Conditions: Mesothelioma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2)
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
This is a multicenter, open-label, non-randomized, study of pembrolizumab in combination with cisplatin and pemetrexed in treatment of naïve participants with a histologically confirmed diagnosis of advanced/unresectable malignant pleural mesothelioma (MPM) in Japanese participants. This study will evaluate the safety, tolerability, and preliminary efficacy of pembrolizumab in combination with cisplatin and pemetrexed. The primary objective is to evaluate the safety and tolerability of treatment with pembrolizumab in combination with cisplatin and pemetrexed.

Detailed description:

Arms:
arm 1: Pembrolizumab 200 mg IV every 3 weeks (Q3W) in combination with Cisplatin 75 mg/m\^2 IV, and Pemetrexed 500 mg/m\^2 IV for 4-6 cycles followed by monotherapy of Pembrolizumab up to 35 cycles from the first dose of the study in treatment phase (approximately 2 years).

Interventions: intervention 1: Pembrolizumab intervention 2: Pemetrexed intervention 3: Cisplatin
Intervention descriptions: intervention 1: Participants will receive Pembrolizumab 200 mg IV every 3 weeks (Q3W) until disease progression, or until participant has received 35 administrations of Pembrolizumab (approximately 2 years). intervention 2: Participants will receive Pemetrexed 500 mg/m\^2 IV on Day 1 of each cycle up to 4-6 cycles where each cycle = 3 weeks intervention 3: Participants will receive Cisplatin 75 mg/m\^2 IV on Day 1 of each cycle up to 4-6 cycles where each cycle = 3 weeks

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase Ib Clinical Study to Evaluate the Safety 
and Efficacy of Pembrolizumab (MK-3475) in 
Combination with Cisplatin and Pemetrexed in 
Treatmentnaive Participants with Advanced 
Malignant Pleural Mesothelioma (KEYNOTE-A17).
NCT04153565
26-JUL-2022


