A Phase 2, Open-Label, Single Arm Study to Evaluate the Safety and Efficacy of Pembrolizumab in Participants With Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma (R/M cSCC)
Phase: PHASE2
Conditions: Squamous Cell Carcinoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 2, Open-label, Single-arm Study to
Evaluate the Safety and Efficacy of
Pembrolizumab in Participants with Recurrent
or Metastatic Cutaneous Squamous Cell
Carcinoma (R/M cSCC)
NCT03284424
10-Feb-2023

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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 2, Open-label, Single-arm Study to Evaluate the Safety and 
Efficacy of Pembrolizumab in Participants with Recurrent or Metastatic Cutaneous 
Squamous Cell Carcinoma (R/M cSCC) 
Protocol Number: 629-06
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   134,760
EudraCT NUMBER: 2017-000594-37
Approval Date:  10 February 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-629-06
10-FEB-2023
To add language to allow participants to continue in a pembrolizumab 
extension study.
3475-629-05
21-JUN-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.
3475-629-04
03-JUN-2021
To update the dose modification and toxicity management guidelines for 
immune-related adverse events (irAEs) and incorporate updates from Protocol 
Clarification Letter (PCL) #3.
3475-629-03
25-SEP-2018
To add a cohort of 50 participants with locally advanced unresectable cSCC.
3475-629-02
08-FEB-2018
To add German-specific requirements to the study in response to a request from 
the German regulatory agency.
3475-629-01
27-MAR-2018
To add inclusion of 1L participants to the study.
3475-629-00
21-APR-2017
To test the clinical activity of pembrolizumab in participants with unresectable 
and/or metastatic cSCC.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 06
Overall Rationale for the Amendment:
To add language to allow participants to continue in a pembrolizumab extension study.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
5.3 Beginning and End of 
Study Definition
Added that upon study completion, participants 
are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
To allow participants to continue in a 
pembrolizumab extension study.
7.7 Concomitant Therapy
Clarified that live attenuated vaccines are not 
permitted during the study.
Added that licensed COVID-19 vaccines are 
allowed, but investigational vaccines are not 
allowed.
To clarify which vaccines are permitted.
9.8 Future Biomedical 
Research Sample Collection
Deleted list of samples and replaced with 
“Leftover samples listed in Section 9.9.”
To reduce ambiguity and eliminate a source of 
confusion.
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Section # and Name
Description of Change
Brief Rationale
9.9 Biomarkers
Changed “Tissue Collection” to “Tumor 
Tissue.”
To reduce ambiguity and eliminate a source of 
confusion. “Tumor tissue” represents all tumor 
collections (archival tissue, newly obtained, 
biopsies, etc.).
Throughout Document
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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Table of Contents
DOCUMENT HISTORY ....................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 4
Synopsis...................................................................................................................... 16
Schedule of Activities (SoA)..................................................................................... 19
Schedule of Activities – Recurrent/Metastatic cSCC ........................................ 19
Schedule of Activities – Locally Advanced Unresectable cSCC....................... 27
Second Course Phase (Retreatment) for Pembrolizumab (MK-3475) ............ 33
Introduction............................................................................................................... 36
Study Rationale..................................................................................................... 36
Background ........................................................................................................... 36
Pharmaceutical and Therapeutic Background .................................................... 36
Benefit/Risk Assessment....................................................................................... 46
Objectives/Hypotheses and Endpoints.................................................................... 46
Study Design.............................................................................................................. 48
Overall Design....................................................................................................... 48
Study Diagram .................................................................................................... 50
Number of Participants........................................................................................ 50
Beginning and End of Study Definition.............................................................. 51
Clinical Criteria for Early Trial Termination...................................................... 51
Scientific Rationale for Study Design.................................................................. 51
Rationale for Endpoints ...................................................................................... 51
Primary Efficacy Endpoints......................................................................... 51
Secondary Efficacy Endpoints..................................................................... 51
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Exploratory Efficacy Endpoints................................................................... 52
5.4.1.3.1
Immune-related RECIST ...................................................................... 52
Rationale for Patient-reported Outcomes..................................................... 52
Rationale for Safety Endpoints.................................................................... 53
Pharmacokinetic Endpoints ......................................................................... 53
Planned Exploratory Biomarker Research................................................... 53
5.4.1.7.1
Germline Genetic Analyses .................................................................. 54
5.4.1.7.2
Tumor Genetic Analyses ...................................................................... 54
5.4.1.7.3
Tumor and Blood RNA Analyses......................................................... 54
5.4.1.7.4
Proteomic Biomarkers and IHC............................................................ 54
5.4.1.7.5
Other Blood Derived Biomarkers......................................................... 55
Future Biomedical Research........................................................................ 55
Justification for Dose............................................................................................ 55
Rationale for Pembrolizumab Dose.................................................................... 55
Study Population....................................................................................................... 56
Inclusion Criteria.................................................................................................. 57
Exclusion Criteria................................................................................................. 61
Lifestyle Restrictions ............................................................................................ 63
Meals and Dietary Restrictions........................................................................... 63
Caffeine, Alcohol, and Tobacco ......................................................................... 63
Activity ............................................................................................................... 63
Contraception...................................................................................................... 63
Pregnancy............................................................................................................ 64
Use in Nursing Women....................................................................................... 64
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Screen Failures...................................................................................................... 64
Participant Replacement Strategy ...................................................................... 64
Treatments................................................................................................................. 65
Treatments Administered .................................................................................... 65
Dose Modification (Escalation/Titration/Other)................................................ 66
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)........................................................................................................ 66
Second Course Phase (Retreatment) for Pembrolizumab (MK-3475) ............... 71
Pembrolizumab (MK-3475) Administration....................................................... 72
Method of Treatment Assignment....................................................................... 72
Stratification........................................................................................................ 73
Blinding.................................................................................................................. 73
Preparation/Handling/Storage/Accountability .................................................. 73
Dose Preparation................................................................................................. 73
Handling, Storage, and Accountability............................................................... 73
Treatment Compliance......................................................................................... 74
Concomitant Therapy........................................................................................... 74
Rescue Medications & Supportive Care............................................................. 75
Treatment After the End of the Study................................................................ 76
Clinical Supplies Disclosure................................................................................. 76
Discontinuation/Withdrawal Criteria..................................................................... 76
Discontinuation of Study Treatment................................................................... 76
Withdrawal From the Study................................................................................ 78
Lost to Follow Up.................................................................................................. 78
Study Assessments and Procedures......................................................................... 78
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Administrative and General Procedures ............................................................ 79
Informed Consent................................................................................................ 79
General Informed Consent........................................................................... 79
Consent and Collection of Specimens for Future Biomedical Research ..... 80
Inclusion/Exclusion Criteria ............................................................................... 80
Participant Identification Card............................................................................ 80
Medical History .................................................................................................. 80
Cutaneous Squamous Cell Carcinoma......................................................... 80
Prior and Concomitant Medications Review ...................................................... 81
Prior Medications......................................................................................... 81
Concomitant Medications............................................................................ 81
Assignment of Screening Number...................................................................... 81
Assignment of Treatment/Randomization Number............................................ 81
Treatment Administration................................................................................... 81
Timing of Dose Administration................................................................... 82
Withdrawal/Discontinuation............................................................................... 82
Withdrawal From Future Biomedical Research .......................................... 82
Participant Blinding/Unblinding......................................................................... 82
Calibration of Equipment.................................................................................... 82
Efficacy Assessments ............................................................................................ 83
Tumor Imaging and Assessment of Disease....................................................... 83
Initial Tumor Imaging.................................................................................. 83
Tumor Imaging During the Trial ................................................................. 84
End of Treatment and Follow-up Tumor Imaging....................................... 85
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Second Course (Retreatment) Tumor Imaging............................................ 85
RECIST 1.1 Assessment of Disease............................................................ 86
irRECIST Assessment of Disease................................................................ 86
Photography for Cutaneous Lesions............................................................ 90
Tumor Tissue Collection and Assessment of Disease Recurrence.............. 91
Quality of Life Assessments ............................................................................... 91
Patient Reported Outcomes.......................................................................... 91
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events..................................................................................................................... 91
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information.................................................................................... 92
Method of Detecting AE, SAE and Other Reportable Safety Events................. 94
Follow-up of AE, SAE and Other Reportable Safety Event Information........... 94
Regulatory Reporting Requirements for SAE .................................................... 94
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs ....................................................................................................... 94
Pregnancy and Exposure During Breastfeeding ................................................. 95
Events of Clinical Interest (ECI)......................................................................... 95
Treatment of Overdose......................................................................................... 96
Safety...................................................................................................................... 96
Physical Examinations........................................................................................ 96
Vital Signs........................................................................................................... 96
Electrocardiograms ............................................................................................. 96
Clinical Safety Laboratory Assessments............................................................. 96
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis).................................................................................................... 97
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Pregnancy Test............................................................................................. 98
Performance Assessments................................................................................... 98
Eastern Cooperative Oncology Group Performance Scale.......................... 98
Pharmacokinetics.................................................................................................. 98
Blood Collection for PK ..................................................................................... 99
Pharmacodynamics............................................................................................... 99
Tumor Tissue Collection..................................................................................... 99
Future Biomedical Research Sample Collection................................................ 99
Biomarkers ............................................................................................................ 99
Planned Genetic Analysis Sample Collection................................................... 100
Visit Requirements ............................................................................................. 100
Screening........................................................................................................... 100
Treatment Period Visits .................................................................................... 101
Discontinued Participants Continuing to be Monitored in the Study ............... 101
Post-treatment Visit .......................................................................................... 101
Safety Follow-up Visit............................................................................... 101
Follow-up Visits......................................................................................... 101
