Clinical trial NCT03783078
Conditions: Merkel Cell Carcinoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Cell Death 1 Ligand 1 (PDL1, PD-L1) Programmed Cell Death 1 Ligand 2 (PDL2, PD-L2) Merkel cell carcinoma
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-02-25; Completion date: 2024-02-15
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, open-label, multicenter, efficacy, and safety study of pembrolizumab in adult and pediatric participants with previously untreated advanced Merkel Cell Carcinoma (MCC). The primary objective of the trial is to assess the objective response rate, as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, following administration of pembrolizumab.

Detailed description:

Arms: arm 1: Pembrolizumab (MK-3475) 200 mg (adult participants) or 2 mg/kg (up to 200 mg; pediatric participants) on Day 1 of each 3-week cycle (Q3W) intravenous (IV), for up to 35 administrations (approximately 2 years)
Interventions: intervention 1: Pembrolizumab (MK-3475)
Intervention descriptions: intervention 1: 200 mg (adult participants) or 2 mg/kg (up to 200 mg; pediatric participants) on Day 1 of each 3-week cycle (Q3W) IV up to 35 administrations (approximately 2 years).

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 3 Open-label, Single Arm Study to Evaluate the Safety and 
Efficacy of Pembrolizumab (MK-3475) as First-line Therapy in 
Participants With Advanced Merkel Cell Carcinoma (KEYNOTE-913)
01-JUL-2022
NCT03783078


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 3 Open-label, Single Arm Study to Evaluate the Safety and Efficacy 
of Pembrolizumab (MK-3475) as First-line Therapy in Participants With Advanced Merkel 
Cell Carcinoma (KEYNOTE-913)
Protocol Number: 913-03
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
127548
EudraCT
2018-002601-57
Approval Date: 01 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 3
01-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.
Amendment 2
08-JUN-2021
To harmonize the presentation of safety information across all FDA-approved PD-1/L1 
antibody prescribing information and to update imaging frequency.
Amendment 1
25-SEP-2020
Country-specific change, procedural updates, clarification of ORR, and removal of 
substudy references for Future Biomedical Research.
Original Protocol
25-SEP-2018
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
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.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities (SoA)................................................................................17
2
INTRODUCTION..........................................................................................................24
2.1
Study Rationale....................................................................................................24
2.2
Background ..........................................................................................................24
2.2.1
Pharmaceutical and Therapeutic Background .............................................24
2.2.1.1
Pembrolizumab ..................................................................................24
2.2.1.2
Merkel Cell Carcinoma: Epidemiology and Current Therapeutic 
Options...............................................................................................25
2.2.1.3
Ongoing Clinical Studies in the Merkel Cell Carcinoma 
Indication ...........................................................................................27
2.2.2
Preclinical and Clinical Studies ...................................................................28
2.3
Benefit/Risk Assessment......................................................................................28
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................29
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
4.2.1.1.1
RECIST 1.1..............................................................................32
4.2.1.1.2
RECIST 1.1 for Immune-based Therapeutics (iRECIST) .......32
4.2.1.2
Safety Endpoints................................................................................33
4.2.1.3
Pharmacokinetic Endpoints ...............................................................33
4.2.1.4
Pharmacodynamic Endpoints.............................................................33
4.2.1.5
Future Biomedical Research..............................................................33
4.2.2
Rationale for the Use of Comparator/Placebo .............................................33
4.3
Justification for Dose...........................................................................................34
4.3.1
Maximum Dose/Exposure for This Study ...................................................34
4.4
Beginning and End of Study Definition .............................................................34
4.4.1
Clinical Criteria for Early Study Termination .............................................35
5
STUDY POPULATION ................................................................................................35
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5.1
Inclusion Criteria.................................................................................................35
5.2
Exclusion Criteria................................................................................................38
5.3
Lifestyle Considerations......................................................................................40
5.3.1
Meals and Dietary Restrictions....................................................................40
5.3.2
Pregnancy.....................................................................................................40
5.4
Screen Failures.....................................................................................................40
5.5
Participant Replacement Strategy......................................................................41
6
STUDY INTERVENTION............................................................................................41
6.1
Study Intervention(s) Administered...................................................................42
6.1.1
Medical Devices...........................................................................................43
6.2
Preparation/Handling/Storage/Accountability .................................................43
6.2.1
Dose Preparation..........................................................................................43
6.2.2
Handling, Storage, and Accountability........................................................43
6.3
Measures to Minimize Bias: Randomization and Blinding..............................44
6.3.1
Intervention Assignment..............................................................................44
6.3.2
Stratification.................................................................................................44
6.3.3
Blinding........................................................................................................44
6.4
Study Intervention Compliance..........................................................................44
6.5
Concomitant Therapy..........................................................................................44
6.5.1
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
6.7
Intervention After the End of the Study............................................................51
6.8
Clinical Supplies Disclosure................................................................................51
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................52
7.1
Discontinuation of Study Intervention...............................................................52
7.2
Participant Withdrawal From the Study...........................................................53
7.3
Lost to Follow-up .................................................................................................53
8
STUDY ASSESSMENTS AND PROCEDURES........................................................54
8.1
Administrative and General Procedures ...........................................................54
8.1.1
Informed Consent/Assent.............................................................................54
8.1.1.1
General Informed Consent/Assent.....................................................55
8.1.1.2
Consent/Assent and Collection of Specimens for Future 
Biomedical Research .........................................................................55
8.1.2
Inclusion/Exclusion Criteria ........................................................................55
8.1.3
Participant Identification Card.....................................................................55
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8.1.4
Medical History ...........................................................................................56
8.1.5
Prior and Concomitant Medications Review...............................................56
8.1.5.1
Prior Medications...............................................................................56
8.1.5.2
Concomitant Medications..................................................................56
8.1.6
Assignment of Screening Number...............................................................56
8.1.7
Assignment of Treatment/Randomization Number.....................................56
8.1.8
Study Intervention Administration ..............................................................57
8.1.8.1
Timing of Dose Administration.........................................................57
8.1.9
Discontinuation and Withdrawal .................................................................57
8.1.9.1
Withdrawal From Future Biomedical Research ................................57
8.1.10
Participant Blinding/Unblinding..................................................................58
8.1.11
Calibration of Equipment.............................................................................58
8.2
Efficacy Assessments ...........................................................................................58
8.2.1
Tumor Imaging and Assessment of Disease................................................58
8.2.1.1
Initial Tumor Imaging........................................................................59
8.2.1.2
Tumor Imaging During the Study......................................................59
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................59
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................60
8.2.1.5
iRECIST Assessment of Disease.......................................................60
8.2.2
Patient-reported Outcomes...........................................................................63
8.3
Safety Assessments...............................................................................................63
8.3.1
Physical Examinations.................................................................................63
8.3.1.1
Full Physical Examination.................................................................63
8.3.1.2
Directed Physical Examination..........................................................63
8.3.2
Vital Signs....................................................................................................63
8.3.3
Electrocardiograms (ECG)...........................................................................64
8.3.4
Clinical Safety Laboratory Assessments .....................................................64
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................65
8.3.4.2
Pregnancy Test...................................................................................65
8.3.5
Performance Assessments............................................................................65
8.3.5.1
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale...................................................................................................65
8.3.5.2
Lansky Play-Performance Scale (LPS)..............................................65
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................65
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................66
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......67
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...68
8.4.4
Regulatory Reporting Requirements for SAE .............................................68
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................68
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................69
8.4.7
Events of Clinical Interest (ECIs)................................................................69
8.5
Treatment of Overdose........................................................................................69
8.6
Pharmacokinetics.................................................................................................70
8.7
Pharmacodynamics..............................................................................................70
8.8
Future Biomedical Research Sample Collection...............................................70
8.9
Planned Genetic Analysis Sample Collection....................................................70
8.10
Biomarkers ...........................................................................................................70
8.11
Health Economics Medical Resource Utilization and Health Economics.......70
8.12
Visit Requirements...............................................................................................70
8.12.1
Screening......................................................................................................70
8.12.2
Treatment Period..........................................................................................71
8.12.3
Discontinued Participants Continuing to be Monitored in the Study ..........71
8.12.3.1
Safety Follow-up Visit.......................................................................71
8.12.3.2
Follow-up Visits.................................................................................71
8.12.3.3
Survival Follow-up ............................................................................72
8.12.4
Survival Status .............................................................................................72
9
STATISTICAL ANALYSIS PLAN .............................................................................72
9.1
Statistical Analysis Plan Summary.....................................................................72
9.2
Responsibility for Analyses/In-house Blinding .................................................73
9.3
Hypotheses/Estimation ........................................................................................73
9.4
Analysis Endpoints...............................................................................................73
9.4.1
Efficacy Endpoints.......................................................................................73
9.4.1.1
Primary...............................................................................................73
9.4.1.2
Secondary...........................................................................................74
9.4.2
Safety Endpoints..........................................................................................74
9.5
Analysis Populations............................................................................................74
9.5.1
Efficacy Analysis Population.......................................................................74
9.5.2
Safety Analysis Population..........................................................................74
9.6
Statistical Methods...............................................................................................74
9.6.1
Statistical Methods for Efficacy Analyses...................................................75
9.6.1.1
Objective Response Rate (ORR) .......................................................75
9.6.1.2
Duration of Response (DOR).............................................................75
9.6.1.3
Progression-free Survival...................................................................75
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9.6.1.4
Overall Survival.................................................................................76
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints..................................76
9.6.2
Statistical Methods for Safety Analyses ......................................................77
9.6.3
Demographics and Baseline Characteristics................................................77
9.7
Interim Analyses ..................................................................................................77
9.8
Multiplicity ...........................................................................................................77
9.9
Sample Size and Power Calculations .................................................................77
9.10
Subgroup Analyses...............................................................................................78
9.11
Compliance (Medication Adherence).................................................................78
9.12
Extent of Exposure...............................................................................................78
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................79
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........79
10.1.1
Code of Conduct for Clinical Trials.............................................................79
10.1.2
Financial Disclosure.....................................................................................81
10.1.3
Data Protection.............................................................................................81
10.1.3.1
Confidentiality of Data ......................................................................82
10.1.3.2
Confidentiality of Participant Records...............................................82
10.1.3.3
Confidentiality of IRB/IEC Information............................................82
10.1.4
Committees Structure...................................................................................82
10.1.5
Publication Policy........................................................................................82
10.1.6
Compliance with Study Registration and Results Posting Requirements ...83
10.1.7
Compliance with Law, Audit, and Debarment ............................................83
10.1.8
Data Quality Assurance ...............................................................................84
10.1.9
Source Documents .......................................................................................85
10.1.10
Study and Site Closure.................................................................................85
10.2
Appendix 2: Clinical Laboratory Tests..............................................................86
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................88
10.3.1
Definition of AE ..........................................................................................88
10.3.2
Definition of SAE ........................................................................................89
10.3.3
Additional Events Reported in the Same Manner as SAE...........................90
10.3.4
Recording AE and SAE ...............................................................................90
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................94
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation....................................96
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing........................97
10.5.1
Definitions....................................................................................................97
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10.5.2
Contraception Requirements........................................................................98
10.5.3
Pregnancy Testing........................................................................................98
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................99
10.7
Appendix 7: Country-specific Requirements..................................................104
10.7.1
Germany.....................................................................................................104
10.7.2
United Kingdom.........................................................................................104
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................105
10.9
Appendix 9: Performance Scales......................................................................109
10.10 Appendix 10: Abbreviations .............................................................................111
11
REFERENCES.............................................................................................................113
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LIST OF TABLES
Table 1
Study Schedule of Activities............................................................................17
Table 2
Adequate Organ Function Laboratory Values .................................................37
Table 3
Study Interventions..........................................................................................42
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................47
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ........................................................................................................50
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.............................................................................................................61
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................67
Table 8
Censoring Rules for Analysis of DOR.............................................................75
Table 9
Censoring Rules for Analysis of PFS ..............................................................76
Table 10
Analysis Strategy for Key Efficacy Endpoints................................................76
Table 11
Two-sided 95% Confidence Interval of ORR With 50 Participants................78
Table 12
Protocol-required Safety Laboratory Assessments..........................................86
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LIST OF FIGURES
Figure 1
KEYNOTE-913 Study Design.........................................................................16
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator ......................................................................................................62
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3 Open-label, Single Arm Study to Evaluate the Safety and Efficacy 
of Pembrolizumab (MK-3475) as First-line Therapy in Participants With Advanced Merkel 
Cell Carcinoma (KEYNOTE-913)
Short Title: Pembrolizumab (MK-3475) as First-line Therapy for Advanced Merkel Cell 
Carcinoma
Acronym: KEYNOTE-913
Hypotheses, Objectives, and Endpoints:
There are no hypotheses for this study.