PRODUCT: MK-3475  
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase Ib Clinical Study to Evaluate the Safety and Efficacy of 
Pembrolizumab (MK-3475) in Combination with Cisplatin and Pemetrexed in Treatment-
naive Participants with Advanced Malignant Pleural Mesothelioma (KEYNOTE-A17).
Protocol Number: A17-02
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
Not applicable
Approval Date: 26 July 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 02
26-JUL-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity 
name change and update to the address.
After approval of Protocol amendment 02, the study will end 90 days after the last dose 
of the last participant. Participants in the Imaging Follow-up or Survival Follow-up 
phase will be discontinued from the study and no further visits will be required.
Amendment 01
25-AUG-2021
To update the dose modification and toxicity management guidelines for irAEs and 
update some text to align with program standards. 
(English protocol only) To clarify some inclusion/exclusion criteria in line with the 
actual criteria.
Original Protocol
23-AUG-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
After approval of Protocol amendment 02, the study will end 90 days after the last dose of the last participant. Participants in the 
Imaging Follow-up or Survival Follow-up phase will be discontinued from the study and no further visits will be required.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of Conduct for 
Clinical Trials
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an 
entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. 
This conversion resulted only in an entity 
name change and update to the address.
1.1 Synopsis
1.3.2 Treatment Phase 
(pembrolizumab monotherapy) and 
Post Treatment Phase
4.1 Overall Design
8.10.4.2 Imaging Follow-up Visits
8.10.4.3 Survival Follow-up Visits
Add the following wordings: "After 
approval of Protocol amendment 02, the 
study will end 90 days after the last dose of 
the last participant. Participants in the 
Imaging Follow-up or Survival Follow-up 
phase will be discontinued from the study 
and no further visits will be required.”
To clarify the study completion.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.2 Treatment Phase 
(pembrolizumab monotherapy) and 
Post Treatment Phase
Add Notes to “Anti-cancer therapy status”
To clarify.
1.3.2 Treatment Phase 
(pembrolizumab monotherapy) and 
Post Treatment Phase
4.1 Overall Design
8.2.3 Tumor Imaging During the 
Study 
8.10.4.2 Imaging Follow-up Visits 
Add “pregnancy” and “the end of the study” 
(only added to section 8.2.3) to the 
definition of the end of imaging assessments 
To align with the section 8.2.4.
4.4 Beginning and End of Study 
Definition
Add the following wordings: "The time 
point when the last participant completes the 
last observation (last study-related 
telephone-call or visit) will be 90 days after 
the last dose of the last participant."
To clarify when the last participant 
completes the last observation.
8.3.7 Submission of images for
Interstitial Lung Disease (ILD)
Add the following wordings: "However, 
after approval of Protocol amendment 02, 
any imaging acquired more than 90 days 
after the last dose of the last participant need 
not be submitted."
No additional imaging submission is required 
due to the end of the study.
Minor grammatical, typographical and editorial changes have been made throughout the document.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
1.3.1
Screening Phase and Treatment Phase (combination therapy)....................18
1.3.2
Treatment Phase (pembrolizumab monotherapy) and Post Treatment 
Phase ............................................................................................................22
2
INTRODUCTION..........................................................................................................25
2.1
Study Rationale....................................................................................................25
2.2
Background ..........................................................................................................27
2.2.1
Pharmaceutical and Therapeutic Background .............................................27
2.2.1.1
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 
Background........................................................................................27
2.2.2
Preclinical and Clinical Studies ...................................................................28
2.2.3
Ongoing Clinical Studies of Pembrolizumab ..............................................28
2.2.4
Information on Other Study-related Therapy ..............................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................28
4
STUDY DESIGN............................................................................................................30
4.1
Overall Design......................................................................................................30
4.2
Scientific Rationale for Study Design.................................................................31
4.2.1
Rationale for Endpoints ...............................................................................31
4.2.1.1
Efficacy Endpoints.............................................................................31
4.2.1.2
Safety Endpoints................................................................................32
4.3
Justification for Dose...........................................................................................32
4.3.1
Starting Dose for This Study........................................................................32
4.3.1.1
Rationale for Starting and Maximum Dose of MK-3475..................32
4.3.1.2
Rationale for Cisplatin and Pemetrexed Dosing Regimen ................33
4.4
Beginning and End of Study Definition .............................................................33
4.4.1
Clinical Criteria for Early Study Termination .............................................33
5
STUDY POPULATION ................................................................................................33
5.1
Inclusion Criteria.................................................................................................33
5.2
Exclusion Criteria................................................................................................36
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5.3
Lifestyle Considerations......................................................................................39
5.4
Screen Failures.....................................................................................................39
5.5
Participant Replacement Strategy......................................................................39
6
STUDY INTERVENTION............................................................................................39
6.1
Study Intervention(s) Administered...................................................................40
6.2
Preparation/Handling/Storage/Accountability .................................................42
6.2.1
Dose Preparation..........................................................................................42
6.2.2
Dose Administration....................................................................................42
6.2.3
Handling, Storage, and Accountability........................................................42
6.3
Measures to Minimize Bias: Randomization and Blinding..............................43
6.3.1
Intervention Assignment..............................................................................43
6.3.2
Stratification.................................................................................................43
6.3.3
Blinding........................................................................................................43
6.4
Study Intervention Compliance..........................................................................43
6.5
Concomitant Therapy..........................................................................................44
6.5.1
Acceptable Concomitant Medications .........................................................44
6.5.2
Prohibited Concomitant Medications ..........................................................44
6.5.3
Rescue Medications and supportive care.....................................................45
6.6
Dose Modification (Escalation/Titration/Other)...............................................46
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................46
6.6.1.1
Dose Modification and Toxicity Management for Immune-related 
AEs Associated with Pembrolizumab................................................46
6.6.1.2
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab................................................51
6.6.1.3
Dose Modification and Toxicity Management AEs Associated 
with Chemotherapy............................................................................52
6.6.2
Dose Administration/Escalation ..................................................................53
6.6.2.1
Dose Administration (Preparation)....................................................53
6.6.3
Tolerability Evaluation Rules ......................................................................53
6.6.4
Definition of Dose‑limiting Toxicity ..........................................................53
6.7
Intervention After the End of the Study............................................................54
6.8
Clinical Supplies Disclosure................................................................................54
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................54
7.1
Discontinuation of Study Intervention...............................................................54
7.2
Participant Withdrawal From the Study...........................................................56
7.3
Lost to Follow-up .................................................................................................56
8
STUDY ASSESSMENTS AND PROCEDURES........................................................56
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8.1
Administrative and General Procedures ...........................................................57
8.1.1
Informed Consent.........................................................................................57
8.1.1.1
General Informed Consent.................................................................57
8.1.1.2
Reconsent before the starting Cycle 2 ...............................................58
8.1.2
Inclusion/Exclusion Criteria ........................................................................58
8.1.3
Participant Identification Card.....................................................................58
8.1.4
Medical History ...........................................................................................58
8.1.5
Prior and Concomitant Medications Review...............................................59
8.1.5.1
Prior Medications...............................................................................59
8.1.5.2
Concomitant Medications..................................................................59
8.1.6
Assignment of Screening Number...............................................................59
8.1.7
Assignment of Treatment/Randomization Number.....................................59
8.1.8
Study Intervention Administration ..............................................................60
8.1.8.1
Timing of Dose Administration.........................................................60
8.1.9
Discontinuation and Withdrawal .................................................................61
8.1.10
Participant Blinding/Unblinding..................................................................61
8.1.11
Domiciling ...................................................................................................61
8.1.12
Calibration of Equipment.............................................................................61
8.2
Efficacy Assessments ...........................................................................................61
8.2.1
Tumor Imaging and Assessment of Disease................................................61
8.2.2
Initial Tumor Imaging..................................................................................61
8.2.3
Tumor Imaging During the Study................................................................62
8.2.4
End of Treatment and Follow-up Tumor Imaging.......................................62
8.2.5
modified RECIST in Malignant Pleural Mesothelioma...............................63
8.2.5.1
Pleural Tumor Measurement..............................................................63
8.2.5.2
Other Measurable Disease .................................................................63
8.2.5.3
Non-Measurable Disease ...................................................................63
8.2.5.4
Target Lesion .....................................................................................63
8.2.5.5
Non-target lesions ..............................................................................64
8.2.5.6
Response ............................................................................................64
8.3
Safety Assessments...............................................................................................65
8.3.1
Physical Examinations.................................................................................66
8.3.1.1
Full Physical Examination.................................................................66
8.3.1.2
Directed Physical Examination..........................................................66
8.3.2
Vital Signs....................................................................................................66
8.3.3
Electrocardiograms ......................................................................................66
8.3.4
Clinical Safety Laboratory Assessments .....................................................66
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8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................67
8.3.4.2
Pregnancy Test...................................................................................67
8.3.5
Performance Assessments............................................................................68
8.3.5.1
Eastern Cooperative Oncology Group Performance Status...............68
8.3.6
Peripheral Capillary Oxygen Saturation (SpO2)..........................................68
8.3.7
Submission of images for Interstitial Lung Disease (ILD)..........................68
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................68
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................69
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......71
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...71
8.4.4
Regulatory Reporting Requirements for SAE .............................................71
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................71
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying
as AEs or SAEs............................................................................................72
8.4.7
Events of Clinical Interest............................................................................72
8.5
Treatment of Overdose........................................................................................72
8.6
Pharmacokinetics.................................................................................................73
8.7
Pharmacodynamics..............................................................................................73
8.8
Biomarkers ...........................................................................................................73
8.8.1
Planned Genetic Analysis Sample Collection..............................................73
8.9
Future Biomedical Research Sample Collection...............................................73
8.10
Visit Requirements...............................................................................................73
8.10.1
Screening......................................................................................................73
8.10.2
Treatment Period..........................................................................................74
8.10.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................74
8.10.4
Posttreatment Visit.......................................................................................74
8.10.4.1
Safety Follow-up Visit.......................................................................74
8.10.4.2
Imaging Follow-up Visits ..................................................................74
8.10.4.3
Survival Follow-up Visits..................................................................75
8.10.5
Vital Status...................................................................................................75
9
STATISTICAL ANALYSIS PLAN .............................................................................75
9.1
Statistical Analysis Plan Summary.....................................................................75
9.2
Responsibility for Analyses/In-house Blinding .................................................76
9.3
Hypotheses/Estimation ........................................................................................76
9.4
Analysis Endpoints...............................................................................................77
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9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................77
9.4.2
Safety Endpoints..........................................................................................77
9.5
Analysis Populations............................................................................................77
9.5.1
Safety Analysis Populations ........................................................................77
9.5.2
Pharmacokinetic Analysis Populations........................................................78
9.5.3
Efficacy Analysis Populations.....................................................................78
9.6
Statistical Methods...............................................................................................78
9.6.1
Statistical Methods for Efficacy Analysis....................................................78
9.6.2
Statistical Methods for Safety Analysis.......................................................80
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................80
9.6.3.1
Demographic and Baseline Characteristics .......................................80
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis............80
9.7
Interim Analyses ..................................................................................................80
9.8
Multiplicity ...........................................................................................................80
9.9
Sample Size and Power Calculations .................................................................80
9.10
Subgroup Analyses...............................................................................................81
9.11
Compliance (Medication Adherence).................................................................82
9.12
Extent of Exposure...............................................................................................82
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................83
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........83
10.1.1
Code of Conduct for Clinical Trials.............................................................83
10.1.2
Financial Disclosure.....................................................................................85
10.1.3
Data Protection.............................................................................................85
10.1.3.1
Confidentiality of Data ......................................................................86
10.1.3.2
Confidentiality of Participant Records...............................................86
10.1.3.3
Confidentiality of IRB/IEC Information............................................86
10.1.4
Publication Policy........................................................................................86
10.1.5
Compliance with Study Registration and Results Posting Requirements ...87
10.1.6
Compliance with Law, Audit, and Debarment ............................................87
10.1.7
Data Quality Assurance ...............................................................................88
10.1.8
Source Documents .......................................................................................89
10.1.9
Study and Site Closure.................................................................................89
10.2
Appendix 2: Clinical Laboratory Tests..............................................................90
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................92
10.3.1
Definition of AE ..........................................................................................92
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10.3.2
Definition of SAE ........................................................................................93
10.3.3
Additional Events Reported in the Same Manner as SAE...........................94
10.3.4
Recording AE and SAE ...............................................................................94
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................98
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................100
10.5
Appendix 5: Contraceptive Guidance..............................................................101
10.5.1
Definitions..................................................................................................101
10.5.2
Contraception Requirements......................................................................102
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................104
10.7
Appendix 7: Country-specific Requirements..................................................105
10.8
Appendix 8: Abbreviations ...............................................................................106
10.9
Appendix 9: Dose Limiting Toxicity evaluation..............................................108
11
REFERENCES.............................................................................................................109
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .................................................34
Table 2
Study Interventions..........................................................................................41
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................47
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................51
Table 5
Definition of DLT............................................................................................54
Table 6
Integration of Target, non-Target and New Lesions into Response 
Assessment.......................................................................................................65
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................70
Table 8
Censoring Rules for DOR................................................................................79
Table 9
Analysis Strategy for Key Efficacy Variables.................................................79
Table 10
Precision of the Estimated DLT Rates (N=18)................................................81
Table 11
Precision of the Estimated ORR/DCR (N=18)................................................81
Table 12
Protocol-required Safety Laboratory Assessments..........................................91
Table 13
Dose-finding Rules per modified Toxicity Probability Interval Design........108
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LIST OF FIGURES
Figure 1
The study design ..............................................................................................17
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase Ib Clinical Study to Evaluate the Safety and Efficacy of 
Pembrolizumab (MK-3475) in Combination with Cisplatin and Pemetrexed in Treatment-
naive Participants with Advanced Malignant Pleural Mesothelioma (KEYNOTE-A17).
Short Title: A Phase Ib Study of Pembrolizumab in Combination with Cisplatin and 
Pemetrexed in Advanced MPM
Acronym: MK-3475-A17
Hypotheses, Objectives, and Endpoints:
In males and females with advanced/unresectable malignant pleural mesothelioma (MPM)
who are treatment naïve;
Primary Objectives
Primary Endpoints
To evaluate the safety and tolerability of 
treatment with pembrolizumab in 
combination with cisplatin and pemetrexed.
•
Dose limiting toxicities (DLTs) rate
•
Adverse events (AEs)
•
Discontinuing study treatment due to 
AEs
Secondary Objectives
Secondary Endpoints
To evaluate the preliminary anti-tumor 
activity [objective response, disease control,
and duration of response (DOR)] by 
