group Name
Drug
Dose
Level
Dose 
Strength
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Selumetinib
MK-
5618
DL 1
50 mg
BID
Oral
2 weeks on 
followed by 
1 week off 
Experi-
mental
MK-
5618
DL 2
75 mg
BID
Oral
2 weeks on 
followed by 
1 week off
Experi-
mental
MK-
5618
DL3
100 mg
BID
Oral
2 weeks on 
followed by 
1 week off
Experi-
mental
MK-
5618
DL4
125 mg
BID
Oral
2 weeks on 
followed by 
1 week off
Experi-
mental
MK-
5618
DL5
150 mg
BID
Oral
2 weeks on 
followed by 
1 week off
Experi-
mental
MK-
5618
DL6
200 mg
BID
Oral
2 weeks on 
followed by 
1 week off
Experi-
mental
MK-
5618
DL7 
onwards
Above 
200 mg 
(up to 
300 mg)
BID
Oral
2 weeks on 
followed by 
1 week off
Experi-
mental
Pembrolizumab
MK-
3475
DL1-
DL7
200 mg
Once 
every 3 
weeks
IV 
Infusion
Every 3 
weeks 
(Q3W)
Experi-
mental
Abbreviations: BID = twice daily; IV = intravenous
Based on the emerging safety and/or efficacy signals, an alternate dose level, 
alternative drug administration frequency and dosing schedule(s) may be 
explored and an optimal dose will be selected based on totality of data (PK, 
PD and safety) emerging throughout the trial.
Total 
Number
There is 1 intervention group (selumetinib + pembrolizumab) in this dose 
escalation study.
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Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the informed consent form (ICF) through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned to 
receive study treatment until disease progression is radiographically 
documented, confirmed by the site per modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics (iRECIST) 
when clinically appropriate; unacceptable adverse event(s) (AEs); 
intercurrent illness that prevents further administration of treatment; 
investigator’s decision to discontinue the participant; or administrative 
reasons requiring cessation of treatment; or until the participant has received 
35 treatment cycles of selumetinib and pembrolizumab treatment
(approximately 2 years). 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.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1 
and when clinically appropriate, confirmed by the site per iRECIST (for 
participants treated with pembrolizumab), the start of a new anti-cancer 
treatment, withdrawal of consent, pregnancy, death, or loss to follow-up. 
All participants will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first.
Upon identification of the preliminary RP2D of selumetinib for use in 
combination with pembrolizumab, additional participants with solid tumors 
will be enrolled in the dose expansion phase of this trial. Participants in the 
expansion phase of this trial will receive selumetinib in combination with 
pembrolizumab as dual therapy. The dose expansion phase in this study will 
be initiated through an amendment to this protocol.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Insert Other Oversight 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.
1.2
Schema
Figure 1
Study Design: Dose Escalation of Selumetinib in Combination with 
Pembrolizumab
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1.3
Schedule of Activities (SoA)
Dose Escalation
Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treatment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow-
up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D14
D1
D1
D1
D14
D1
D1
D1
At time of 
Treatment 
Discon-
tinuation
30 days 
Post-
last 
dose
Q9W 
or 
Q12W 
Post-
discon
Every 
12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Administrative Procedures
Informed Consent
X
Informed Consent for 
optional on-treatment 
tumor biopsy
X
Informed Consent for 
FBR (optional)
X
Participant 
Identification Card
X
X
Card will be updated 
once the participant is
allocated and receives a 
treatment number.
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
X
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treatment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow-
up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D14
D1
D1
D1
D14
D1
D1
D1
At time of 
Treatment 
Discon-
tinuation
30 days 
Post-
last 
dose
Q9W 
or 
Q12W 
Post-
discon
Every 
12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Selumetinib 
Administration
X
X
Administered BID, 2 
weeks on/1 week off.
Administered prior to 
pembrolizumab infusion 
on days when study 
treatments are 
administered on the same 
day.
Pembrolizumab 
Administration
X
X
X
X
X
X
X
X
Administered IV, Q3W
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) 
/ Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow
-up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Efficacy 
Assessments
Tumor Imaging
X
X
X
X
X
Screening: must be obtained 
within 28 days prior to the 
date of Cycle 1 Day 1 (C1D1). 
On-study imaging: 
First 12 months: Obtain 
Q9W (63 days ±7 days) 
calculated from the date of 
first dose. See Section 8.2.
After first 12 months: Obtain 
Q12W (±14 days) calculated 
from the date of first dose. 
See Section 8.2.
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) 
/ Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow
-up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Clinical 
Procedures/Assessments
Review Adverse 
Events
X
X
X
X
X
X
AEs that occur after the IC 
form 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
Follow-up Visits: AEs will be 
collected when participant is 
in the clinic for tumor imaging 
assessment.
Full Physical 
Examination
X
X
Directed Physical
Examination
X
X
X
X
X
X
X
X
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Height, Weight, and 
Vital Signs
X
X
X
X
X
X
X
X
X
X
Height will be measured at 
Visit 1 only. 
Vital signs: temperature, 
pulse, respiratory rate, and 
blood pressure
12-Lead 
Electrocardiogram
X
X
X
X
X
X
X
X
X
X
ECG will be performed in 
triplicate to confirm QTcF 
interval at screening. ECG 
will be performed predose, 
every cycle, starting at C2.
Full Ophthalmic 
Examination
(Q8W)
X
X
X
X
X
Performed at screening, 
Cycle 2, Day 1 and then 
Q8W (±7 days) from C2D1
and EoT.
An ophthalmic examination 
at the 30-day follow up is 
only required if there was a 
clinically significant 
abnormality noted at EoT 
(± 7 days)
Echocardiogram/
MUGA scan 
(Q12W)
X
X
X
X
X
Obtain scans as follows:
Screening
Treatment: C2D1 and 
C5D1, then Q12W
EoT
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
ECOG Performance 
Scale
X
X
X
X
X
X
X
X
X
X
Screening: assess within 3 
days prior to the first dose 
of study intervention. 
Day 1 of treatment cycle 
visits: Obtain prior to 
administration of study 
intervention 
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Survival Status
X
X
X
X
X
X
After investigator 
determined PD or start of 
new anticancer 
treatment. In addition, 
upon Sponsor request, 
participants may be 
contacted for survival 
status at any time during 
the study.
LOCAL Laboratory Assessments
Pregnancy Test – Urine 
or Serum β-hCG, if 
applicable
X
X
X
X
X
X
X
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
X
Testing may be more 
frequent if participant is 
receiving anticoagulant 
therapy.
CBC with Differential
X
X
X
X
X
X
X
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
X
X
X
X
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Urinalysis
X
X
X
X
X
X
X
To be performed at 
screening, and every 
other cycle starting at 
C2.
T3 and T4 or FT3, FT4, 
TSH
X
X
X
X
X
X
X
To be performed at 
screening, and every 
other cycle starting at 
C2. T3 and T4 are 
preferred; if not 
available, Free T3 and 
T4 may be tested.
Creatine kinase
Obtain as clinically 
indicated.
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle 
(C) / Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling 
Window (Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
CENTRAL Laboratory 
Assessments
Selumetinib 
Pharmacokinetics
X
X
X
X
X
Samples will be collected 
C1D1:
Pre-dose: Collect at time 0; 
morning dose(s) should be 
withheld until after PK 
(pre-dose) sample has been 
drawn, and 
Post-dose: Hours Post-dose: 
Hours 1 (± 10 minutes), 
2 (± 10 minutes), 
4 (± 10 minutes), 
6 (± 10 minutes), and 1 
sample any time between 8 
and 12 hrs (prior to PM 
dosing for BID regimen).
Additional samples will be 
collected at C2D1, C2D14, 
C5D1 and C5D14 at time 0 
pre-dose (- 10 minutes). 
Morning dose(s) should be 
withheld until after PK (pre-
dose) sample has been drawn. 
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) 
/ Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
Pembrolizumab 
Pharmacokinetics
X
X
X
X
X
Samples will be collected:
Pre-dose Cycle 1: Collect 
at time 0 (pre-dose)
within 24 hrs before 
infusion.
Cycles 2, 3, 5, 8 and every 4 
cycles thereafter: Collect at 
time 0 within 24 hrs before 
infusion.  
Blood for Genetic 
Analysis
X
Collected predose. 
Blood for RNA 
Analyses
X
X
X
X
X
Samples will be collected:
Pre-dose: C1D1, C2D1, 
C2D14, and C5D14
EoT visit
Blood for Plasma 
Biomarker Analyses
X
X
X
X
X
Samples will be collected:
Pre-dose: C1D1, C2D1, 
C2D14, and C5D14
EoT visit
Blood for Serum 
Biomarker Analyses
X
X
X
X
X
Samples will be collected:
Pre-dose: C1D1, C2D1, 
C2D14, and C5D14
EoT visit
Blood for ctDNA
X
X
X
X
X
Samples will be collected:
Pre-dose: C1D1, C2D1, 
C2D14, and C5D14
EoT visit
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Study Period:
Screening 
Phase
Treatment Cycles
(3-week Cycles)
End of 
Treat-
ment 
(EoT)
Post-treatment
Notes
Treatment Cycle (C) / 
Visit:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 
to 
35
Discon-
tinuation
Safety 
Follow
-up
Follow-
up 
Visits
Survival 
Follow-
up
Time point:
D1
D1
D1
4
D
1
D
1
D
1
D14
D1
D1
D1
At time 
of Treat-
ment 
Discon-
tinuation
30 
days 
Post-
last 
dose
Q9W 
or 
Q12W  
Post-
discon
Every 12 
weeks 
Post-
discon
Scheduling Window 
(Days)
-28 to -1
±3
-3
±3
±3
±3
-3
±3
±3
±3
±7
±7
±14
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; Discon=discontinuation; dMMR= deficient mismatch repair; DNA=deoxyribonucleic acid ; ECG=electrocardiogram; ECHO=echocardiogram; 
ECOG=Eastern Cooperative Oncology Group; EoT=end of treatment; FBR=future biomedical research; FT3=free triiodothyronine; FT4=free thyroxine; IHC= 
immunohistochemistry; IV=intravenous; MSI/MMR= microsatellite instability/mismatch repair; MUGA= multigated acquisition; PD=progressive disease; 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; QTcF = Fridericia’s Q-T interval corrected formula; RNA=ribonucleic acid; TSH=thyroid stimulating hormone.
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2
INTRODUCTION
The mitogen-activated protein kinase (MAPK) pathway is a conserved developmental 
pathway that regulates organ development and tissue homeostasis by transmitting signals 
through a series of phosphorylation events emanating from receptor tyrosine kinases (RTKs), 
RAS family members, RAF family members, mitogen-activated extracellular signal-
regulated kinase 1/2 (MEK1/2) (MAP2K1/2), and extracellular signal-regulated kinase 1/2 
(ERK1/2) (MAPK3/1). Nuclear translocation of activated ERK1/2 then triggers the 
transcriptional activation of multiple target genes involved in modulating the cellular 
processes of differentiation, proliferation, survival, migration, and angiogenesis [McCubrey, 
J. A., et al 2007]. With constitutive activation of ERK1 and ERK2 found frequently in human 
cancer cells from a variety of tissues (eg, lung, pancreas, colon, ovary, kidney, skin, and 
thyroid) {050Q2N}. Amplification, overexpression, or mutations in RTKs and genetic 
alterations in upstream components of the MAPK pathway, including KRAS, NRAS, HRAS, 
CRAF, BRAF, MEK1, and MEK2, alter cell signaling in tumors {050QBQ}.
Dysregulation of MAPK pathway in the majority of melanoma and other malignancies, 
including colon, pancreatic, and non-small-cell lung cancer, makes MEK an attractive 
therapeutic target as one of the main downstream molecules of MAPK pathway {050PR2}.
Numerous potent, selective allosteric MEK inhibitors have been developed and have 
undergone clinical evaluation of their ability to inhibit tumor growth {050QB3, 050NYY}. 
However, most MEK inhibitors have demonstrated limited clinical efficacy as single-agent 
therapies. Only trametinib showed improved progression-free and overall survival (OS) both 
as a single agent and in combination with the BRAF inhibitor, dabrafenib {050QBQ}. More 
recently, another MEK inhibitor, cobimetinib—when used in combination with the BRAF-
inhibitor, vemurafenib—was reported to improve progression-free survival among patients 
with BRAF V600-mutated metastatic melanoma [Ascierto, P. A., et al 2016]. 
Selumetinib (MK-5618) is an orally available highly selective inhibitor of both MEK1 and 
MEK2 with a favorable toxicity profile (see Investigator’s Brochure [IB]). Preclinical data 
have demonstrated that MEK inhibition by selumetinib is one of the effective strategies for 
targeting dysregulated MAPK pathway that leads to unregulated cell proliferation and 
development and progression of melanoma. Clinical studies have proven the potential 
antitumor activity of selumetinib in a subset of melanoma patients such as BRAF mutant 
melanoma and uveal melanoma harboring GNAQ/GNA11 mutations[Yeh, T. C., et al 2007].
In clinical studies, a phase I trial in pediatric patients with recurrent or refractory low-grade 
glioma has been reported. In this study, 25 subjects received a median of 13 cycles (range: 1