In participants at least 12 years of age with advanced Merkel cell carcinoma (MCC):
Primary Objectives
Primary Endpoints
- Objective: To assess the objective response 
rate (ORR), as assessed by blinded 
independent central review (BICR) per 
Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST 1.1) modified 
to follow a maximum of 10 target lesions and 
a maximum of 5 target lesions per organ, 
following administration of pembrolizumab
- Objective response (OR): Complete 
response (CR) or partial response (PR)
Secondary Objectives
Secondary Endpoints
- Objective: To assess duration of response 
(DOR), as assessed by BICR per 
RECIST 1.1 modified to follow a maximum 
of 10 target lesions and a maximum of 
5 target lesions per organ, following 
administration of pembrolizumab
- DOR: For participants who demonstrate 
confirmed CR or PR, the time from first 
documented evidence of CR or PR until 
disease progression or death from any 
cause, whichever occurs first
- Objective: To assess the progression-free 
survival (PFS), as assessed by BICR per 
RECIST 1.1 modified to follow a maximum 
of 10 target lesions and a maximum of 
5 target lesions per organ, following 
administration of pembrolizumab
- PFS: The time from the first day of study 
treatment to the first documented disease 
progression per RECIST 1.1 by BICR or 
death due to any cause, whichever occurs 
first
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- Objective: To assess overall survival (OS) 
following administration of pembrolizumab
- OS: The time from the first day of study 
treatment to death due to any cause
- Objective: To assess safety and tolerability 
of treatment with pembrolizumab
- Adverse events (AEs)
Overall Design:
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Treatment of unresectable Stage III and Stage IV MCC
Population
Participants with no prior systemic therapy for advanced 
MCC (prior adjuvant therapy is permitted)
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study
Type of Control
No Treatment Control
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 13 years from the time the first participant 
signs the informed consent/assent until the last 
participant’s last study-related telephone call or visit.
Number of Participants:
Approximately 50 participants will be allocated to study intervention.
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group Name
Drug
Dose 
Strength
Dose 
Fre-
quency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
Pembrolizumab Pembrolizumab 
(MK-3475)
200 mg
(adult 
participants) 
or 2 mg/kg 
(up to 
200 mg;
pediatric 
participants) 
on Day 1 of 
each cycle
Q3W
IV
Up to 35 
administrations 
(approximately
2 years)
Experi-
mental
IV=intravenous; Q3W=every 3 weeks
Total 
Number
1 intervention group
Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-specified 
contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until disease progression is radiographically 
documented, confirmed by the site per modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics (iRECIST) 
when clinically appropriate, unacceptable adverse event(s) (AEs), 
pregnancy, intercurrent illness that prevents further administration of 
treatment, investigator’s decision to discontinue the participant, 
administrative reasons requiring cessation of treatment, or until the 
participant has received 35 administrations of pembrolizumab 
(approximately 2 years).
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1, 
and when clinically appropriate, confirmed by the site per iRECIST, the 
start of a new anticancer treatment, withdrawal of consent, pregnancy, 
death, or loss to follow-up. All participants will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the 
study.
Once the participant has achieved the study objective or the study has 
ended, the participant is discontinued from this study and will be enrolled in 
an extension study to continue protocol-defined assessments and treatment.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
KEYNOTE-913 Study Design
BICR=blinded independent central review; C1D1=Cycle 1 Day 1; DOR=duration of response; ORR=objective 
response rate; OS=overall survival; PFS=progression-free survival; Q3W=every 3 weeks; Q12W=every 12 weeks; 
Q24W=every 24 weeks; RECIST=Response Evaluation Criteria In Solid Tumors
a Prior adjuvant therapy may be allowed as detailed in Section 5.1, inclusion criterion #2.
b Imaging to be performed Q12W or sooner if clinically indicated after C1D1 (±7 days) until Week 54 of study
intervention, Q24W thereafter or sooner if clinically indicated, or more frequently if required by local standard of care,
until disease progression per RECIST 1.1. 
c If End of Treatment visit occurs >30 days after last dose of study intervention, a Safety Follow-up Visit is not required.
d For participants discontinuing for reasons other than disease progression, tumor imaging should continue to be performed 
as if on study intervention (ie, Q12W until Week 54 after C1D1 (±7 days), Q24W thereafter or sooner if clinically 
indicated, or more frequently if required by local standard of care, until disease progression per RECIST 1.1). 
e Participants in Survival Follow-up will be contacted approximately Q12W or sooner to assess for survival status or death, 
withdrawal of consent, or the end of study, whichever occurs first.
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1.3
Schedule of Activities (SoA)
Procedures and activities are outlined in Table 1.
Table 1
Study Schedule of Activities
Study Period
Screening
Phase
Intervention Phase 
(Q3W)
End of 
Treatment
Post-treatment Follow-up
Notes
Treatment Cycle
1
2
3 and 
onwards
Discontinu-
ation
Safety 
Follow-
upa
Follow-
upb
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each cycle 
unless otherwise noted.
Post-treatment Period: Refer to 
Section 8.12.3.
Scheduled Timing
-28 to -1
At time of 
d/c
30 days 
post last 
dose
~Q12W 
(telephone)
Window (days):
+ 3
± 3
± 3
+ 7
± 7
± 7
Administrative Procedures
Informed Consent/Assent
X
Consent/assent form can be 
signed at any time prior to any 
protocol-specific screening 
procedures being performed.
Additional consent/assent is 
required at disease progression.
Informed Consent/Assent for 
Future Biomedical Research
X
Participation in future 
biomedical research is not 
mandatory for participation in 
this study.
Inclusion/Exclusion Criteria
X
Participant Identification 
Card
X
Medical/Surgical History and 
Demographics
X
Significant medical/surgical 
history will be captured for last 
10 years.
Staging
X
At initial diagnosis and at study 
entry.
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Study Period
Screening
Phase
Intervention Phase 
(Q3W)
End of 
Treatment
Post-treatment Follow-up
Notes
Treatment Cycle
1
2
3 and 
onwards
Discontinu-
ation
Safety 
Follow-
upa
Follow-
upb
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each cycle 
unless otherwise noted.
Post-treatment Period: Refer to 
Section 8.12.3.
Scheduled Timing
-28 to -1
At time of 
d/c
30 days 
post last 
dose
~Q12W 
(telephone)
Window (days):
+ 3
± 3
± 3
+ 7
± 7
± 7
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
Record all prior medications 
taken within 28 days before 
C1D1. Enter new medications 
started during the study through 
the post-treatment Safety 
Follow-up. Record concomitant 
medications beyond 30 days 
after treatment discontinuation 
if related to SAE or ECI.
Study Intervention
Intervention Allocation 
X
Participants will be allocated 
on C1D1 (-3 days) after 
confirmation of eligibility.
Pembrolizumab (MK-3475) 
Administration
X
X
X
Pembrolizumab 200 mg Q3W 
for adult participants or
2 mg/kg (up to 200 mg) Q3W 
for pediatric participants.
Poststudy Anticancer 
Therapy
X
X
X
All anticancer therapy will be 
recorded until time of death or 
termination of Survival Follow-
up. If a clinic visit is not 
feasible, follow-up information 
may be obtained via telephone 
or e-mail.
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Study Period
Screening
Phase
Intervention Phase 
(Q3W)
End of 
Treatment
Post-treatment Follow-up
Notes
Treatment Cycle
1
2
3 and 
onwards
Discontinu-
ation
Safety 
Follow-
upa
Follow-
upb
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each cycle 
unless otherwise noted.
Post-treatment Period: Refer to 
Section 8.12.3.
Scheduled Timing
-28 to -1
At time of 
d/c
30 days 
post last 
dose
~Q12W 
(telephone)
Window (days):
+ 3
± 3
± 3
+ 7
± 7
± 7
Survival Status
<------------------------------------------------------------------->
X
After investigator-determined 
PD or start of new anticancer 
treatment. In addition, upon 
Sponsor request, participants 
may be contacted for survival 
status at any time during the 
course of the study (unless this 
information is not allowed to 
be provided due to 
confidentiality).
Efficacy Procedures
Tumor Imaging (CT/MRI; 
Chest, Abdomen, and Pelvis)
X
<---------------------->
c
Xd
X
Prior scans performed within 
the screening period but before 
signing informed consent may 
be used if consistent with 
protocol requirements per SIM. 
All imaging visits have a 
scheduling window of ±7 days. 
Imaging to be performed 
Q12W or sooner if clinically 
indicated from the date of 
C1D1 until Week 54 of study
treatment, Q24W or sooner if 
clinically indicated thereafter,
or more frequently if required 
by local standard of care until 
disease progression per 
RECIST 1.1.
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Study Period
Screening
Phase
Intervention Phase 
(Q3W)
End of 
Treatment
Post-treatment Follow-up
Notes
Treatment Cycle
1
2
3 and 
onwards
Discontinu-
ation
Safety 
Follow-
upa
Follow-
upb
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each cycle 
unless otherwise noted.
Post-treatment Period: Refer to 
Section 8.12.3.
Scheduled Timing
-28 to -1
At time of 
d/c
30 days 
post last 
dose
~Q12W 
(telephone)
Window (days):
+ 3
± 3
± 3
+ 7
± 7
± 7
Safety Procedures
Height
X
X
X
X
X
Pediatric height to be measured 
at every visit. Adult height 
measured at Screening only.