Survival Follow-up Assessments............................................................... 102
Post-Study.................................................................................................. 102
Survival Status ........................................................................................... 102
Statistical Analysis Plan ......................................................................................... 102
Statistical Analysis Plan Summary ................................................................... 103
Responsibility for Analyses/In-House Blinding ............................................... 103
Hypotheses/Estimation....................................................................................... 104
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Analysis Endpoints ............................................................................................. 104
Efficacy Endpoints............................................................................................ 104
Safety Endpoints ............................................................................................... 104
Analysis Populations........................................................................................... 104
Efficacy Analysis Population............................................................................ 104
Safety Analysis Population............................................................................... 105
Statistical Methods.............................................................................................. 105
Statistical Methods for Efficacy Analyses........................................................ 105
Statistical Methods for Primary Efficacy Endpoint................................... 105
Statistical Methods for Secondary Efficacy Endpoints ............................. 105
Summary of Efficacy Analysis Methods................................................... 106
Statistical Methods for Safety Analyses ........................................................... 107
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 107
Interim Analyses ................................................................................................. 107
Multiplicity .......................................................................................................... 108
Sample Size and Power Calculations ................................................................ 108
Sample Size and Power for Efficacy Analyses................................................. 108
Sample Size and Power for Safety Analyses .................................................... 109
Subgroup Analyses ............................................................................................. 110
Compliance (Medication Adherence)................................................................ 110
Extent of Exposure.............................................................................................. 110
References................................................................................................................ 111
Appendices............................................................................................................... 121
Appendix 1: Abbreviations and Trademarks .................................................. 121
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Appendix 2: Clinical Laboratory Tests ............................................................ 125
Appendix 3: Study Governance Considerations.............................................. 127
Code of Conduct for Clinical Trials.............................................................................. 127
Financial Disclosure...................................................................................................... 129
Data Protection.............................................................................................................. 130
Confidentiality of Data ................................................................................................. 130
Confidentiality of Participant Records.......................................................................... 130
Confidentiality of IRB/IEC Information....................................................................... 130
Publication Policy ......................................................................................................... 131
Compliance with Trial Registration and Results Posting Requirements...................... 131
Compliance With Law, Audit and Debarment.............................................................. 131
Data Quality Assurance ................................................................................................ 132
Source Documents ........................................................................................................ 133
Study and Site Closure.................................................................................................. 133
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................. 134
Definition of AE ........................................................................................................... 134
Definition of SAE ......................................................................................................... 135
Recording AE and SAE ................................................................................................ 136
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............... 139
Appendix 5: Contraceptive Guidance and Pregnancy Testing ...................... 141
Highly Effective Contraception Requirements............................................................. 141
Pregnancy Testing......................................................................................................... 143
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research........................................................................................... 144
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LIST OF TABLES
Table 1
Prospective Single-arm Clinical Trials of Chemotherapy for Unresectable 
and/or Metastatic cSCC ..................................................................................... 44
Table 2
Prospective Single-arm Clinical Trials for Incurable Unresectable and/or 
Metastatic cSCC................................................................................................. 44
Table 3
Adequate Organ Function Laboratory Values................................................... 59
Table 4
Trial Treatments................................................................................................. 65
Table 5
Study Treatment(s)............................................................................................. 66
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ................................................................. 67
Table 7
Pembrolizumab Infusion Reaction Dose modification and Treatment 
Guidelines .......................................................................................................... 70
Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease............................................................................................................... 89
Table 9
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events................................................................................... 93
Table 10
Eastern Cooperative Oncology Group Performance Status............................... 98
Table 11
Censoring Rules for DOR................................................................................ 106
Table 12
Summary of Analysis Strategy for Efficacy Endpoints................................... 107
Table 13
Two-sided 95% CI for ORR with 100 R/M cSCC Participants....................... 108
Table 14
Two-sided 95% CI for ORR with 50 LA Unresectable cSCC Participants..... 109
Table 15
Estimate of and 95% CI for Incidence of Participants Experiencing AEs 
With 100 R/M cSCC Participants.................................................................... 109
Table 16
Estimate of and 95% CI for Incidence of Participants Experiencing AEs 
With 50 LA Unresectable cSCC Participants.................................................. 110
Table 17
Protocol-Required Safety Laboratory Assessments......................................... 125
Table 18
Highly Effective Contraception Methods........................................................ 142
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LIST OF FIGURES
Figure 1
Trial Design ....................................................................................................... 50
Figure 2
Imaging and Treatment for Clinically Stable Participants After First 
Radiologic Evidence of PD Assessed by the Site.............................................. 90
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Synopsis
Protocol Title:  
A Phase 2, Open-Label, Single Arm Study to Evaluate the Safety and Efficacy of 
Pembrolizumab in Participants with Recurrent or Metastatic Cutaneous Squamous Cell 
Carcinoma
Short Title: 
Phase 2 Study of Pembrolizumab in Participants With Recurrent or Metastatic Cutaneous 
Squamous Cell Carcinoma 
Objectives/Hypothesis and Endpoints:
In male/female participants aged 18 years or older with R/M cSCC or LA unresectable 
cSCC.
Objective/Hypothesis
Endpoint
Primary
(1) To estimate the objective response rate 
(ORR) per RECIST 1.1 as assessed by 
blinded independent central review 
(BICR). 
(1) Objective response: defined as complete 
response (CR) or partial response (PR).
Secondary
(1) To evaluate the duration of response 
(DOR) per RECIST 1.1 as assessed by 
BICR.
(1) DOR: for participants who demonstrate 
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.
(2) To evaluate the disease control rate 
(DCR) per RECIST 1.1 as assessed by 
BICR
(2) Disease control: defined as CR or PR or 
stable disease (SD) for at least 12 weeks.
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(3) To evaluate the progression-free 
survival (PFS) per RECIST 1.1 as 
assessed by BICR.
(3) PFS: defined as the time from first day of 
study treatment to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
Note: A new primary low-risk cSCC 
lesion is not considered as a PFS event.
(4) To evaluate the overall survival (OS) of 
the participants.
(4) OS: defined as the time from first day of 
study treatment to death due to any cause.
(5) To determine the safety and tolerability 
of pembrolizumab in study participants 
with R/M cSCC.
(5) Adverse events (AEs).
Study drug discontinuations due to AEs.
Overall Design:
Trial Phase
Phase 2
Clinical Indication
Recurrent or metastatic (R/M) cutaneous squamous cell 
carcinoma (cSCC) or locally advanced (LA) unresectable 
cSCC.
Population
Participants with cSCC not amenable to surgery and/or 
radiation and/or systemic therapies
Trial Type
Interventional
Type of Design
Single arm, nonrandomized
Type of Control
No treatment control
Trial Blinding
Unblinded Open-label
Estimated Duration 
of Trial
The Sponsor estimates that the trial will require approximately 
54 months from the time the first participant (or their legally 
acceptable representative) provides documented informed 
consent until the last participant’s last study-related contact.
Number of Participants:
Up to approximately 150 participants will be enrolled.
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Treatment Groups and Duration:
Treatment Groups
Pembrolizumab 200 mg every 3 weeks (Q3W)
Duration of 
Participation
Each participant will participate in the trial from the time the 
participant provides documented informed consent form (ICF) 
through the final protocol-specified contact. 
After a screening phase of 28 days, each participant will be 
assigned to receive trial treatment until disease progression is 
assessed by the site per Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1*, unacceptable adverse event(s)
(AE[s]), intercurrent illness that prevents further administration 
of treatment, investigator’s decision to discontinue the 
participant from study treatment, administrative reasons 
requiring cessation of treatment, or until the participant has 
received 35 administrations of pembrolizumab (approximately 
2 years). Participants who stop trial treatment after receiving 
35 administrations of pembrolizumab for reasons other than 
disease progression or intolerability, or participants who attain 
a CR and stop trial treatment may be eligible for up to 17 
additional administrations of pembrolizumab (approximately 
1 year) upon experiencing disease progression (Section 5.1 and
7.2.2). 
* For participants without RECIST 1.1 measurable disease on 
CT or MRI scans that were deemed eligible by digital 
photography, a tissue biopsy is required within 30 days of 
investigator determined CR for central pathology review and 
confirmation of a CR. For participants considered to have 
obtained CR prior to the release of Amendment 03, a biopsy 
will be required within 30 days of Protocol Amendment 03 
approval in the respective country. 
After the end of treatment, each participant will be followed for 
the occurrence of AEs and spontaneously reported pregnancy 
as described under Section 9.3.6
Participants who discontinue for reasons other than disease 
progression will have post-treatment follow-up for disease 
status until disease progression is assessed by the site per 
RECIST 1.1, initiating a non-trial cancer treatment, 
withdrawing consent, or becoming lost to follow-up. All 
participants will be followed by telephone for OS until death, 
withdrawal of consent, or the end of the study. 
A list of abbreviations used in this document can be found in Appendix 1.
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Schedule of Activities (SoA)
Schedule of Activities – Recurrent/Metastatic cSCC
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
Administrative Procedures
Informed 
Consent
X
Additional consent is required at 
disease progression.
Informed 
Consent for 
Future 
Biomedical 
Research
X
Participant 
Identification 
Card
X
X
At D1 the participants allocation 
number is added to the participant 
identification card
Inclusion/
Exclusion 
Criteria
X
Demographics 
and Medical 
History
X
Prior/
Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Record all medications taken within 
28 days of the Screening Visit and 
enter new medications started during 
the trial.
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Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
Pembrolizumab 
Administration
X
X
X
X
X
X
Treatment 1, Cycle 1 must be given 
within 3 days after treatment 
allocation. Study drug to be 
administered on D1 of each cycle after 
all procedures/ assessments have been 
completed.
Post-study
Anticancer 
Therapy Status
X
X
X
X
Survival Status
X*
*Survival FU begins after investigator 
determined progression or start of next 
line anticancer treatment. By telephone 
contact every 12 weeks (84 ± 7 days) 
until death, withdrawal of consent, 
becoming lost to follow-up, or the end 
of the study, whichever occurs first. 
In addition, upon Sponsor request, 
participants may be contacted for 
survival status at any time during the 
course of the study.
Clinical Procedure/Assessments
Review Adverse 
Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record all AEs and ECIs occurring 
within 30 days after last dose of study
treatment and SAEs for 90 days after 
the end of treatment or 30 days after 
end of treatment if the participant 
initiates new anticancer therapy 
(whichever is earlier). Report treatment 
related SAEs regardless of when they 
occur.
08H6WY

Product:  MK-3475 
21
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
12-lead ECG 
(Local)
X
Full Physical 
Examination and 
Height*
X
X
To be performed by the investigator or 
qualified designee. *Height will be 
measured at Screening only.
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior to dosing assess and record BP, 
pulse, temperature, and weight. 
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Must be performed prior to each dose 
of trial treatment where ECOG is 
collected.
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Serum or Urine 
Pregnancy Test  
(if applicable)
X
X
X
X
X
X
X
X
X
Serum or urine pregnancy test must 
occur 72 hours prior to administration 
of trial treatment.
Monthly pregnancy tests are required
for participants enrolled from German 
sites. For all other countries, monthly 
pregnancy testing should be conducted 
as per local regulations where 
applicable.
HIV/HBV/HCV
serology
X
Testing is required at screening for 
participants enrolled from German 
sites. All other countries should follow 
local regulations where applicable
08H6WY

Product:  MK-3475 
22
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
PT/INR and 
aPTT
X
Screening - within 10 days prior to the 
start of study treatment. Samples to be 
taken prior to pembrolizumab 
administration. Any participant 
receiving anticoagulant therapy should 
have coagulation tests monitored 
closely throughout the study. PTT may 
be performed if the local laboratory is 
unable to perform aPTT.
CBC with 
Differential
X
X*
X*
X
X*
X*
X
X
X
X
X
X†
Screening -within 10 days prior to the 
start of study treatment. Samples to be 
taken prior to study drug 
administration. After Cycle 1, lab 
samples can be collected up to 
72 hours prior to the scheduled time 
point. See Section 9.5.4.
Total T3 or free T3 are acceptable as 
well as FT4 and TSH
* D8 and D15 are required safety visits 
for the first 2 pembrolizumab 
infusions. Collection of Day 8 and
Day 15 laboratory samples of Cycles 1 
and 2 are optional at the discretion of 
the investigator. 