modified Response Evaluation Criteria in 
Solid Tumors (modified RECIST) as 
assessed by the investigator of 
pembrolizumab in combination with cisplatin 
and pemetrexed.
•
Objective response (OR): confirmed 
complete response (CR) or partial 
response (PR)
•
Disease control (DC): a response of 
confirmed CR or PR, or stable disease 
(SD)
•
DOR: the time from the first 
documented evidence of OR (CR or 
PR) to the earliest date of PD or death 
due to any cause, whichever comes 
first, for individuals with a confirmed 
CR or PR.
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Tertiary/Exploratory
•
To evaluate the preliminary anti-tumor 
activity [progression free survival (PFS)]
by modified RECIST as assessed by the
investigator, and overall survival (OS) of 
pembrolizumab in combination with 
cisplatin and pemetrexed.
•
PFS: the time from the first dose of 
study treatment to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
OS: the time from the first dose of 
study treatment to death due to any 
cause. 
•
To explore the predictive effect of 
programmed cell death ligand 1 (PD-L1)
expression at baseline in participants 
treated with pembrolizumab in 
combination with cisplatin and 
pemetrexed. (optional)
•
OR
•
PFS
•
OS
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Advanced malignant pleural mesothelioma
Population
Treatment naïve participants with advanced malignant 
pleural mesothelioma 
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study in Japan.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
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Number of Participants:
Approximately 18 participants will be allocated.
Intervention Groups and Duration:
Intervention 
Groups
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/
Treatment 
Period
Use
Pembrolizumab 200 mg
Q3W
IV
Day 1 of each 
cycle for up to 
35 cycles
(approximately 
2 years)
Experimental
Pemetrexed
500 mg/m2
Q3W
IV
Day 1 of each 
cycle up to 4-6
cycles
Combination 
therapy
Cisplatin
75 mg/m2
Q3W
IV
Day 1 of each 
cycle up to 4-6
cycles
Combination 
therapy
Abbreviations: IV=intravenous, Q3W = every 3 weeks
Note:
Pembrolizumab should be administered prior to chemotherapies. Cisplatin should be 
administered after 30 minutes from pemetrexed administration.
Refer to the local institutional practice for replacement therapy of vitamin B12 and folic acid, and 
prophylaxis of corticosteroids for pemetrexed administration, and appropriate hydration for 
cisplatin administration.
Total 
Number
Single Arm
Duration of 
Participation
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form through the final protocol-specified 
contact. 
After a screening phase of 28 days, each participant will be assigned to 
receive study intervention until one of the conditions for discontinuation of 
study intervention is met.
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy.
Participants who discontinue study intervention for reasons other than 
radiologic disease progression will have posttreatment follow-up imaging 
for disease status until any on the conditions for discontinuation of imaging 
are met. 
All participants will be followed for overall survival until death, withdrawal 
of consent, or the end of the study.
After approval of Protocol amendment 02, the study will end 90 days after 
the last dose of the last participant. Participants in the Imaging Follow-up or 
Survival Follow-up phase will be discontinued from the study and no further 
visits will be required.
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
The study design
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1.3
Schedule of Activities
1.3.1
Screening Phase and Treatment Phase (combination therapy)
Study Period:
Screening
Treatment phase (3-Week Cycles)
Notes
Treatment Cycle
1
2
3-6
Treatment Days per Cycle:
1
8
15
1
1
Visit Name/Number
1
2
3
4
5
6-9
Scheduled Hour, Day, Week, etc., 
and Window:
-28 ~ -1
NA
NA
NA
-1 ~ +3
±3
Administrative Procedures
Informed Consent
X
X
Signed before any protocol-specific screening procedures are 
performed. Reconsent is required if a participant will receive 
the study treatments after Cycle 1 and beyond continuously.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
X
Add allocation number at the Visit 2 (C1D1). 
Demographic and Medical 
History
X
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
Administration
Pembrolizumab a
X
X
X
200 mg Q3W up to 35 cycles.
Pemetrexed a
X
X
X
500 mg/m2 Q3W 4-6 cycles.  Refer to the local institutional 
practice for replacement therapy of vitamin B12 and folic acid, 
and prophylaxis of corticosteroids.
Cisplatin a
X
X
X
75 mg/m2 Q3W 4-6 cycles.
Appropriate hydration should be performed based on the local 
institutional practice.
Tumor Tissue Collection
Archival or Newly Obtained 
Tissue Collection for PD-L1 
analysis (Optional)
X
An optional archival tumor tissue sample or newly obtained
tumor sample will be submitted.
Submission of an archival tumor sample after Screening period 
is acceptable.
Efficacy Procedures
CT/MRI (Chest, abdomen and 
pars pelvis)
X
X
The same modality should be used for all scans. Perform at 
Screening (within 28 days prior to the first dose); Q6W (42 ± 7 
days) from first dose during the treatment phase up to the first 
24 weeks (i.e., W6, W12, W18, and W24).  Subsequent tumor 
imaging should be continued as described in Section 8.2.3. 
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Study Period:
Screening
Treatment phase (3-Week Cycles)
Notes
Treatment Cycle
1
2
3-6
Treatment Days per Cycle:
1
8
15
1
1
Visit Name/Number
1
2
3
4
5
6-9
Scheduled Hour, Day, Week, etc., 
and Window:
-28 ~ -1
NA
NA
NA
-1 ~ +3
±3
MRI (Brain) (as needed)
X
X
Participants with previously treated brain metastases may 
participate provided they are stable (i.e., without evidence of 
progression) for at least 4 weeks by repeat imaging (note that 
the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid 
treatment for at least 14 days prior to the first dose of study 
intervention. Participants with carcinomatous meningitis are 
excluded regardless of clinical stability.
After the start of the study medication, additional MRI will be 
performed based on the investigator’s decision.
Safety Procedures
Review Adverse Events
X
All adverse events that occur after the consent form is signed 
but before treatment allocation must be reported by the 
investigator if they cause the participant to be excluded from 
the trial, or are the result of a protocol-specified intervention, 
including but
not limited to washout or discontinuation of usual therapy, diet, 
or a procedure.
Report AEs occurring within 30 days after the last dose of 
study intervention, regardless of initiation of new therapy.
Report SAEs occurring within 90 days after the last dose of 
study intervention, or within 30 days after the last dose of study 
intervention if new anti-cancer therapy is initiated, whichever is 
earlier
Full Physical Examination 
X
Directed Physical Examination
X
X
X
X
X
Assessments should be performed prior to the study medication 
at each cycle. 
Vital Signs (temperature, pulse, 
respiratory rate, height, weight 
and blood pressure)
X
X
X
X
X
X
Vital signs will be performed per local institutional practices. At 
Day 1 of each cycle, assessments should be performed prior to 
the study medication.  Height will be measured at Screening 
only.
Peripheral
Capillary Oxygen Saturation 
(SpO2) Measurement
X
X
X
X
X
X
SpO2 will be performed using local standard procedures once at 
Screening, prior to the study medication at each cycle, EOT and 
Safety FU.
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Study Period:
Screening
Treatment phase (3-Week Cycles)
Notes
Treatment Cycle
1
2
3-6
Treatment Days per Cycle:
1
8
15
1
1
Visit Name/Number
1
2
3
4
5
6-9
Scheduled Hour, Day, Week, etc., 
and Window:
-28 ~ -1
NA
NA
NA
-1 ~ +3
±3
12-Lead ECG
X
12-Lead ECG will be performed per local institutional 
practices. An additional test may be performed if the 
investigator deems to be medically necessary.
Hematology
X
X
X
X
X
X
Within 7 days prior to the first dose in the Screening phase.  
Pre-dose laboratory safety tests for Cycle 2 should be 
conducted after Day 20 of Cycle 1.  After Cycle 2, pre-dose 
laboratory safety tests can be conducted within 3 days prior to 
dosing for each cycle unless otherwise noted on the flow charts.
Chemistry
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Within 7 days prior to the first dose in the Screening phase.
Pre-dose tests for Cycle 2 should be conducted after Day 20 of 
Cycle 1.  
After Cycle 2, Pre-dose tests will be repeated every 6 cycles 
after beginning with Cycle 6 (i.e. Cycle 6, Cycle 12, and Cycle 
18.).
Thyroid Function Testing (T3 or 
FT3, FT4, and TSH)
X
X
Test will be performed within 7 days prior to the first 
administration.  After Cycle 1, the tests will be performed every 
other cycle within 3 days before the administration (i.e., Cycle 
3, Cycle 5, Cycle 7…) starting with Cycle 3. Participants may 
be dosed while results are pending from Cycle 3.
CRP, KL-6 and SP-D
X
X
X
Test will be performed within 7 days prior to the first 
administration.  After Cycle 1, the tests will be performed pre-
dose at Day 1 within 3 days before the administration of each 
cycle. Participants may be dosed in subsequent cycles from 
Cycle 2 while results are pending.
Calculated CrCl
X
X
X
X
CrCl must be ≥45 mL/min prior to the administration of
pemetrexed and/or cisplatin. CrCl should be calculated per 
institutional standard.
Pregnancy Test (WOCBP only)
X
X
Pregnancy test within 72 hours prior to the first dose is required 
for WOCBP only. Pregnancy test should be conducted at 
monthly intervals during intervention, and for the time required 
to eliminate systemic exposure after the last dose of each study 
interventions (Refer to Section 8.3.4.2 in details). Additional 
pregnancy test is performed if clinically warranted. If a urine 
test is positive or not evaluable, a serum test will be required.
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Study Period:
Screening
Treatment phase (3-Week Cycles)
Notes
Treatment Cycle
1
2
3-6
Treatment Days per Cycle:
1
8
15
1
1
Visit Name/Number
1
2
3
4
5
6-9
Scheduled Hour, Day, Week, etc., 
and Window:
-28 ~ -1
NA
NA
NA
-1 ~ +3
±3
PT or INR and aPTT
X
Within 10 days of the first dose, PTT is acceptable if aPTT 
cannot be determined. Additional testing may be performed as 
clinically indicated.
ECOG Performance Status
X
X
X
X
X
X
At Screening, assess within 3 days before first treatment. After 
cycle 1, assess ECOG on Day 1 of each cycle prior to the 
dosing.
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; CrCl = creatinine clearance; CRP = C-reactive protein; CT = computed tomography; ECG = 
electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT3 = free triiodothyronine; FT4 = free thyroxine; FU = follow-up; INR = 
international normalized ratio; KL-6 = Krebs von den Lungen-6; MRI = magnetic resonance imaging;  NA = Not Applicable;  PD-L1 = programmed death ligand 1; PT = 
prothrombin time; PTT = partial thromboplastin time; Q3W = every 3 weeks; Q6W = every 6 weeks; SAE = serious adverse event; SP-D = surfactant protein-D; T3 = 
triiodothyronine; TSH = thyroid-stimulating hormone; W = week; WOCBP = women of childbearing potential; 
a.
All administrations of study intervention will begin on Day 1 of each cycle after all pre-dose study procedures and assessments have been completed. First study treatment 
should begin within 3 days of intervention allocation. The study intervention for Cycle 2 may be administered within 3 days after the scheduled Day 1 of Cycle 2. The 
following study intervention for Cycle 3 and beyond may be administered within 3 days before or after the scheduled Day 1 of each cycle.
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1.3.2
Treatment Phase (pembrolizumab monotherapy) and Post Treatment Phase
Study Period:
Treatment Phase
 (3-Week Cycles)
End of 
Treatment
Post-Treatment Visits
Notes
Treatment Cycle
Up to 35
Treatment Days per Cycle:
1
Visit Name/Number
10-38
Discontinuation
Safety 
Follow-Upa
Imaging 
Follow-Upb, c 
Survival 
Follow-Upc
Scheduled Hour, Day, Week, 
etc., and Window:
±3
At the time of
discontinuation
30 (+7) 
days Post 
Discon
Every 12 
(±14 days) 
weeks Post 
Discon
Administrative Procedures
Pembrolizumab
X
200 mg Q3W up to 35 cycles.
Concomitant 
Medication 
Review
X
X
X
X
Anti-cancer therapy status
X
X
X
X
Any changes in new treatment will be collected.
Vital Status
Participants who experience radiologically 
confirmed disease progression or start a new 
anti-cancer therapy will move into the survival 
follow-up visit.
Upon Sponsor request, participants may be 
contacted for survival status at any time during 
the study.
Efficacy Procedures
CT/MRI (Chest, abdomen and 
pars pelvis)
X
X
X
The same modality should be used for all scans. 
Up to the first 24 weeks from the first dose, 
perform Q6W (42±7 days) (i.e., W6, W12, 
W18, and W24) and then Q9W (63±7 days) 
from the first dose until the end of first year (i.e. 
W33, W42, W51 and W60); and then Q12W 
(84±7 days) (i.e., W72, W84, etc.) thereafter. 
Schedule should be followed regardless of 
treatment delays. If imaging is obtained within 
4 weeks before the end of treatment, an 
additional scan at the end of treatment is not 
mandatory.
MRI (Brain)
X
X
X
Additional MRI will be performed based on the 
investigator’s decision.
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Study Period:
Treatment Phase
 (3-Week Cycles)
End of 
Treatment
Post-Treatment Visits
Notes
Treatment Cycle
Up to 35
Treatment Days per Cycle:
1
Visit Name/Number
10-38
Discontinuation
Safety 
Follow-Upa
Imaging 
Follow-Upb, c 
Survival 
Follow-Upc
Scheduled Hour, Day, Week, 
etc., and Window:
±3
At the time of
discontinuation
30 (+7) 
days Post 
Discon
Every 12 
(±14 days) 
weeks Post 
Discon
Safety Procedures
Review Adverse Events
X
X
X
X
Report AEs occurring within 30 days after the 
last dose of study intervention, regardless of 
initiation of new therapy.
Report SAEs occurring within 90 days after the 
last dose of study intervention, or within 30 
days after the last dose of study intervention if 
new anti-cancer therapy is initiated, whichever 
is earlier.
Full Physical Examination 
X
Directed Physical Examination
X
X
During treatment phase, assessments should be 
performed prior to the study medication at each 
cycle.
Vital Signs (temperature, pulse, 
respiratory rate, weight and 
blood pressure)
X
X
X
Vital signs will be performed per local 
institutional practices. During treatment phase, 
assessments should be performed prior to the 
study medication at each cycle.
Peripheral Capillary Oxygen 
Saturation (SpO2) Measurement
X
X
X
SpO2 will be performed using local standard 
procedures once at Screening, prior to the study 
medication at each cycle, EOT and Safety FU.
12-Lead ECG
X
12-Lead ECG will be performed per local 
institutional practices. An additional test may be 
performed if the investigator deems to be 
medically necessary.
Hematology
X
X
X
Within 3 days before Day 1 of each cycle, EOT 
and Safety FU.
Chemistry
X
X
X
Urinalysis
X
X
X
Within 3 days before Day 1 of every 6 cycles 
after beginning with Cycle 6 (i.e. Cycle 6, 
Cycle 12, Cycle 18.)., EOT and Safety FU.
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Study Period:
Treatment Phase
 (3-Week Cycles)
End of 
Treatment
Post-Treatment Visits
Notes
Treatment Cycle
Up to 35
Treatment Days per Cycle:
1
Visit Name/Number
10-38
Discontinuation
Safety 
Follow-Upa
Imaging 
Follow-Upb, c 
Survival 
Follow-Upc
Scheduled Hour, Day, Week, 
etc., and Window:
±3
At the time of
discontinuation
30 (+7) 
days Post 
Discon
Every 12 
(±14 days) 
weeks Post 
Discon
Thyroid Function Testing (T3, or 
FT3, FT4, and TSH)
X
X
X
Performs every other cycle (i.e., Cycle 5, Cycle 
7…), EOT and Safety FU. Participants may be 
dosed in subsequent cycles after Cycle 1 while 
results are pending.
CRP, KL-6 and SP-D
X
X
X
Pre-dose at Day 1 of each cycle, EOT and 
Safety FU. Participants may be dosed in 
subsequent cycles after Cycle 1 while results 
are pending.
Calculated CrCl
X
X
X
CrCl should be calculated per institutional 
standard.
Urine Pregnancy Test (WOCBP 
only)
X
X
X
Pregnancy test should be conducted at monthly 
intervals during intervention, and for the time 
required to eliminate systemic exposure after 
the last dose of each study interventions (Refer 
to Section 8.3.4.2 in details). If a urine test is 
positive or not evaluable, a serum test will be 
required.
ECOG Performance Status
X
X
Obtain on Day 1 of each cycle prior to dosing 
and EOT.
Abbreviations: AE = adverse event; CrCl = creatinine clearance; CRP = C-reactive protein; CT = computed tomography; D/C = discontinuation; ECG = electrocardiogram; ECOG = 
Eastern Cooperative Oncology Group; EOT = end of treatment; FT3 = free triiodothyronine; FT4 = free thyroxine; FU = follow-up; KL-6 = Krebs von den Lungen-6; MRI = magnetic 
resonance imaging; Q3W = every 3 weeks; Q6W = every 6 weeks; Q9W = every 9 weeks; Q12W = every 12 weeks; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = 
serious adverse event; SP-D = surfactant protein-D; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; W = week; WOCBP = women of childbearing potential; 
a.
If the D/C visit takes place ≥30 days after the last dose of study intervention, a Safety FU visit is not required. In that event, all procedures required for both the D/C visit and the 
Safety FU visit will be performed at the D/C visit. The D/C date is the date when the decision was made to discontinue further study intervention(s).
b.
Participants who discontinue study intervention for reasons other than radiologically verified disease progression by the investigator based on modified RECIST (Section 8.2.5)  
should continue with imaging assessments per the protocol-defined schedule until: (1) disease progression is radiologically verified by the investigator, (2) initiation of a new anti-
cancer treatment, (3) death, (4) withdrawal of consent, (5) pregnancy, or (6) study conclusion or early termination, whichever occurs first.
c.
After approval of Protocol amendment 02, the study will end 90 days after the last dose of the last participant. Participants in the Imaging Follow-up or Survival Follow-up phase 
will be discontinued from the study and no further visits will be required.
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2
INTRODUCTION
This clinical study will evaluate safety and tolerability of pembrolizumab in combination 
with cisplatin and pemetrexed in treatment naïve participants with advanced MPM.
2.1
Study Rationale
Malignant mesothelioma is a malignant tumor that develops in the pleura, peritoneum, 
pericardium, testicular sheath membrane; 80% to 85% of pleura, 10% to 15% of peritoneum, 
and 1% or less of the other sites [Gemba K., et al 2012].  Malignant pleural mesothelioma 
(MPM) is a rare cancer and the disease has a poor prognosis.  The main cause of MPM is 
exposure to asbestos.  Still, even among asbestos-exposed people, the number of patients 
diagnosed as pleural mesothelioma is rare due to the long latency period (approximately 40 
years) from initial exposure to asbestos and the presentation of MPM [Kishimoto T., et al 
2010] [Wagner JC., et al 1960], it is predicted that the new cases of MPM will be increased.
Actually, in Japan, approximately 2000 new cases diagnosed as MPM and approximately 
1550 death cases due to MPM were annually reported in 2017.  Considering that 
approximately 870 death cases due to MPM was reported in 2003, the number was 
significantly increasing in recent years in Japan [Ministry of Health, Labour and Welfare 
(Internet)].  Given the fact that exposure to asbestos had been continued until 2006 when 
newly use of asbestos was finally prohibited by the Building Standards Act, and the lag time 
from the exposure to the development of MPM, the incidence of MPM will continue to rise
also in Japan.  
The treatment of malignant pleural mesothelioma is determined by the International 
Mesothelioma Interest Group (IMIG) TNM classification and the World Health Organization 
(WHO) classification comprehensively. In general, systemic chemotherapy treatment is used 
for subjects with clinically inoperable and post-operative recurrent cases [Baas P., et al 2015]
[Kindler HL., et al 2018] [The Japan Lung Cancer Society. 2018]. Advanced MPM patients 
with good performance status and organ function treated with the combination of cisplatin 
and an antifolate (pemetrexed or raltitrexed) derive less than 3 months of OS benefit over 
cisplatin alone, resulting in a median OS of approximately 1 year [Vogelzang NJ., et al 2003]
[van Meerbeeck JP., et al 2005]. More than decade, there is no new regulatory approved first
line treatment for advanced MPM.
In 2016, phase III randomized trial compared adding bevacizumab to cisplatin and 
pemetrexed (with maintenance bevacizumab) versus cisplatin and pemetrexed in patients 
with unresectable MPM and Eastern Cooperative Oncology Group performance status 
(ECOG PS) 0 to 2 who did not have bleeding or thrombosis was reported. Addition of 
bevacizumab to doublet chemotherapy improved OS compared with doublet chemotherapy 
arm [18.8 months (95%CI:15.9-22.6) vs 16.1 months (95%CI:14.0-17.9): HR=0.77
(95%CI:0.62-0.95), P=.0167] [Zalcman G., et al 2016] with expected manageable toxic 
effects.  However, front-line patients with advanced MPM who would benefit from 
bevacizumab is limited and there are a still high unmet medical needs in treatment of 
advanced MPM.
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In Japan, a phase II study of nivolumab: a multicenter, open-label, single-arm study in 
malignant pleural mesothelioma (MERIT) was conducted and 34 patients with advanced or 
metastatic Japanese MPM who had previously treated with up to two regimens of 
chemotherapy including pemetrexed-platinum doublet were treated with nivolumab 240 mg 
every 2 weeks (Q2W). Nivolumab showed durable efficacy and manageable safety profile in 
these patients [Nakano T., et al 2018]. Based on the results, nivolumab was approved in 
Japan for 2nd/3rd line MPM patients on Aug 2018.  However, there is an unmet medical need 
for first line therapy for advanced MPM.  
As for the clinical study with pembrolizumab in MPM, Alley EW, et al. reported the 
preliminary result of pembrolizumab at 10 mg/kg Q2W in previously treated MPM patients 
in a phase Ib study. As of June 20, 2016, 25 patients received pembrolizumab. 
Pembrolizumab appeared to be well tolerated and might confer anti-tumor activity in patients 
with PD-L1-positive malignant pleural mesothelioma [Alley EW., et al 2017].
Desai A, et al. reported the result of pembrolizumab at 200 mg Q3W in previously treated 
pleural or peritoneal malignant mesothelioma patients in a phase II study (ClinicalTrials.gov 
Identifier: NCT02399371). Pembrolizumab had robust activity in PD-L1 unselected,
previously-treated mesothelioma.  There were no unexpected toxicities.  Although an optimal 
PD-L1 threshold could not be identified, a trend towards a higher response rate and more 
durable PFS with increasing PD-L1 expression was observed [Desai A., et al 2018].
Canadian Cancer Trials Group (CCTG) has been conducting a multi-center, randomized 
phase II/III study of pembrolizumab given alone or with standard chemotherapy (cisplatin 
and pemetrexed) vs. standard chemotherapy alone in patients with advanced MPM 
(ClinicalTrials.gov Identifier: NCT02784171).
With regards to the clinical study with the regimen of pembrolizumab plus chemotherapy, 
KEYNOTE-189 was the confirmatory Phase III study, with the treatments of pembrolizumab
in combination with pemetrexed/platinum chemotherapy (cisplatin or carboplatin) provided a
clinically meaningful and significant improvement in OS, PFS and ORR for previously
untreated patients with metastatic non-squamous Non-Small Cell Lung Cancer (NSCLC) 
[Gandhi L., et al 2018]. In KEYNOTE-189, all subgroups benefited from pembrolizumab in 
combination with chemotherapy regardless of PD-L1 expression status. Regulatory agencies 
have approved pembrolizumab in combination with pemetrexed and platinum for non-
squamous NSCLC globally including Japan.
Given the activity of pembrolizumab monotherapy on MPM described above and there are 
still high unmet medical needs in treatment of advanced MPM as a first line treatment, we 
plan to conduct a multi-center, phase Ib study of pembrolizumab in combination with the 
standard chemotherapy (cisplatin and pemetrexed) in Japanese participants with treatment 
naïve advanced MPM.
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2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-
1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across a number of indications. For more details on specific 
indications refer to the IB.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis ML. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley ME., et al 2005] [Hunder 