Weight
X
X
X
X
X
To be measured at every visit.
Full Physical Examination
X
Within 7 days prior to C1D1.
Directed Physical 
Examination
X
X
X
X
A symptom-directed physical 
examination may be performed 
at any time during the study, as 
clinically indicated.
Vital Signs (resting BP, pulse 
rate, respiratory rate, 
temperature)
X
X
X
X
X
X
BP and pulse rate will be 
measured after the participant
has been resting for 5 minutes.
12-lead ECG
X
Single 12-lead ECG. After the 
participants has been 
recumbent for 5 minutes.
ECOG Performance Status 
(or Lansky scale)
X
X
X
X
X
Within 3 days prior to C1D1. 
Thereafter, prior to dosing at 
treatment visits. Lansky scale 
to be used instead of ECOG in 
pediatric participants ≤16 years 
old.
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Study Period
Screening
Phase
Intervention Phase 
(Q3W)
End of 
Treatment
Post-treatment Follow-up
Notes
Treatment Cycle
1
2
3 and 
onwards
Discontinu-
ation
Safety 
Follow-
upa
Follow-
upb
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each cycle 
unless otherwise noted.
Post-treatment Period: Refer to 
Section 8.12.3.
Scheduled Timing
-28 to -1
At time of 
d/c
30 days 
post last 
dose
~Q12W 
(telephone)
Window (days):
+ 3
± 3
± 3
+ 7
± 7
± 7
AE/SAE Review
X
X
<------------------------------------------------------------>
AEs: monitored up to 30 days 
after last dose.
SAEs and pregnancy: 
monitored up to 90 and 
120 days after last dose, 
respectively, or 30 days after 
last dose if participant starts a 
new anticancer therapy, 
whichever is sooner.
Laboratory Procedures
(LOCAL laboratory)
Pregnancy Test – Serum or 
Urine (WOCBP only)
X
X
X
X
X
X
Refer to Appendix 5.
Within 72 hours prior to C1D1, 
then repeat prior to each cycle 
of treatment and as required by 
local guidelines up to 120 days 
after last dose of study 
intervention or the start of a 
new anticancer therapy, 
whichever comes first.
HIV, hepatitis B and C 
screen (per local regulations)
X
Not required unless mandated 
by local health authority.
PT/INR and aPTT
X
Within 3 days prior to C1D1.
Repeat as needed for 
participants on warfarin-based 
anticoagulation therapy.
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Study Period
Screening
Phase
Intervention Phase 
(Q3W)
End of 
Treatment
Post-treatment Follow-up
Notes
Treatment Cycle
1
2
3 and 
onwards
Discontinu-
ation
Safety 
Follow-
upa
Follow-
upb
Survival 
Follow-up
Procedures should occur 
predose on Day 1 of each cycle 
unless otherwise noted.
Post-treatment Period: Refer to 
Section 8.12.3.
Scheduled Timing
-28 to -1
At time of 
d/c
30 days 
post last 
dose
~Q12W 
(telephone)
Window (days):
+ 3
± 3
± 3
+ 7
± 7
± 7
T3 (or Free T3), Free T4, and 
TSH
X
X
X
X
Within 10 days prior to C1D1.
Then within 1 day prior to Day 
1 of every other cycle starting 
from Cycle 2 (eg, Cycle 2, 4, 6, 
8, etc.) and at EOT. Free T3 is 
acceptable where T3 cannot be 
determined.
Hematology
X
X
X
X
X
Blood for hematology and 
chemistry panel should be 
collected within 3 days prior to
C1D1 and then within 1 day 
prior to Day 1 of every cycle. 
Urine for urinalysis should be 
collected within 3 days prior to 
C1D1 and then within 1 day 
prior to Day 1 of every 4 cycles 
starting from Cycle 4 (eg, 
Cycle 4, 8, 12, 16, etc.). Every 
effort should be made to collect 
samples at the same time of 
day.
Chemistry Panel
X
X
X
X
X
Urinalysis
X
X
X
X
Laboratory Procedures
(CENTRAL laboratory)
Blood for Future Biomedical 
Research
X
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AE=adverse event; aPTT=activated partial thromboplastin time; BP=blood pressure; C=Cycle; C1D1=Cycle 1 Day 1; CR=complete response; CT=computed 
tomography; D=Day; ECG=electrocardiogram; ECI=Event of Clinical Interest; ECOG=Eastern Cooperative Oncology Group; EOT=End of Treatment; 
HIV=human immunodeficiency virus; INR=international normalized ratio; MRI=magnetic resonance imaging; PD=progressive disease; PT=prothrombin time; 
Q3W=every 3 weeks; Q12W=every 12 weeks; Q24W=every 24 weeks; RECIST=Response Evaluation Criteria In Solid Tumors; SAE=serious adverse event; 
SIM=Site Imaging Manual; T3=triiodothyronine; T4=thyroxine; TSH=thyroid stimulating hormone; WOCBP=women of childbearing potential.
a
If the EOT visit occurs ≥30 days after the last dose of study intervention, a Safety Follow-up Visit is not required. In this situation, all procedures required at 
the 30-day Safety Visit and EOT are performed once and entered into the EOT visit only. 
b
In the Follow-up Phase, participants should be assessed Q12W until Week 54 after C1D1 (±7 days); Q24W thereafter or sooner if clinically indicated, or 
more frequently if required by local standard of care, until disease progression per RECIST 1.1, to monitor disease status.
c
The same imaging technique regarding modality and the use of contrast should be used in a participant throughout the study to optimize the visualization of 
existing and new tumor burden. Imaging of any anatomy that shows disease either at Screening or in subsequent evaluations will be required and should be 
submitted to the imaging contract research organization (iCRO). 
d
Participants who attain an investigator-determined CR and stop study intervention with pembrolizumab will have a Safety Follow-up Visit and move to the 
Follow-up Visits per SoA. Imaging at EOT is not required if the previous tumor imaging assessment was within 4 weeks prior to EOT visit. On-study brain 
or bone scans should be performed if clinically indicated or to confirm CR (if other lesions indicate CR and brain or bone lesions existed at baseline).
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2
INTRODUCTION
2.1
Study Rationale
The current study is a postmarketing requirement designed to continue to evaluate the safety 
and efficacy of pembrolizumab in adult and pediatric participants with previously untreated 
advanced Merkel cell carcinoma (MCC).
2.2
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (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 intravenous (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 Investigator’s Brochure (IB).
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
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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 CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in MCC.
2.2.1.2
Merkel Cell Carcinoma: Epidemiology and Current Therapeutic Options
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer causally associated with 
exposure to ultraviolet light and/or Merkel cell polyoma virus (MCPyV) [Nghiem, P., et al
2017] [Iyer, J. G., et al 2014] [Hodgson, N. C. 2005]. Incidence rates of MCC have risen 
worldwide, including Australia, China, France, Germany, Sweden, and the United States
(US). During 2000-2013, the number of MCC reported cases in the US increased 95%. In 
2013, the US incidence rate was 0.5 to 0.7 cases/100,000 person-years, corresponding to 
2488 diagnoses per year. This number is expected to increase to >3000 diagnoses per year by 
2025 [Paulson, K. G., et al 2018]. This increasing incidence is partly due to improved 
detection methods [Moll, I. 1992] but may also be due to the higher prevalence of known risk 
factors for MCC, including chronic T-cell immune suppression [Penn, I.First, M. R. 1999] 
[Engels, E. A., et al 2002] and extensive exposure to ultraviolet light [Heath, M., et al 2008]. 
Merkel cell carcinoma is most frequently diagnosed in people older than 50 years of age 
(median age from 54 to 78.5 years across publications) and is extremely rare in the pediatric 
population. It occurs 8 times more commonly in whites than blacks and is more frequent in 
men than in women [Nghiem, P., et al 2017] [Iyer, J. G., et al 2014] [Hodgson, N. C. 2005] 
[Paulson, K. G., et al 2018]. Head and neck, limbs and extremities are common primary 
tumor sites, and liver, skin, lymph nodes and lung are common sites of metastases [Nghiem, 
P., et al 2017]. Merkel cell carcinoma has a propensity for locoregional recurrence and early 
microscopic spread to nodes and distant sites, making it challenging to control with local 
therapy alone [National Comprehensive Cancer Network 2018]. Approximately 19% to 24% 
of patients present with regional nodal metastasis (Stage III disease) and 5% of patients with 
distant metastasis (Stage IV disease) at diagnosis [Ramahi, E., et al 2013] [Becker, J. C. 
2010]. 
Approximately 48% of the patients with local or regional disease ultimately develop 
recurrent disease. Studies have shown that among patients who experienced recurrence, the 
median time between diagnosis of the primary tumor and recurrence is 9 months [Allen, P. J., 
et al 2005] [Santamaria-Barria, J. A. 2013]. When MCC becomes metastatic or develops an 
unresectable recurrence, the prognosis is poor and the intention of systemic therapy is 
palliative. 
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Recommended treatment options for advanced MCC are based on treatments for small cell 
lung carcinoma due to the similar neuroendocrine properties [National Comprehensive 
Cancer Network 2018] [Lebbe, C., et al 2015]. In patients with advanced unresectable or 
metastatic MCC, systemic cytotoxic chemotherapy has been the mainstay of therapy before 
the development of anti-PD-1 (or anti-PD-L1) agents and remains the benchmark against 
which new therapies such as pembrolizumab are to be considered. Frequently used regimens 
include a platinum agent ± etoposide phosphate, cyclophosphamide, doxorubicin (or 
epirubicin), and vincristine (CAV), and topotecan [National Comprehensive Cancer Network 
2018] [Lebbe, C., et al 2015]. However, there are no randomized controlled studies that have 
evaluated the efficacy of one regimen over another [National Comprehensive Cancer 
Network 2018] [Tai, P. T., et al 2000]. Retrospective studies assessing patients with distant 
metastases have shown objective responses in approximately 52% to 61% of the patients in 
the first-line and in 23% of the patients in the second-line setting [Iyer, J. G., et al 2014] [Tai, 
P. T., et al 2000] [Satpute, S. R. 2014] [Voog, E., et al 1999] [Sharma, D., et al 1991]. 
Irrespective of the line of therapy, responses to chemotherapy are not durable and only last 
up to a median of 6 months [Iyer, J. G., et al 2014] [Tai, P. T., et al 2000] [Satpute, S. R. 
2014]. Median progression-free survival (PFS) with chemotherapy has been reported to be 
short regardless of the line of therapy; 3.1 months in the first-line setting and 2 months in the 
second-line setting, and median overall survival (OS) ranged from 9 to 9.5 months [Iyer, J. 
G., et al 2014] [Satpute, S. R. 2014]. There are no specific recommendations for the 
management of pediatric MCC patients [National Comprehensive Cancer Network 2018].
Based on these data, for adult and pediatric patients with advanced unresectable or metastatic 
MCC, standard of care chemotherapy agents has limited clinical benefit and there is a 
considerable need for effective therapies in this disease with a poor prognosis. 