‡ To be repeated every 2 cycles after 
Cycle 6.
†Unresolved abnormal labs that are 
drug-related AEs should be followed 
until resolution. Labs do not need to be 
repeated after the EOT if labs are 
within normal range.
Chemistry Panel
X
X*
X*
X
X*
X*
X
X
X
X
X
X†
Urinalysis
X
T3, FT4, and 
TSH
X
X
X
X‡
X†
08H6WY

Product:  MK-3475 
23
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Pharmacokinetic 
Samples
X
X
X
X
Predose drawn within 24 hrs before 
pembrolizumab infusion at C1, 2, 4, 6, 
8 and Q4C thereafter, until discon of 
study drug or participants starts new 
anti-cancer therapy. Post-dose will be 
drawn within 30 minutes after 
pembrolizumab infusion at C1
Blood for 
Genetic Analysis
X
This sample should be drawn for 
planned analysis of the association 
between genetic variants in DNA and 
drug response. This sample will not be 
collected at that site if there is either a 
local law or regulation prohibiting 
collection, or if the IRB/IEC does not 
approve the collection of the sample 
for these purposes. If the sample is 
collected, leftover extracted DNA will 
be stored for future biomedical 
research if the participant (or their 
legally acceptable representative) 
provides documented informed 
consent for FBR. If the planned 
genetic analyses are not approved, but 
FBR is approved and consent is given, 
this sample will be collected for the 
purpose of FBR.
08H6WY

Product:  MK-3475 
24
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
Blood for RNA 
Analyses
X
X
X
X
Samples will be collected on Day 1 of 
Cycles 1, 2, 5 and at 
EOT/discontinuation.
Blood for Plasma 
Biomarker 
Analysis
X
X
X
Samples will be collected on Day 1 of 
Cycles 1, 2, and at 
EOT/discontinuation. 
Blood for Serum 
Biomarker 
Analyses
X
X
X
08H6WY

Product:  MK-3475 
25
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
Efficacy Measurements
Tumor Imaging
X
X
X
X‡
X*
X
Initial tumor imaging, including any digital 
photography, will be performed within 28 days 
prior to the date of treatment allocation and 
must be sent to the central vendor.
The first on-study imaging assessment should 
be performed at 6 weeks (42 days + 7 days) 
from the date of treatment allocation.  
‡Subsequent tumor imaging should be 
performed every 6 weeks (±7 days) until 
Year 1, thereafter ever 9 weeks(±7 days), or 
more frequently if clinically indicated. For all 
imaging, the clock will start from the date of 
treatment allocation. 
Pelvic imaging is not required during the study 
with the exception of the primary involvement 
of the pelvis and lower extremities.
*For participants who discontinue study 
treatment, tumor imaging should be performed 
at the time of treatment discontinuation 
(±4 week window). If previous imaging was 
obtained within 4 weeks prior to the date of 
discontinuation, then imaging at treatment 
discontinuation is not required and the 
participant should continue with the protocol 
specified tumor imaging time points. For 
participants who discontinue study treatment 
due to documented disease progression, this is 
the final required tumor imaging if the 
Investigator elects not to implement 
irRECIST.
Digital 
Photography; 
cutaneous lesions
X
X
X
X‡
X*
X
08H6WY

Product:  MK-3475 
26
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – R/M cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Treatment cycles are 3 weeks.
Cycles will be repeated up to 35 infusions 
or until protocol specific criteria to 
discontinue treatment is met.
*For participants who discontinue study 
therapy without documented disease 
progression by imaging assessment, every 
effort should be made to continue 
monitoring their disease status as per 
protocol.
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FU*
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D post 
discon
(± 14)
Q6W post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D8
D15
D1
D8
D15
D1
D1
D1
D1
Tumor Tissue Collection
Tissue Collection
X
------If clinically indicated*------
Screening for biomarker analysis only 
(Section 9.7.1).
*For participants deemed eligible via 
digital photography only. Participants 
considered to have obtained a CR 
require biopsy within 30 days of initial 
confirmation. For participants 
considered to have obtained CR prior 
to the release of Amendment 03, a 
biopsy will be required within 30 days 
of Protocol Amendment 03 approval in 
the respective country. All samples to 
be submitted for central pathology 
review.
Patient Reported Outcomes
EuroQol EQ-5D
X
X
X
X
X
X
Questionnaires will be administered 
prior to dosing at Cycle 1, Cycle 2, 
Cycle 3, and every 2 cycles (ie, every 
6 weeks) through Year 1, then every 
3 cycles (ie., every 9 weeks) after 
Year 1 until End of Treatment, and at 
the 30-day Safety Follow-up Visit.
EORTC QLQ-
C30
X
X
X
X
X
X
AE = adverse events; aPTT = activated partial thromboplastin time; BP = blood pressure; C1D1= cycle one day one; CBC= complete blood count; D = day(s); discon = 
discontinuation; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECI = events of clinical interest; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = 
European Organization for Research and Treatment of Cancer; EOT = End of treatment; EuroQol EQ-5D = European Quality of Life; FBR = future biomedical research; FNA = 
fine needle aspirate; FT4 = free thyroxine; FU = Follow-up; HBV = Hepatitis B virus; HCV = Hepatitis C virus; HIV = Human Immunodeficiency Virus; IEC = Independent 
Ethics Committee; IRB = Institutional Review Board; INR = international normalized ratio; PD-L1 = Programmed Death Ligand 1; PT = prothrombin time; PTT = partial 
thromboplastin time; Q = every; RNA = ribonucleic acid; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; W = weeks.
08H6WY

Product:  MK-3475 
27
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – Locally Advanced Unresectable cSCC
Schedule of Activities – LA unresectable cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Cycles will be repeated up to 35 infusions or until 
protocol specific criteria to discontinue treatment is 
met
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FUb
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D1
D1
D1
D1
D1
Administrative Procedures
Informed Consent
X
Additional consent is required at disease progression.
Informed Consent 
for Future 
Biomedical 
Research
X
Participant 
Identification 
Card
X
X
At D1 the participants allocation number is added to the 
participant identification card
Inclusion/
Exclusion Criteria
X
Demographics and 
Medical History
X
Prior/Concomitant 
Medication 
Review
X
X
X
X
X
X
X
X
X
Record all medications taken within 28 days of the 
Screening Visit and enter new medications started during 
the trial.
Pembrolizumab 
Administration
X
X
X
X
X
X
Treatment 1, Cycle 1 must be given within 3 days after 
treatment randomization via IRT. Study drug to be 
administered on D1 of each cycle after all procedures/ 
assessments have been completed.
Post-study 
Anticancer 
Therapy Status
X
X
X
X
08H6WY

Product:  MK-3475 
28
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – LA unresectable cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Cycles will be repeated up to 35 infusions or until 
protocol specific criteria to discontinue treatment is 
met
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FUb
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D1
D1
D1
D1
D1
Survival Status
X*
* Survival FU begins after investigator determined 
progression or start of next line anticancer treatment.
By telephone contact every 12 weeks (84 ± 7 days) for 
survival until death, withdrawal of consent, becoming lost 
to follow-up, or the end of the study, whichever occurs 
first. 
In addition, upon Sponsor request, participants may be 
contacted for survival status at any time during the course 
of the study.
Clinical Procedure/Assessments
Review Adverse 
Events
X
X
X
X
X
X
X
X
X
X
Record all AEs and ECIs occurring within 30 days after 
last dose of study treatment and SAEs for 90 days after 
the end of treatment or 30 days after end of treatment if 
the participant initiates new anticancer therapy 
(whichever is earlier). Report treatment related SAEs 
regardless of when they occur.
12-lead ECG 
(Local)
X
Full Physical 
Examination and 
Height*
X
X
To be performed by the investigator or qualified 
designee. *Height will be measured at Screening only.
Directed Physical 
Examination
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
Prior to dosing assess and record BP, pulse, temperature,
and weight. Height at screening only.
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
Must be performed prior to each dose of trial treatment
where ECOG is collected.
08H6WY

Product:  MK-3475 
29
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – LA unresectable cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Cycles will be repeated up to 35 infusions or until 
protocol specific criteria to discontinue treatment is 
met
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FUb
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D1
D1
D1
D1
D1
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
Serum or Urine 
Pregnancy Test (if 
applicable)
X
X
X
X
X
X
X
X
X
Serum or urine pregnancy test must occur 72 hours prior 
to administration of trial treatment.
Monthly pregnancy tests are required for participants 
enrolled from German sites. For all other countries, 
monthly pregnancy testing should be conducted as per 
local regulations where applicable.
HIV/HBV/HCV
serology
X
Testing is required at screening for participants enrolled 
from German sites. All other countries should follow 
local regulations where applicable.
PT/INR and aPTT
X
Screening -within 10 days prior to the start of study 
treatment. Samples to be taken prior to study drug 
administration. After Cycle 1, lab samples can be 
collected up to 72 hours prior to the scheduled time point. 
See Section 9.5.4.
Any participant receiving anticoagulant therapy should 
have coagulation tests monitored closely throughout the 
study. PTT may be performed if the local laboratory is 
unable to perform aPTT.
Total T3 or free T3 are acceptable as well as FT4 and 
TSH
‡ To be repeated every 2 cycles after Cycle 6.
†Unresolved abnormal labs that are drug-related AEs 
should be followed until resolution. Labs do not need to 
be repeated after the EOT if labs are within normal range.
CBC with 
Differential
X
X
X
X
X
X
X
X†
Chemistry Panel
X
X
X
X
X
X
X
X†
Urinalysis
X
T3, FT4, and TSH
X
X
X
X‡
X†
08H6WY

Product:  MK-3475 
30
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – LA unresectable cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Cycles will be repeated up to 35 infusions or until 
protocol specific criteria to discontinue treatment is 
met
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FUb
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D1
D1
D1
D1
D1
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Pharmacokinetic 
Samples
X*
X
X
X
Predose drawn within 24 hrs before pembrolizumab 
infusion at C1, 2, 4, 6, 8 and Q4C thereafter, until discon 
of SD or participants starts new anti-cancer therapy.
*Post-dose will be drawn within 30 minutes after 
pembrolizumab infusion at C1
Blood for Genetic 
Analysis
X
This sample should be drawn for planned analysis of the 
association between genetic variants in DNA and drug 
response. This sample will not be collected at that site if 
there is either a local law or regulation prohibiting 
collection, or if the IRB/IEC does not approve the 
collection of the sample for these purposes. If the sample 
is collected, leftover extracted DNA will be stored for 
future biomedical research if the participant (or their 
legally accepted representative) provides documented 
informed consent for FBR. If the planned genetic 
analyses are not approved, but FBR is approved and 
consent is given, this sample will be collected for the 
purpose of FBR.
Blood for RNA 
Analyses
X
X
X
X
Samples will be collected at on Day 1 of Cycles 1, 2, 5 
and at EOT/ discontinuation
Blood for Plasma 
Biomarker 
Analysis
X
X
X
Samples will be collected at on Day 1 of Cycles 1, 2, and 
at EOT/discontinuation.