NN., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald RJ., et al 2005] [Okazaki T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
which are involved in the CD3 T-cell signaling cascade [Okazaki T., et al 2001] [Chemnitz 
JM., et al 2004] [Sheppard KA., et al 2004] [Riley JL. 2009]. The mechanism by which PD-1 
down-modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because 
both molecules regulate an overlapping set of signaling proteins [Parry RV., et al 2005] 
[Francisco LM., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in MPM (refer to Section 2.1).
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2.2.2
Preclinical and Clinical Studies
Refer to the respective IB for pembrolizumab for additional preclinical and clinical study 
data for pembrolizumab.
2.2.3
Ongoing Clinical Studies of Pembrolizumab
Ongoing clinical studies with pembrolizumab are being conducted in multiple solid tumors.
In addition, multiple combinations with pembrolizumab are also being investigated. Refer to 
pembrolizumab IB for study details.
2.2.4
Information on Other Study-related Therapy
As described in Section 2.1, the combination therapy of cisplatin and an antifolate 
(pemetrexed or raltitrexed) is widely used as a first line therapy for MPM globally. Also in 
Japan, cisplatin and pemetrexed combination provides promising activity and an acceptable 
safety profile for systemic chemotherapy naïve Japanese MPM patients with the same 
recommend dosage and schedule used in rest of the world (500 mg/m2 pemetrexed Q3W and 
75 mg/m2 cisplatin Q3W) [Nakagawa K., et al 2008].  The combination therapy of cisplatin 
and pemetrexed is recommended for advanced MPM patients with ECOG performance status
0-2 in Guidelines for Diagnosis and Treatment of the Lung Cancer 2018 [The Japan Lung 
Cancer Society. 2018].
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In males and females with advanced/unresectable MPM who are treatment naïve;
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Objectives
Endpoints
Primary
•
To evaluate the safety and tolerability of 
treatment with pembrolizumab in 
combination with cisplatin and 
pemetrexed.
•
DLTs rate
•
AEs
•
Discontinuing study treatment due to 
AEs
Secondary
•
To evaluate the preliminary anti-tumor 
activity (objective response, disease 
control and DOR by modified RECIST as 
assessed by the investigator) of 
pembrolizumab in combination with 
cisplatin and pemetrexed.
•
Objective response (OR): confirmed 
CR or PR
•
Disease control (DC): a response of 
confirmed CR or PR, or SD
•
DOR: the time from the first 
documented evidence of OR (CR or 
PR) to the earliest date of PD or death 
due to any cause, whichever comes 
first, for individuals with a confirmed 
CR or PR.
Tertiary/Exploratory
•
To evaluate the preliminary anti-tumor 
activity [progression free survival (PFS)]
by modified RECIST as assessed by the
investigator, and OS of pembrolizumab in 
combination with cisplatin and 
pemetrexed.
•
PFS: the time from the first dose of
study treatment to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
OS: the time from the first dose of 
study treatment to death due to any 
cause. 
•
To explore the predictive effect of PD-L1 
expression at baseline in participants 
treated with pembrolizumab in 
combination with cisplatin and 
pemetrexed. (optional)
•
OR
•
PFS
•
OS
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4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, open-label, non-randomized, phase Ib study of pembrolizumab in 
combination with cisplatin and pemetrexed in treatment naïve participants with a 
histologically confirmed diagnosis of advanced MPM in Japanese. This study will evaluate 
the safety, tolerability, and preliminary efficacy of pembrolizumab in combination with 
cisplatin and pemetrexed.
The study design is shown in Figure 1. Approximately 18 participants will be enrolled. The 
details about the eligible criteria are described in Section 5.1 and 5.2. 
In Treatment phase, participants will receive pembrolizumab in combination with the 
standard chemotherapy up to 4-6 cycles with reference to Figure 1. Pembrolizumab will be 
administered as fixed dose of 200 mg Q3W in combination with cisplatin 75 mg/m2 Q3W
and pemetrexed 500 mg/m2 Q3W. The main objective of this study is to evaluate the 
tolerability of the study regimen by DLT observation rate as a part of safety endpoint. 
Cycle 1 is defined as an DLT assessment period and the number of participants experiencing 
a DLT will be evaluated. If ≤8 participants among 18 participants develop a DLT, the study 
regimen will be considered to be tolerated. Details of DLT assessment schedules and rules 
are described in Section 1.3 and 6.6.3. The definition of DLTs is outlined in Section 6.6.4.
During DLT assessment period, participants will be basically hospitalized. There is no dose 
escalation/reduction of pembrolizumab in this study. When participants wish to receive 
consecutive study intervention after DLT assessment period (i.e. Cycle 2 and over), 
reconsent is required at the end of treatment in Cycle 1 and just before the starting Cycle 2.
Participants will receive pembrolizumab 200 mg Q3W up to 35 cycles from the first dose of 
the study, or until disease progression is radiographically documented by the investigator 
based on modified RECIST, or unacceptable AEs, or recurrent Grade 2 pneumonitis, or 
investigator’s decision to discontinue treatment, or other reasons requiring cessation of 
treatment (Section 7.1).
Adverse event monitoring will be ongoing throughout the study and graded in severity
according to the guidelines outlined in the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v5.0 (Section 8.4). Adverse events will be 
reported by the investigator or delegate from the time of intervention allocation through 30
days following cessation of study intervention. Serious AEs (SAEs) will be reported by the 
investigator or delegate from first dose of the study through either 90 days following 
cessation of study intervention, or 30 days following cessation of study intervention if the 
participant initiates new anti-cancer therapy, whichever is earlier.
In addition, tumor sample (archival or fresh) will be obtained for the biomarker analysis of 
PD-L1 (optional). PD-L1 expression in tumor sample will be assessed using combined 
positive score (CPS). CPS is defined as number of PD-L1 staining cells (tumor cells, 
lymphocytes, macrophages) relative to the total number of viable tumor cells, multiplied by 
100.
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Participants who discontinue study intervention for reasons other than radiologically 
confirmed disease progression by the investigator based on modified RECIST (Section 8.2.5)
should continue imaging follow-up visit per the protocol-defined schedule until: (1) disease 
progression is radiologically verified by the investigator, (2) initiation of a new anti-cancer 
treatment, (3) death, (4) withdrawal of consent, (5) pregnancy or (6) study conclusion or 
early termination, whichever occurs first.  
Participants who experience radiologically confirmed disease progression or start a new anti-
cancer therapy will move into the Survival Follow-up Phase and should be contacted by 
telephone approximately every 12 weeks (84 ±14 days) 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 course of the 
study. For example, these additional time points may be requested prior to an efficacy 
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.
After approval of Protocol amendment 02, the study will end 90 days after the last dose of 
the last participant. Participants in the Imaging Follow-up or Survival Follow-up phase will 
be discontinued from the study and no further visits will be required.
No interim analyses are planned in this study.
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.
4.2
Scientific Rationale for Study Design
This is a phase Ⅰb study because primary endpoint is to evaluate the safety and tolerability 
of pembrolizumab in combination with cisplatin and pemetrexed. As mentioned in section 
2.2.4, cisplatin and pemetrexed is the standard treatment of advanced MPM patients globally.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use OR, DC, DOR and PFS by the investigator based on modified RECIST
(Section 8.2.5) and OS as the secondary or exploratory endpoints. OR, DC, DOR and PFS
are acceptable measures of clinical benefit for a clinical study that demonstrates superiority 
of a new antineoplastic therapy, especially if the magnitude of the effect is large and the 
therapy has an acceptable risk/benefit profile.
MPM most commonly grows as a ‘rind’ around the pleural surface, and the selection of 
measurement sites bidimensionally based on RECIST 1.1 is difficult on computed 
tomography (CT) scan. With this reason, modified RECIST criteria in MPM is commonly 
used to assess anti-tumor activity for malignant mesothelioma instead of RECIST 1.1. In this 
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study, the final determination of radiologic disease progression will be evaluated by the site 
investigator with radiological assessment based on modified RECIST.
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in clinical studies.
4.2.1.2
Safety Endpoints
The primary objective of this study is to characterize the safety and tolerability of 
pembrolizumab as combination therapy with cisplatin and pemetrexed in treatment naïve 
Japanese participants with advanced MPM. The primary safety analysis will be based on 
participants who experience toxicities as defined by NCI CTCAE Version 5.0 criteria. 
Safety will be assessed by evaluating the DLT observation rate in Cycle 1 and quantifying 
the toxicities and grades of toxicities experienced by participants throughout the study.
For AEs, attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. Adverse events that will be analyzed 
include, but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
As mentioned in Section 2.1, in KEYNOTE-189, which is the confirmatory Phase III study 
for treatment naïve patients with metastatic non-squamous NSCLC, patients were treated 
with pembrolizumab in combination with pemetrexed/platinum chemotherapy (cisplatin or 
carboplatin).  The clinical data of KEYNOTE-189 indicated that the study regimen was well 
tolerated and safe for these patients including Japanese.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
Rationale for Starting and Maximum Dose of MK-3475
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 10 
mg/kg Q2W representing an approximate 5 to 7.5 fold exposure range (refer to IB, 
Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and
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•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.3.1.2
Rationale for Cisplatin and Pemetrexed Dosing Regimen
This study will evaluate the safety, tolerability, and preliminary efficacy of pembrolizumab 
in addition to the standard chemotherapy (combination of cisplatin and pemetrexed) to 
advanced MPM, dose of cisplatin (75 mg/m2 Q3W) and pemetrexed (500 mg/m2 Q3W) are 
selected as per the approved local product label(s). These doses are approved globally for 
advanced MPM.
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 
consent, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator). The time point when the last participant completes the last observation (last 
study-related telephone-call or visit) will be 90 days after the last dose of the last participant.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Male/Female participants with diagnosis of advanced malignant pleural mesothelioma at 
least 20 years of age 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
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1.
Is male or female at least 20 years of age and has histologically confirmed diagnosis 
of advanced/unresectable MPM.
2.
Have at least one measurable disease (one dimension as ≥10 mm or malignant lymph 
nodes ≥ 15 mm in the short axis), which is systemic therapy naïve, radiologically 
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assessed by the local site investigator per modified RECIST (refer to Section 8.2.5)
using imaging scanned within 28 days prior to the first dose in this study.
3.
Has a performance status of 0 or 1 on the ECOG Performance Scale within 3 days 
before the first administration.
4.
Has a life expectancy of at least 3 months.
5.
Demonstrate adequate organ function as defined in Table 1 Adequate Organ Function 
Laboratory Values.
Table 1
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
GFR in place of CrCl
≤1.5 X ULN or 
≥60 mL/min for participants 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) or Partial Thromboplastin Time 
(PTT) c
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use 
of anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper 
limit of normal.
a Criteria must be met without 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.
c If aPTT is not available, PTT may be tested.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
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Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
6.
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 90 days after the last dose of chemotherapy or 120 
days after the last dose of pembrolizumab:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
Agree to 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. Note: Men 
with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile-vaginal penetration.
•
Male participants must also agree to use male condom when engaging in any activity that 
allows for passage of ejaculate to another person of any sex.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
7.
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix [5] during the intervention period and for at least 180 
days after the last dose of chemotherapy or 120 days after the last dose of pembrolizumab 
after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to 
others or freeze/store for her own use for the purpose of reproduction during this period. 
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The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention. 
•
A WOCBP must have a negative highly sensitive pregnancy test (urine) within 72 hours 
before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (e.g., an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix [5].
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
8.
The participant (or legally acceptable representative if applicable) provides written 
informed consent/assent for the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1.
A WOCBP who has a positive pregnancy test within 72 hours prior to treatment 
allocation (see Appendix 5). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Note: In the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study intervention, another pregnancy test (urine or serum) must 
be performed and must be negative in order for participant to start receiving study 
medication. 
Prior/Concomitant Therapy
2.
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or 
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., 
CTLA-4, OX-40, CD137).
3.
Has previously received systemic anti-cancer therapy (including investigational 
agents) to MPM.
Note: Participants who received (neo) adjuvant previously may be eligible, only if the 
last dose of chemotherapy was completed at least 6 months before registration. Such 
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participants must have recovered from all AEs due to previous (neo) adjuvant 
therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be 
eligible.
4.
Received radiation therapy to the lung that is > 30 Gy within 6 months of the first
dose of trial treatment.
5.
Completed palliative radiotherapy within 7 days of the first dose of trial treatment.
Note: Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. 
6.
Had a major surgery within 3 months prior to the first administration in this study. 
7.
Has received a live vaccine within 30 days prior to the first dose of study drug. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection as killed virus vaccines are 
allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated 
vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
8.
Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
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.
Diagnostic Assessments
9.
Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.
10.
Has a known additional malignancy that is progressing or has required active 
treatment within the past 5 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
11.
Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging 
(note that the repeat imaging should be performed during study screening), clinically 
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stable and without requirement of steroid treatment for at least 14 days prior to first 
dose of study intervention. 
12.
Has had a severe hypersensitivity reaction (≥Grade 3) to treatment a monoclonal
antibody/components of the study intervention.
13.
Is unable or unwilling to take folic acid or vitamin B12 supplementation.
14.
Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment and is allowed.
15.
Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease. The definition of 
pneumonitis includes radiation pneumonitis.
16.
Is being treated for pericardial effusion, or has symptomatic ascites or pleural 
effusion. A participant who is clinically stable following treatment for these 
conditions (including therapeutic thoraco- or paracentesis) is eligible.
17.
Has an active infection requiring systemic therapy.
18.
Has a known history of HIV infection. 
19.
Has a known history of Hepatitis B (defined as HBsAg reactive) or  known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. 
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority. 
20.
Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
21.
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, or is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.
22.
Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
23.
Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of pembrolizumab or 180 days after the last dose of 
chemotherapies.
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24.
Participants with a history of allogeneic tissue / organ transplantation
5.3
Lifestyle Considerations
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently allocated in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
In order to adequately evaluate DLT during Cycle 1 and the safety of the doses administered 
in this study, all participants enrolled must meet the criteria for evaluability for Cycle 1. 
Participants are considered non-evaluable and will be replaced if:
•
They are allocated but not treated.
•
They discontinue from the study prior to completing all the safety evaluations for reasons 
other than treatment-related AEs.
•
They receive less than 90% of the total planned infusion of either drug (pembrolizumab, 
cisplatin or pemetrexed) in Cycle 1 and did not experience a DLT.
Non-evaluable participants will not be counted toward the total number of participants DLT 
evaluation.
If a participant experiences a DLT in Cycle 1, study intervention may be discontinued 
following discussion between the Sponsor and investigator. However, if the participant is 
deriving clinical benefit from the study intervention, the participant may be allowed to 
continue after discussion between the Sponsor and the investigator.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies study intervention(s) provided by the Sponsor will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
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supplies. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2 Study Interventions.
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Table 2
Study Interventions
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
NA
Experi-
mental
Pembrolizumab
Drug
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Q3W; Day 1 
in each cycle
up to 35 
cycles
Experimental
IMP
Central
NA
Experi-
mental
Pemetrexed
Drug
Solution for 
Infusion
500 mg/m2
500
mg/m2
IV Infusion
Q3W; Day 1 
in each cycle
up to 4-6 
cycles
Background 
Treatment
IMP
Local 
Site
NA
Experi-
mental
Cisplatin
Drug
Solution for 
Infusion
75 mg/m2
75 
mg/m2
IV Infusion
Q3W; Day 1 
in each cycle
up to 4-6 
cycles
Background 
Treatment
IMP
Local 
Site
IV = intravenous; NA = Not Applicable; 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.
The order of administration is that pembrolizumab is administered first, then pemetrexed is administered followed by a 30-minute interval once the infusion is 
completed. Cisplatin will be administered following a 30 minutes interval after the completion of pemetrexed infusion. Participants should take appropriate 
replacement therapy of vitamin B12 and folic acid, and prophylaxis of corticosteroids for pemetrexed treatment and receive appropriate hydration for cisplatin 
treatment based on the local institutional practice.  Please see the Section 8.1.8 and refer to the pharmacy manual for more details.
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All supplies indicated in Table 2 Study Interventions 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.
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
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Concomitant chemotherapeutic agents will be prepared and administered based on 
the local institutional practice.
6.2.2
Dose Administration
Pembrolizumab 200 mg Q3W in combination with cisplatin 75 mg/m2 Q3W and pemetrexed 
500 mg/m2 Q3W will be administered 4-6 cycles. After discontinuation of the combination 
therapy, pembrolizumab 200 mg Q3W will be treated as a monotherapy up to 35 cycles from 
the first dose.  
Participants should take appropriate replacement therapy of vitamin B12 and folic acid, and 
prophylaxis of corticosteroids for pemetrexed treatment and receive appropriate hydration for 
cisplatin treatment based on the local institutional practice.  
The order of administration is that pembrolizumab is administered first, then pemetrexed is 
administered followed by a 30-minute interval once the infusion is completed. Cisplatin will 
be administered following a 30 minutes interval after the completion of pemetrexed infusion.
Any variability in dosage, administration and time window from the protocol-specified 
dosing, pembrolizumab, cisplatin, or pemetrexed, should be documented in the participant’s 
study record and recorded in the Case Report Form (eCRF)s.
First study treatment should begin within 3 days of intervention allocation. The study 
intervention for Cycle 2 may be administered within 3 days after the scheduled Day 1 of 
Cycle 2. The following study intervention for Cycle 3 and beyond may be administered
within 3 days before or after the scheduled Day 1 of each cycle. All administrations of study 
intervention will begin on Day 1 of each cycle after all pre-dose study procedures and 
assessments have been completed as described in the SoA (Section 1.3).
6.2.3
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.
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Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants in this study will be allocated by nonrandom assignment.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record. 
Refer to Section 6.6.1 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruptions of pembrolizumab.
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Interruptions from the protocol-specified treatment plan for more than 12 consecutive weeks 
between pembrolizumab doses or more than 6 consecutive weeks between chemotherapy 
(cisplatin or pemetrexed) for nondrug-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 medication or vaccination 
specifically prohibited, discontinuation from study intervention may be required. The 
investigator is to discuss prohibited medication/vaccination with the Sponsor’s Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant’s primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
6.5.1
Acceptable Concomitant Medications
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 CRF including all prescription, OTC, herbal 
supplements, and IV medications and fluids. If changes occur during the study period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or events of clinical interest (ECIs)
are to be recorded. SAEs and ECIs are defined in Section 8.4.
6.5.2
Prohibited Concomitant Medications
The following medications and vaccinations are prohibited from the screening period to 
finishing the last dose in this study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion after the DLT observation period.
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
Live or live attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. 
Note: Killed virus vaccines are allowed.