Agents targeting the PD-1 pathway, including pembrolizumab, avelumab (BavencioTM), and 
nivolumab (OpdivoTM), may address this unmet need. The National Comprehensive Cancer 
Network (NCCN) guidelines previously recommended only chemotherapeutic treatments 
such as cisplatin/carboplatin with or without etoposide; topotecan or CAV [National 
Comprehensive Cancer Network 2016] or participation in clinical studies for patients with 
metastatic MCC. Use of immunotherapy such as pembrolizumab was added for the first time
to the NCCN Version 1.2017 dated 03-OCT-2016 [National Comprehensive Cancer Network 
(NCCN) 2017], based on published data from Study P017/CITN-09/KEYNOTE-017
[Nghiem, P. T., et al 2016] demonstrating both a high response rate and durability of 
responses with pembrolizumab, as described in Section 2.2.1.3. On 23-MAR-2017, the Food 
and Drug Administration (FDA) granted accelerated approval to avelumab for the treatment 
of adult and pediatric patients 12 years and older with metastatic MCC, including those who 
have not received prior chemotherapy. The approval of avelumab was based on a single-arm 
study and a total of 88 patients with previously treated MCC. The objective response rate 
(ORR) was 33% by central review [Center for Drug Evaluation and Research 2016]. With a 
median follow-up of 16.4 months, median time to response was 6.1 weeks and median 
duration of response (DOR) was not reached [Kaufman, H. L., et al 2017]. First-line data 
with avelumab has recently shown a confirmed objective response rate of 62.1% (95% CI:
42, 79) in 29 patients with advanced MCC who have at least 3 months of follow-up 
[D'Angelo, S. P., et al 2018]. Data presented with nivolumab, with a primary endpoint of 
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ORR, confirms the observations that anti-PD-1/L1 agents produce a high rate of response in 
patients with MCC [Topalian, S. L., et al 2017].
2.2.1.3
Ongoing Clinical Studies in the Merkel Cell Carcinoma Indication
Study P017/CITN-09/KEYNOTE-017 is an ongoing multicenter, single-arm study of 
pembrolizumab in patients with advanced unresectable or metastatic MCC who have not 
been previously treated with systemic cytotoxic therapy for their advanced disease. 
Participants are administered a dose of pembrolizumab at 2 mg/kg Q3W. Participants
continue to receive up to 2 years of study intervention unless they experience disease 
progression, unacceptable adverse events (AEs), intercurrent illness that prevents further 
administration of study intervention, investigator’s decision to withdraw the participant, 
participant withdrawal of consent, or administrative reasons requiring cessation of study 
intervention. Participants who achieve a complete response (CR) are allowed to discontinue 
treatment after 6 months of therapy provided the patient has received at least 2 cycles of 
pembrolizumab past the confirmation of CR. 
The primary endpoint of ORR in Study P017/CITN-09/KEYNOTE-017 is measured 
according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by 
investigator assessment. The secondary endpoints are PFS, DOR, and OS. The protocol was 
initially designed to enroll approximately 26 participants. The protocol was subsequently 
amended in January 2016 to enroll an additional 24 participants for a total of 50 participants. 
Preliminary results based on investigator assessment have been described in a publication 
[Nghiem, P. T., et al 2016] and were the basis for the 2017 NCCN guidelines incorporating 
the use of pembrolizumab in patients with advanced MCC [National Comprehensive Cancer 
Network (NCCN) 2017].
Results of Study P017/CITN-09/KEYNOTE-017 based on a data cutoff of 06-FEB-2018 are 
summarized below. Among all 50 participants, the majority of participants were ≥65 years, 
and 34 participants (68%) were male. The majority of participants (86%) had Stage IV MCC 
at study entry. A total of 84% (42 of 50) and 70% of participants (35 of 50) had received 
previous surgery or radiation therapy as local or locoregional treatment for their disease stage 
at presentation, respectively. Fourteen percent of participants (7 of 50) received prior drug 
therapy for their local or locoregional disease. According to blinded independent central 
review (BICR), 28 participants had a confirmed response (CR = 12, partial response 
[PR] = 16), representing an ORR by BICR of 56% (95% CI: 41, 70). Five participants (10%) 
had a best overall response (BOR) of stable disease (SD) and 16 participants (32%) had 
progressive disease (PD). The median time to response was 2.8 months and median DOR had 
not been reached at the time of data cutoff. Among patients with a confirmed response by 
BICR (n=28), the minimum duration of follow-up from first treatment to death or data cutoff 
is approximately 8.6 months, and the median duration of follow-up is 24.2 months. Of 
28 responses, 26 occurred by approximately 3 months on treatment (first on-study scan), and 
20 responses remain ongoing at the time of the data cutoff. Progression-free survival was 
defined as the time from first treatment to the first documented evidence of PD per 
RECIST 1.1 or death due to any cause, whichever occurred first. Median PFS for all 
participants was 16.8 months at the time of the analysis, and Kaplan-Meier estimates of PFS 
rates at 12, 16, 18, and 24 months were 52%, 52%, 48%, and 48%, respectively. Overall 
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survival was defined as the time from first treatment to death due to any cause. Median OS 
was not reached at the time of the data cutoff. Kaplan-Meier estimates of OS rates at 12, 18, 
and 24 months were 72%, 69%, and 69%, respectively. The safety of pembrolizumab in 
patients with MCC is generally consistent with the established safety profile of 
pembrolizumab. 
The current protocol is intended as a confirmatory study for P017/CITN-09/KEYNOTE-017.
2.2.2
Preclinical and Clinical Studies
Refer to the IB for preclinical and clinical study data for pembrolizumab.
2.3
Benefit/Risk Assessment
As discussed in Section 2.2.1.2, there is an unmet need for effective treatments for advanced
unresectable or metastatic MCC, which currently has a poor prognosis. Beneficial effects of 
several agents targeting the PD-1 pathway have been observed in patients with metastatic 
MCC, and use of immunotherapy for advanced MCC was recently added to the NCCN 
guidelines [National Comprehensive Cancer Network (NCCN) 2017] [National 
Comprehensive Cancer Network 2018]. A significantly positive benefit/risk ratio was
reported for pembrolizumab in P017/CITN-09/KEYNOTE-017, a single-arm monotherapy
study in participants with advanced unresectable or metastatic MCC who have not been 
previously treated with systemic cytotoxic therapy for their advanced disease [Nghiem, P. T., 
et al 2016]. The existing data suggest that PD-1 blockade is an effective therapeutic strategy 
and the current protocol is intended as a confirmatory study for P017/CITN-09/KEYNOTE-
017. 
Based on pembrolizumab data from other indications and from data in MCC patients treated 
with pembrolizumab as well as with other agents in the class, a favorable benefit/risk profile 
is anticipated. No unexpected risks have been reported in MCC with other immune 
checkpoint inhibitors.
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 in this clinical study 
may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There are no hypotheses for this study.
In participants at least 12 years of age with advanced Merkel cell carcinoma (MCC):
Objectives
Endpoints
Primary
•
Objective: To assess the objective 
response rate (ORR), as assessed by 
blinded independent central review 
(BICR) per Response Evaluation Criteria 
in Solid Tumors version 1.1 
(RECIST 1.1) modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ, 
following administration of 
pembrolizumab
•
Objective response (OR): Complete 
response (CR) or partial response (PR)
Secondary
•
Objective: To assess duration of response 
(DOR), as assessed by BICR per 
RECIST 1.1 modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ, 
following administration of 
pembrolizumab
•
DOR: For participants who 
demonstrate confirmed CR or PR, the 
time from first documented evidence 
of CR or PR until disease progression 
or death from any cause, whichever 
occurs first
•
Objective: To assess the progression-free 
survival (PFS), as assessed by BICR per 
RECIST 1.1 modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ, 
following administration of 
pembrolizumab
•
PFS: The time from the first day of 
study treatment to the first documented
disease progression per RECIST 1.1 by 
BICR or death due to any cause, 
whichever occurs first
•
Objective: To assess overall survival 
(OS) following administration of 
pembrolizumab
•
OS: The time from the first day of
study treatment to death due to any 
cause
•
Objective: To assess safety and 
tolerability of treatment with 
pembrolizumab
•
Adverse events (AEs)
•
Study intervention discontinuation due 
to AEs
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Objectives
Endpoints
Tertiary/Exploratory
•
To assess ORR, DOR, and PFS, as 
assessed by the investigator using 
modified RECIST 1.1 for immune-based 
therapeutics (iRECIST), following
administration of pembrolizumab 
•
PFS using iRECIST
•
DOR using iRECIST
•
OR using iRECIST
4
STUDY DESIGN
4.1
Overall Design
This is a single-arm, open-label, multicenter, efficacy and safety study of pembrolizumab in 
adult and pediatric patients with previously untreated advanced MCC.
Approximately 50 participants will be enrolled into the study. 
Study intervention administration will begin on Day 1 of each 3-week dosing cycle. Study 
intervention should begin on the day of allocation or as close as possible to the date on which 
the participant is allocated/assigned.
Participants will have baseline imaging performed at Screening and the first on-study 
imaging will be done at Week 12 (± 7 days) after C1D1. Subsequently, imaging will be 
performed Q12W (± 7 days) or sooner if clinically indicated until Week 54 (±7 days) of 
study intervention, independent of any treatment delays, Q24W thereafter or sooner if 
clinically indicated or more frequently if required by local standard of care. Pembrolizumab
administration will continue until confirmed PD, unacceptable AE(s), pregnancy, intercurrent 
illness that prevents further administration of treatment, investigator’s decision to discontinue 
the participant, administrative reasons requiring cessation of treatment, or until the 
participant has received 35 administrations of pembrolizumab (approximately 2 years).
Participants who attain an investigator-determined confirmed CR may consider stopping 
study intervention after receiving at least 8 study intervention administrations in total and at 
least 2 additional administrations of study intervention beyond the date when the initial CR 
was declared. 
Participants will be permitted to continue study intervention beyond RECIST 1.1-defined PD 
as long as the treating investigator considers that the participant may experience clinical 
benefit with continued treatment, and the participant is tolerating study intervention as per 
iRECIST. Treatment beyond disease progression per iRECIST may be permitted upon 
Sponsor consultation and approval.
The primary endpoint of ORR (the proportion of participants with OR) will be assessed by 
BICR per RECIST 1.1 criteria. Safety and tolerability will be assessed by clinical review of 
all relevant parameters including AEs, laboratory tests, vital signs, and electrocardiogram 
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(ECG) measurements, as appropriate. Adverse events will be monitored throughout the study 
and graded in severity according to the guidelines outlined in the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.0.
After the end of treatment, each participant will have a 30-day follow-up safety assessment 
for AE monitoring (refer to Section 8.4.1 for time periods for reporting of serious adverse 
events [SAEs] and pregnancy). Participants who discontinue treatment for reasons other than 
PD will have post-treatment follow-up imaging for disease status until PD, the start of a new
anticancer treatment, withdrawal of consent/assent, pregnancy, death, or loss to follow-up. 
All participants will be contacted approximately every 12 weeks, or more often as needed, 
for OS until death, withdrawal of consent/assent, or the end of the study, whichever comes 
first.