Blood for Serum 
Biomarker 
Analyses
X
X
X
08H6WY

Product:  MK-3475 
31
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – LA unresectable cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Cycles will be repeated up to 35 infusions or until 
protocol specific criteria to discontinue treatment is 
met
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FUb
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D1
D1
D1
D1
D1
Efficacy Measurements
Tumor Imaging
X
X
X
X‡
X*
X
Initial tumor imaging, including any digital photography, 
will be performed within 28 days prior to the date of 
treatment allocation and must be sent to the central 
vendor.
The first on-study imaging assessment should be 
performed at 6 weeks (42 days + 7 days) from the date of 
treatment allocation. 
‡Subsequent tumor imaging should be performed every 
6 weeks (±7 days) until Year 1, thereafter ever 9 weeks 
(±7 days), or more frequently if clinically indicated. For 
all imaging, the clock will start from the date of treatment 
allocation. Pelvic imaging is not required during the study 
with the exception of the primary involvement of the 
pelvis and lower extremities.
*For participants who discontinue study treatment, tumor 
imaging should be performed at the time of treatment 
discontinuation (±4 week window). If previous imaging 
was obtained within 4 weeks prior to the date of 
discontinuation, then imaging at treatment 
discontinuation is not required and the participant should 
continue with the protocol specified tumor imaging time 
points. For participants who discontinue study treatment 
due to documented disease progression, this is the final 
required tumor imaging if the Investigator elects not to 
implement irRECIST.
Digital 
Photography; 
cutaneous lesions
X
X
X
X‡
X*
X
Tumor Tissue Collection
Tissue Collection
X
------If clinically indicated*------
Screening for biomarker analysis only (Section 9.7.1).
*For participants deemed eligible via digital photography 
only. Participants considered to have obtained a CR 
require biopsy within 30 days of initial confirmation. All 
samples to be submitted for central pathology review.
08H6WY

Product:  MK-3475 
32
Protocol/Amendment No.: 629-06
MK-3475-629-06 Final Protocol
10-Feb-2023
Confidential
Schedule of Activities – LA unresectable cSCC
Trial Period
Screening
Treatment Cyclea
EOT
Post-Treatment
Notes:
Cycles will be repeated up to 35 infusions or until 
protocol specific criteria to discontinue treatment is 
met
Treatment 
Cycle/Title
Screening 
(Visit 1)
1
2
3
4
5
6 to 
35
Discon
Safety
FUb
Survival
Scheduled 
Window (Days)
- 28 to - 1
± 3
± 3
± 3
± 3
± 3
At time 
of discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W
(± 14)
Day of visit
D1
D1
D1
D1
D1
D1
Patient Reported Outcomes
EuroQol EQ-5D
X
X
X
X
X
X
Questionnaires will be administered by trained site 
personnel on D1 of Cycles 1, 2, 3, and then every 
2 cycles (ie, every 6 weeks) until Year 1, thereafter every 
3 cycles (ie, every 9 weeks) after until 
EOT/discontinuation, and at the 30-day Safety Follow-up 
Visit. It is strongly recommended that PROs are 
completed by participants prior to all 
procedures/assessments, and in the following order: 
EQ-5D then EORTC QLQ-C30.
EORTC QLQ-
C30
X
X
X
X
X
X
AE = adverse events; aPTT = activated partial thromboplastin time; BP = blood pressure; C1D1= cycle one day one; CBC= complete blood count; D = days; discon = 
discontinuation; DNA = deoxyribonucleic acid; ECI = events of clinical interest; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EORTC QLQ-C30 = 
European Organization for Research and Treatment of Cancer; EOT = End of treatment; EuroQol EQ-5D = European Quality of Life; FBR = future biomedical research; FNA = 
fine needle aspirate; FT4 = free thyroxine; FU = Follow-up; HBV = Hepatitis B virus; HCV = Hepatitis C virus; HIV = Human Immunodeficiency Virus; IEC = Independent 
Ethics Committee; IRB = Institutional Review Board; INR = international normalized ratio; PD-L1 = Programmed Death Ligand 1; PT = prothrombin time; PTT = partial 
thromboplastin time; Q = every; RNA = ribonucleic acid; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid-stimulating hormone; W = weeks.
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Second Course Phase (Retreatment) for Pembrolizumab (MK-3475)
Trial Period:
Treatment Cycles (3-week Cycles)
EOT
Post-Treatment
Notes: 
Cycles will be repeated up to 17 infusions or until protocol 
specific criteria to discontinue treatment is met
Treatment Cycle/Title:
1
2
3
4
5
6 to 
17
Discon
Safety 
FU
FU 
Visits
Survival 
FU
Scheduling Window 
(Days):
+ 3
± 3
± 3
± 3
± 3
± 3
At time 
of 
discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W   
(± 14)
Administrative Procedures
Eligibility Criteria
X
Participants who either a) attain a CR and discontinue 
treatment or b) discontinue treatment after 24 months on 
pembrolizumab for reasons other than disease progression or 
intolerability may restart trial treatment if they meet the 
criteria provided in the protocol
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Enter new medications started during the trial through the 
Safety Follow-up Visit.
Pembrolizumab 
Administration
X
X
X
X
X
X
Post-study Anti-cancer 
Therapy Status
X
X
Survival Status 
X
*Survival FU begins after investigator determined 
progression or start of next line anticancer treatment. By 
telephone contact every 12 weeks (84 ± 7 days) until death, 
withdrawal of consent, becoming lost to follow-up, or the end 
of the study, whichever occurs first. In addition, upon Sponsor 
request, participants may be contacted for survival status at 
any time during the course of the study.
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Record all AEs and ECIs occurring within 30 days after last 
dose of study treatment and SAEs for 90 days after the end of
treatment or 30 days after end of treatment if the participant 
initiates new anticancer therapy (whichever is earlier). Report 
treatment related SAEs regardless of when they occur.
Full Physical 
Examination
X
X
Directed Physical 
Examination
X
X
X
X
X
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Trial Period:
Treatment Cycles (3-week Cycles)
EOT
Post-Treatment
Notes: 
Cycles will be repeated up to 17 infusions or until protocol 
specific criteria to discontinue treatment is met
Treatment Cycle/Title:
1
2
3
4
5
6 to 
17
Discon
Safety 
FU
FU 
Visits
Survival 
FU
Scheduling Window 
(Days):
+ 3
± 3
± 3
± 3
± 3
± 3
At time 
of 
discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W   
(± 14)
Vital Signs 
X
X
X
X
X
X
X
X
Prior to dosing assess and record BP, pulse, temperature, and 
weight. 
ECOG Performance 
Status
X
X
X
X
X
X
X
X
Must be performed prior to each dose of trial treatment where 
ECOG is collected.
Laboratory Procedures/Assessments:  analysis performed by LOCAL laboratory
Serum or Urine 
Pregnancy Test  (if 
applicable)
X
X
X
X
X
X
X
X
Serum or urine pregnancy test must occur 72 hours prior to 
administration of trial treatment.
Monthly pregnancy tests are required for participants enrolled 
from German sites. For all other countries, monthly 
pregnancy testing should be conducted as per local 
regulations where applicable.
PT/INR and aPTT
X*
*Laboratory tests for determining eligibility for retreatment 
are to be performed within 10 days prior to the first 
retreatment dose of pembrolizumab.
After Cycle 1, lab samples can be collected up to 72 hours 
prior to the scheduled time point. 
†Unresolved labs that are drug-related AEs should be 
followed until resolution. Labs do not need to be repeated 
after the end of trial treatment if labs are within normal range.
Urinalysis required at Cycle 1 only.
Total T3 or free T3 are acceptable as well as FT4, and TSH.
Thyroid panel will continue to be collected every other cycle 
after cycle 5
See Section 9.5.4
CBC with Differential
X*
X
X
X
X
X
X
X†
Chemistry Panel
X*
X
X
X
X
X
X
X†
Urinalysisa
X*
T3, FT4, and TSH
X
X
X
X†
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Trial Period:
Treatment Cycles (3-week Cycles)
EOT
Post-Treatment
Notes: 
Cycles will be repeated up to 17 infusions or until protocol 
specific criteria to discontinue treatment is met
Treatment Cycle/Title:
1
2
3
4
5
6 to 
17
Discon
Safety 
FU
FU 
Visits
Survival 
FU
Scheduling Window 
(Days):
+ 3
± 3
± 3
± 3
± 3
± 3
At time 
of 
discon
30D 
post 
discon
(± 14)
Q6W 
post 
discon
(± 14)
Q12W   
(± 14)
Efficacy Measurements
Tumor Imaging
X
X
X
X
X
Tumor imaging, including any digital photography, must be 
performed within 28 days prior to restarting treatment with 
pembrolizumab. Imaging should be performed at 6 weeks 
(42 days + 7 days) from the first dose of trial treatment and 
continue every 6 weeks (42 ± 7 days) or more frequently if 
clinically indicated. The processes for image collection and 
transmission to the central vendor are in the Site Imaging 
Manual. Pelvic imaging is not required during the second 
course imaging schedule with exception of the primary 
involvement of pelvis and lower extremities.
For participants who discontinue study treatment, tumor 
imaging should be performed at the time of treatment 
discontinuation (±4 week window). If previous imaging was 
obtained within 4 weeks prior to the date of discontinuation, 
then imaging at treatment discontinuation is not required and 
the participant should continue with the protocol specified 
tumor imaging time points. For participants who discontinue 
study treatment due to documented disease progression, this is 
the final required tumor imaging if the Investigator elects not 
to implement irRECIST.
Digital Photography: 
cutaneous lesions
X
X
X
X
X
AE = adverse events; aPTT = activated partial thromboplastin time; BP = blood pressure; CR = complete response; D = day(s); Discon/discon = discontinuation; ECI = events of 
clinical interest; ECOG = Eastern Cooperative Oncology Group; EOT = End of treatment; FT4 = free thyroxine; FU = Follow-up; INR = international normalized ratio; PT = 
prothrombin time; PTT = partial thromboplastin time; Q = every; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid- stimulating hormone; W = weeks.
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Introduction
Pembrolizumab (trade name KEYTRUDA®) is a potent and highly selective humanized 
monoclonal antibody (mAb) of the immunoglobulin G4 (IgG4) / kappa isotype designed to 
directly block the interaction between Programmed Cell Death 1 (PD-1) receptor and its 
ligands, Programmed Death Ligand 1 (PD-L1), and Programmed Death Ligand 2 (PD-L2). 
For more detail on specific indications, please refer to the Pembrolizumab Investigator’s
Brochure (IB).
Study Rationale
Due to the paucity of clinical trial data in the unresectable and/or metastatic cutaneous 
squamous cell carcinoma (cSCC) population, there is no current standard of care treatment 
for these participants. Therefore, since there are no clear standard of care recommendations 
and no approved treatments for this population, we propose to test the clinical activity of 
pembrolizumab in a single arm Phase 2 study for unresectable and/or metastatic cSCC, a 
disease with limited treatment options and a significant unmet clinical need.