Systemic glucocorticoids except when used for the following purposes
o
To modulate symptoms of an AE that is suspected to have an immunologic etiology.
o
For the prevention of emesis
o
To premedicate for IV contrast allergies
o
To treat chronic obstructive pulmonary disease (COPD) exacerbations (only short-
term oral or IV use in doses >10 mg/day prednisone equivalent)
o
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent

Other glucocorticoid use except when used for the following purposes:
o
For topical use or ocular use
o
Intraarticular joint use
o
For inhalation in the management of asthma or COPD

Prophylactic use of colony-stimulating factors including Granulocyte Colony-Stimulating
Factor (G-CSF) during DLT assessment period (Cycle 1) is NOT allowed.
Participants may receive other medications that the investigator deems to be medically 
necessary.
6.5.3
Rescue Medications and supportive care
Participants 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, Table 3 .
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab,
the investigator does not need to follow the treatment guidance. Refer to Table 3 in Section
6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
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6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
6.6.1.1
Dose Modification and Toxicity Management for Immune-related AEs 
Associated with Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
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Table 3
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 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics 
for opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer antihyperglycemic 
in participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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 based on 
the event e
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
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating  
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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6.6.1.2
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 4.
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 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 participant is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (eg, from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the participant 
should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study drug intervention.
Participant may be 
premedicated 1.5 h (±30 
minutes) prior to infusion of
study intervention with:
Diphenhydramine 50 mg PO
(or equivalent dose of
antihistamine).
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) 
at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 3 weeks (21 days) of the originally scheduled dose and within 42 days of 
the previously administered dose, unless otherwise discussed with the Sponsor. The reason 
for study intervention interruption is to be documented in the participant's study record.
6.6.1.3
Dose Modification and Toxicity Management AEs Associated with 
Chemotherapy
Dose modification of chemotherapy will not be permitted in DLT evaluation period (Cycle
1). Dose modification of cytotoxic chemotherapies due to AE except for creatinine clearance 
will conform to the site’s standards procedures (See below).
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Creatinine clearance (CrCl):
CrCl must be ≥45 mL/min prior to the administration of chemotherapy. Pemetrexed and/or
cisplatin may be delayed for up to 42 days to allow the subject time to recover from the
toxicity. If CrCl value is not recovered and continues to record <45 mL/min over 42 days, 
consider discontinuing treatment with pemetrexed and/or cisplatin. CrCl should be calculated 
per institutional standard.
6.6.2
Dose Administration/Escalation
6.6.2.1
Dose Administration (Preparation)
Details on preparation and administration of pembrolizumab are provided in the appropriate 
Pharmacy Manual.
6.6.3
Tolerability Evaluation Rules
DLT evaluation period is Cycle 1 (the first 3 weeks after the initiation of the study 
treatments).  As a general rule, a participant should be hospitalized during the DLT 
evaluation period (Cycle 1).
The number of participants who are enrolled but are not yet fully evaluable for DLT 
assessment may not exceed the number of remaining participants who are at risk of 
developing a DLT (see Appendix 9).  Enrollment will continue until 18 evaluable 
participants are enrolled, or a "DU (it means that the current dose is unacceptably toxic)" is 
reached. If a "DU" is reached, enrollment will be paused to consider next steps of this study 
(ex, alteration of the chemotherapy dosing regimen, or discontinuation of the study).
The total number of DLT observed participants will be used to determine the tolerability of 
pembrolizumab in combination with the standard chemotherapy regimen. The tolerability 
evaluation rules in this study are as follows:

If ≤8 participants among 18 participants develop a DLT, the study regimen will be 
considered to be tolerated.

If ≥9 participants among 18 participants develop a DLT, the study regimen will be 
considered to be NOT tolerated.
6.6.4
Definition of Dose‑limiting Toxicity
All toxicities experienced during the DLT evaluation period (the first 3 weeks after initiation 
of study treatment, Cycle 1) will be graded using NCI-CTCAE Version 5.0 based on the 
investigator assessment in patients included in DLT evaluation. The DLT window of 
observation will be during Cycle 1. The occurrence of any of the following toxicities (Table 
5) during Cycle 1 will be considered a DLT, if assessed by the investigator to be related to 
any of the study interventions in Table 2.
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Table 5
Definition of DLT
Hematologic Toxicities:

Grade 4 hematologic toxicities (any period), except neutropenia and febrile 
neutropenia as below

Grade 4 neutropenia lasting >7 days despite appropriate supportive treatment

Grade 4 febrile neutropenia (any period) only if the event is considered as clinically 
significant for the participant deemed by investigator and sponsor.
Non-Hematologic Toxicities:

Any Grade 4 non-hematologic toxicity (except laboratory test abnormal including 
transient electrolyte abnormalities)

Any Grade 3 non-hematologic toxicity lasting >72 hours despite appropriate 
supportive treatment (not laboratory)

Any Grade 4 laboratory test value abnormality (refer to the hematologic toxicities for 
platelet count decreased and neutrophil count decreased)

Any Grade 3 laboratory test value abnormality lasting >7 days
General：

The start of the second course is delayed by more than 2 weeks (more than 35 days 
after the first dose) due to toxicity related to study procedures