No interim analyses will be performed in this study. Further details on the Statistical 
Analysis Plan are provided in Section 9.
NOTE: Country-specific protocol operational items are described in Appendix 7.
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
If the safety profile is acceptable and pembrolizumab shows robust ORR and durable 
responses per RECIST 1.1 by BICR, this study will support the postmarketing requirement 
for the accelerated approval of pembrolizumab in patients with advanced MCC.
This Phase 3 study is designed to evaluate the efficacy and safety of pembrolizumab in 
participants with advanced MCC. Treatment will be open-label.
There are no randomized controlled studies in MCC that have evaluated the efficacy of 1
chemotherapeutic regimen over another [National Comprehensive Cancer Network 2018] 
[Tai, P. T., et al 2000] or of chemotherapy over immunotherapy [D'Angelo, S. P., et al 2018] 
[Nghiem, P. T., et al 2016]. The NCCN panel recognized MCC as a rare disease that 
precludes robust randomized studies. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
This study will use ORR, defined as the proportion of participants who have best response as 
CR or PR. Responses are based on RECIST 1.1 criteria as assessed by blinded independent 
central review (BICR) as the primary endpoint. Objective response rate (ORR) is an 
acceptable measure of clinical benefit for a late stage 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. The use of BICR and RECIST 1.1 to assess ORR is 
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typically considered acceptable by regulatory authorities. Images will be submitted to an 
imaging CRO (iCRO) and read by independent central review blinded to treatment 
assignment to minimize bias in the response assessments.
Secondary efficacy endpoints include DOR, PFS, and OS.
Duration of response (DOR) as assessed by BICR per RECIST 1.1 criteria is a commonly 
accepted endpoint by both regulatory authorities and the oncology community to assess 
durability of responses to oncology treatments.
In this study, PFS is to be assessed by BICR per RECIST 1.1 criteria. The use of BICR and 
RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities. 
Images will be submitted to an iCRO and read by independent central review blinded to 
treatment assignment to minimize bias in the response assessments. In addition, the final 
determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment. 
Overall survival (OS) is the gold standard for a “hard endpoint” in clinical studies in the area 
of oncology.
4.2.1.1.1
RECIST 1.1 
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility Section 8.2.1.4. Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
4.2.1.1.2
RECIST 1.1 for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab Section 8.2.1.5. Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and patients treated with 
pembrolizumab may manifest a clinical response after an initial increase in tumor burden or 
even the appearance of new lesions. Thus, standard RECIST 1.1 may not provide an accurate 
response assessment of immunotherapeutic agents such as pembrolizumab. Based on an 
analysis of participants with melanoma enrolled in KEYNOTE-001 (KN001), 7% of 
evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had progressive disease (PD) by RECIST 1.1 but not by the immune-related 
response criteria [Wolchok, J. D., et al 2009] had longer overall survival than participants 
with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest that RECIST 
1.1 may underestimate the benefit of pembrolizumab in approximately 15% of participants. 
These findings support the need to apply a modification to RECIST 1.1 that takes into 
account the unique patterns of atypical responses in immunotherapy and enables treatment 
beyond initial radiographic progression, if the participant is clinically stable.
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Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions when applicable: as well as for 
exploratory efficacy analyses when specified.
4.2.1.2
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/ SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by CTCAE, Version 4.0.
4.2.1.3
Pharmacokinetic Endpoints
No pharmacokinetic endpoints are planned for this study.
4.2.1.4
Pharmacodynamic Endpoints
No pharmacodynamic endpoints are planned for this study.
4.2.1.5
Future Biomedical Research
The Sponsor will conduct FBR on DNA specimens for which consent was provided during 
this clinical study.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure participants receive the correct dose of the 
correct drug/vaccine at the correct time. The details of FBR are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable.
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4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is an appropriate dose of 
pembrolizumab for adults across all indications. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
To date, pembrolizumab (2 mg/kg Q3W) has been evaluated in 85 pediatric participants 
(aged 1 to 18 years) with advanced melanoma, PD-L1 positive advanced, relapsed, or 
refractory solid tumors, or lymphoma. The exposures in pediatric participants following the 
2 mg/kg Q3W regimen were found to be similar to that observed in adult participants. 
Pediatric data has also been incorporated in an integrated population PK analysis, which 
confirmed that a pembrolizumab dose of 2 mg/kg Q3W (up to a maximum of 200 mg Q3W) 
in pediatric participants renders exposures similar to adults. Based on these results, the 
pediatric dose for evaluation in this study is 2 mg/kg Q3W (up to a maximum of 200 mg 
Q3W).
4.3.1
Maximum Dose/Exposure for This Study
The maximum dose/exposure of pembrolizumab allowed in this study is 200 mg Q3W in 
adult participants (or 2 mg/kg [up to 200 mg] Q3W in pediatric participants) for
35 administrations (approximately 2 years).
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent/assent. The overall study ends when the last 
participant completes the last study-related contact, withdraws consent/assent, or is lost to 
follow-up (ie, the participant is unable to be contacted by the investigator).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
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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, Good Clinical 
Practice (GCP), and/or other applicable regulatory requirements, procedure-related problems 
or an unacceptably high number of discontinuations or withdrawals due to administrative 
reasons.
5
STUDY POPULATION
Participants with advanced MCC who are at least 12 years old will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
1. Have histologically confirmed diagnosis of locoregional MCC that has recurred 
following standard locoregional therapy with surgery and/or radiation therapy and is not 
amenable to local therapy or metastatic MCC (Stage IV) as per American Joint 
Committee on Cancer (AJCC) 8th edition guidelines.
2. Have been untreated for advanced or metastatic disease except as follows:
a.
Prior intratumoral therapy will be permitted.
b. Prior adjuvant or neoadjuvant therapy containing systemic chemotherapy will be 
permitted if treatment concluded at least 3 months prior to C1D1.
c.
Prior adjuvant or neoadjuvant therapy containing anti-PD-1/L1 or anti-CTLA-4 
therapy will not be permitted.
3. Have at least 1 measurable lesion by computed tomography (CT) or magnetic resonance 
imaging (MRI) per RECIST 1.1 criteria as determined by the local site 
investigator/radiology assessment. Measurable disease will be verified by BICR prior to 
treatment allocation. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions. 
Note: Cutaneous lesions and other superficial lesions are not considered measurable 
lesions for the purposes of this protocol but may be considered as non-target lesions. 
4. Toxic effect(s) of the most recent prior therapy have resolved to Grade 1 or less (except 
alopecia). If participant received major surgery or radiation therapy of >30 Gy, they must 
have recovered from the toxicity and/or complications from the intervention.
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Demographics
5. Be male or female and at least 12 years of age, at the time of signing the informed 
consent/assent.
Male Participants
6.
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
7.
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
•
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 woman of childbearing potential (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 120 days (corresponding to the time needed to eliminate any study intervention) 
after the last dose of study intervention. The investigator should evaluate the potential 
for contraceptive method failure (ie, noncompliance, recently initiated) in relationship 
to the first dose of study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 72 hours before the first dose of study 
intervention.
-
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
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.
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Informed Consent
8.
Participant (or legally acceptable representative if applicable) has provided documented 
informed consent/assent for the study and agrees to OS data collection until the study 
endpoints are reached. The participant may also provide consent/assent for future 
biomedical research; however, the participant may participate in the main study without 
participating in future biomedical research. 
Additional Categories
9.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 
or Lansky Play-Performance Scale (LPS) ≥50 for pediatric participants up to and 
including 16 years of age (Appendix 9).
10. Have adequate organ function as defined in the following table (Table 2). Specimens 
must be collected within 3 days prior to C1D1.
Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT), ALT (SGPT), and alkaline 
phosphatase (ALP)c
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
b Creatinine clearance (CrCl) should be calculated per institutional standard.
c Participants with ALP values >3 times the ULN and known to have bone metastases can be included.
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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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, non-ulcerated primary melanoma <1 mm in depth with no nodal involvement, or 
carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone 
potentially curative therapy are not excluded.
2. 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 stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention.
3. 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 to C1D1.
4. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
5. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease-modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
6. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
7. Has an active infection requiring systemic therapy.
8. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing 
is required unless mandated by local health authority.
9. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [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.
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10. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
11. Has clinically significant cardiac disease within 6 months of C1D1, including New York 
Heart Association Class III or IV congestive heart failure, unstable angina, myocardial 
infarction, cerebral vascular accident, or cardiac arrhythmia associated with 
hemodynamic instability.
Note: Medically controlled arrhythmia is permitted.
12. 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.
13. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Prior/Concomitant Therapy
14. Has not received standard locoregional therapy with surgery and/or radiation therapy for 
the treatment of local or locoregional disease. Note: This exclusion criterion does not 
apply to participants who are diagnosed with unresectable or metastatic MCC.
15. 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 (eg, CTLA-4, 
OX-40, CD137).
16. Has received prior systemic anticancer therapy including investigational agents within 
12 weeks prior to C1D1.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to C1D1.
17. Has received radiotherapy within 2 weeks prior to start of study intervention. Participants 
must have recovered from all radiation-related toxicities and not require corticosteroids.
18. Has received a live vaccine within 30 days prior to C1D1. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster 
(chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.
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Prior/Concurrent Clinical Study Experience
19. 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 C1D1.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Other Exclusions
20. Removed
21. Has had an allogenic tissue/solid organ transplant.
Refer to Appendix 7 for country-specific requirements.
5.3
Lifestyle Considerations
No restrictions are required.
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention. The site will contact 
the participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the
mother or newborn). The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 8.4.5.
5.4
Screen Failures
Screen failures are defined as participants who consent/assent to participate in the clinical 
study, but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
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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
A participant who discontinues from study intervention or withdraws consent/assent will not 
be replaced.
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 (pembrolizumab) will be packaged to support enrollment. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.
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6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 3.
Table 3
Study Interventions
Arm 
Name
Arm 
Type
Interventi
on Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen
Use
IMP/
NIMP
Sourcing
Pembro-
lizumab
Experi
mental
Pembrol-
izumab 
(MK-3475)
Biological/
Vaccine
Solution 
for 
Infusion
25 mg/mL 
vial
200 mg (adult 
participants) or 
2 mg/kg (up to 
200 mg -
pediatric 
participants) on 
Day 1 of each 
cycle
IV 
Infusion
Q3W for up to 
35 
administrations 
(approximately 
2 years)
Experi
mental
IMP
Provided 
centrally 
by the 
Sponsor
IMP=investigational medicinal product; IV=intravenous; NIMP=noninvestigational medicinal product; Q3W=every 3 weeks
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 3 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements .
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an interactive response technology (IRT) 
system. There is one study intervention arm. All participants will be assigned to 
pembrolizumab.
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
Study intervention(s) will be administered by the investigator and/or study staff. The total 
volume of study medication infused will be compared with the total volume prepared to 
determine compliance with each dose administered.
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 interruption of pembrolizumab.
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 or vaccination 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.