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD-
1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1.
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an intravenous (IV) immunotherapy for various malignancies. KEYTRUDA®
(pembrolizumab) is indicated for the treatment of patients across a number of indications 
because of its mechanism of action to bind the PD-1 receptor on the T-cell. For more details 
on specific indications refer to the IB. 
Pharmaceutical and Therapeutic Background
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 (TILs) 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 (Tregs) 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 
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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 antigen-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) 
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 patients with solid tumors.
Evidence of Clinical Efficacy of Pembrolizumab in Head and Neck Squamous Cell 
Carcinoma 
Evidence of both clinical efficacy and safety has been reported in studies evaluating 
pembrolizumab in head and neck squamous cell carcinoma (HNSCC). Participants with 
incurably recurrent and/or metastatic (R/M) HNSCC whose tumor tissues contained at least 
1% of tumor cells or stroma that were PD-L1 positive by immunohistochemistry (IHC), were 
enrolled onto the KEYNOTE 012 trial, a Phase 1b global, multi-cohort clinical trial utilizing 
pembrolizumab at 10 mg/kg intravenously every 2 weeks. Of the 60 participants enrolled, 
approximately 38% (n=23) were human papilloma virus (HPV) positive. Approximately 63% 
(n=38) of participants had been treated with both platinum and cetuximab based therapies 
prior to enrolling on study, and 70% (n=42 of 60) had at least 2 or more prior lines of 
treatment for R/M disease prior to study entry. In this heavily pretreated population, the 
proportion of participants with an overall response by central imaging review was 18% (n=8 
of 45 evaluable for response; 95% confidence interval [CI] 8%to 32%) with a median time to 
response of 8 weeks (95% CI 7 to 17 weeks) and a median duration of response (DOR) of 
53 weeks (95% CI 13 weeks to not reached). Median progression-free survival (PFS) and 
overall survival (OS) were 2 (95% CI 2 to 4 months) and 13 (95% CI 5 months to not 
reached) months, respectively. Pembrolizumab was well tolerated with the overall proportion 
of patients with drug related adverse events (AEs) of any grade being 63% (n=38), with the 
most common events being fatigue, pruritus, nausea, decreased appetite, and rash. 
Approximately 17% (n = 10 of 60) of participants experienced Grade 3 or 4 drug-related 
AEs, and 27 participants (45%) experienced a serious adverse event (SAE) [Seiwert, T. Y., et 
al 2016]. 
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Further support for the efficacy and safety of pembrolizumab in HNSCC has been provided 
by a separate report of the larger expansion cohort of the KEYNOTE 012 trial [Chow, L. Q., 
et al 2016]. This Phase 1b, multi-center, clinical trial enrolled a cohort of incurably R/M
HNSCC irrespective of PD-L1 biomarker tumor status and treated these participants with 
pembrolizumab at the fixed dose of 200 mg every 3 weeks. Of the 132 participants enrolled, 
125 participants had tumors that had at least 1% of PD-L1 positivity by IHC in either tumors 
cells or their associated infiltrating immune cells, 28 (21%) were HPV positive, and 
approximately 57% of participants had been treated with at least 2 or more lines of therapy 
for R/M HNSCC. After a median follow-up duration of 9 months, objective response rate 
(ORR) was found to be 18% (95% CI, 12 % to 26%) by independent review, with a median 
time to response of 2 months (range, 2 to 11 months), and a median duration of response that 
was not reached (range, ≥2 to ≥11 months). Progression-free survival and OS were 
2 months (95% CI, 2.0 to 2.2 months) and 8 months (95% CI, 6 to 10 months), respectively. 
For participants whose tumors expressed at least 1% of PD-L1 positivity as described above, 
ORR was further confirmed at 22%.
The safety profile of pembrolizumab remained consistent utilizing the fixed dose of 200 mg 
every 3 weeks, with approximately 62% (n=82) participants experiencing treatment-related 
AEs, and 12 participants (9%) who experienced a Grade 3 or 4 treatment-related AE. Thus, 
both the safety and efficacy of pembrolizumab for R/M HNSCC have been described. 
Additionally, the activity or checkpoint inhibitors for R/M HNSCC have been confirmed as a 
class of agents [Ferris, R. L., et al 2016].
Cutaneous Squamous Cell Carcinoma
Cutaneous squamous cell carcinoma is the second most frequent non-melanoma skin cancer,
representing approximately 20% of all non-melanoma skin cancers and 20% of all skin
cancer deaths. cSCC is diagnosed at a rate of 100 to 150 per 100,000 persons per year in the
US [Vandergriff, T., et al 2010], and is expected to increase as much as 2% to 4% per year. 
The age-adjusted incidence rates of cSCC in Europe is generally lower, with Northern 
European countries such as Norway, Finland, and Denmark, reporting rates <10 per 100,000 
person-years, and the UK, Ireland, and Germany reporting 20 to 30 cSCC cases per 100,000 
person-years [Lomas, A., et al 2012] [Vandergriff, T., et al 2010] [Eisemann, N., et al 
2014]. It is estimated that over 3.3 million persons with non-melanoma skin cancers or 
keratinocyte carcinoma were treated in the US in 2012, with ~ 38% of those cases being 
invasive cSCCs [Rogers, H. W., et al 2015]. Because of the daily exposure of the head
and neck region to the ionizing ultraviolet (UV) rays of the sun, the head and neck region is 
one of the most common anatomic regions for cSCC to develop. Due to its ability to 
metastasize, when not cured by local therapy, cSCC ultimately results in death with mortality 
rates that exceed 70% [Burton, K. A., et al 2016]. The rate of local recurrence and regional 
metastasis may be as high as 20% in tertiary care centers [Moore, B. A., et al 2005]. Patients 
with regional metastasis have 3-year disease-free survival (DFS) rate of 56%. While 5-year
OS ranges from 25% to 35%, 10-year OS appears to be less than 20% [Johnson, T. M., et al 
1992] [Kraus, D. H., et al 1998] [Kwa, R. E., et al 1992].
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cSCC carries a low but significant risk of metastasis and death. A US study of 974 cSCC 
patients at Brigham and Women’s Hospital reported a risk of nodal metastasis of 3.4%
[Karia, P. S., et al 2014], and approximately 3,000 deaths are attributed to locally advanced 
(LA)/high-risk cSCC annually [Jennings, L. 2010] [Brantsch, K. D., et al 2008].
Locally Advanced (LA) high-risk cSCC
LA high-risk cSCC is defined as cSCC that has high-risk features, including regional nodal
disease, and has no distant metastasis. High-risk features of cSCC defined per National 
Comprehensive Cancer Network (NCCN) Guidelines for Squamous Cell Skin Cancer 
[National Comprehensive Cancer Network 2017] include depth of invasion, histologic 
features, anatomical location, horizontal size, perineural involvement, tumor recurrence, 
incomplete excision, multiple tumors, patient characteristics, and genetic/molecular markers 
[Burton, K. A., et al 2016] [National Comprehensive Cancer Network 2017]. The majority of 
patients with cSCC are successfully treated with surgical resection of the primary site. 
Patients with high-risk features are at risk for local recurrence and regional metastasis and 
these patients have significantly worse outcomes compared to those cured by initial surgery.
The Association Between Ultraviolet Light and cSCC
In contrast to basal cell carcinoma (BCC), the development of cSCC has been found to be 
due to multi-step carcinogenic events that accumulate over a lifetime of outdoor UV 
exposure, commonly associated with chronic occupational sun exposure [World Health 
Organization 1992] [International Agency for Research on Cancer 2007]. The typical pattern 
of UV-B induced mutations (C>T transitions), as well as a high frequency of double base 
(CC>TT) transitions, have been found to occur commonly within the p53gene and are 
thought to be an early event in the carcinogenic process [Lawrence, M. S., et al 2013] 
[Davoli, T., et al 2013] [Boukamp, P. 2005]. Of interest, as reviewed by Boukamp, both 
alleles can be affected with each allele carrying a different and mostly UV-type specific 
mutation [Boukamp, P. 2005].
Karyotypic complexity and cytogenetic heterogeneity, most commonly affecting 
chromosomes 3, 8, 5, 9, and 11 have also been implicated in the initiation, maintenance, and 
propagation of this disease [Boukamp, P. 2005]. Ultraviolet-A rays that directly induce 
deoxyribonucleic acid (DNA) damage by inducing double-strand DNA breaks that generate 
genomic instability occur throughout the initiation and development of cSCC. Thus, while 
the UV-B dependent mutational inactivation of p53 may be an early carcinogenic event 
resulting in loss of protection of chromosomal integrity, with continued sun exposure, 
repetitive UV-A exposure propagates genomic and karyotypic instability by inducing DNA 
damage that is not efficiently repaired. It is hypothesized that in this setting of loss of p53 
mediated protective tumor suppression, with time, continued repetitive UV exposure may 
lead to an increase in the number and complexity of chromosomal and cytogenetic 
aberrations. The accumulation of these karyotypic and chromosomal aberrations ultimately 
results in a cumulative high mutational burden within cSCC.
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More recently, Pickering and colleagues attempted to characterize a somatic mutation gene 
signature of cSCC that might be implicated in the propagation of the disease by restricting 
whole exome sequencing of cSCC tissue specimens to those obtained from patients with 
clinically aggressive disease. Similar to HNSCC, the mutational landscape was dominated by 
tumor suppressor genes. Potential novel candidate driver genes were also described (eg,
NOTCH2, PARD3, and RASA1). Importantly, the mutation frequency seen in this analysis, 
was one of the highest reported, with a total of 108,034 mutations in 16,588 genes. This 
mutation frequency was noted to be more than four times higher than the mutation frequency 
for melanoma, as well as higher than the rate of several other squamous cell malignancies, 
including HNSCC [Pickering, C. R., et al 2014].
The Role of HPV Infection and cSCC
Human papilloma viruses replicate exclusively in keratinocytes, are dependent upon 
keratinocyte differentiation to complete their life cycle [Cardoso, J. C. 2011] [Aldabagh, B., 
et al 2013] [Doorbar, J. 2005], and have been historically implicated in the development of 
the common wart (verrucae vulgaris). Subsequent initial evidence for a role for cutaneous 
HPVs in the pathogenesis of skin malignancies came from the identification of HPV 5 and 8 
from patients with epidermodysplasia verruciformis (EV), the rare autosomal recessive 
condition characterized by diffuse wart-like lesions over broad areas of the skin associated 
with a 30% to 50% lifetime risk of progression to invasive cSCC [Cardoso, J. C. 2011]. Since 
then, more than 200 different types of the papillomaviridae family have been identified, with 
approximately 90% of HPV viruses being encompassed by the alpha, beta, and gamma 
genotypes [Bzhalava, D., et al 2014] [Aldabagh, B., et al 2013]. The alpha HPV genotypes 
are associated with mucosal malignancies such as HNSCC, cervical, and anogenital cancers 
(ie, HPV 16, 18, 31, 33, 45). However, the beta genotypes are associated with cutaneous non-
melanoma malignancies that include cSCC and BCC. 