Any Grade 5
The SPONSOR and the principal investigator will decide the appropriateness of the DLT, 
and enrollment of additional participants in consultation with the external Efficacy and 
Safety Evaluation Committee if needed.
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-
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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.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in Section 
6.6.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant interrupts study administration of pembrolizumab for more than 12
consecutive weeks or administration of chemotherapy (cisplatin or pemetrexed) for more 
than 6 consecutive weeks.
•
Clinical progression (without radiographic disease progression).
•
Disease progression is radiographically documented by the investigator per modified 
RECIST outlined in Section 8.2.5.
•
Any progression or recurrence of any malignancy, or occurrence of another malignancy 
that requires active treatment (new non-study anti-cancer therapy).
•
Investigator’s decision to discontinue treatment.
•
The participant has a confirmed positive serum pregnancy test.
•
Sponsor’s decision.
•
Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks) receiving 2 
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cycles of the combination including 2 doses of pembrolizumab beyond the date when the 
initial CR was declared. 
•
Completion of 35 treatments (approximately 2 years) with pembrolizumab.
Note: The number of treatments is calculated starting with the first dose.
For participants who are discontinued from study intervention all applicable discontinuation 
activities will be performed according to Section 1.3.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued
from study intervention, he/she shall not be allowed to restart study intervention.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study 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.
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•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
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. 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.
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The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Reconsent before the starting Cycle 2
When participants wish to receive consecutive study intervention after DLT period (i.e. 
Cycle 2 and over), reconsent is required at the end of treatment in Cycle 1 and just before the 
starting Cycle 2.
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, 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
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically important by the investigator. 
Details regarding the disease for which the participant has enrolled in the study will be 
recorded separately and not listed as medical history.
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If a medical condition is diagnosed at the time of Screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study medication.
Treatment for the disease for which the participant has enrolled in this study will be recorded 
separately and not listed as a prior medication.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and ECIs should be recorded as defined in 8.4.
All new anti-cancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anti-cancer 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 anti-cancer 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 intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.10.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation.  Once a 
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treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual. The total volume of study intervention 
infused will be compared to the total volume prepared to determine compliance with each 
dose administered.
8.1.8.1
Timing of Dose Administration
All study intervention should be administered on Day 1 of each cycle after all pre-dose 
procedures and assessments have been completed as described in Section 1.3.
First study treatment should begin within 3 days of intervention allocation. The study 
intervention for Cycle 2 may be administered within 3 days after the scheduled Day 1 of 
Cycle 2. The following study intervention for Cycle 3 and beyond may be administered 
within 3 days before or after the scheduled Day 1 of each cycle.
The administration order is that pembrolizumab is administered first, then pemetrexed is 
administered followed by a 30-minute interval once the infusion is completed, then cisplatin 
will be administered following a 30 minutes interval after the completion of pemetrexed 
infusion.
Pembrolizumab
Participants will be received pembrolizumab 200 mg on Day 1 of each cycle (every 3 weeks)
as a 30 minute IV infusion (25-40 min) up to 35 cycles. The Pharmacy Manual contains 
specific instructions for pembrolizumab reconstitution, preparation of the infusion fluid, and 
administration.
Pemetrexed
Pemetrexed 500 mg/m2 will be administered after pembrolizumab infusion on Day 1 of each 
cycle (every 3 weeks) up to 4-6 cycles an IV infusion. Subjects should also receive 
appropriate replacement therapy of vitamin B12 and folic acid, and prophylaxis of 
corticosteroids before and after the administration of pemetrexed to reduce the appearance of 
severe adverse events based on the local institutional practice.
Cisplatin
Cisplatin 75 mg/m2 will be administered after pemetrexed infusion on Day 1 of each cycle 
(every 3 weeks) up to 4-6 cycles as an IV infusion. Appropriate hydration should be treated 
to reduce renal toxicities.
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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 (Section 1.3) and Section 8.10.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
As a general rule, a participant should be hospitalized during the DLT evaluation period (the 
first 3 weeks after the initiation of study medications, Cycle 1).
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 are 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
Tumor imaging should be acquired by CT (strongly preferred) and should include the chest, 
abdomen, and pelvis. MRI should be used when CT is contraindicated or for imaging in the 
brain. The same imaging technique regarding modality and use of contrast should be used in 
a participant throughout the study to optimize the visualization of existing and new tumor 
burden, per the local institutional practice.
8.2.2
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the first dose of 
study medication.
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 the first treatment.
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Brain imaging is not mandatory at the screening, but participants with previously treated 
brain metastases may participate provided they are stable (i.e., without evidence of 
progression) for at least 4 weeks by repeat imaging (note that the repeat imaging by the same 
imaging technique regarding modality should be performed during study screening).
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 14 days prior to study initiation per local site assessment. This 
exception does not include carcinomatous meningitis, as participants with carcinomatous 
meningitis are excluded regardless of clinical stability.
8.2.3
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 6 weeks (42 days ±7 days) 
from the first dose. Subsequent tumor imaging should be performed every 6 weeks (Q6W) 
(42 days ±7 days) up to the first 24 weeks from the first dose (i.e., W12, W18, and W24). 
After 24 weeks, participants will have imaging performed every 9 weeks (Q9W) (63±7 days) 
from the first dose until the end of first year (i.e. W33, W42, W51, and W60), and then every 
12 weeks (Q12W) (84±7 days) (i.e., W72, W84, etc.).  Imaging assessment may be 
performed more frequently if clinically indicated. Imaging timing should follow calendar 
days and should not be adjusted for delays in cycle starts. Imaging are to be performed until 
radiological disease progression is identified by the investigator, or until the start of new anti-
cancer treatment, pregnancy, death, withdrawal of consent, or the end of the study, whichever 
occurs first.
PR and CR should be confirmed by a repeat imaging assessment. The imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan, whichever is clinically indicated. Participants will 
then return to regular scheduled imaging, starting with the next scheduled imaging time 
point. Participants who receive additional imaging for confirmation do not need to undergo 
the next scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume 
at the subsequent scheduled imaging time point. 
8.2.4
End of Treatment and Follow-up Tumor Imaging
In participants who discontinue study intervention, tumor imaging should be performed at the 
time of intervention discontinuation (±4 weeks 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 intervention due to documented disease progression, 
this is the final required tumor imaging.
For participants who discontinue study intervention without documented radiological disease 
progression by the investigator based on modified RECIST (Section 8.2.5), every effort 
should be made to continue monitoring their disease status by tumor imaging on the same 
imaging schedule used while on treatment to monitor disease status until the start of a new 
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anti-cancer treatment, radiological disease progression, pregnancy, death, withdrawal of 
consent, or the end of the study, whichever occurs first.
8.2.5
modified RECIST in Malignant Pleural Mesothelioma
All participants who have received at least one cycle should be assessed their response and 
progression using the modified RECIST in MPM by investigator’s assessment.
8.2.5.1
Pleural Tumor Measurement  
The method of pleural tumor measurement is followed by Byrne and Nowak [Byrne MJ., et 
al 2004]. The pleural tumor thickness should be measured perpendicular to the chest wall or 
mediastinum. It should be measured in 2 positions at 3 different levels (‘cuts’) on the thoracic 
CT scan. The transverse cuts should be at least 1 cm apart, and for ease of re-assessment, be 
related to anatomical landmarks in the thorax. Cuts should preferably be above the level of 
the main bronchi. At reassessment, the pleural thickness must be measured at the same level 
and position. 
The pleural unidimensional measures are considered to be one organ.
8.2.5.2
Other Measurable Disease 
Other measurable tumor lesions (nodal, subcutaneous, lung parenchyma, solid organ 
metastases) are defined as those that can be accurately measured in at least one dimension 
(longest diameter to be recorded) as ≥ 10 mm with CT scan or clinical examination. Bone 
lesions are considered measurable only if assessed by CT scan and have an identifiable soft 
tissue component that meets these requirements (soft tissue component ≥ 10 mm by CT 
scan). Malignant lymph nodes must be ≥ 15 mm in the short axis to be considered 
measurable; only the short axis will be measured and followed.
All tumor measurements must be recorded in millimeters (or decimal fractions of 
centimeters). Previously irradiated lesions are not considered measurable unless progression 
has been documented in the lesion.
8.2.5.3
Non-Measurable Disease  
All other lesions (or sites of disease), including small lesions are considered non-measurable 
disease. Bone lesions without a measurable soft tissue component, leptomeningeal disease, 
ascites, pleural/pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of lung or skin and abdominal masses followed by clinical examination are all non-
measurable. Lesions in previously irradiated areas are non-measurable, unless progression 
has been demonstrated.
8.2.5.4
Target Lesion
When more than one measurable tumor lesion is present at baseline all lesions up to a 
maximum of 5 lesions total (and a maximum of 2 lesions per organ) representative of all 
involved organs should be identified as target lesions and will be recorded and measured at 
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baseline. Note that the pleural unidimensional measures are considered to be one lesion of 
one organ.
Target lesions should be selected on the basis of their size (lesions with the longest diameter), 
be representative of all involved organs, but in addition should be those that lend themselves 
to reproducible repeated measurements. 
Note that pathological nodes must meet the criterion of a short axis of ≥ 15 mm by CT scan 
and only the short axis of these nodes will contribute to the baseline sum. All other 
pathological nodes (those with short axis ≥ 10 mm but < 15 mm) should be considered non-
target lesions. Nodes that have a short axis < 10 mm are considered non-pathological and 
should not be recorded or followed. 
At baseline, the sum of the target lesions is to be recorded.
After baseline, a value should be provided on the eCRF for all identified target lesions for 
each assessment, even if very small. If extremely small and faint lesions cannot be accurately 
measured but are deemed to be present, a default value of 5 mm may be used. If lesions are 
too small to measure and indeed are believed to be absent, a default value of 0 mm may be 
used.
8.2.5.5
Non-target lesions
All non-measurable lesions (or sites of disease) plus any measurable lesions over and above 
those listed as target lesions are considered non-target lesions. Measurements are not 
required but these lesions should be noted at baseline and should be followed as “present” or 
“absent”. Note: For this study, skin lesions will be considered as non-target lesions.
8.2.5.6
Response
After baseline, all participants will be assessed all selected site and “Overall Response”
classified as outlined below and Table 6 at each assessment point. The assessment should be 
provided on the eCRF.
Complete Response (CR): disappearance of target and non-target lesions and normalization 
of tumor markers. Pathological lymph nodes must have short axis measures < 10 mm (Note: 
continue to record the measurement even if < 10 mm and considered CR). Residual lesions 
(other than nodes < 10 mm) thought to be non-malignant should be further investigated (by 
cytology specialized imaging or other techniques as appropriate for individual cases 
[Eisenhauer EA., et al 2009]) before CR can be accepted. 
Partial Response (PR): at least a 30% decrease in the sum of measures (pleural 
unidimensional measure, plus longest diameter of tumor lesions, plus short axis of lymph 
nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target lesions 
must be non-PD. 
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Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD taking as reference the smallest sum of diameters on study.
Progressive Disease (PD): at least a 20% increase in the sum of diameters of measured 
lesions taking as references the smallest sum of diameters recorded on study (including 
baseline) AND an absolute increase of ≥ 5 mm. Appearance of new lesions and/or 
unequivocal progression in Non-target lesions will also constitute progressive disease 
(including lesions in previously unassessed areas). 
Table 6
Integration of Target, non-Target and New Lesions into Response Assessment
Target Lesions 
Non-Target Lesions 
New Lesionsa
Overall Response 
Best Response for 
this Category also 
Requires 
Target lesions ± non target lesions 
CR 
CR 
No 
CR 
Normalization of 
tumor markers, 
tumor nodes 
<10 mm 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not all evaluated 
No 
PR 
PR 
Non-PD/ not all 
evaluated 
No 
PR 
SD 
Non-PD/ not all 
evaluated 
No 
SD 
documented at least 
once ≥ 4 wks. from 
baseline 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Any 
PD 
Any 
PD 
Any 
PD 
Any 
Any 
Yesa
PD 
Non target lesions ONLY 
No Target 
CR 
No 
CR 
Normalization of 
tumor markers, 
tumor nodes < 
10 mm 
No Target 
Non-CR/non-PD 
No 
Non-CR / non-PD 
No Target 
Not all evaluated 
No 
NE 
No Target 
Unequivocal PD 
Any 
PD 
No Target 
Any 
Yesa
PD 
a Investigators should record all new lesions; if the new lesion is felt to be equivocal, treatment may be continued pending 
further assessments.
Note: Participants with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “clinical progression”. This is a reason for stopping 
therapy, but is NOT objective PD. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 
Confirmation of response (PR or CR) is required and the imaging for confirmation of response may be performed at the 
earliest 4 weeks after the first indication of response, or at the next scheduled scan, whichever is clinically indicated.
8.3
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
Screening period as defined in the SoA (Section 1.3). Clinically significant abnormal 
findings should be recorded as medical history. The time points for full physical exams are 
described in SoA (Section 1.3). After the first dose of study intervention, new clinically 
significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical exam, the investigator or qualified designee 
will perform a directed physical exam as clinically indicated prior to study intervention 
administration as defined in the SoA (Section 1.3). New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at Screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3). Vital signs include temperature, pulse, respiratory rate, 
weight and blood pressure. Height will be measured at Screening only.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA (Section 1.3). Clinically significant abnormal findings should
be recorded as medical history. Additional ECGs may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the SoA.
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•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
8.3.4.1
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 7 days prior to the first dose of 
study intervention. An exception is PT/INR and aPTT, which may be performed within 10
days prior to first dose. Pre-dose laboratory safety tests for Cycle 2 should be conducted after 
Day 20 of Cycle 1.  After Cycle 2, pre-dose laboratory safety tests can be conducted within 3
days prior to dosing for each cycle unless otherwise noted on the flow charts.
CrCl should be calculated per institutional standard prior to the administration of 
pemetrexed. Pemetrexed and/or cisplatin may be delayed for up to 42 days to allow the 
participant time to recover from the toxicity. If CrCl value is not recovered and continues to 
record <45 mL/min over 42 days, consider discontinuing treatment with pemetrexed and/or 
cisplatin.
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 intervention. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within normal range.
8.3.4.2
Pregnancy Test
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
at monthly intervals during intervention.
-
Pregnancy testing (urine or serum as required by local regulations) should be conducted 
for the time required to eliminate systemic exposure after the last dose of each study 
intervention(s) as noted in Section 5.1. The length of time required to continue pregnancy 
testing for each study intervention is as follows:
MK-3475: 120 days
Chemotherapy: 180 days
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-
Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study.
8.3.5
Performance Assessments
8.3.5.1
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc.) with grades 0 to 5. 
The investigator or qualified designee will assess ECOG status at Screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA (Section 1.3).
8.3.6
Peripheral Capillary Oxygen Saturation (SpO2)
SpO2 will be performed using local standard procedures once at Screening, prior to the study 
medication at each cycle, end of treatment and Safety follow-up.
8.3.7
Submission of images for Interstitial Lung Disease (ILD)
In the case that pneumonitis/ILD occurs regardless of causality with study medication, an 
independent ILD evaluation committee will conduct adjudication of cases of the 
pneumonitis/ILD. For this purpose, relevant data such as chest imaging (from the baseline to 
the recovery of pneumonitis/ILD) will be submitted to MSD K.K. However, after approval of 
Protocol amendment 02, any imaging acquired more than 90 days after the last dose of the 
last participant need not be submitted.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE 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.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before intervention allocation must be reported by the investigator if the participant is 
receiving placebo run-in or other run-in treatment, if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation through 30 days following cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation 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, through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Section 5.1 and 8.3.4.2, 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 related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and the investigator 
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 7.
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Table 7
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:
- participant has been 
exposed to any protocol-
specified intervention 
(eg, procedure, washout 
or run-in treatment 
including placebo run-
in)
Exception: A positive 
pregnancy test at the 
time of initial screening 
is not a reportable event.
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
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
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in allocated participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
a.
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
b. 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
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
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8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
Biomarkers are not evaluated in this study other than the optional PD-L1 analysis.
8.8.1
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.9
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 28 days prior to the allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5. Screening 
procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be provided 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 7 days prior to the first dose of study 
intervention. An exception is PT or INR and aPTT testing, which may be done up to 10
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.
•
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).
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•
Archival or newly obtained tumor sample is not required to be obtained within 28 days 
prior to the first dose of study intervention (optional). Submission of an archival tumor 
sample after Screening period is acceptable.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
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
Participants Discontinued From Study Intervention but 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
Posttreatment Visit
8.10.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anti-cancer 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).
8.10.4.2
Imaging Follow-up Visits
Participants who discontinue study intervention for reasons other than radiologically verified 
PD should continue with imaging assessments per the protocol-defined schedule until: (1) PD 
is radiologically verified by the investigator, (2) initiation of a new anti-cancer treatment, (3) 
death, (4) withdrawal of consent, (5) pregnancy, or (6) study conclusion or early termination, 
whichever occurs first.  The protocol-defined schedule is described in the SoA; up to the first 
24 weeks from the first dose, perform Q6W (42±7 days) (i.e., W6, W12, W18, and W24) and 
then every 9 weeks (Q9W) (63±7 days) from the first dose until the end of first year (i.e.,
W33, W42, W51, and W60); and then every 12 weeks (Q12W) (84±7 days) (i.e., W72, W84, 
etc.) thereafter. After approval of Protocol amendment 02, the study will end 90 days after 
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the last dose of the last participant. Participants in the Imaging Follow-up or Survival 
Follow-up phase will be discontinued from the study and no further visits will be required.
8.10.4.3
Survival Follow-up Visits
Participants who experience disease progression or start a new anti-cancer therapy will move 
into the Survival Follow-up Phase and should be contacted by telephone every 12 weeks (84 
±14 days) to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first. After approval of Protocol amendment 02, the study will end 
90 days after the last dose of the last participant. Participants in the Imaging Follow-up or 
Survival Follow-up phase will be discontinued from the study and no further visits will be 
required.
8.10.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, interim and/or final 
analysis. Upon Sponsor notification, all participants who do not/will not have a scheduled 
study visit or study contact during the Sponsor-defined time period will be contacted for their 
vital status.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes 
to analyses made after the protocol has been finalized, but prior to database lock, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
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Study Design Overview
A Phase Ib Clinical Study to Evaluate the Safety and Efficacy of 
Pembrolizumab (MK-3475) in Combination with Cisplatin and Pemetrexed 
in Treatment-naive Participants with Advanced Malignant Pleural 
Mesothelioma (KEYNOTE-A17).
Intervention Assignment
This is a single arm, non-randomized and open-label study.
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT)
Efficacy (Secondary and exploratory): All-Participants-as-Treated (APaT)
Primary Endpoints