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Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:
•
Antineoplastic systemic chemotherapy or biological therapy
Note: Topical anticancer agents to treat skin lesions (eg, in situ melanoma, basal cell 
carcinoma or squamous cell carcinoma) are allowed.
•
Immunotherapy 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.
•
Palliative surgery of a target lesion.
Note: Palliative surgery to treat a non-target symptomatic solitary lesion or to the brain is 
allowed at the investigator’s discretion
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention must be discontinued.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days 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 ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.7.
All anticancer therapy will be recorded until time of death or termination of Survival 
Follow-up. If a clinic visit is not feasible, follow-up information may be obtained via 
telephone or e-mail.
Refer to Appendix 7 for country-specific requirements.
6.5.1
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 
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Section 6.6, Table 4. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer Table 4 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.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 after 
corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms of 
pneumonitis
•
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
•
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 
2 or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
•
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
•
Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold
•
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
•
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withhold a
•
Initiate insulin replacement 
therapy for participants 
with T1DM
•
Administer anti-
hyperglycemic in 
participants with 
hyperglycemia
•
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
•
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
•
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism 
Grade 2
Continue
•
Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
•
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
•
Initiate thyroid replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per standard 
of care
•
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
•
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
•
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue b
Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically important irAEs 
(eg, vasculitis and sclerosing cholangitis).
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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 5.
Table 5
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 v4.0 
(CTCAE) at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
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.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 (Schedule of 
Activities [SoA]) and Section 8.12.3.
Participants may discontinue study intervention at any time for any reason or be dropped 
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.
•
Unacceptable adverse events as described in Appendix 3.
•
After prolonged study intervention interruption that prohibits restarting study intervention 
if agreed upon with the Sponsor.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Prohibited concomitant medication requiring withdrawal (refer to Section 6.5). 
•
Recurrent Grade 3 colitis.
•
Radiographic disease progression outlined in Section 8.2.1.5 (after obtaining informed 
consent addendum and Sponsor communication, the investigator may elect to continue 
treatment beyond disease progression).
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
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•
Recurrent Grade 2 pneumonitis.
•
Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving at least 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 but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical 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, and assent if applicable, be obtained from 
the participant. In these cases, such evaluations/testing will be performed in accordance 
with those regulations.
The maximum amount of blood collected from each participant in any one visit will not 
exceed 18.5 mL (refer to the Procedures Manual).
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent, and assent if applicable, from each potential 
participant or their legally acceptable representative prior to participating in this clinical 
study or future biomedical research. If there are changes to the participant’s status during the 
study (eg, health or age of majority requirements), the investigator or medically qualified 
designee must ensure the appropriate documented informed consent/assent is in place.
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8.1.1.1
General Informed Consent/Assent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent form. The form must include the study protocol 
number, study protocol title, dated signature, and agreement of the participant (or his/her 
legally acceptable representative) and of the person conducting the consent/assent discussion.
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial informed consent/assent form, any subsequent revised informed consent/assent 
forms, 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/assent form or addendum to the original consent/assent form that captures the 
participant’s or the participant’s legally acceptable representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent/assent.
Specifics about the study and the study population are to be included in the study informed 
consent/assent form.
Informed consent/assent will adhere to IRB/IEC requirements, applicable laws and 
regulations, and Sponsor requirements.
8.1.1.2
Consent/Assent and Collection of Specimens for Future Biomedical 
Research
The investigator or medically qualified designee will explain the FBR consent/assent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent/assent before performing any procedure 
related to FBR. A copy of the informed consent/assent will be given to the participant before 
performing any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
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designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent/assent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The 
medical/surgical history will collect all active conditions and any condition diagnosed within 
the prior 10 years that the investigator considers to be clinically important. Details regarding 
the disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. 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 through the Safety Follow-up Visit. Concomitant medications will be 
recorded for 30 days after the last dose (or longer if related to an SAE or ECI). Refer to 
Section 6.5.
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.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will receive a treatment/randomization number. The 
treatment/randomization number identifies the participant for all procedures occurring after 
treatment allocation/randomization. Once a 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.
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8.1.8
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
Study intervention should begin within 3 days of treatment/randomization number 
assignment.
8.1.8.1
Timing of Dose Administration
Pembrolizumab will be administered as a 30-minute IV infusion on Day 1 of each 21-day 
cycle. Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. However, given the variability of infusion pumps from site to site, a window 
of -5 minutes and +10 minutes is permitted (ie, infusion time is 30 minutes: -5 min/+10 min).
The first dose of study intervention may be administered up to 3 days after the scheduled 
Day 1. After C1D1, pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each subsequent cycle due to administrative reasons.
Refer to Section 6.1 for details on study intervention administration.
Refer to Section 6.6 for information on allowed dosing interruptions.
Refer to Section 7 for criteria for discontinuation of study intervention.
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.12.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
If discontinuation occurs ≥30 days after the last dose of study intervention, a Safety 
Follow-up Visit (Section 8.12.3.1) is not required. In this situation, all procedures required at 
the 30-day Safety Visit and End of Treatment (EOT) are performed once and entered into the 
EOT visit only.
8.1.9.1
Withdrawal From Future Biomedical Research
A participant’s consent for Future Biomedical Research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate). A participant’s consent 
may be withdrawn at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
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letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term 'scan' refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
Survival Follow-up. The process for scan collection and transmission to the iCRO can be 
found in the Site Imaging Manual (SIM). Tumor scans by CT are strongly preferred. For the 
abdomen and pelvis, contrast-enhanced MRI may be used when CT with iodinated contrast is 
contraindicated, or when mandated by local practice. The same scan technique should be 
used in a participant throughout the study to optimize the reproducibility of the assessment of 
existing and new tumor burden and improve the accuracy of the response assessment based 
on scans. 
Note: for the purposes of assessing tumor scans, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
In general, scans should include the chest, abdomen, and pelvis.
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Expedited confirmation of measurable disease based on RECIST 1.1 by BICR at Screening 
will be used to determine participant eligibility. Confirmation by the BICR that the 
participant’s imaging shows at least 1 lesion that is appropriate for selection as a target lesion 
per RECIST 1.1 is required prior to participant allocation.
All scheduled imaging for all study participants will be submitted to the iCRO. In addition, 
imaging that is obtained at an unscheduled time point for any reason (including suspicion of
progression or other clinical reason) should also be submitted to the iCRO if it shows 
progression, or if it is used to support a response assessment. All imaging acquired within the 
protocol-specified window of time around a scheduled imaging visit can be classified as 
pertaining to that visit. Photographs of cutaneous lesions do not need to be submitted to the 
iCRO.
8.2.1.1
Initial Tumor Imaging
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
allocation. Any scans obtained after Cycle 1 Day 1 cannot be included in the screening 
assessment. The site must review screening scans to confirm the participant has measurable 
disease per RECIST 1.1. The site study team must submit screening scans to the iCRO to 
confirm the participant has measurable disease per RECIST 1.1 prior to allocation. Tumor 
scans at Screening includes CT (preferred) or MRI of the abdomen and pelvis and CT of the 
chest. See the SIM for additional details.
8.2.1.2
Tumor Imaging During the Study
The first on-study scan should be performed at 12 weeks (84 days 7 days) from the date of 
allocation. Subsequent tumor scans should be performed every 12 weeks (84 days 7 days) 
or more frequently if clinically indicated. After 54 weeks (378 days 7 days), participants 
who remain on treatment will have scans performed every 24 weeks (168 days 7 days). 
Scan timing should follow calendar days and should not be adjusted for delays in cycle starts. 
Scans are to be performed until disease progression is identified by the investigator or 
notification by the Sponsor, or until the start of new anticancer treatment, withdrawal of 
consent, or death, whichever occurs first.
Objective response should be confirmed by a repeat scan performed at least 4 weeks after the 
first indication of a response is observed. Participants will then return to the regular scan 
schedule, starting with the next scheduled time point. Participants who receive additional 
scans for confirmation do not need to undergo the next scheduled scan if it is fewer than 4 
weeks later; scans may resume at the subsequent scheduled time point.
On-study brain or bone scans should be performed if clinically indicated or to confirm CR (if 
other lesions indicate CR and brain or bone lesions existed at baseline).
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
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within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to confirmed
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without confirmed disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment (Q12W until Week 54 after C1D1 [±7 
days], Q24W thereafter or sooner or more frequently if required by local standard of care, 
until disease progression per RECIST 1.1) until the start of a new anticancer treatment, 
disease progression, pregnancy, death, withdrawal of consent, or the end of the study, 
whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
Figure 2 illustrates the imaging flow involving verification of PD for clinically stable 
participants.
8.2.1.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status (or Lansky scale, if appropriate)
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
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Any participant deemed clinically unstable should be discontinued from study intervention at
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in  Appendix 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in 
Section 8 and submitted to the iCRO.
A description of the adaptations and iRECIST process is provided in  Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 6 and illustrated as a flowchart in Figure 2.
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment.
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD.
May continue study 
intervention at the 
assessment of the 
investigator and after 
the participant’s 
consent.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator 
assessment.
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD.
May continue study 
intervention at the 
investigator’s 
discretion while 
awaiting confirmatory 
tumor imaging by site 
by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
Repeat tumor 
imaging confirms PD 
(iCPD) by iRECIST 
per investigator 
assessment.
No additional 
imaging 
required.
Discontinue treatment 
(exception is possible 
upon consultation 
with Sponsor).
No additional 
imaging required.
Not applicable.
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
Repeat tumor 
imaging shows iUPD 
by iRECIST per 
investigator 
assessment.
Repeat 
imaging at 4 to 
8 weeks to 
confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment.
Repeat tumor 
imaging shows iSD, 
iPR, or iCR by 
iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue 
regularly 
scheduled 
imaging 
assessments.
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iPR=iRECIST partial 
response; iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed progressive disease; 
PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
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iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid 
Tumors 1.1
8.2.2
Patient-reported Outcomes
Not applicable.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn over the course of the study (from prestudy 
to poststudy visits), including approximate blood volumes drawn by visit and by sample type 
per participant, can be found in the Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or medically qualified designee (consistent with local requirements) will 
perform a complete physical examination per institutional standards during the Screening 
period. Height and weight will also be measured and recorded. Clinically significant 
abnormal findings should be recorded as medical history. The time points for full physical 
examinations are described in Section 1.3 (SoA). After the first dose of study intervention, 
new clinically significant abnormal findings should be recorded as AEs.
In pediatric participants, height and weight will be measured at every visit. In adult
participants, height will be measured at Screening only and weight will be measured at every 
visit.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical examination, as defined in Section 1.3 (SoA), 
the investigator or medically qualified designee (consistent with local requirements) will 
perform a directed physical examination per institutional standard prior to the administration 
of the study intervention, as clinically indicated. New clinically significant abnormal findings 
should be recorded as AEs.
8.3.2
Vital Signs
Vital signs (body temperature [in centigrade], pulse rate [beats per minute], respiratory rate
[per minute], and systolic and diastolic blood pressure [mmHg]) will be assessed by the 
investigator or medically qualified designee (consistent with local requirements) as specified 
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in Section 1.3 (SoA). Blood pressure and pulse rate will be measured after the participant has 
been resting for 5 minutes. All blood pressure measurements should be performed on the 
same arm, preferably by the same person. After the first dose of study intervention, new 
clinically significant abnormal findings should be recorded as AEs.