to 26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 
1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 
(standard error) 9.8% [Banerjee, A., et al 2017]. The study showed that selumetinib had 
promising antitumor activity in children with low-grade glioma (LGG); in the early Phase 2 
result, selumetinib was effective in treating children with recurrent/refractory LGG, including 
those with neurofibromatosis type 1 (NF-1)-associated LGG and pilocytic astrocytomas (PA) 
harboring BRAF V600E mutation or BRAF-KIAA 1549 fusion. Larger prospective studies 
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are necessary to determine the specific role of this agent in treating children with LGG 
harboring specific molecular aberrations in the future [Fangusaro, J., et al 2017]; Selumetinib 
also show antitumor response in adult patients as pretreatment prior to RAI therapy for 
patients with high risk Differentiated Thyroid Cancer (DTC) [Hong, C. M. 2017]. 
In the last decade, cancer immunotherapy has positively revolutionized outcomes and basic 
concepts of oncological treatments. Most of such breakthroughs are due to the discovery and 
therapeutic modulation of key immune-regulatory molecules (checkpoints) at the interface 
between immune effectors and tumor microenvironment [Zou, W. and Chen, L. 2008].
Monoclonal antibodies targeting co-inhibitory immune checkpoints (eg, PD-1 and CTLA-4) 
have demonstrated clinical activity in several malignances, including melanoma, non-small 
cell lung cancer, renal cell carcinoma, bladder cancer, head and neck squamous cell 
carcinoma, MSI-high colorectal carcinoma, Merkel cell carcinoma, and Hodgkin lymphoma, 
and have changed the practice of medical oncology [Jenkins, R. W., et al 2018], however,
most patients do not respond to immunotherapy, likely because of intrinsic tumor resistance
[Le, A. V. P., et al 2018]. The proposed mechanisms have included a lack of immune cell 
infiltration, poor antigen expression, and tumor-mediated silencing of the immune system via 
cytokine release. With cancer cells escaping immune recognition and elimination, cancer 
cells may begin to utilize additional mechanisms to create an immunosuppressive 
environment. This can be induced by the recruitment of immunosuppressive cells (myeloid-
derived suppressor cells [MDSCs] and regulatory T cells) to create a “wound healing” 
environment and the generation of tolerogenic signals, such as interleukin-10 (IL-10), 
transforming growth factor-beta (TGF-β) and extracellular adenosine [Lindau, D., et al 
2012].
2.1
Study Rationale
Emerging data suggest that combining programmed death 1 (PD1)/programmed death–ligand 
1 (PD-L1) inhibitors with other agents might sensitize tumors to immunotherapy and/or 
provide additive efficacy [Weinstock, M. 2015] [Bever, K. M. 2017].
Preclinical studies showed that MEK inhibition (MEKi) reduces accumulation of MDSCs
(CD11b+ MHCII−Ly6Chi cells) in tumor-bearing mice [Allegrezza, M. J., et al 2016], and 
selumetinib, as a monotherapy, or in combination with anti-CTLA-4, decreased intratumoral 
CD11b+ Ly6G+ neutrophil or MDSCs cells in the CT26 mouse tumor model [Poon, E., et al 
2017]; MEKi induces a more favorable immune infiltrate within a tumor [Ebert, P. J., et al 
2016]; Braf/MEKi treatment leads to higher rates of viable melanoma cell expressing PD-1 
and PD-L2, and therefore it could sensitize the tumor to a direct inhibitory effect of anti-PD-
1 antibody [Sanlorenzo, M., et al 2018].
Previous clinical data supporting this hypothesis were presented at the American Society of 
Clinical Oncology (ASCO) meeting in 2018 [Bendell, J. C., et al 2018]. Atezolizumab (a PD-
L1 inhibitor) in combination with cobimetinib (a MEKi), across all 84 colorectal cancer
(CRC) patients, median OS was 9.8 months, with 6-month and 12-month landmark OS at 65 
and 43 percent, respectively. In the previously described Phase 1 dose escalating trial of 
atezolizumab and cobimetinib and in metastatic CRC [Bendell, J. C., et al 2017], no dose-
limiting toxicities were observed, and expansion occurred at atezolizumab 800 mg Q2W and 
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cobimetinib 60 mg (Daily for 21 days of each 28-day cycle). This dose of cobimetinib is the 
same as the recommended monotherapy cobimetinib dose found in the labeled prescribing 
information. However, according to topline findings from the Phase 3 IMblaze370 study, 
combination therapy with the PD-L1 inhibitor atezolizumab (Tecentriq®) and the MEKi 
cobimetinib (Cotellic®) failed to improve overall survival (OS) versus regorafenib 
(Stivarga®) in previous treated patients with locally advanced or metastatic CRC, 
(https://www.onclive.com/web-exclusives/atezolizumab-cobimetinib-combo-falls-short-in-
phase-iii-mcrc-trial).
All these results indicate that MEKi selumetinib may combine with PD-1 antibody such as 
pembrolizumab for antitumor treatment. Consequently, this study is designed to assess 
safety, tolerability, pharmacokinetics (PK), and explore preliminary efficacy in participants 
with advance metastatic solid tumors.
2.2
Background
Refer to the respective IB for detailed background information on selumetinib and the MK-
3475 IB/approved labeling for detailed background information on pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Selumetinib Pharmaceutical and Therapeutic Background
Selumetinib is a MEKi, under clinical evaluation in multiple indications. For more details, 
refer to the selumetinib IB.
2.2.1.2
Pembrolizumab Pharmaceutical and Therapeutic Background
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across several 
indications. For more details on specific indications, refer to the pembrolizumab IB.
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.
The objective of this study is to assess the safety and tolerability of the combination study 
medication. 
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
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no hypothesis testing in this study. 
The objectives and endpoints apply to the study population of male and female participants at 
least 18 years of age with metastatic/advanced solid tumors. Participants receiving 
selumetinib in combination with pembrolizumab will be evaluated as follows:
Objectives
Endpoints
Primary
•
To determine the safety and tolerability 
and to establish a preliminary 
recommended Phase 2 dose (RP2D) of 
selumetinib when used in combination 
with pembrolizumab
•
Dose-limiting toxicities (DLTs)
•
Adverse events (AEs)
•
Study drug discontinuations due to an AE
Secondary
•
To evaluate the pharmacokinetics (PK)
of selumetinib
•
Pharmacokinetic parameters including
area under the curve (AUC), minimum 
concentration (Cmin) and maximum 
concentration (Cmax)
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 1 multicenter, worldwide, open-label study of selumetinib in combination 
with pembrolizumab in participants with histologically or cytologically confirmed diagnosis 
of metastatic/advanced solid tumor.
The monotherapy RP2D dose for selumetinib is 75 mg twice-daily (BID) with continuous 
dosing. At the monotherapy RP2D, trough inhibition of phosphorylation of ERK as an 
indirect measure of MEK inhibition by selumetinib was reported to be approximately 20%, 
where studies in non-small cell lung cancer (NSCLC) and melanoma failed to demonstrate 
efficacy. For the intermitted dose schedule, it may be possible to increase the selumetinib 
dose beyond what was tolerated for continuous monotherapy dosing because of the 
observation that intermittent MEK dosing is tolerated at higher doses. The potential 
maximum dose of selumetinib in the escalation maybe above 200 mg (up to 300 mg) BID
with intermittent dosing (14 days on/7 days off). While this dose is higher than the RP2D for 
continuously administered monotherapy selumetinib, preclinical and clinical observations 
suggest higher doses may be tolerated with intermittent dosing.
In each dose level, the modified toxicity probability interval (mTPI) design with a target 
DLT rate of approximately 30% will be applied to identify a potential maximum tolerated 
dose (MTD). Based on the emerging safety and/or efficacy signals, other dose levels may 
also be explored in consultation and agreement with the investigator and Sponsor. The 
totality of the data will be considered before deciding on the dose level(s) to carry forward to 
further development (ie, preliminary RP2D).
Pre-treatment tumor tissue is required to be provided prior to allocation into the study. If not 
available, a tumor biopsy must be obtained prior to entry in the study. Upon identification of 
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the preliminary RP2D of selumetinib for use in combination with pembrolizumab, additional 
participants with specified solid tumor types will be enrolled in the dose expansion phase of 
this study. The specific tumor types (cohorts) will be selected based on the totality of the data 
at the time of the RP2D determination. Up to 30 participants for each cohort in the expansion 
phase of this study will receive selumetinib in combination with pembrolizumab as dual 
therapy. The details for the dose expansion phase in this study will be specified in an 
amendment to this protocol and will include up to 3 disease cohorts.
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 modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants 
will be monitored carefully for the development of adverse events (AEs), and for clinical 
and/or radiographic evidence of disease progression according to RECIST 1.1. In participants 
who have initial evidence of radiological progressive disease by RECIST 1.1, it will be at the 
discretion of the investigator whether to continue a participant on study treatment until repeat 
imaging is obtained. This clinical judgment decision should be based on the 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 Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0, to establish the safety and tolerability of MK-5618 in combination with 
pembrolizumab as per the primary objective of this study. The definition of DLTs and 
criteria for dose modification are outlined in Sections 6.6.2.2 and 6.6.1.
Participants will be treated until progressive disease, unacceptable toxicity, intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
treatment, participant withdrawal of consent, pregnancy of the participant, noncompliance 
with study intervention or procedure requirements, participant completes treatment, or 
administrative reasons requiring cessation of treatment, at which point they will be 
discontinued from the study. 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. Tumor measurements will continue to be made every 9 weeks until 
progressive disease is observed, and each participant will be followed for survival. Imaging 
will not be collected during Survival Follow-up.
Participants may also agree to provide an optional on-treatment biopsy for biomarker 
analysis as outlined in the Schedule of Activities (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 Endpoints
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4.2.1.2
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, SAEs and events of clinical interest (ECIs) will be 
summarized. Other safety measures evaluated in study include laboratory tests, ECGs, 
echocardiogram (ECHO)/multigated acquisition (MUGA) scan, vital signs, ECG 
measurements, physical examinations, and eye examination.
4.2.1.3
Pharmacokinetic Endpoints
Pharmacokinetic endpoint is secondary
for selumetinib
 Pharmacokinetic profile of selumetinib and pembrolizumab will be 
characterized. The PK concentrations of 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 selumetinib.  
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4.2.1.5
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 
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.
4.2.2
Rationale for the Use of Comparator/Placebo
This study does not include comparators or placebo.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
Rationale for Starting and Maximum Dose of Selumetinib
The RP2D for selumetinib as monotherapy is 75 mg PO BID, administered continuously. In 
this study, the starting dose of selumetinib will be 50 mg oral BID dosed intermittently for 
the first 14 days of each 21-day cycle. The dose will be escalated, in 25-mg increments, to 
above 200 mg (up to 300 mg) oral BID per the mTPI rule, maintaining the intermittent 
schedule. Outcomes of phase II trial of selumetinib propose that enhanced inhibition of MEK 
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is associated with a greater clinical response, but MEK inhibition also causes dose dependent 
AEs. Thus, intermittent dosing might have better results than continuous administration. 
Preclinical studies have demonstrated that intermittent dosing may delay the development of 
acquired resistance [Faghfuri, E., et al 2018] [Xue, Y., et al 2017].
4.3.1.2
Rationale for Dose Interval and Escalation Increments
Doses of selumetinib will start at 50 mg BID, below the monotherapy RP2D dose for 
selumetinib of 75 mg BID. Dose escalation increments for selumetinib in combination with 
pembrolizumab will be to 75 mg (50% increase) initially, to the monotherapy RP2D for 
selumetinib, and then 33% or lower afterwards in increments of 25 mg.