Evidence for HPV involvement in the pathogenesis of cSCC includes the products of the 
early expressed genes, the viral proteins E6 and E7. E6 binds to and mediates the degradation 
of the p53 tumor suppressor gene, while E7 has been shown to activate telomerase and 
inactivate the retinoblastoma protein, thus preventing cell cycle inhibition. Therefore, E6 and 
E7 may act synergistically to facilitate the accumulation of UV-mediated DNA damage. 
Additionally, there is evidence of a dose-response relationship between HPV and cSCC, as 
the risk of development of cSCC has been demonstrated to increase with increasing numbers 
of infection with HPV genus β-species [Farzan, S. F., et al 2013]. Although there seems to be 
consensus for a role for beta HPVs in the initiation of cSCC, the role in the maintenance and 
propagation of the disease is less clear as a greater number of HPV types are present in
premalignant lesions, and the number and frequency of HPV types decrease in 
advanced/metastatic lesions [Hampras, S. S., et al 2016] [Toll, A., et al 2014] [Aldabagh, B., 
et al 2013]. Although there is no consensus regarding the specific HPV species involved in 
cSCC, HPV local infection can vary depending on anatomic location. One study using serial 
skin sampling, showed that HPV DNA from topical skin infection was higher from sun-
exposed areas (forehead and back of hand) compared to non-sun-exposed areas (buttocks)
[Aldabagh, B., et al 2013].
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Ultraviolet light and HPV can interact to alter the body’s local immunity at sun exposed or 
sunburned sites. Increased numbers of HPV DNA species were found in plucked eyebrow 
samples from participants reporting a history of prior sunburns, without any association 
between HPV seropositivity and lifetime sun exposure [Termorshuizen, F., et al 2004]. 
Additional evidence from Cestari et al. demonstrated an altered local T-cell and cell-
mediated response in the UV-radiated skin, thus increasing susceptibility to HPV infection in 
that area [Halprin, K. M., et al 1981] [Cestari, T. F., et al 1995]. Although the immune 
response to HPV infection is both antibody- and cell-mediated, functional T-cell response is 
the major mechanism of immunity against HPV [Aldabagh, B., et al 2013]. Thus UV light 
exposure is hypothesized to promote localized HPV infection through localized cutaneous 
immunosuppression.
Merkel Cell Carcinoma and Responsiveness to Pembrolizumab
Similar to cSCC, the rare neuroendocrine Merkel cell carcinoma (MCC) particularly 
affecting older Caucasian patients is another UV exposure and virally based skin cancer
[Cassler, N. M., et al 2016]. Merkel cells are thought to arise from epidermal stem cells, 
which can also give rise to keratinocytes [Cassler, N. M., et al 2016]. A highly aggressive 
cancer, MCC or primary cutaneous neuroendocrine carcinoma, has been found to be caused 
by 2 independent mechanisms of carcinogenesis – the UV light associated signature of 
mutations associated with increased genomic instability and a high mutational burden, as 
well as the Merkel cell polyomavirus (MCPyV) infection [Cassler, N. M., et al 2016]. 
Approximately 80% of MCC can be directly linked to the clonal integration of the MCPyV
into the host genome. The MCPyV is a double-stranded nonenveloped DNA virus ubiquitous 
in the general population from early childhood, and usually clinically asymptomatic without 
evidence of detectable viremia [Chang, Y. 2012]. However, in the elderly and 
immunosuppressed, where mechanisms of immune surveillance are decreased, disease 
progression has been correlated with increasing detectable viremia [Chang, Y. 2012] 
[Pastrana, D. V., et al 2009] [Tolstov, Y. L., et al 2009] [Touze, A., et al 2011]. 
Using whole exome sequencing and next-generation sequencing, the approximately 20% of
MCC that are MCPyV negative, have been found to have a high mutation burden resulting in 
single nucleotide variants that can be as high as over 1000 per-exome with frequent 
mutations in the p53 and Rb genes [Goh, G., et al 2016] [Harms, P. W., et al 2015]. This high 
mutation burden displayed the distinctive UV signature (C > T, CC>TT) similar to other 
cancers, including cSCC, also resulting in increased genetic instability. Of note, virus 
negative MCC were also shown to harbor more tumor neoantigens than either melanomas or 
non-small cell lung cancer. Moreover, when correlated with PD-L1 expression, MCPyV 
negative tumors that were PD-L1 positive by IHC were found to have a significantly 
increased mutational burden compared with PD-L1 negative tumors [Wong, S. Q., et al 
2015]. In contrast, MCPyV positive MCC harbor very few single nucleotide variants (median 
12.5 SSNVs/tumor), but may initiate tumorigenesis by causing mutational inactivation within 
tumor suppressor genes such as the p53 and RB1 genes and NOTCH signaling pathway.
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In possibly the largest correlation of PD-L1 expression with survival in MCC, evaluating 67 
MCC specimens from 49 patients, consistent with multiple reports of the prevalence of the 
MCPyV in MCC, 78% were found to be virus positive. Of virus positive specimens, 50% 
were PD-L1 positive with the virus co-localizing with the visualized moderate-to-severe 
immune infiltrate in a so-called “adaptive immunity” pattern, and associated with an 
improvement in OS. This was in contrast to MCPyV negative specimens, which were all 
negative for PD-L1 expression and had very little associated infiltrating immune cells and a 
worse survival prognosis. Based on this, it was postulated that checkpoint inhibitor therapy 
may play a therapeutic role in the treatment of MCPyV positive MCC with the role for 
MCPyV negative MCC less clear [Lipson, E. J., et al 2013].
The first prospective clinical trial evidence for a role for checkpoint inhibitor therapy may 
have come from the Phase 1 study of pembrolizumab, in which the 1 of the 2 participants 
with a complete response (CR) were MCC (the other tumor type being metastatic 
melanoma). PD-L1 status was untested in these 2 participants, but these results served to 
confirm the potential clinical utility of checkpoint inhibitors [Patnaik, A., et al 2015]. 
This initial evidence was subsequently confirmed in a multicenter Phase 2 noncontrolled 
clinical trial of participants with advanced MCC not amenable to curative therapy, who had 
received no prior systemic therapy and were all treated with pembrolizumab for a maximum 
of 2 years of continuous treatment, or until a CR was achieved, progressive disease (PD), or 
unacceptable toxicity. Of the 26 evaluable patients with Stage IIIB or IV MCC, based on 
central radiology review, 14 had a confirmed response (4 with CR and 10 with partial 
response [PR]) for an ORR of 56% (95% CI, 35 to 76 patients). An additional one patient 
had an unconfirmed response and was continued on treatment at the time of reporting, and 
another one patient (4%) had stable disease (SD). With a median follow-up of 33 weeks 
(range, 7 to 53 weeks), the DOR ranged from at least 2.2 months to at least 9.7 months. 
Importantly, clinically relevant responses were seen in both MCPyV positive and negative 
participants with response rates of 62% and 44%, respectively. PD-L1 expression (defined as 
at least 1% staining by IHC on tumor cells) was more frequent in virus positive tumors than 
virus negative tumors (71% versus 25%, P=0.049), but, was not required for clinical activity 
of pembrolizumab. Additionally, pembrolizumab was reported to be well tolerated in this 
population (median age = 68 years [range 57-91 years]) with drug-related Grade 3 or 4 AEs
occurring in 15% of patients [Nghiem, P. T., et al 2016]. These results have been 
subsequently confirmed with other checkpoint inhibitors [Kaufman, H. L., et al 2016].
HPV Positive HNSCC and Responsiveness to Pembrolizumab
Further evidence supporting the robust response of checkpoint inhibitors to the dichotomous 
biologies of mutational burden as well as viral etiology within a single tumor type comes 
from HNSCC. In the aforementioned KEYNOTE 012 clinical trial of R/M HNSCC, in which 
all tumors were PD-L1 positive by trial design, similar clinical efficacy was seen in either 
HPV positive or negative disease (25% ORR, range 7-52, and 14% ORR, range 4-32, 
respectively). In the KEYNOTE 012 expansion cohort that enrolled participants whose 
tumors were both PD-L1 positive or negative, response rates were 21% and 27% in HPV 
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positive and HPV negative, respectively [Seiwert, T. Y., et al 2015]. Thus, similar to MCC, 
evidence of broad clinical activity was seen regardless of viral etiology.
Current Therapies for Incurably R/M cSCC
Due to the overall low prevalence of incurably R/M cSCC, no randomized clinical systemic 
therapy trials have been conducted in this malignancy, and evidence based clinical treatment 
guidelines are sparse. Although the overall incidence of this skin cancer is increasing 
worldwide, the overall majority will be cured with local measures such as surgery and/or 
radiotherapy. Metastasis occurs in only about 5% of participants, making it challenging to 
conduct large, randomized trials. 
For early-stage low-risk disease, surgery, with or without adjuvant radiotherapy, is 
commonly employed for the treatment of unresectable disease or localized disease with high 
risk features. In patients with incurably R/M cSCC, no clear consensus regarding treatment 
guidelines exist due to the paucity of robust clinical trial data. National Comprehensive 
Cancer Network (NCCN) guidelines have stated that “cisplatin either as a single agent or 
combined with 5-FU [5-fluorouracil] has occasionally produced useful responses, but data 
supporting efficacy are limited.” European consensus guidelines acknowledge the potential 
clinical utility of platinum- based treatment regimens, as well as 5-fluorouracil (5-FU)-based 
treatment while noting that no established standard regimen exists based on clinical trial 
evidence [Garbe, C., et al 2012]. German guidelines from the German Cancer Society and the 
German Society of Dermatology note that there “is insufficient evidence-based data on 
systemic treatment of metastasized cSCC”; however, outside of clinical trial participation, 
polychemotherapy with cisplatin in combination with 5-FU, or 5-FU monotherapy, or 
cetuximab can be considered. Globally, there are no treatment recommendations from any 
consensus group for second line therapy(ies), thus making the need for well-studied 
treatments for all unresectable and/or metastatic cSCC an unmet clinical need.
One of the only studies acknowledged by the NCCN guidelines is the prospective Phase 2,
single-arm, single institution clinical trial conducted at M.D. Anderson Cancer Center testing 
the combination regimen of interferon alpha, cis-retinoic acid, and cisplatin that enrolled 39 
participants from 1993 to 1999 with unresectable and/or distant metastatic disease. Of the 35 
participants who were assessable for response, the overall ORR was 34% (17% CR and 17% 
PR), and included 1 of 11 participants with metastatic disease who experienced a CR. There 
is no consensus recommendation regarding the use of this regimen in advanced cSCC as it is 
not recommended by the European consensus guidelines. 
Below in Table 1 is a summary of prospective single-arm trials of chemotherapy conducted 
for unresectable and/or distant metastatic disease, all in the first line setting, all conducted 
from approximately 15 to 30 years ago.