Dose limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study treatment due to an AE
Secondary Endpoints
Objective response (confirmed CR or PR), disease control (SD, or 
confirmed CR or PR) and duration of response by modified Response 
Evaluation Criteria in Solid Tumors (modified RECIST) for Malignant 
Pleural Mesothelioma (MPM).
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
ORR and DCR will be estimated using an exact method based on the 
binomial distribution together with its 95% confidence interval (Clopper-
Pearson interval). For DOR, Kaplan-Meier (KM) curves and median 
estimates from the KM curves will be provided, as appropriate.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints as 
appropriate. The estimate of the DLT rate among participants treated with 
pembrolizumab in combination with cisplatin and pemetrexed, and the 
90% Bayesian credible intervals based on a prior distribution of Beta (1,1) 
for the estimate will be provided.
Interim Analyses
Data will be examined on a continuous basis to allow for dose 
confirmation decisions.
Multiplicity
No multiplicity adjustment is planned in this Phase Ib study.
Sample Size and Power
The sample size for this study is expected to be ~18.
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.
This study is being conducted as a non-randomized and open-label study, i.e., participants, 
investigators, and sponsor personnel will be aware of participant intervention assignment 
after each participant is enrolled and treatment is assigned.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
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9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Efficacy endpoints are secondary and exploratory endpoints in this study. 
Objective response in participants treated with pembrolizumab in combination with cisplatin 
and pemetrexed as assessed by investigator using modified RECIST criteria for Malignant 
Pleural Mesothelioma (MPM) is a secondary endpoint. Objective response is defined as a 
confirmed complete response (CR) or partial response (PR). ORR is the proportion of 
participants in the analysis population with objective response.
Disease control is defined as a response of confirmed CR or PR, or stable disease (SD). 
Disease control rate (DCR) is the proportion of participants in the analysis population with 
disease control.
Duration of response (DOR) is defined as the time from the first documented evidence of CR
or PR to the earliest date of Progressive Disease (PD) or death due to any cause, whichever 
comes first, for individuals with a confirmed CR or PR.
Progression-free survival (PFS) and Overall survival (OS) are the exploratory endpoints.
PFS is defined as the time from the first dose of study treatment to the first documented 
disease progression or death due to any cause, whichever occurs first.
OS is defined as the time from the first dose of study treatment to death due to any cause. 
Participants who do not die will be censored on the date of the last study assessment or 
contact.
A description of efficacy measures is provided in Section 4.2.1.1.
9.4.2
Safety Endpoints
The primary safety endpoints are DLTs, adverse events and discontinuing study treatment 
due to an AE. In addition, safety and tolerability will be assessed by clinical review of all 
relevant parameters including AEs, laboratory tests, ECGs, vital signs.
A description of safety measures is provided in Section 4.2.1.2.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all participants who received at least 1 dose of study intervention.
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The DLT evaluable population includes APaT participants that meet the criteria for DLT
evaluability (e.g., finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 5.5, 6.6.3 and 6.6.4 for details.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention 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
No pharmacokinetic analysis is planned in this study.
9.5.3
Efficacy Analysis Populations
The APaT population will be used for the analysis of efficacy data in this study. The APaT 
population consists of all participants who received at least 1 dose of study intervention.
In addition, Full Analysis Set (FAS) which consists of all participants who received at least 1 
dose of study intervention and who had post-baseline scan for response evaluation will be 
used for supportive purposes. A patient who was lost to follow-up and didn’t have any post 
baseline scan, resulting in a response of ‘No Assessment’ due to reasons other than patient 
disease status will be removed from the FAS population.
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
For ORR and DCR, the point estimate and 95% CI will be evaluated in participants treated 
with pembrolizumab in combination with cisplatin and pemetrexed, using an exact method 
based on the binomial distribution (Clopper-Pearson interval).
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will be 
provided, as appropriate. Participants who are alive, have not progressed, have not initiated 
new anti-cancer treatment, have not been determined to be lost to follow-up and have had a 
disease assessment within ~5 months of the data cutoff date are considered ongoing 
responders at the time of analysis. Censoring rules for DOR are summarized in Table 8.
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Table 8
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no 
new anti-cancer therapy initiated.
Last adequate disease assessment.
Censor
(non-
event)
No progression nor death, new 
anti-cancer therapy initiated.
Last adequate disease assessment before 
new anti-cancer therapy initiated.
Censor
(non-
event)
Death or progression after ≥2 
consecutive missed disease 
assessments or after new anti-
cancer therapy, if any.
Earlier date of last adequate disease 
assessment prior to ≥2 missed adequate 
disease assessments and new anti-cancer 
therapy, if any.
Censor
(non-
event)
Death or progression after ≤1 
missed adequate disease 
assessment and before new anti-
cancer therapy, if any.
PD or death.
End of 
response
(Event)
The key efficacy analyses are summarized in Table 9.
Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time 
Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Secondary Objectives
ORR based on 
modified RECIST 
Exact method based on 
binomial distribution
APaT
Participants with missing 
data are considered non-
responders
DCR based on 
modified RECIST
Exact method based on 
binomial distribution
APaT
Participants with missing 
data are considered non-
responders
DOR based on
modified RECIST 
Summary statistics 
using Kaplan-Meier 
method
All 
responders
Censoring rules follow 
Table 8.
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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. Laboratory tests, vital signs, 
and other safety endpoints will be summarized as appropriate.
Dose limiting toxicities will be listed and summarized. The estimate of the DLT rate among 
participants treated with pembrolizumab in combination with cisplatin and pemetrexed, and 
the 90% Bayesian credible interval based on a prior distribution of Beta (1,1) for the estimate 
will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
No pharmacokinetic analysis is planned in this study.
9.7
Interim Analyses
Data will be examined on a continuous basis to allow for dose confirmation decisions.
9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
The sample size for this study is expected to be ~18.
Precision of the DLT Rate
The estimated DLT rate, and its 90% Bayesian credible interval will be calculated from the 
posterior distribution of the DLT rate. If 18 participants are dosed, the estimated DLT rate 
and its 90% credible interval should be similar to one of the rows in Table 10.
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Table 10
Precision of the Estimated DLT Rates (N=18)
Number of participants with 
DLT
Estimated DLT rate (%)
90% credible interval (%)†
1
5.6
(1.9, 22.6)
2
11.1
(4.4, 29.6)
3
16.7
(7.5, 35.9)
4
22.2
(10.9, 41.9)
5
27.8
(14.7, 47.6)
6
33.3
(18.8, 53.0)
7
38.9
(23.0, 58.2)
8
44.4
(27.4, 63.2)
9
50.0
(32.0, 68.0)
†A prior distribution of Beta (1,1) is assumed.
Precision of the ORR/DCR
Table 11 shows the ORR/DCR estimate and the 95% CI (Clopper-Pearson interval) for 
N=18.
Table 11
Precision of the Estimated ORR/DCR (N=18)
Number of Responses
Observed ORR/DCR (%)
95%CI for ORR/DCR (%)
1
5.6
(0.1, 27.3)
2
11.1
(1.4, 34.7)
3
16.7
(3.6, 41.4)
4
22.2
(6.4, 47.6)
5
27.8
(9.7, 53.5)
6
33.3
(13.3, 59.0)
7
38.9
(17.3, 64.3)
8
44.4
(21.5, 69.2)
9
50.0
(26.0, 74.0)
9.10
Subgroup Analyses
Subgroup analyses of the efficacy endpoints of OR, PFS and OS may be conducted by 
baseline PD-L1 status as appropriate.
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9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. 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 (or individuals acting on behalf of MSD) 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 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, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues 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 the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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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.
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 
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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.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical 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 Council 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 Trials.
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.
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The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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 
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the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 12 will be performed by the local laboratory.
•
All on-treatment samples will be collected prior to administration of study intervention.
•
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.
•
Pregnancy testing:
Pregnancy testing requirements for study inclusion are described in Section 5.1.
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of treatment and 30 days follow-up after the last dose of study 
intervention.
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the subject's participation in the study.
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at monthly intervals during intervention, and for the time required to 
eliminate systemic exposure after the last dose of each study intervention(s) (Refer 
to Section 8.3.4.2 in details).
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Table 12
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
β-hCG Pregnancy test (serum or urine)
a
Hemoglobin
Alkaline phosphatase
Glucose
Prothrombin Time (PT) or 
International Normalized Ratio (INR) 
Platelet count
Alanine 
aminotransferase
Protein
Activated Partial Thromboplastin 
Time (aPTT) or Partial 
Thromboplastin Time (PTT) b
WBC (total and 
differential d)
Aspartate 
aminotransferase
Specific gravity 
Total triiodothyronine T3 (or Free T3 
[FT3]c) e
RBC count
Calcium
Microscopic exam (if 
blood or protein is 
abnormal)
Free thyroxine (FT4) e
Absolute 
lymphocyte count
Chloride
Thyroid-stimulating hormone (TSH) e
Absolute neutrophil 
count
Creatinine
Surfactant protein-D (SP-D) e
Glucose
Krebs von den Lungen-6 (KL-6) e
Lactate dehydrogenase
(LDH)
C-Reactive Protein (CRP)
Magnesium
Creatinine clearance
Phosphorus
Potassium
Sodium
Total bilirubin
Direct bilirubin (if 
total bilirubin is 
elevated above the 
upper limit of normal)
Total protein
Blood urea nitrogen
(BUN)
Amylase e
Lipase e
a  Perform on women of childbearing potential within 72 hours prior to Day 1 of Cycle 1.
b  If aPTT is not available, PTT may be tested.
c T3 is preferred; if not available, Free T3 (FT3) may be tested.
d Report % of Neutrophil, Lymphocyte, Monocyte, Eosinophil and Basophil.
e Participants may be dosed while any lab results are pending in after Cycle 1.
Investigators must document their review of each laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
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 a reportable event. Refer to Section 8.4.6 for additional details.
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 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:

Results in death

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.

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.

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.

Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.

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 (e.g., 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 CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
Grade 4: Life threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
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•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
Exposure: Is there evidence that the participant was actually exposed to the Sponsor’s 
product such as: reliable history, acceptable compliance assessment (pill count, diary, etc.), 
expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
the Sponsor’s product? Is the time of onset of the AE compatible with a drug-induced effect 
(applies to studies with investigational medicinal product)?
Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors.
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge.
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
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 their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
Yes, there is a reasonable possibility of Sponsor’s product relationship:
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent 
of the combination. In general, causality attribution should be assigned to the combination 
regimen (ie, to all agents in the regimen). However, causality attribution may be assigned to a 
single agent if in the investigator’s opinion, there is sufficient data to support full attribution 
of the AE to the single agent.
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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 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).
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.
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•
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
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required.
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
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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Women of Nonchildbearing Potential (WONCBP)
Women in the following categories are considered WONCBP:
•
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. 
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two 
FSH measurements in the postmenopausal range is required. 
Females on HRT and whose menopausal status is in doubt will be required to use one of the 
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.
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.
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○
The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and 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.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to
consistent and correct use of a highly effective method of contraception as described in
below during the protocol-defined time frame in Section 5.1.
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb
•
IUSc
•
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.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
Male condom with cap, diaphragm, or sponge with spermicide.
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
Study Intervention
Definition of 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.
SPONSOR does not deal with background treatment (s) as IMP in Japan in clinical trials in 
which the investigational drug and the background treatment (s) are used in combination.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
APaT
All-Participants-as-Treated
BCG
Bacillus Calmette–Guérin
β-hCG
β-human chorionic gonadotropin
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAEv5.0
Common Terminology Criteria for Adverse Events, Version 5.0
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DILI
drug-induced liver injury
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
EMA
European Medicines Agency
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-Stimulating Factor
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
INR
International Normalized Ratio
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Abbreviation
Expanded Term
IMP
Investigational Medicinal Product
IO
immuno-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
LAM
lactational amenorrhea method
mAb
monoclonal antibody
MRI
magnetic resonance imaging
mTPI
modified Toxicity Probability Interval
NIMP
Non-Investigational Medicinal Product
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PD
Progressive Disease
PD-1
programmed cell-death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression free survival
PK
Pharmacokinetic
PKCθ
protein kinase C-theta
PP
per-protocol
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TMDD
target-mediated drug disposition
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
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10.9
Appendix 9: Dose Limiting Toxicity evaluation
The total number of DLT observed participants during the DLT evaluation period (Cycle 1) 
will be used to determine the tolerability of pembrolizumab in combination with the standard 
chemotherapy regimen using a modified Toxicity Probability Interval (mTPI) design (target 
DLT rate: 30%) [Ji Y., et al 2007]. In this study, it will be considered the decision of “E 
(Escalation)” or “S (Stay)” based on the modified TPI design as “tolerated” for further 
investigation.
Table 13
Dose-finding Rules per modified Toxicity Probability Interval Design
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target DLT = 30%, N = 18, ε1 = ε2 = 0.03, prior distribution = Beta (1,1)
6
7
8
9
10 11 12 13 14 15 16 17 18
0
E
E
E
E
E
E
E
E
E
E
E
E
E
1
E
E
E
E
E
E
E
E
E
E
E
E
E
2
S
S
S
S
S
E
E
E
E
E
E
E
E
3
S
S
S
S
S
S
S
S
S
S
E
E
E
4
DU D
D
S
S
S
S
S
S
S
S
S
S
5
DU DU DU DU D
S
S
S
S
S
S
S
S
6
DU DU DU DU DU DU D
S
S
S
S
S
S
7
DU DU DU DU DU DU DU D
D
S
S
S
8
DU DU DU DU DU DU DU DU DU D
S
9
DU DU DU DU DU DU DU DU DU DU
10
DU DU DU DU DU DU DU DU DU
11
DU DU DU DU DU DU DU DU
12
DU DU DU DU DU DU DU
13
DU DU DU DU DU DU
14
DU DU DU DU DU
15
DU DU DU DU
16
DU DU DU
17
DU DU
18
DU
Number of toxicities
Number of patients treated at current dose
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11
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00VMQC
08BJ2F


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112
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