Starting Dose (Dose Level [DL] 1): MK-5618 50 mg (oral) twice daily (BID), 2 
weeks on/1 week off + MK-3475 200 mg IV every 3 weeks (Q3W)

Escalation Dose (DL2): MK-5618 75 mg (oral) BID, 2 weeks on/1 week off + 
MK-3475 200 mg IV Q3W

Escalation Dose (DL3): MK-5618 100 mg (oral) BID, 2 weeks on/1 week off + 
MK-3475 200 mg IV Q3W

Escalation Dose (DL4): MK-5618 125 mg (oral) BID, 2 weeks on/1 week off + 
MK-3475 200 mg IV Q3W

Escalation Dose (DL5): MK-5618 150 mg (oral) BID, 2 weeks on/1 week off + 
MK-3475 200 mg IV Q3W

Escalation Dose (DL6): MK-5618 200 mg (oral) BID, 2 weeks on/1 week off + 
MK-3475 200 mg IV Q3W

Escalation Dose (DL7 onwards): MK-5618 above 200 mg (up to 300 mg; oral) BID, 
2 weeks on/1 week off + MK-3475 200 mg IV Q3W
This Dose Escalation study will follow the mTPI method (Section 4.3.1.4) to identify the 
preliminary RP2D of selumetinib used in combination with pembrolizumab.
4.3.1.3
Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W). Based 
on the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W), 
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
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK analysis) 
at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). These studies demonstrated flat dose- and exposure-response relationships across 
the doses studied representing an approximate 5- to 7.5-fold difference in exposure. The 2 
mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied. 
Subsequently, flat dose-exposure-response relationships were also observed in other tumor 
types including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin 
Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the tumor type. 
These findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Second, a 
physiologically-based PK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.1.4
Dose Finding Using a Modified Toxicity Probability Interval Design
Dose finding will follow the mTPI design [Ji Y, Li Y, Bekele BN 2007] with a target DLT 
rate of 30%. Dose escalation and de-escalation decisions are based on the mTPI design and 
depend on the number of participants enrolled and number of DLTs (Section 6.6.2.2)
observed at the current dose level. The DLT observation period for this trial is defined as 21 
days for the participant.
A minimum of 3 participants are required at each dose. However, depending on the accrual 
rate, 3, 4, 5, or 6 participants may be enrolled within 7 to 14 days of initiating the current
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dose level. In Table 1, the columns indicate the numbers of participants treated at the current 
dose level, and the rows indicate the numbers of participants experiencing DLT. The entries 
of the table are the dose-finding decisions: E, S, D, and DU represent escalating the dose, 
staying at the same dose, de-escalating the dose, and excluding the dose from the trial due to 
unacceptable toxicity, respectively. For example, if 0 out of 3 participants at a given dose 
level develop a DLT, then the dose can escalate to the next level. If 2 participants out of 3 
develop a DLT, the dose will be de-escalated to the next lower dose level. If 3 out of 3 
participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose 
should be de-escalated and the current dose will not be explored further. If 1 out of 3 
participants at a given dose level develops a DLT, then additional participants should be 
enrolled at that dose level following the rules below.
When adding participants to a dose level in response to a “stay” decision, the number of 
additional participants to be enrolled is capped to minimize the exposure to a dose that may 
be unacceptably toxic (denoted as DU in Table 1). Secondly, to determine how many more 
participants can be enrolled at the dose level, one can count steps in diagonal direction (down 
and to the right) from the current cell to the first cell marked DU. For example, if 1 of 3 
participants have experienced a DLT at a given dose level, no more than an additional 3 
participants should be enrolled at this dose level until additional DLT data are available. This 
is because this dose level would be considered unacceptably toxic if all 3 of the additional 
participants experience a DLT (ie, 4/6 participants with DLT in Table 1). The same 
principles will be applied whether 3, 4, 5, or 6 participants are initially enrolled at that dose 
level.
A D or DU decision at the lowest dose level will stop the trial. An E decision at the highest 
dose level will result in staying at that level. 
Dose finding will end after 14 participants have been enrolled at any of the tested doses and 
the decision is to stay at the current dose. After 14 participants have been enrolled at any of 
the tested doses, dose finding will stop if the mTPI table indicates “S” for staying at current 
dose. Otherwise, up to 14 new participants may be enrolled at a lower dose if “D” or “DU” is 
indicated, or at a higher dose if “E” is indicated.
The pool-adjacent-violators-algorithm [Ji, Y. 2013] will be used to estimate the DLT rates 
across doses. The dose with an estimated DLT rate closest to 30% will be treated as a 
preliminary MTD. However, the totality of the data will be considered before deciding on the 
dose(s) to carry forward to Part 2, and the escalation schedule may be adjusted based on PD, 
PK, and safety data emerging throughout the trial. 
Note that although 30% was the target toxicity rate used to generate the guidelines in 
Table 1, the observed rates of participants with DLTs at the MTD may be slightly above or 
below 30%).
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Table 1
Dose-finding Rules per mTPI Design
Number of Participants Evaluable for DLT at Current Dose
Number of 
Participants with 
at least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
Abbreviations: 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. 
2013] [Ji, Y., et al 2010]
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
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4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, Good Clinical Practice (GCP) and/or other applicable 
regulatory requirements, procedure-related problems or the number of discontinuations for 
administrative reasons is too high.
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 that negatively impact the risk:benefit ratio
2. Plans to modify or discontinue the development of the study drug
Ample notification will be provided in the event of Sponsor decision to no longer supply
selumetinib or pembrolizumab.
5
STUDY POPULATION
Male/Female participants who are at least 18 years of age with advanced metastatic solid 
tumors will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have a histologically or cytologically confirmed advanced or metastatic solid tumor by 
pathology report and have received, or been intolerant to, all treatment known to confer 
clinical benefit.
2. Have measurable disease by RECIST 1.1 as assessed by local site investigator/radiology. 
Target lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.
3. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
4. Have the ability to swallow and retain oral medication and not have any clinically 
significant gastrointestinal abnormalities that might alter absorption.
Examples of clinically significant gastrointestinal abnormalities: perforation, 
diverticulitis, duodenal resection, esophageal stenosis.
Examples of gastric surgeries that can potentially impact absorption: lap band, 
Roux-en Y, sleeve.
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5. Demonstrate adequate organ function as defined in Table 2.
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL 
Platelets
>100,000/mcL 
Hemoglobin
>9 g/dL or >5.6 mmol/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
>30mL/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 × 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); 
GFR = glomerular filtration rate; 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. If no local guideline is available, 
CrCl should be calculated using the Cockcroft-Gault Method: CrCl = [(140-age) * weight (kg) * (0.85 for 
females only)] / (72 * serum creatinine).
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines.
Demographics
6. Is male or female and a minimum of 18 years of age inclusive at the time of signing the 
informed consent.
Male Participants
7. 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
8. Not be pregnant (Appendix 5) or breastfeeding, and at least 1 of the following conditions 
applies:
a.
Not be a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b. A WOCBP must agree 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
9. 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.
Additional Criteria
10. Human immunodeficiency virus (HIV) infected participants must have well controlled 
HIV on anti-retroviral therapy (ART), defined as:

Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at the time of 
screening 

Participants on ART must have achieved and maintained virologic suppression 
defined as confirmed HIV RNA level below 50 or the lower limit of quantification
(below the limit of detection) using the locally available assay at the time of screening 
and for at least 12 weeks prior to screening

Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks prior to study entry (Day 1)
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has 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.
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2. Has 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.
3. Has had a severe hypersensitivity reaction (≥ Grade 3) to treatment with a monoclonal
antibody/component of the study treatment, and/or has a history of allergic reactions 
attributed to compounds of similar chemical or biologic composition to agents and/or 
excipients used in the study.
4. Has an active infection requiring therapy.
5. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
6. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) 
except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed. Use 
of nonsystemic steroids is permitted.
7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to allocation.
8. Participants with known Hepatitis B or C infections, or known to be positive for Hepatitis 
B antigen/Hepatitis B virus 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.
Note: No testing for Hepatitis B, Hepatitis C, and HIV is required unless mandated by 
local health authority.
9. HIV infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease.
10. Has undergone major surgery and has not recovered adequately from any toxicity and/or 
complications from the intervention prior to starting study therapy.
Note: Surgery that required general anesthesia must be completed at least 2 weeks 
before first study intervention administration.
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Note: Surgery requiring regional/epidural anesthesia must be completed at least 72 
hours before first study intervention administration and participants should be 
recovered.
11. Has baseline peripheral neuropathy/paresthesia Grade 1.
12. Have any medical, psychiatric, cognitive, or other condition that may compromise the 
participant’s ability to understand the participant information, give informed consent, 
comply with the study protocol, or complete the study, in the opinion of the treating 
investigator.
13. Patients with clinically significant cardiovascular disease as defined by the following:
a.
Uncontrolled hypertension (at randomization: systolic blood pressure ≥150 mmHg or 
diastolic blood pressure ≥95 mmHg, despite optimal therapy)
b. Left ventricular ejection fraction (LVEF) <55% measured by echocardiography (or 
MUGA)
c.
Symptomatic heart failure (NYHA grade II to IV), prior or current cardiomyopathy, 
or severe valvular heart disease
d. Uncontrolled angina (Canadian Cardiovascular Society grade II to IV despite medical 
therapy)
e.
Clinically significant cardiac arrhythmia and/or conduction abnormality ≤6 months 
prior to start of study treatment
f.
Myocardial infarction or acute coronary syndrome ≤6 months prior to start of study 
treatment
g. Mean QT interval calculated according to the Frederica method (QTcF) interval: 
Male >450 ms; Female >470 ms
14. Have a history of thromboembolic or cerebrovascular event(s) within 6 months prior to 
study enrollment, including transient ischemic attack, cerebrovascular accident, deep vein 
thrombosis, or pulmonary embolism.
15. Have neuromuscular disorder associated with an elevated creatine kinase (eg, 
inflammatory myopathy, muscular dystrophy, amyotrophic lateral sclerosis, spinal 
muscular atrophy.
16. Have a history of, or current, retinal vein occlusion (RVO) or current risk factors for 
RVO (eg, uncontrolled glaucoma, ocular hypertension, history of hyperviscosity, or 
hypercoagulability syndromes).
17. Have retinal degenerative disease.
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18. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s participation 
for the full duration of the study, make administration of the study treatments hazardous 
or make it difficult to monitor adverse effects such that it is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
19. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
20. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
Prior/Concomitant Therapy
21. Has received a live-virus vaccine within 28 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted.
22. Has received prior therapy with compounds targeting PD-1, PD-L1, PD-L2, an MEK 
inhibitor (eg, cobimetinib, trametinib), or an ERK inhibitor (eg, MK-8353, GCD-0994, 
ulixertinib).
Prior/Concurrent Clinical Study Experience
23. 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 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.
Pregnancy Exclusion
24. 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 Consideration for Participants 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 PKs 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.
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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. The Patient Information and Consent form for studies of selumetinib includes 
information on the possibility of higher selumetinib plasma levels and occurrence of AEs in 
Asian subjects than in subjects who are not of Asian origin. 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).
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.
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
They receive less than 75% of the total selumetinib or pembrolizumab study 
treatment in Cycle 1 and did not experience a DLT.
Participants who are not evaluable will be replaced unless accrual to the cohort has stopped. 
Nonevaluable participants will not be counted toward the total number of participants in the 
cohort for DLT evaluation.
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 intervention supplies provided by the Sponsor will be packaged to support enrollment.
Study intervention supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 3.
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Table 3
Study Interventions
Arm Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen /
Treatment 
Period /
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Selumetinib + 
Pembrolizumab
Experi-
mental
Selumetinib 
(MK-5618)
Drug
Capsule
25 mg
50 mg
75 mg 
100 mg 
125 mg 
150 mg
200 mg
Above 
200 mg
(up to 
300 mg)
Oral
BID:
2 weeks on 
followed by 
1 week off
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
Selumetinib + 
Pembrolizumab
Experi-
mental
Pembrolizumab 
(MK-3475)
Drug
Vial
200 mg
200 mg
IV 
Infusion
Q3W
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
Abbreviations: BID = twice daily; IV = intravenous; Q3W = every 3 weeks
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study intervention.
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.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
This is an open-label study. Study intervention assignment will occur centrally using an 
interactive response technology system.
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 for ≥12 weeks for 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
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed
during the ongoing study. If there is a clinical indication for any medications or vaccinations
specifically prohibited, discontinuation from study intervention will be required. 
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, 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.
Of note, selumetinib can 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.  
All concomitant medications received within 28 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.
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6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than selumetinib (MK 5618) and pembrolizumab (MK-
3475).

For agents that may affect the metabolism of selumetinib (eg, strong inhibitors and 
inducers of CYP2C19 or CYP3A4), caution should be taken. However, changes in 
exposure of selumetinib with strong inhibitors/inducers would be moderate based on 
clinical evidence (1.5-fold).

Participants should not take any supplemental vitamin E. High doses of vitamin E have 
been reported to cause bleeding and interrupt blood coagulation processes.
Note: 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.

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. 

Live vaccines within 28 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus
Calmette–Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza vaccines 
(eg, FluMist®) are live attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
of suspected immunologic etiology. The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
Participants may receive other medications that the investigator deems to be medically 
necessary.
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6.5.3
Supportive Care
6.5.3.1
Selumetinib Supportive Care Guidelines
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, metoclopramide, ondansetron, or aprepitant 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 6.6.1.
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], 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
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 1 day, or 3) unusually 
high volume of stool. Loperamide should be taken in the following manner: 4 mg at first 
onset of diarrhea, then 2 mg after each unformed stool. The daily dose of loperamide should 
not exceed 16 mg/day. Loperamide should be deferred if blood or mucus is present in the 
stool or if diarrhea is accompanied by fever. In this setting, appropriate diagnostic 
microbiologic specimens should be obtained to exclude an infectious etiology. Subjects 
should be also advised to drink liberal quantities of clear fluids to help prevent dehydration.
Supportive care with steroids (as described in Section 6.5.3.2).
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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 5 Dose Modification and Toxicity Management 
Guidelines for Immune-related Adverse Events Associated with Pembrolizumab 
Monotherapy, Coformulations or IO Combinations: 

Prophylaxis of skin toxicity to be initiated 24 hours prior to the first treatment with study 
drug or later as needed. 