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Table 1
Prospective Single-arm Clinical Trials of Chemotherapy for Unresectable and/or 
Metastatic cSCC
Regimen
Line
Study Phase
N
ORR
Year Reported
Cis/Dox
1st
2
3a
67%
1985
Cis/5-FU/Bleomycin
1st
2
14
84%
1990
Cis/5-FU
1st
2
7
86%
1991
Oral 5-FU
1st
2
14
14%
2000
Ifn2/13-cRA
1st
2
32
68%
1992
aThis clinical trial enrolled participants with either cSCC or Basal Cell Carcinoma. Three of the 11 participants 
enrolled had cSCC.
Cis = cisplatin; 13-cRA = 13-cis retinoic acid; cSCC = cutaneous squamous cell carcinoma; Dox = 
Doxorubicin; 5-FU = fluorouracil; Ifn2 = interferon; ORR = objective response rate.
Source: [Guthrie, T. H., et al 1985] [Khansur, T. 1991]
More recently, because of the epithelial origin of cSCC, epithelial growth factor inhibitors 
have been investigated for the treatment of advanced cSCC with modest results. Below in 
Table 2 are the results of 2 single-arm Phase 2 trials assessing these agents in incurably R/M
cSCC.
Table 2
Prospective Single-arm Clinical Trials for Incurable Unresectable and/or 
Metastatic cSCC
Regimen
Line
Study
Phase
N
ORR
Year Reported
Cetuximab
1st
2
36
28%
2011
Panitumumab
1st/2nd
2
16
31%
2014
cSCC = cutaneous squamous cell carcinoma; ORR = objective response rate  
Source: [Foote, M. C., et al 2014]
Similar to MCC, where 2 distinct causes of carcinogenesis have been identified, UV light and 
viral infection, cSCC has also been long considered to be an immunogenic cancer. 
Ultraviolet light associated with a high mutation burden, karyotypic and chromosomal 
instability, and increased neoantigens, as well as chronic HPV infection with T-cell 
dysfunction, make this malignancy a likely candidate to benefit from checkpoint inhibitor 
therapy. In malignancies with dichotomous etiologies such as MCC and HNSCC, checkpoint 
inhibitor therapy has provided similar benefit for each dichotomous subpopulation, and has 
proven to be an important clinical treatment advance for diseases with limited treatment 
options. Therefore, we propose to test the clinical activity of pembrolizumab (MK-3475) in 
unresectable and/or metastatic cSCC, a disease population with limited treatment options and 
a significant unmet clinical need.
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Immunosuppression has long been associated with increased risk of cSCC. Participants with 
prior allogeneic transplantation on chronic immunosuppression have been found to be up to 
65 times as likely to develop the risk of developing an invasive cSCC compared to age-
matched control participants. However, several recent case reports of allograft rejection 
following treatment of anti-PD-1 therapy have recently been described [Spain, L., et al 
2016]. Although there is evidence of robust clinical response in allograft organ recipients, 
including PR and CR, the potential risk for allograft rejection may not justify the potential 
therapeutic benefit. Therefore, participants with a history of prior solid organ or allogeneic 
bone marrow transplant will be excluded in this clinical trial.
Inclusion of First-line (1L) Participants in the Study:
There are regional differences when it comes to recommended standard of care guidelines for 
R/M cSCC. However, widely accepted treatment practice guidelines recommend using either 
platinum based chemotherapy (as monotherapy or in combination with 5-FU) or epidermal 
growth factor inhibitors such as cetuximab. They specifically note that “cisplatin either as a 
single agent or combined with 5-FU has occasionally produced useful responses, but data 
supporting efficacy are limited” [National Comprehensive Cancer Network 2017]. There are 
no prospective Phase 3 studies available, and the supporting data for cytotoxic based 
treatments come from a limited number of smaller single arm Phase 2 trials (Table 1 on 
current therapies for incurable R/M cSCC section summarizes 1L chemotherapy studies). 
One such platinum based Phase 2 study, tested the combination of cisplatin with interferon 
alpha and cis-retinoic acid therapies in 39 patients with R/M cSCC. Of the 35 patients who 
were assessable for response, the ORR was 34% [Shin, D. M., et al 2002]. More recently, 
because of the epithelial origin of cSCC, epithelial growth factor (EGFR) inhibitors have 
been investigated for the treatment of advanced cSCC with modest results (Table 2 on 
current therapies for incurable R/M cSCC section summarizes EGFR inhibitor based studies). 
In a Phase 2 study of cetuximab as first line therapy for patients with unresectable cSCC, 
Maubec et al. reported an ORR of approximately 28%, with a median PFS of 4.1 months and 
mean OS of 8.1 months (median OS not reached) [Maubec, E., et al 2011].
Recent prospective data on cemiplimab (REGN2810), a human anti-PD-1 mAb, provides 
evidence that PD-1 inhibitors, could provide a well-tolerated, effective, and durable response 
in patients with local/regionally advanced or metastatic cSCC. In a Phase 1 open-label study 
(NCT02383212), patients with metastatic cSCC, including 1L metastatic patients (n=10) 
were treated for up to 48 weeks with cemiplimab (3 mg/kg every 2 weeks [Q2W]). Results 
presented by Owonikoko et al [Owonikoko, T. K., et al 2018] at the American Society of 
Clinical Oncology (ASCO) 2018 revealed an ORR, based on RECIST 1.1 by independent 
central review, of 60% (95% CI: 26.2 to 87.8) and a disease control rate (DCR) of 80% (95% 
CI: 44.4 to 97.5) in the metastatic population. Primary analysis of the ongoing pivotal Phase 
2 study (NCT02760498) of cemiplimab (REGN2810) in 59 patients with metastatic cSCC 
reported an ORR of 47.5% (95% CI: 34.3 to 60.9) and DCR of 61.0% (95% CI: 47.4 to 
73.5), as determined by independent review [Rischin, D., et al 2018]. Based on these 
encouraging data demonstrating efficacy of an anti-PD-1 mAb in the 1L metastatic cSCC 
setting, the addition of 1L R/M patients to be treated with pembrolizumab monotherapy is 
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justified by the Sponsor, and this scientifically, peer reviewed data justified the inclusion of 
the 1L R/M population in the KEYNOTE-629 study.
Current Therapies for LA Unresectable cSCC
Currently, there is no widely accepted systemic therapy standard of care therapy for LA
unresectable cSCC [National Comprehensive Cancer Network 2017]. Yet these subjects have 
a substantial risk of disease-specific death, and endure significant morbidity associated with 
disease recurrence. In a retrospective study of 55 patients, treated at 2 tertiary referral centers 
between 1997 and 2006 with T3 and T4 disease of the trunk and extremities (according to the 
2002 AJCC staging guidelines), the overall cancer-specific survival at 5 years was 49.7%; 
and no patients with T4 nor lymph node metastasis were alive at 5 years [de Lima Vazquez, 
V., et al 2011]. 
Although the standard of care for LA high-risk disease is surgical resection and radiotherapy, 
patients with LA cSCC, who are often older and less tolerant of chemotherapy, considered 
medically unfit or not amenable for surgical resection (due to disease with extensive local 
involvement and/or invasion) and have a poor prognosis [Samstein, R. M., et al 2014]. 
Although, these patients might receive modest benefit from radiation therapy, newer 
treatment modalities, including checkpoint inhibitor therapy, can be considered. Recent 
Phase 1 data on cemiplimab (REGN2810), provides evidence of clinical activity of anti-PD-1 
inhibitors in patients with unresectable locally and/or regionally advanced cSCC. In study 
NCT02383212 (discussed above) cemiplimab administered to 16 patients with unresectable 
LA cSCC demonstrated an ORR of 43.8% [Owonikoko, T. K., et al 2018]. Based on the 
encouraging evidence of clinical activity for the checkpoint inhibitor therapeutic class, we 
hypothesize that pembrolizumab would be able to provide substantial clinical benefit for this 
group of patients with an unmet medical need. Therefore, we propose to study 
pembrolizumab in a similar LA population by adding a single arm cohort of participants with 
LA unresectable cSCC to study KEYNOTE-629. 
Benefit/Risk Assessment
Participants in clinical trials generally cannot expect to receive direct benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
Objectives/Hypotheses and Endpoints
All objectives and hypotheses apply to male/female participants aged 18 years or older with 
R/M cSCC and LA unresectable cSCC.
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Objective/Hypothesis
Endpoint
Primary
(1) To estimate the ORR per Response 
Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 as assessed by blinded 
independent central review (BICR). 
(1) Objective response: defined as CR or PR.
Secondary
(1) To evaluate the DOR per RECIST 1.1 as 
assessed by BICR.
(1) DOR: for participants who demonstrate 
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.
(2) To evaluate the DCR per RECIST 1.1 as 
assessed by BICR.
(2) Disease control: defined as CR or PR or 
SD for at least 12 weeks.
(3) To evaluate the PFS per RECIST 1.1 as 
assessed by BICR.
(3) PFS: defined as the time from first day of 
study treatment to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
Note: A new primary low-risk cSCC
lesion is not considered as a PFS event.
(4) To evaluate the OS of the participants.
(4) OS: defined as the time from first day of 
study treatment to death due to any cause.
(5) To determine the safety and tolerability 
of pembrolizumab in study participants 
with R/M cSCC.
(5) AEs.
Study drug discontinuations due to AEs.
Tertiary/Exploratory
(1) To evaluate ORR, DOR, DCR, and PFS 
using immune-related RECIST 
(irRECIST) as assessed by BICR.
(1) ORR, DOR, DCR, and PFS.
(2) To identify molecular (genomic, 
metabolic, and/or proteomic) biomarkers 
that may be indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of MK-3475 and 
other treatments.
(2) Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood ribonucleic acid (RNA) variation, 
proteomics and IHC, and other blood-
derived biomarkers
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Objective/Hypothesis
Endpoint
(3) To investigate the relationship between 
pembrolizumab treatment and the 
checkpoint inhibitor pathway including 
but not limited to PD-L1 and/or PD-L2, 
utilizing newly obtained or archival 
tumor tissue and blood, including serum 
and plasma.
(3) PD-L1 and/or PD-L2 checkpoint 
inhibition pathway at baseline and post-
baseline time points.
(4) To evaluate pharmacokinetic (PK) 
exposure
(4) PK exposure
(5) To evaluate changes from baseline in 
health-related quality of life using the 
EORTC QLQ-C30 and characterize 
utilities using EuroQol EQ-5D.
(5) Changes from baseline in patient-
reported outcome (PRO) assessments at 
post-baseline time points
Study Design
Overall Design
This is a multi-site, open-label, non-randomized, single-arm Phase 2 study of pembrolizumab 
therapy in Male/Female participants aged 18 years or older with R/M cSCC and LA 
unresectable cSCC. 
All participants must obtain baseline radiographic evidence showing measurable disease 
assessed by blinded independent central review (BICR) based on RECIST 1.1 before 
enrollment into this study. Up to approximately 150 study participants will be enrolled in this 
study; 100 with R/M cSCC and 50 with LA unresectable cSCC. It is at the discretion of the 
Sponsor to stop the study or terminate the study earlier due to futility of accrual.