8.3.3
Electrocardiograms (ECG)
A standard 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) at Screening. Participants must be in 
the recumbent position for a period of 5 minutes prior to the ECG. Clinically significant 
abnormal findings should be recorded as medical history. Assessments may be repeated 
during the study, as clinically indicated.
Note: A 6-lead ECG is allowed per institutional standard.
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 case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the Procedures Manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. 
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Refer to Section 1.3 (SoA) for the timing of laboratory assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.4.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to
C1D1. If a urine test is positive or not evaluable, a serum test will be required. Participants 
must be excluded/discontinued from the study in the event of a positive test result. Repeated 
pregnancy test should be conducted according to Section 1.3 (SoA) and as required by local 
guidelines. Refer to Appendix 5.
8.3.5
Performance Assessments
The performance scale to be used is dependent upon age: Lansky Play-Performance Scale 
(LPS) for participants up to and including 16 years of age; ECOG for participants >16 years 
of age. The performance scale used for a given participant at baseline will be the 
performance scale used throughout the study.
8.3.5.1
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or medically qualified designee (consistent with local requirements) will 
assess ECOG status (refer to Appendix 9) at the time points specified in Section 1.3 (SoA).
The ECOG status must be assessed within 3 days prior to C1D1.
8.3.5.2
Lansky Play-Performance Scale (LPS)
The LPS score is a standard way of measuring the functionality of pediatric participants up to 
and including the age of 16 years. The LPS is rated by parents based on their child’s activity 
over the past week. Parents fill out the assessment based on the directions on the form, and 
the form is re-administered over time to assess for changes in performance status. A higher 
score means the child is functioning better. See Appendix 9 for a description of the full scale. 
The LPS will be assessed as specified in Section 1.3 (SoA).
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
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Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent 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 after cessation of study 
intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 
90 days after cessation of study intervention or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must 
be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1, or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy must be reported by the 
investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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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.
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:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (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 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply wth country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
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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 monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study. 
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The 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
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
DNA for future research
8.9
Planned Genetic Analysis Sample Collection
Not applicable.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.11
Health Economics Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the electronic case 
report form (eCRF), from the time of treatment 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.
8.12
Visit Requirements
Visit requirements are outlined in Section 1.3 (SoA). Specific procedure-related details are 
provided in Section 8.
8.12.1
Screening
Documented consent/assent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent/assent as part 
of routine clinical management are acceptable in lieu of a screening test if performed within 
the specified time frame. Screening procedures are to be completed within 28 days prior to 
C1D1 except for the following:
•
Laboratory tests are to be performed within 3 days prior to C1D1. Except:
-
Hepatitis and HIV testing (if mandated by the local health authority) may be done up 
to 28 days prior to C1D1.
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-
Thyroid function tests may be done up to 10 days prior to C1D1. 
Repeated laboratory evaluation to establish eligibility is not allowed unless discussed 
and agreed upon with the Sponsor.
•
Full physical examination is to be performed within 7 days prior to C1D1.
•
Evaluation of ECOG (or LPS, as appropriate) is to be performed within 3 days prior to 
C1D1.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to C1D1. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required (performed by the local study site 
laboratory).
Rescreening
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.
8.12.2
Treatment Period
Visit requirements are outlined in Section 1.3 (SoA). Specific procedure-related details are 
provided in Section 8.1 through Section 8.11. Unless otherwise specified, the window for 
each visit is ± 3 days. Unless otherwise specified, assessments/procedures are to be 
performed prior to administration of study intervention.
8.12.3
Discontinued Participants Continuing to be Monitored in the Study
8.12.3.1
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 anticancer treatment, 
whichever comes first. If the EOT visit occurs ≥30 days after the last dose of study 
intervention, a Safety Follow-up Visit is not required. In this situation, all procedures 
required at the 30-day Safety Visit and EOT are performed once and entered into the EOT 
visit only.
8.12.3.2
Follow-up Visits
Participants who discontinue study intervention for a reason other than disease progression 
will move into the Follow-up Phase and should be assessed Q12W until Week 54 after C1D1 
(±7 days), Q24W thereafter or sooner if clinically indicated or more frequently if required by 
local standard of care, until disease progression per RECIST 1.1, to monitor disease status. 
Every effort should be made to collect information regarding disease status until the start of 
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new anticancer therapy, disease progression, death, end of study. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated. Participants 
who attain an investigator-determined CR and stop study intervention with pembrolizumab 
will have a Safety Follow-up Visit and move to follow-up visits per Section 1.3 (SoA).
8.12.3.3
Survival Follow-up
Participants who experience confirmed disease progression and are not treated beyond 
confirmed disease progression or start a new anticancer therapy, will move into the Survival 
Follow-up Phase and should be contacted by telephone approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
8.12.4
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, 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 survival status (excluding 
participants that have a previously recorded death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized but prior to the conduct of any analysis, will be 
documented in a supplemental Statistical Analysis Plan (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 through 9.12.
Study Design Overview
A Phase 3 Open-label, Single Arm Study to Evaluate the Safety and 
Efficacy of Pembrolizumab (MK-3475) as First-line Therapy in 
Participants With Advanced Merkel Cell Carcinoma (KEYNOTE-913)
Treatment Assignment
Approximately 50 participants will be enrolled to treatment with
pembrolizumab. This is a single-arm open-label study
Analysis Populations
Efficacy and Safety: All Participants as Treated (APaT)
Primary Endpoint
Objective Response (OR) per RECIST 1.1 by BICR
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Secondary Endpoints
3. Duration of Response (DOR) per RECIST 1.1 assessed by BICR
4. Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
5. Overall Survival (OS)
Statistical Methods for
Key Efficacy Analyses
Estimation of Objective Response Rate (ORR) and 95% exact binomial 
confidence interval (CI) for the true ORR;
Estimation of PFS, OS, and DOR using the Kaplan-Meier method
Statistical Methods for 
Key Safety Analyses
Counts and percentages of participants with AEs
Interim Analyses
There are no planned interim analyses for this study
Multiplicity
No multiplicity adjustment is planned
Sample Size and Power 
The planned sample size is approximately 50 participants. If the ORR is
56%, this sample size will produce a 95% CI for the true ORR of 
approximately ±15%
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis 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 
nonrandomized, open-label study, ie, participants, investigators, and Sponsor personnel will 
be aware of participant treatment assignments after each participant is enrolled and treatment 
is assigned.
9.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3. There are no hypotheses in this study.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
9.4.1.1
Primary
Objective Response Rate (ORR) per RECIST 1.1 assessed by BICR
The ORR is defined as the percentage of participants who achieve a confirmed complete 
response (CR) or partial response (PR) per RECIST 1.1 as assessed by BICR. Details of the 
ORR analysis can be found in Section 9.6.1.1.
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9.4.1.2
Secondary
Duration of Response (DOR) per RECIST 1.1 assessed by BICR
For participants who demonstrate confirmed CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. Response duration will be calculated for RECIST 1.1 based on BICR 
by the imaging vendor. See Section 9.6.1.2 for the definition of censoring rules for DOR.
Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
PFS is defined as the time from the first day of study treatment to the first documented 
disease progression per RECIST 1.1 by BICR or death due to any cause, whichever occurs 
first. See Section 9.6.1.3 for the definition of censoring rules for PFS.
Overall Survival (OS)
OS is defined as the time from first day of study treatment to death due to any cause.
Participants without documented death at the time of the final analysis will be censored at the 
last known alive date. To characterize the effects on survival, the final analysis of OS will be 
conducted approximately 13 years after the first participant signs informed consent/assent, 
when it is estimated that ~70% of participants will have died.
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1.2.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The APaT population will serve as the population for the analysis of efficacy data in this 
study. The APaT population consists of all allocated participants who receive at least 1 dose 
of study treatment.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population as defined for efficacy.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required. 
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
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9.6.1
Statistical Methods for Efficacy Analyses
9.6.1.1
Objective Response Rate (ORR)
ORR will be calculated as the ratio of the number of participants reported to have achieved a 
confirmed CR or PR verified by BICR, divided by the number of participants included in the 
APaT population. Participants in the APaT analysis population without ORR assessments 
will be counted as non-responders. A 95% exact binomial CI based on the Clopper and 
Pearson method will be calculated for the true ORR.
9.6.1.2
Duration of Response (DOR)
The non-parametric Kaplan-Meier method will be used to estimate the DOR survival curve.
Only the subset of participants with confirmed CR or PR response verified by BICR will be 
included in the analysis. 95% CIs for the median response duration and point estimates at 
various follow-up times will be calculated. The censoring rules for the analysis of DOR are 
summarized in Table 8.
Table 8
Censoring Rules for Analysis of DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anticancer 
therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anticancer 
therapy initiated
Last adequate disease assessment 
before new anticancer therapy 
initiated
Censor
(non-event)
Death or progression immediately after ≥2 
consecutive missed disease assessments or 
after new anticancer therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anticancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed disease 
assessments and before new anticancer 
therapy, if any
Progressive disease or death
End of response
(Event)
DOR=duration of response
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate 
for evaluation of response.
9.6.1.3
Progression-free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS survival curve. 
95% CIs for the median PFS and PFS point estimates at various follow-up times from the 
first day of study treatment will be calculated.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is
documented. The true date of disease progression will be approximated by the earlier of the 
date of the first assessment at which PD is objectively documented per RECIST 1.1 by BICR
and the date of death. Death is always considered a PD event. Participants who do not 
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experience a PFS event will be censored at the last disease assessment. The censoring rules 
for the analysis of PFS are summarized in Table 9. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
Table 9
Censoring Rules for Analysis of PFS
Situation
Date of Progression or Censoring
PD or death documented after ≤1 missed disease 
assessment, and before new anticancer therapy, if any
Progressed at date of documented PD or death
PD or death documented immediately after ≥2 consecutive 
missed disease assessments or after new anticancer 
therapy, if any
Censored at last disease assessment prior to 
the earlier date of ≥2 consecutive missed 
disease assessment and new anticancer therapy, 
if any
No PD and no death; and new anticancer treatment is not 
initiated
Censored at last disease assessment 
No PD and no death; new anticancer treatment is initiated
Censored at last disease assessment before new 
anticancer treatment
PD=progressive disease; PFS=progression-free survival 
9.6.1.4
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the OS survival curve.
95% CIs for the median OS and OS point estimates at various follow-up times from the first 
day of study intervention will be calculated. Participants without documented death at the 
time of analysis will be censored at the date the participant was last known to be alive.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
Table 10 summarizes the analysis approach for key efficacy endpoints.