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 free, SPF ≥30, ultraviolet 
A/ultraviolet B 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 to 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 by the investigator. 
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 once daily), 
doxycycline (100 mg BID) or minocycline (50 to 100 mg once daily).

Although there has been no evidence of phototoxicity or photosensitivity in participants 
being treated with selumetinib, doxycycline (or minocycline as second-line) should be 
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used with thorough ultraviolet protection (ie, avoidance of direct exposure to sunlight, 
use of sunscreen and sunglasses).

Use of acitretin is not recommended.
Severe rash (CTCAE Grade 3 to 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:

For pruritic lesions, use cool compresses and oral antihistaminic agents

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®

For desquamation, use emollients with mild pH 5/neutral (best containing urea 10%)

For paronychia, antiseptic bath and local potent corticosteroids, use oral antibiotics and if 
no improvement is seen, refer to a dermatologist or surgeon

For infected lesions, obtain bacterial and fungal cultures and treat with topical or 
systemic antibiotics based on sensitivity of culture
6.5.3.2
Pembrolizumab Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.1.2, Table 6. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
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not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Section 6.6.1.2, 
Table 6 for guidelines regarding dose modification and supportive care.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Modifications Due to Adverse Events
In previous studies of selumetinib and pembrolizumab monotherapy, overlapping toxicities 
have been observed for selumetinib and pembrolizumab (refer to IBs). These overlapping 
toxicities include pneumonitis, diarrhea/colitis, cardiac function decrease, and skin rash.
In the current study, the relationship of these AEs to selumetinib and/or pembrolizumab may 
be difficult to unambiguously assign. Therefore, if a participant experiences an AE related to 
either treatment, both selumetinib and pembrolizumab will be modified or discontinued as 
described in Table 4 and Table 5.
If 2 different therapies are proposed in these tables, the most conservative/effective treatment 
should be chosen (ie, steroid). Further, if the investigator believes the treatment emergent 
toxicity is unambiguously related to only one of the agents, they may continue the participant 
on the unrelated agent following consultation with the Sponsor.
6.6.1.1
Selumetinib Dose Modification Due to Adverse Events
The starting dose level for selumetinib is 50 mg BID, and a dose reduction below 50 mg BID 
is not allowed. Participants requiring additional reductions must discontinue selumetinib 
treatment. 
Missed/skipped doses will not be made up (ie, the participant should not double their dose if 
the previous dose was missed). When a toxicity results in a dose reduction, the dose cannot 
be re-escalated. 
Dose reduction/interruption/discontinuation decisions should be based on the CTCAE grade 
of the toxicity and the guidelines provided below. In general, doses should not be reduced or 
interrupted for Grade 1 toxicities, but treatment to control symptoms should be provided as 
appropriate. 
Table 4 provides dose adjustment recommendations for selumetinib-induced toxicities.
During dose interruption the site should consult with the Sponsor regarding the 
discontinuation and/ or resumption of treatment.
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Table 4
Dose Modification Guideline for Selumetinib
Eye disorders- Retinal Events (including serious detachment of the retina) 
Grade 1
Maintain dose level of selumetinib and repeat ophthalmic monitoring 
including visual acuity assessment and OCT within 10 days.
Grade 2
Interrupt 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; continue the schedule of visual assessments 
established per protocol.

If not resolved to baseline or Grade ≤1 within 10 days, resume 
treatment at 1 reduced dose level (1 level below that previously 
received); continue the schedule of visual assessments established 
per protocol.

If on retreatment Grade 2 reoccurs, permanently discontinue 
selumetinib.
Grade 3
Interrupt 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 current dose level; continue the schedule of visual assessments 
schedule established per protocol.

If not resolved to baseline or Grade ≤1 within 7 days, continue to 
hold the selumetinib dose and repeat ophthalmic assessment in 10 
days.

If resolved to baseline or Grade ≤1, resume treatment at 1 reduced 
dose level; continue the schedule of visual assessments established 
per protocol.

If remains Grade 3, permanently discontinue selumetinib.

If on retreatment Grade 3 reoccurs, permanently discontinue 
selumetinib.
Grade 4
Permanently discontinue selumetinib and immediately follow up with 
ophthalmic monitoring.
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Eye disorder - RVO
Any Grade
Permanently discontinue selumetinib.
Other eye disorders (ie, Non-retinal Events)
Grade 1 to -2
Maintain dose level of selumetinib and increase frequency of ophthalmic 
monitoring to at least 14 days until stabilization or resolution.
Grade 3
Interrupt selumetinib and refer participant to ophthalmologist within 1 
week:

If resolved to Grade ≤1 in ≤21 days, resume treatment at 1 reduced 
dose level.

If not resolved to Grade ≤1 in ≤21 days, permanently discontinue 
selumetinib.
Grade 4
Permanently discontinue selumetinib.
Liver-related adverse events
Grade 1 AST or 
ALT (>ULN to 
3 x ULN)
Maintain dose level of selumetinib.
Grade 2 AST or 
ALT 
(>3 to 5.0 x 
ULN) or 3 x 
baseline value 
(if liver 
metastasis) 
AND blood 
bilirubin ≤2.0 x 
ULN
Interrupt dose of selumetinib until resolved to Grade ≤1 (or Grade ≤2 in 
case of liver metastasis), then:

If resolved in ≤14 days, resume treatment at current dose level and 
schedule.

If resolved in >14 days, resume treatment at 1 reduced dose level.
Recurrence: 

Interrupt dosing of selumetinib until resolved to Grade ≤1 (or Grade 
≤2 in case of liver metastasis), then resume treatment at 1 reduced 
dose level.
Grade 2 AST or 
ALT 
(>3 to 5.0 x 
ULN or 3 x 
baseline value 
(if liver 
metastasis) 
AND blood 
bilirubin >2.0 x 
ULN
Interrupt dose of selumetinib until resolved to Grade ≤1 (or Grade ≤2 in 
case of liver metastasis), then:

If resolved in ≤7 days, resume treatment at 1 reduced dose level.  If 
not resolved in ≤7 days, permanently discontinue selumetinib.
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Grade 3 AST or 
ALT 
(>5.0 to 8.0 x 
ULN) AND 
blood bilirubin
≤2.0 x ULN
Interrupt dose of selumetinib until resolved to Grade ≤1 (or Grade ≤2 in 
case of liver metastasis), then:

If resolved in ≤14 days, resume treatment at current dose level and 
schedule.

If resolved in >14 days, resume treatment at 1 reduced dose level.
Recurrence: 

Interrupt dosing of selumetinib until resolved to Grade ≤1 (or Grade 
≤2 in case of liver metastasis), then resume treatment at 1 reduced 
dose level.
AST or ALT 
(>8 x ULN) 
AND blood 
bilirubin* ≤2.0 x 
ULN
Permanently discontinue selumetinib.
AST or ALT 
(>5.0 x ULN) 
AND blood 
bilirubin*
>2.0 x ULN
Permanently discontinue selumetinib.
AST or ALT 
Grade 4 
(>20.0 x ULN)
Permanently discontinue selumetinib.
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 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, resume treatment at 
1 reduced dose level after approval by the Sponsor Medical Monitor. 
Monitor LVEF 2 weeks after restarting on 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 to 4
Permanently discontinue participant from selumetinib. Closely monitor 
LVEF until resolution (or 16 weeks).
CK elevation
Grade 1 to 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).
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Grade 3 
(>5.0 to 10.0 x 
ULN) without 
renal 
impairment (ie, 
serum creatinine
<1.5 x ULN or 
1.5 x baseline)
If asymptomatic, maintain dose of selumetinib. Monitor closely and 
measure isoenzymes and myoglobin in blood and urine.
If symptomatic (muscle pain/spasms or muscle weakness), interrupt 
dose of selumetinib until resolved to CTCAE Grade ≤1 and monitor 
closely, then:

If resolved in ≤21 days, then resume treatment at 1 reduced dose 
level.

If resolved in >21 days, permanently discontinue selumetinib.
Grade 4 
(10 x ULN)
without renal 
impairment (ie, 
serum creatinine 
<1.5 x ULN or 
1.5 x baseline)
If asymptomatic, interrupt dose of 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, then resume treatment at 1 reduced dose 
level.

If resolved in >21 days, permanently discontinue selumetinib.
If symptomatic, permanently discontinue selumetinib.
If symptomatic (muscle pain/spasms), permanently discontinue 
selumetinib.
Grade 3 or 4 
with renal 
impairment (ie, 
serum creatinine 
≥1.5 x ULN or 
1.5 x baseline)
Interrupt 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, then resume treatment at 1 reduced dose 
level.

If resolved in >21 days, permanently discontinue selumetinib.
Recurrence:

Permanently discontinue selumetinib.
Rash
Grade 1
Treatment with selumetinib will be maintained at the current dose. 
Initiate prophylactic regimen if it was not already and monitor closely.
Grade 2
First occurrence: 

Treatment with selumetinib will be maintained at the current dose 
and rash will 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 current 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 a 1 reduced dose level.

Only one dose reduction is permitted.
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Grade 3
First occurrence: 

Treatment with selumetinib will 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 of the current dose level and schedule.
Second occurrence: 

Interrupt treatment until improvement to Grade ≤1. Resume 
treatment with selumetinib at a reduced dose level. If participant is at 
the lowest dose, participant will be discontinued.

Consider referral to dermatologist and manage rash per 
dermatologist’s recommendation.
Grade 4
Permanently discontinue selumetinib.
Diarrhea
Uncomplicated 
Grade 1 to 2
Consider temporary interruption of selumetinib until resolved to 
Grade ≤1. Resume treatment of the current dose level and schedule.
Complicated 
Grade 1 to 2
Temporarily interrupt selumetinib treatment until resolved to Grade ≤1. 
Resume treatment at 1 reduced dose level. If participant is at the lowest 
dose, participant will be discontinued.
Grade 3 to 4
Temporarily interrupt selumetinib treatment until resolved to Grade ≤1. 
Resume treatment at 1 reduced dose level. If participant is at the lowest 
dose, participant will be discontinued.
Nausea/Vomiting
Grade 1 to 2
Treatment with selumetinib will be maintained at the current dose. 
Promptly institute antiemetic measure. 
Grade 3
Temporarily interrupt selumetinib treatment until resolved to Grade ≤1. 
Resume treatment at the current dose level if, in the judgment of the 
investigator, the toxicity is considered to be unrelated to selumetinib, or 
at 1 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 selumetinib treatment
Interstitial lung disease/pneumonitis
Grade 1
Maintain dose level of selumetinib Monitor weekly.
Grade 2
Withhold selumetinib for up to 3 weeks.
If improved to Grade 0 or 1, resume treatment at 1 reduced dose level. 
If not resolved within 3 weeks, permanently discontinue selumetinib.
Grade 3 to 4
Permanently discontinue selumetinib.
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Venous Thromboembolism
Uncomplicated 
DVT or PE
Withhold selumetinib for up to 3 weeks.
If improved to Grade 0 or 1, resume treatment at 1 reduced dose.
If not improved, permanently discontinue.
Life threatening 
PE
Permanently discontinue selumetinib.
All other adverse events (suspected to be related)
Grade 1 to 2
If the event is a persistent Grade 2 AE not responsive to a specific 
therapy, consider study drug interruption or reduction.
Grade 3
For other AEs, interrupt study drug until resolution to Grade ≤1 or to 
pre-treatment/baseline level. 
If the event resolves within 21 days, then study drug may be resumed at 
1 reduced dose level (1 level below that previously received) based upon 
the investigator’s discretion.
Grade 4
Permanently discontinue study drug.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate 
aminotransferase; BID= twice daily; CK=creatine kinase; CTC=Common Terminology 
Criteria; DVT=deep vein thrombosis; ECG=electrocardiogram; LLN= lower limit of normal; 
LVEF=left ventricular ejection fraction; OCT= ocular coherence tomography; 
PE=pulmonary embolism; RVO=retinal vein occlusion; QTc=Q-T interval QTcF=QT 
interval calculated according to the Fridericia method; ULN= upper limit of normal.
6.6.1.2
Pembrolizumab Dose Modification Due to Adverse Events
6.6.1.2.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation.  
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Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events.
Holding Study Interventions: 
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions: 
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment
   Add prophylactic antibiotics for opportunistic infections
Recurrent Grade 
2 or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
   Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
   Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withhold a
   Initiate insulin 
replacement therapy for 
participants with T1DM
   Administer anti-
hyperglycemic in 
participants with 
hyperglycemia
   Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
   Treat with non-selective 
beta-blockers (eg, 
propranolol) or 
thionamides as appropriate
   Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid 
replacement hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
   Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology and/or 
exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 
1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b     Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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6.6.1.2.2
Dose Modification and Toxicity Management of Infusion-Reactions 
Related to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 6.
Table 6
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator.
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (e.g. 
from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held 
until symptoms resolve and the 
subject should be premedicated for 
the next scheduled dose.
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug treatment
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 500 to 
1000 mg po (or equivalent 
dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
subject is deemed medically stable 
in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Subject is permanently 
discontinued from further study 
drug treatment.
No subsequent dosing
Abbreviations: po = taken by mouth/oral.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
6.6.1.2.3
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
6.6.2
Dose Administration/Escalation
6.6.2.1
Dose Administration (Preparation)
Details on preparation and administration of selumetinib and pembrolizumab are provided in 
the appropriate Pharmacy/Procedures Manual.
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6.6.2.2
Definition of Dose-limiting Toxicity
All toxicities will be graded using NCI CTCAE Version 4.0 based on the investigator 
assessment. The DLT window of observation will be during first 21-days of treatment.  
The occurrence of any of the following toxicities will be considered a DLT, if assessed by 
the investigator to be possibly, probably or definitely related to study drug administration, 
excluding toxicities clearly not related to the drug, such as disease progression, 
environmental factors, unrelated trauma:
1. Grade 4 non-hematologic toxicity (not laboratory).
2. Hematologic toxicity:

Grade 4 neutropenia >5 days

Grade 4 thrombocytopenia of any duration

Grade 3 thrombocytopenia with clinically significant bleeding

Other Grade 4 hematologic toxicity lasting ≥7 days
3. Any non-hematologic AE Grade 3 severity (not laboratory) should be considered a 
DLT, with the following exceptions: 

Grade 3 fatigue lasting ≤3 days 

Grade 3 diarrhea, nausea, or vomiting lasting <72 hours in the absence of 
maximal medical therapy

Grade 3 rash without use of corticosteroids or anti-inflammatory agents per 
standard of care
4. Any Grade 3 or Grade 4 non-hematologic laboratory value if:

Clinically significant medical intervention is required to treat the participant, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week

The abnormality results in a Drug-induced Liver Injury (DILI) (see Sections 
8.4.1 and 8.4.7 for criteria).
Examples of some exceptions: Clinically nonsignificant, treatable, or reversible 
laboratory abnormalities include liver function tests, urine acid.
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5. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as absolute neutrophil count <1000/mm3 with a single 
temperature of >38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) 
for more than 1 hour.

Grade 4 is defined as absolute neutrophil count <1000/mm3 with a single 
temperature of >38.3°C (101°F) or a sustained temperature of ≥38°C (100.4°F) 
for more than 1 hour, with life-threatening consequences and urgent intervention 
indicated.
6. An elevated AST or ALT lab value that is ≥3X the upper limit of normal and an 
elevated total bilirubin lab value that is ≥2X the upper limit of normal and, at the 
same time, an alkaline phosphatase lab value that is <2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory 
testing.
7. Any prolonged delay (>2 weeks) in initiating Cycle 2 study treatment due to a 
treatment-related toxicity. 
8. Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1.
9. Missing >25% of selumetinib doses as a result of drug-related AE(s) during the first 
treatment 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
13. Eye disorders

Retinopathy or retinal detachment Grade ≥3, confirmed by ophthalmic
examination
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
Retinal vein disorder including RVO, confirmed by ophthalmic examination

Visual disturbances without ocular (retinal) changes

Blurred vision, flashing lights, floaters: Grade ≥3

Other (not listed above)