Table 10
Analysis Strategy for Key Efficacy Endpoints
Endpoint 
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Endpoints
ORR per RECIST 1.1 by BICR
Estimation: Exact 
method based on 
binomial distribution 
(Clopper-Pearson 
method)
APaT
Participants without 
assessments are considered 
non-responders and 
conservatively included in 
the denominator
Key Secondary Endpoint
DOR per RECIST 1.1 by 
BICR
Estimation: Summary
statistics using Kaplan-
Meier method
Participants in
APaT
population with 
an objective 
response
Non-responders are excluded 
from analysis; Responders 
are censored according to 
rules in Table 8
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Endpoint 
Statistical Methoda
Analysis 
Population
Missing Data Approach
PFS per RECIST 1.1 by BICR 
Estimation: Summary 
statistics using Kaplan-
Meier method
APaT
Censoring according to 
Table 9
OS
Estimation: Summary 
statistics using Kaplan-
Meier method
APaT
Censored at the last known 
alive date 
APaT=All Patients as Treated; BICR=blinded independent central review; DOR=duration of response; 
ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response 
Evaluation Criteria in Solid Tumors
a   Statistical methods are described in further detail in the text.
9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory parameters, and vital signs measurements.
AEs (specific terms as well as system organ class terms), consisting of the percentage of 
participants with any AE, any drug-related AE, any Grade 3 to 5 AE, any serious AE, any 
AE which is both drug-related and Grade 3 to 5, any AE which is both serious and drug-
related, and who discontinued due to an AE, and death will be summarized as counts and 
frequencies.
Laboratory assessments and vital signs will be summarized using appropriate descriptive
statistics.
9.6.3
Demographics and Baseline Characteristics
Demographic variables (eg, age, gender, race, and ethnicity), baseline characteristics, and 
concomitant therapies will be summarized either by descriptive statistics or categorical 
tables.
9.7
Interim Analyses
No interim analyses are planned in this study.
9.8
Multiplicity
No multiplicity adjustment is planned in this study.
9.9
Sample Size and Power Calculations
Approximately 50 participants will be enrolled to treatment with pembrolizumab. Table 11
provides 2-sided 95% CIs of ORR with 50 participants for different observed response rates 
based on the method of Clopper and Pearson. If the ORR is 56%, this sample size will 
produce a 95% CI for the true ORR of approximately ±15%.
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Table 11
Two-sided 95% Confidence Interval of ORR With 50 Participants
Number of Observed Responders
ORR Estimate
95% CI of ORR
18
36%
(22.9%, 50.8%)
20
40%
(26.4%, 54.8%)
22
44%
(30.0%, 58.8%)
24
48%
(33.7%, 62.6%)
26
52%
(37.4%, 66.3%)
28
56%
(41.3%, 70.0%)
30
60%
(45.2%, 73.6%)
CI=confidence interval; ORR=objective response rate 
9.10
Subgroup Analyses
To determine whether the response rate is consistent across subgroups, the estimate of 
response rate with 95% CI for the primary endpoint will be estimated within each category of 
the following classification variables: 
•
Age category (<65 vs ≥65 years)
•
Sex (female vs male)
•
ECOG status (0 vs 1)
•
Prior adjuvant therapy (yes vs no)
For safety endpoints, broad AE categories consisting of the percentage of participants with 
any AE, any drug-related AE, any Grade 3 to 5 AE, any serious AE, any AE which is both 
drug-related and Grade 3 to 5, any AE which is both serious and drug-related, and who 
discontinued due to an AE, and death will be summarized by the same subgroups of age 
category, sex, ECOG status, and prior adjuvant therapy.
Any specified subgroups that have less than 10 participants will be excluded from analysis.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure for pembrolizumab will be summarized as duration of treatment in 
cycles. Summary statistics will be provided on extent of exposure for the APaT population.
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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 of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
No committees are planned for this study.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
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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.
10.1.8
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 participants’ documented informed consent/assent, 
pertaining to the conduct of this study must be retained by the investigator for 15 years after 
study completion unless local regulations or institutional policies require a longer retention 
period. No records may be destroyed during the retention period without the written approval 
of the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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10.1.9
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.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 12 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 12
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCVa
MCHa
%Reticulocytesa
WBC count with Differentialb:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNc
Potassium
AST/SGOT
Total bilirubin (and direct 
bilirubin, if total bilirubin is 
elevated above the upper limit 
of normal)
Albumin
Bicarbonatea
Chloridea
Phosphorousa
Creatinined
Sodium
ALT/SGPT
Total Proteina
Glucose 
[nonfasting]
Calcium
Alkaline 
phosphatase
Magnesiuma
Lactate 
dehydrogenasea
Amylase
Lipase
Cholesterola
Triglyceridesa
CPKa
Thyroid function tests (T3 [or 
free T3e], free T4, and TSH)
Pregnancy testf
Routine 
Urinalysisg
Specific gravity
pH, glucose, protein, blood, ketones, by dipstick
Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests
Coagulation panel (PT/INR, aPTT)h
Serology (HIV antibody, HBsAg, and hepatitis C virus antibody), if applicable
Tuberculosis test, if applicable 
Follicle-stimulating hormone (as needed in women of nonchildbearing potential only)
Serum or urine β human chorionic gonadotropin (β hCG) pregnancy test (as needed for 
WOCBP)f
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate 
aminotransferase; BUN=blood urea nitrogen; CPK=creatine phosphokinase; HBsAg=hepatitis B surface 
antigen; HIV=human immunodeficiency virus; INR=international normalized ratio; MCH=mean cell 
hemoglobin; MCV=mean cell volume; PT=prothrombin time; RBC=red blood cell; SGOT=serum glutamic
oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid stimulating hormone; WBC=white blood cell; WOCBP=women of childbearing potential
NOTES:
a. If the test is considered part of local standard of care.
b. Absolute or % acceptable per institutional standard.
c. Urea is acceptable if BUN is not available as per institutional standard.
d. Glomerular filtration rate (measured or calculated) or creatinine clearance can be used in place of 
creatinine at Screening only.
e. T3 is preferred over free T3. If not available, free T3 may be tested. There may be instances when sites 
are unable to obtain thyroid function testing results prior to the scheduled dosing; after Cycle 1, review of 
thyroid function test results after dosing is acceptable. 
f. See Appendix 5.3.
g. If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory.
h. PT/INR should be tested as needed for participants taking warfarin-based anticoagulation therapy.
The investigator (or medically qualified designee) 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:
1. Results in death
2. 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.
3. 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.
4. 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.
5. Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
6. Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any AE that changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components 
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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 his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
-
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
-
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a 
single agent of the combination. In general, causality attribution should be assigned to 
the combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (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 follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormone 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with 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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10.5.2
Contraception Requirements
Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a    Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    Male condoms must be used in addition to female participant hormonal contraception.
d    IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
10.5.3
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Following initiation of treatment additional pregnancy testing will be performed prior to each 
treatment cycle during the treatment period and prior to each cycle of treatment up to 
120 days after the last dose of study intervention or the start of a new anticancer therapy, 
whichever comes first, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
    The biology of how drugs/vaccines work
    Biomarkers responsible for how a drug/vaccine enters and is removed by the body
    Other pathways with which drugs/vaccines may interact
    The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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b. Informed Consent/Assent
Informed consent/assent for specimens (ie, DNA, RNA, protein, etc) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent/assent for 
future biomedical research should be presented to the participants on the visit 
designated in the SoA. If delayed, present consent/assent at next possible Participant 
Visit. Consent/assent forms signed by the participant will be kept at the clinical study 
site under secure storage for regulatory reasons.
A template of each study site’s approved informed consent/assent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent/assent for future biomedical research will be 
captured in the eCRFs. Any specimens for which such an informed consent/assent
cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and 
consent/assent. Future biomedical research specimens remaining with the third party after 
specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research
Participants may withdraw their consent/assent for FBR and ask that their biospecimens 
not be used for FBR. Participants may withdraw consent/assent at any time by contacting 
the study investigator. If medical records for the study are still available, the investigator 
will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent/assent and/or destruction cannot be processed.
7. Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
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to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent/assent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/ 
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Germany
Section 5.2 Exclusion Criteria
Has a known history of HIV infection. HIV testing is required as mandated by local 
regulation.
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. Testing for Hepatitis B or 
Hepatitis C is required at Screening.
Has a known history of active TB. Testing for TB is required at Screening.
Throughout
Persons of legal age, who are incapable of comprehending the nature, significance, and 
implications of the clinical study and of determining their will, are excluded from the study at 
German sites; therefore, all references to a participant’s “legally acceptable representative” in 
the protocol are not applicable for participants in Germany.
10.7.2
United Kingdom
Section 5.2 Exclusion Criteria
Has a known history of HIV infection. HIV testing is required at Screening.
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. Testing for Hepatitis B or 
Hepatitis C is required at Screening.
Section 6.5 Concomitant Therapy
Live vaccines are prohibited through 3 months after the end of study intervention.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging 4 to 8 weeks later is obtained (using iRECIST for 
participant management (see Table 6 and Figure 2). This decision by the investigator should 
be based on the participant’s overall clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status (or Lansky scale, if appropriate)
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time point
Visible growth of new nontarget lesions
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit , an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the iCRO.
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
•
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Performance Scales
Eastern Cooperative Oncology Group (ECOG) Performance Scale
ECOG Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without 
restriction
1
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, eg, light housework, 
office work
2
Ambulatory and capable of all self-care but unable to carry out any 
work activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined 
to bed or chair
5
Dead
Source: [ECOG-ACRIN Cancer Research Group 2016]
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Lansky Play-Performance Scale (LPS)
Score
Activity
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of, and less time spent in, active play.
60
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed, but lies around much of the day; no active play; able to 
participate in all quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive
Source: [Lansky, S. B., et al 1987]
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
BCG
Bacillus Calmette–Guérin
BICR
blinded independent central review
BOR
best overall response
C1D1
Cycle 1 Day 1
CAV
cyclophosphamide, doxorubicin (or epirubicin), and vincristine
CD28
cluster of differentiation 28
CD3ζ
cluster of differentiation 3 zeta
CNS
central nervous system
CR
complete response
CRF
Case Report Form 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
eDMC
external Data Monitoring Committee 
EMA
European Medicines Agency
EOT
End of Treatment
FDA
Food and Drug Administration 
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle-stimulating hormone 
GCP
Good Clinical Practice 
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonization
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
iCRO
imaging contract research organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV-type
immunoglobulin-variable–type
IND
Investigational New Drug 
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Abbreviation
Expanded Term
iPR
iRECIST partial response
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics
IRT
interactive response technology
iSD
iRECIST stable disease
IUD
intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
LPS
Lansky Play-Performance Scale
mAb
monoclonal antibody
MCC
Merkel cell carcinoma
MCPyV
Merkel cell polyoma virus
MRI
magnetic resonance imaging
NCCN
National Comprehensive Cancer Network
OR
objective response
ORR
objective response rate
OS
overall survival
PBPK
physiologically-based pharmacokinetics
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
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q12W
every 12 weeks
Q24W
every 24 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RNA
ribonucleic acid
SAE
serious adverse event 
SD
stable disease
SIM
Site Imaging Manual
SoA
schedule of activities
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
ULN 
upper limit of normal
US
United States
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
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11
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