Grade ≥3 for >21 consecutive days

Grade 4 confirmed by ophthalmic examination
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and Section 
8.10.3.
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 and Section 
8.10.3.
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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 for more than 21 consecutive 
days during the 3-week cycle.
•
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 8.3.
•
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue the participant.
•
Recurrent Grade 2 pneumonitis.
•
Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) by local investigator assessments and have been 
treated for at least 8 cycles (at least 24 weeks), receiving 2 cycles of the combination 
including 2 doses of pembrolizumab and at least 80% of the planned doses of selumetinib 
beyond the date when the initial CR was declared. 
•
Completion of 35 treatments with pembrolizumab.
o
Note: 35 cycles (approximately 2 years) are calculated from the first dose.
•
Side effects and/or concomitant medications required for treatment of HIV and/or its 
complications that are incompatible with continued study treatment (exceptions are 
permissible but should be discussed with the Sponsor).
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in Section 1.3 – SoA, and Section 8.10.3 –
Discontinued Participants Continuing to be Monitored in the Study, should be completed.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from 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.
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 
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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 maximum amount of blood collected from each participant over the duration of the study
is outlined 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 
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 
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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 treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in Section 1.3 – SoA, and Section 8.10.3 –
Discontinued Participants Continuing to be Monitored in the Study, should be completed.
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 intervention.
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8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study intervention(s), 
the study intervention(s) should be discontinued and the participant will move into the 
survival follow-up phase; if a participant initiates a new anticancer therapy within 30 days 
after the last dose of the study intervention, the 30-day Safety Follow-up visit should occur 
before the first dose of the new therapy.
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 study intervention assignment. 
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 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated and will receive a treatment number. The treatment 
number identifies the participant for all procedures occurring after treatment allocation. Once 
a treatment number is assigned to a participant, it can never be re-assigned to another 
participant.
A single participant cannot be assigned more than 1 treatment number.
8.1.8
Study Intervention Administration
8.1.8.1
Oral medication: Selumetinib 
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 BID, in the morning and in 
the evening at approximately the same times every day. 
Participants will be given clear instructions on how and when to take their study intervention. 
Participants will self-administer selumetinib except when a clinic visit is scheduled. 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.
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For non-visit days, selumetinib will be taken at home. The participant will note the number 
of capsules taken, the time of administration, as well as any reactions including the date/time.
Participants will be instructed to notify study site personnel of missed doses.
Study site staff will conduct capsule counts at regular intervals during study treatment. After 
the capsule count is performed, the remaining capsules will not be returned to the participant 
but will be retained by the investigative site until reconciliation is completed by the study 
monitor.    
When a participant attends a study visit, he/she will bring any unused capsules. All 
participants must return their bottle(s) of selumetinib at the appropriate scheduled visit, when 
a new bottle will be dispensed.
8.1.8.2
Infusion: Pembrolizumab
Administration of study medication will be witnessed by the investigator and/or study staff. 
The total volume of study intervention infused will be compared to the total volume prepared 
to determine compliance with each dose administered.
Refer to Section 6 for dose and treatment details.
8.1.8.3
Timing of Dose Administration
8.1.8.3.1
Timing for Administration of Selumetinib (MK-5618)
Participants should be instructed to take selumetinib capsules 12 ± 2 hours apart with a large 
glass of water (approximately 250 mL) in the morning and in the evening at approximately 
the same time every day.
On clinical day on which PK samples are scheduled, dosing should be delayed until arrival at 
the clinic and until the pre-dose PK sample has been taken.
Selumetinib will be taken BID for the first 2 weeks of every 3-week treatment cycle. 
Selumetinib will be administered prior to the pembrolizumab infusion on days when study 
treatments are administered on the same day. The Pharmacy Manual contains specific 
instructions for selumetinib storage, administration, and administration sequence for 
combination administration.
Escalation/dosing schedule (eg, direction of dose escalation, BID on/off intermittent dosing 
schedule) may be adjusted based on totality of data (PK, PD and safety) emerging throughout 
the study. Any adjustment made to the dosing schedule will be initiated through an 
amendment to this protocol. 
8.1.8.3.2
Timing for Administration of Pembrolizumab (MK-3475)
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion Q3W. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and +10 
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minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min). The Pharmacy 
Manual contains specific instructions for pembrolizumab preparation of the infusion fluid 
and administration. 
Every effort should be made to begin the first dose of study treatment on the day of 
allocation, but if this is not achieved, trial therapy should be initiated no later than 3 days 
from the date of allocation. All subsequent cycles of study treatment 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 pre-dose study procedures 
and assessments have been completed as detailed on the SoA – Section 1.3. All study 
interventions will be administered on an outpatient basis.
The Pharmacy Manual contains specific instructions for pembrolizumab 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 as outlined in 
the SoA and Section 8.10.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the 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. 
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8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
Not applicable.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the iCRO can be found in the Site 
Imaging Manual. Tumor imaging is strongly preferred to be acquired by computed 
tomography (CT). For the abdomen and pelvis, contrast-enhanced magnetic resonance 
imaging (MRI) may be used when CT with iodinated contrast is contraindicated, or when 
mandated by local practice. MRI is the strongly preferred modality for imaging the brain. 
The same imaging technique regarding modality, ideally the same scanner, and the use of 
contrast should be used in a participant throughout the study to optimize the reproducibility 
of the assessment of existing and new tumor burden and improve the accuracy of the 
assessment of response or progression based on imaging.  
Note: for the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer located at the site or at an offsite 
facility.
Imaging of chest, abdomen, and pelvis is typical. The Site Imaging Manual 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 Screening must be performed within 28 days prior to the date of 
Cycle 1 Day 1 (C1D1).
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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 C1D1.
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 first dose of study drug intervention. Subsequent tumor imaging should be 
performed every 9 weeks (63 days ±7 days) or more frequently if clinically indicated. 
Imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts. Imaging should continue to be performed until disease progression is identified by the 
investigator, the start of new anticancer treatment, withdrawal of consent, or death, 
whichever occurs first.
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.
Per iRECIST (Section 8.2.3), disease progression should be confirmed by the site 4 to 8 
weeks site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed provided they have met the 
conditions detailed in Section 8.2.3. Participants who receive confirmatory imaging do not 
need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if clinically stable. 
Participants who have confirmed disease progression by iRECIST as assessed by the site will 
discontinue the treatment. Exception is detailed in Section 8.2.3.
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8.2.1.3
End of Treatment and Follow-up Tumor 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 the investigator 
elects not to implement iRECIST.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (see Section 8.2.1.2) until the start of a 
new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, or 
the end of the study, whichever occurs first.
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.
8.2.3
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by investigator/local radiology 
reviewers to assess tumor response and progression, and to make treatment decisions. 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. When clinically stable, participants should not 
be discontinued until progression is confirmed by the investigator, working with local
radiology, according to the rules outlined below. This allowance to continue treatment 
despite initial radiologic PD takes into account the observation that some participants can 
have a transient tumor flare in the first few months after the start of immunotherapy, and then 
experience subsequent disease response. These data will be collected captured in the clinical 
database.
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator the investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management, see Table 7).
This decision by the investigator should be based on the participant’s overall condition
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Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from trial treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat imaging for 
confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective blinded, independent central review.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
A summary of imaging and treatment requirements after first radiologic evidence of 
progression is provided in Table 7.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, 
but “sum of diameters” will be used in this protocol, consistent with the 
original RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the subject will be classified as progression confirmed (with an 
overall response of iCPD), or as showing persistent unconfirmed progression (with an overall 
response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening:
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5mm, compared to any prior iUPD time point.
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5mm from a prior 
iUPD time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1.

Any new factor appears that would have triggered PD by RECIST 1.1.
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND
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
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management following the confirmatory imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, subjects will be discontinued from trial 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3, SoA, and submitted to the central imaging vendor.
Detection of progression at visits after pseudo progression resolves
After resolution of pseudoprogression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (20% and 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudoprogression. The 
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nadir is always the smallest SOD seen during the entire trial, either before or after 
an instance of pseudoprogression.

Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for 
the first-time results in iUPD.
o
If non-target lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD. Factors above indicate 
iUPD, the iUPD evaluation process repeats, just as on the first occurrence of iUPD. iUPD 
must be confirmed before iCPD can occur.
Additional details about iRECIST are provided in the iRECIST publication.
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Table 7
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1 
Repeat 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 by 
iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging 
confirms PD 
(iCPD) by 
iRECIST, per 
local assessment
No additional 
imaging 
required
Discontinue treatment 
(exception is possible 
upon consultation 
with Sponsor)
No additional 
imaging required
N/A
Repeat tumor 
imaging shows 
iUPD by 
iRECIST, per 
local assessment
Repeat imaging 
at 4-8 weeks to 
confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
treatment at the local 
site investigator’s 
discretion
Repeat imaging at 
4-8 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST, per 
local assessment
Continue 
regularly 
scheduled 
imaging 
assessments
Continue study 
treatment at the local 
site investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next tumor 
image should occur 
according to the regular 
imaging schedule 
iCPD = immune confirmed progressive disease; iCR = immune complete response; iPR = immune partial 
response; iRECIST = immune-related response evaluation criteria in solid tumors; iSD = immune stable
disease; iUPD = immune unconfirmed progressive disease; PD = progressive disease; PFS = progression-free 
survival 
8.2.4
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status at screening ≤3 days prior to 
dosing on Day 1 Cycle 1, on Day 1 of each treatment cycle visit prior to the administration of 
study intervention, and during the follow-up period as specified in the SoA (Section 1.3).
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8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. Safety assessments are obtained on the specified treatment cycle visit prior to 
administration of study intervention, unless otherwise specified. The total amount of 
blood/tissue to be drawn/collected over the course of the study (from prestudy to poststudy 
visits), including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per participant, can be found in the Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
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.
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 period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical exam as defined in Section 1.3, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study intervention. 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, serous detachment of the retina and RVO, will be performed by an 
ophthalmologist at screening, Cycle 2 Day 1 and then every 8 weeks (±7 days) from Cycle 2 
Day 1 and end of treatment (EOT). An ophthalmic examination at the 30-day follow up is 
only required if there was a clinically significant abnormality noted at EOT (±7 days). For all 
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participants, ophthalmic assessments may be performed more frequently per system organ 
class 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, retinal pigment epithelial 
detachment, 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: 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.
8.3.4
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA. Vital signs include temperature, pulse, respiratory rate, and blood 
pressure. Height will be measured at Visit 1 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. 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.
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
When an ECG is to be performed at the same time point as a blood collection, the 
ECG is to be performed first.

Triplicate 12-lead ECGs will be obtained at screening only. 
o
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 
13 for QTcF withdrawal criteria).

ECG will be performed predose at every visit starting at Cycle 2 Day 1.
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 Section 1.3 - SoA. The same method should be used throughout the study. 
Participants who develop signs/symptoms of congestive heart failure at any point during the 
study are required to have an evaluation of LVEF measurement by ECHO or MUGA.
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.
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8.3.7.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 3 days prior to the first dose of 
study intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. After Cycle 1, predose laboratory safety tests can be 
conducted up to 72 hours prior to dosing unless otherwise noted in the SoA.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study treatment. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within normal range.
8.3.7.2
Pregnancy Testing
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours or the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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 AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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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 intervention 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 intervention 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 intervention 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 intervention
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 AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 8.
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Table 8
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days 
of learning of 
event
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 AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
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cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for 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 
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.
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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 may 
require an additional evaluation for an underlying etiology. The study site guidance 
for assessment and follow up of these criteria can be found in the Investigator Study 
File Binder (or equivalent).
8.5
Treatment of Overdose
8.5.1
Treatment of Overdose for Selumetinib
For the purposes of this study, an overdose will be defined as any dose exceeding the 
prescribed dose for selumetinib ≥20% of the indicated dose. No specific information is 
available on the treatment of overdose for selumetinib. In the event of overdose, selumetinib 
should be discontinued and the participant should be observed closely for signs of toxicity.
Appropriate supportive treatment should be provided if clinically indicated.
8.5.2
Treatment of Overdose for Pembrolizumab
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).
No specific information is available on the treatment of overdose for pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
8.6.1
Blood Collection for Plasma Selumetinib and Serum Pembrolizumab
Sample collection, storage, and shipment instructions for pharmacokinetic samples will be 
provided in the operations/laboratory manual.
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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 selumetinib
and pembrolizumab will be recorded. Pharmacokinetic samples should be drawn according to 
the PK collection schedule for all participants. 
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: Pre-dose at time 0 and 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 C2D1, 
C2D14, C5D1 and C5D14 at time 0 pre-dose (± 10 minutes). Morning dose(s) should be 
withheld until after PK (pre-dose) sample has been drawn.
Blood samples for determination of serum concentrations of pembrolizumab will be obtained 
from consenting participants. Serial serum samples for PK analysis of pembrolizumab will be 
collected at pre-dose (trough) PK and samples within 24 hours before infusion at Cycles 1, 2, 
3, 5, 8, and every 4 cycles thereafter. 
If ongoing PK sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
•
Leftover specimens listed in Section 8.10, Biomarkers
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.
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8.10.1
Screening
Approximately 28 days prior to treatment allocation, potential participants will be evaluated 
to determine that they fulfill the entry requirements (with the exception of MSI status, 
ophthalmologic examination, and MUGA/ECHO will be evaluated within 42 days) as set 
forth in Sections 5.1 and 5.2. Screening procedures may be repeated after consultation with 
the Sponsor. Written consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent as part of 
routine management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of study intervention except for the following:

Laboratory tests are to be performed within 3 days prior to the first dose of study 
intervention. An exception is hepatitis testing, which may be done up to 28 days prior 
to the first dose of study intervention.

Evaluation of ECOG is to be performed within 3 days prior to the first dose of study 
intervention.
CCI
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
For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study intervention. 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 study intervention. Newly obtained tumor tissue may be obtained 
within 90 days of study intervention initiation.
8.10.2
Treatment Period
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.10.4
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-up Visit should be recorded (up to 30 days 
following end of treatment). Participants with an AE of Grade >1 will be followed until the 
resolution of the AE to Grade 0 to 1 or until the beginning of a new anticancer therapy, 
whichever occurs first. SAEs that occur within 30 days (90 days following administration of 
pembrolizumab) of the end of treatment or before initiation of a new anticancer treatment 
should also be followed and recorded.
8.10.5
Imaging Follow-up Visit
Participants who discontinue study intervention for reasons other than verified PD should 
continue with imaging assessments per the protocol-defined schedule until: (1) PD is verified 
or further confirmed by the investigator, (2) initiation of a new anti-cancer treatment, (3) 
death, (4) withdrawal of consent, or (5) study conclusion or early termination, whichever 
occurs first.
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8.10.6
Survival Follow-up Visit
Participants who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
study. For example, these additional time points may be requested prior to an efficacy interim 
analysis, and/or final analysis. All participants who are not known to have died prior to the 
request for these additional survival status time points will be contacted at that time
8.10.7
Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
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).
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 (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR.
Study Design Overview
Phase 1b trial of selumetinib in combination with 
pembrolizumab in participants with histologically or 
cytologically confirmed diagnosis of metastatic/advanced 
solid tumor. The study applies an mTPI design for dose 
escalation and confirmation of RP2D.
Treatment Assignment
Participants will be allocated centrally through IVRS/IWRS 
to selumetinib in combination with pembrolizumab.
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT)
PK (Secondary): Per-Protocol (PP)
Efficacy (Exploratory): Full Analysis Set 
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Primary Endpoint(s)
Dose-limiting toxicities (DLTs)
Adverse events (AEs)
Study drug discontinuations due to an AE
Secondary Endpoints
Pharmacokinetic parameters including area under the curve 
(AUC), minimum concentration (Cmin) and maximum 
concentration (Cmax)
Statistical Methods for 
Efficacy/ 
Immunogenicity/ 
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. 
The pool-adjacent-violators-algorithm [Ji Y, Li Y, Bekele 
BN 2007] will be used to estimate the DLT rates across 
doses. The estimate of the DLT rate among participants 
treated at RP2D of selumetinib (MK-5618) in combination 
with pembrolizumab (MK-3475) and the 80% Bayesian 
credible intervals for the estimate will be provided for each 
treatment arm.
Interim Analyses
An interim analysis may be conducted to enable future trial 
planning at the Sponsor’s discretion and data will be 
examined on a continuous basis to allow for dose-finding 
decisions.
Multiplicity
No multiplicity adjustment is planned in this Phase 1b trial.
Sample Size and Power 
The overall sample size for this study depends on the 
observed DLT profiles of selumetinib in combination with 
pembrolizumab. A target sample size of 50 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. 
Allocation to treatment will not be randomized.
9.3
Hypotheses/Estimation
There is no hypothesis testing in this study. Objectives of the study are outlined in Section 3
– Hypotheses, Objectives, and Endpoints.
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9.4
Analysis Endpoints
9.4.1
Pharmacokinetics/Efficacy Endpoints
Pharmacokinetic endpoint is secondary
for selumetinib
Pharmacokinetic profile of selumetinib
will be 
characterized. The PK concentrations of selumetinib (and its metabolites)
will be used to derive PK parameters of the agents (such as Cmax, AUC 
and/or Cmin). 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 selumetinib.  
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 All-Participants-as-Treated (APaT) population will be used for the analysis of safety 
data in this study. The APaT population consists of all participants who received at least 1 
dose of study treatment.
The DLT evaluable population includes APaT participants that meet the criteria for DLT 
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 6.6.2.2 for details.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.2
Pharmacokinetic Analysis Populations
The Per-Protocol (PP) population will be used for the analysis of PK and target engagement 
data in this study. The PP population consists of the subset of participants who complied with 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
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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 CSR. At the end of the study, all 
participants who were compliant with the study procedures and have available data from at 
least 1 treatment will be included in the PP analysis dataset.
9.5.3
Efficacy Analysis Populations
The Full Analysis Set 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.
Dose limiting toxicities will be listed and summarized by dose level. The isotonic regression 
with pool-adjacent-violators-algorithm [Ji Y, Li Y, Bekele BN 2007], which forces the DLT 
rate estimates to be nondecreasing with increasing dose levels and pools adjacent violators 
for weighted estimates by sample size, will be used to estimate the DLT rates across doses in 
each treatment arm. The estimate of the DLT rate among participants treated at the RP2D and 
the 80% Bayesian credible interval based on a prior distribution of Beta (1,1) for the estimate 
will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 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.
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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
An interim analysis may be conducted to enable future trial planning at the Sponsor’s 
discretion and data will be examined on a continuous basis to allow for dose finding 
decisions.
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 
1 trial is expected to be approximately 50. The maximum overall sample size is 84. The 
actual sample size depends on the safety profiles and number of doses studied.
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study 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 (Institutional 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 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 GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical 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 
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conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
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contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
Table 9 provides a summary of the laboratory tests 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 9
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)d
Bicarbonate
Microscopic exam, 
[FT3]), Total T4 (or Free
RBC
Calcium
if abnormal results 
T4 [FT4]), and TSHb,c
Absolute
Chloride
are noted
Creatine kinase
lymphocyte 
Creatinine
countd
Glucose
Absolute
Phosphorus
neutrophil
Potassium
countd
Sodium
Total bilirubin  
Direct bilirubin
Total protein
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.
T3 and T4 are preferred; if not available, Free T3 and T4 may be tested. 
c.
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Procedure Manual.
d. 
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
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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, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
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.”
•
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.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 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.
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, 
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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 time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.4
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.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI 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.
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 
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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?
-
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.
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•
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.
•
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.
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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 AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
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).
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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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
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,d
•Intrauterine hormone-releasing system (IUS)c,e
•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
1.   Definitions
a.   Biomarker: A biological molecule found in blood, other body fluids, or tissues that is
a sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b.   Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.   Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d.   DNA: Deoxyribonucleic acid.
e.   RNA: Ribonucleic acid.
2.   Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 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.
3.   Summary of Procedures for Future Biomedical Research.
a.   Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
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b.   Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.   eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d.   Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4.   Confidential Participant Information for Future Biomedical 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 intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5.   Biorepository Specimen 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.
6.   Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main 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.
7.   Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. 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.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. 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.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International 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
AE
adverse event 
ART
anti-retroviral therapy
APaT
All-Participants-as-Treated
aPTT
Activated Partial Thromboplastin Time
AUC
area under the curve
BID
twice daily
Cmin
minimum concentration
Cmax
maximum concentration
CR
complete response
CRC
colorectal cancer
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group 
DILI
drug-induced liver injury
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECHO
echocardiogram
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
FBR
Future Biological Research
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle stimulating hormone 
GCP
Good Clinical Practice 
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
iCPD
immune confirmed progressive disease
iCR
immune complete response
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IND
Investigational New Drug 
INR
International Normalized Ratio
iPR
immune partial response
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
modified RECIST 1.1 for immune-based therapeutics
iSD
immune stable disease
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Abbreviation
Expanded Term
IUD
intrauterine device
iUPD
immune unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
LGG
low-grade glioma
LVEF
left ventricular ejection fraction
MAPK
mitogen-activated protein kinase
MEK
mitogen-activated extracellular signal-regulated kinase
MEKi
mitogen-activated extracellular signal-regulated kinase inhibitor
MRI
magnetic resonance imaging
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified toxicity probability interval
MUGA
multigated acquisition
NCI
National Cancer Institute
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
NSCLC
Non-small cell lung cancer
OCT
ocular coherence tomography
ORR
overall response rate
OS
overall survival
PD
progressive disease
PD-1
programmed death 1
PD-L1
programmed death-ligand 1
PD-L2
programmed death-ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic
PO
Taken by mouth; oral
PP
Per-Protocol
QTcF
QT interval calculated according to the Fridericia method
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, Version 1.1 
RNA
ribonucleic acid
RP2D
Recommended Phase 2 dose
RTK
receptor tyrosine kinase
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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