All participants will receive a 200 mg dose of pembrolizumab by IV administration every 
3 weeks (Q3W). Participants will be evaluated at 6 weeks (42 days + 7 days) and then every 
6 weeks (42 days ± 7 days) with radiologic/photographic imaging to assess response to study 
treatment. After 12 months, radiographic/photographic imaging will be conducted every 
9 weeks (63 days ± 7 days). Note: For participants deemed eligible for enrollment by digital 
photography, upon investigator-determined CR, a biopsy is required within 30 days of CR 
for confirmation of CR by central pathology (see Section 9.2.1.8). The primary efficacy 
endpoint will be evaluated by ORR assessed by BICR per RECIST 1.1. Secondary objectives 
include evaluation of safety, DCR, DOR, and PFS per RECIST 1.1 assessed by BICR, and 
OS of the study participants.
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Exploratory endpoints will also be evaluated by ORR, DOR, DCR and PFS based on 
irRECIST as assessed by BICR. Exploratory endpoints also will include PROs as measured 
by EuroQol EQ-5D and EORTC QLQ-C30 questionnaires and exploratory biomarker 
assessment. 
Participants will be monitored carefully for the development of AEs and for clinical and/or 
radiographic evidence of PD according to RECIST 1.1. Adverse events will be monitored
throughout the study and graded in severity according to the guidelines outlined in the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE), Version 4.0. However, central review based on irRECIST (See Section 5.4.1), 
may be used by the investigator for treatment decisions to account for tumor response 
patterns seen with pembrolizumab (eg, tumor pseudoprogression). In participants who have 
initial evidence of radiological PD by RECIST 1.1, it will be at the discretion of the 
investigator whether or not to continue a participant on study treatment until repeat imaging 
is obtained. This clinical judgment decision should be based on the participant’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. 
Participants may continue to receive study treatment until tumor assessment is repeated 
≥4 weeks later in order to confirm PD by irRECIST per the independent central radiologic 
review’s assessment.
Participants may receive pembrolizumab study treatment for up to 35 cycles and no more 
than 24 months of treatment after C1D1. Participants will continue treatment until 
documented PD, unacceptable AE(s) toxicity, intercurrent illness that prevents further 
administration of treatment, investigator’s decision to discontinue treatment, participant 
withdrawal of consent, pregnancy of the participant, participant completes 35 administrations 
of pembrolizumab (no more than 24 months of treatment), or cessation due to administrative 
reasons, at which point they will be discontinued from treatment but continue to be 
monitored in the study except when the subject withdrawals consent resulting in 
discontinuation from the study. Participants will be treated thereafter at the discretion of the 
physician.
Note: Participants who discontinue pembrolizumab after 35 administrations may be eligible 
for up to 17 administrations (approximately one year) of additional study treatment if they 
progress after discontinuing study treatment provided they meet additional criteria. 
Participants who discontinue study treatment before receiving 35 administrations of 
pembrolizumab for reasons other than PD or intolerability, or who attain a CR and 
discontinue study treatment, may also be eligible for up to 17 administrations (approximately 
12 months of retreatment [Second Course Phase] after experiencing PD). The decision to 
begin the second course will be at the discretion of the investigator, provided that the 
participant meets the criteria for treatment, and the study is ongoing (See Section 6.1 and 
6.2).
After the End of Treatment (EoT), each study participant will be followed for 30 days for AE 
and event of clinical interest (ECI) monitoring and 90 days for SAE monitoring. Study 
participants who discontinue treatment for reasons other than PD will have post-treatment 
follow-up of disease status until PD, initiating a non-study cancer treatment, withdrawing 
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consent, or becoming lost to follow-up. All study participants will be followed by telephone 
contact every 12 weeks (84 ± 7 days) for survival until death, withdrawal of consent, 
becoming lost to follow-up, or the end of the study, whichever occurs first. The Sponsor may 
request survival status to be assessed at additional time points during the course of the study. 
For example, survival status may be requested prior to the final analysis. All subjects who are 
in the Survival Follow-Up Phase and not known to have died prior to the request for these 
additional survival status time points will be contacted at that time.
The trial will be conducted in conformance with Good Clinical Practices (GCPs).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
Study Diagram
The study design is depicted in Figure 1.
Figure 1
Trial Design
Number of Participants
Up to approximately 100 study participants with incurably recurrent and/or metastatic cSCC 
and 50 participants with LA unresectable cSCC will be allocated.
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Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, 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.
Clinical Criteria for Early Trial Termination
The clinical trial 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 trial population as 
a whole is unacceptable. In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems, futility of accrual, or the 
number of discontinuations for administrative reasons is too high.
Scientific Rationale for Study Design
This Phase 2 study will evaluate the efficacious advantage of pembrolizumab in participants 
with R/M cSCC or LA unresectable cSCC.
Rationale for Endpoints
Primary Efficacy Endpoints
This study will use ORR based on RECIST 1.1 criteria as assessed by a BICR as the primary 
endpoint. Objective response rate is an acceptable measure of clinical benefit for a late stage 
study that demonstrates safety and efficacy 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 a BICR and RECIST 1.1 to assess ORR is typically considered acceptable by 
regulatory authorities. 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. Real time determination of radiologic progression as determined by central 
review will be communicated to the site. 
Secondary Efficacy Endpoints
Duration of response, DCR, and PFS based on RECIST 1.1 and assessed by BICR, and OS 
are commonly accepted endpoints by both regulatory authorities and the oncology 
community. 
Note: A new primary low-risk cSCC is not considered a PFS event (see Section 9.2.1.6). The 
occurrence of a new primary low-risk cSCC lesion that can be surgically removed without 
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the need for additional radiotherapy and/or systemic therapy would not threaten OS and 
would not be expected to require a clinical need for systemic therapy. The use of 
pembrolizumab will be focused on that of life-threatening disease, which would be the case 
for recurrent/metastatic cSCC.
Overall survival has been recognized as the gold standard for the demonstration of benefit of 
an antineoplastic therapy in randomized clinical studies.
Exploratory Efficacy Endpoints
5.4.1.3.1 Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following the treatment of pembrolizumab. 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 participants may manifest a 
clinical response after an initial increase in tumor burden or even the appearance of new 
lesions. Standard RECIST 1.1 may, therefore, not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab.
Based on an analysis of participants with melanoma enrolled in the KEYNOTE-001 trial, 7% 
of evaluable participants experienced delayed or early tumor pseudo-progression. Of note, 
participants who had PD by RECIST 1.1, but not by irRECIST, had longer OS than 
participants with PD by both criteria. 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 response in immunotherapy and enables treatment beyond initial 
radiographic progression. 
The irRECIST assessment is based on RECIST 1.1 and is adapted to account for the unique 
tumor response seen with immunotherapeutics as described in Nishino et al., CCR 2013
[Nishino, M., et al 2013]. The assessment of unidimensional target lesions and response 
categories per irRECIST are identical to RECIST 1.1. However, MSD has implemented an 
adaptation related to new lesions, non-target lesions, and tumor burden assessment in order to 
confirm radiographic progression. Immune-related RECIST will be used by local site 
investigators to assess tumor response and progression, and to make treatment decisions, as 
well as used by the central imaging vendor in support of the PFS, ORR, DCR, and DOR 
endpoint. For further information on irRECIST, see Section 9.2.1.6.
Rationale for Patient-reported Outcomes
Changes in health-related quality of life (HRQoL) measured using patient-reported outcome 
(PRO) assessments can provide important information on clinical benefit and are accepted 
clinical endpoints by health authorities. Participants will provide information regarding their 
HRQoL using the EORTC QLQ-C30 PRO instrument. Health utilities will be evaluated 
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using the EuroQol-5D (EQ-5D) PRO instrument. These PRO assessments are not pure 
efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability.
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer-specific health-related quality of life 
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology trials [Aaronson, N. K., et al 1993].
EuroQol EQ-5D
The EuroQol-5D is a standardized instrument for use as a measure of health outcome and 
will provide data to develop health utilities for use in health economic analyses [Aaronson, 
N. K., et al 1993]. The 5 health state dimensions in the EQ-5D include the following: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension 
is rated on a 5 point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-
5D also includes a graded (0 to 100) vertical visual analog scale on which the participant
rates his or her general state of health at the time of the assessment. This instrument has been 
used extensively in cancer studies and published results from these studies support its 
validity and reliability [Pickard, A. S., et al 2007].
Rationale for 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. 
Adverse events will be assessed as defined by CTCAE, Version 4.0.
Pharmacokinetic Endpoints
Pharmacokinetics of pembrolizumab will be explored per existing modeling analysis plan 
(MAP).
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of anti-tumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy, as well as determinants of AEs in the 
course of our clinical trials. These efforts will identify novel predictive/PD biomarkers and 
generate information that will better guide single-agent and combination therapy with 
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immune-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood components, 
tumor material, etc.) will be collected to support analyses of cellular components (eg, protein, 
DNA, RNA, metabolites) and other circulating molecules. Investigations may include but are 
not limited to:
5.4.1.7.1 Germline Genetic Analyses
Germline (blood) genetic analyses (eg, single nucleotic polymorphism [SNP] analyses, whole 
exome sequencing, whole genome sequencing): This research will evaluate whether genetic 
variation within a clinical trial population correlates with response to the treatment(s) under 
evaluation. If genetic variation is found to predict efficacy or AEs, the data might inform 
optimal use of therapies in the patient population. Furthermore, it is important to evaluate 
germline DNA variation across the genome in order to interpret tumor-specific DNA 
mutations. 
5.4.1.7.2 Tumor Genetic Analyses
Genetic (DNA) analyses from tumor: The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (ie, mutations, methylation status, microsatellite instability). Key molecular 
changes of interest to immune-oncology drug development include the mutational burden of 
tumors and the clonality of T-cells in the tumor microenvironment. Increased mutational 
burden (sometimes referred to as a ”hyper-mutated” state) may generate neo-antigen 
presentation in the tumor microenvironment. To conduct this type of research, it is important 
to identify tumor-specific mutations that occur across all genes in the tumor genome. Thus,
genome-wide approaches may be used for this effort. Note that in order to understand tumor-
specific mutations it is necessary to compare the tumor genome with the germline genome. 
Microsatellite instability may also be evaluated as this is an important biomarker for some 
cancers (ie, colorectal cancer). 
5.4.1.7.3 Tumor and Blood RNA Analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to a clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
transcriptional pathways) may be evaluated and new signatures may be identified. Individual
genes related to the immune system may also be evaluated (eg, IL-10). MicroRNA profiling 
may also be pursued.
5.4.1.7.4 Proteomic Biomarkers and IHC
Proteomics and IHC using blood or tumor: Tumor and blood samples from this trial may 
undergo proteomic analyses (eg, PD-L1 IHC). PD-L1 protein level in tumor sections,
assessed by IHC, has been shown to correlate with response to pembrolizumab in patients 
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with non-small cell lung cancer (NSCLC), and an in vitro diagnostic (IVD) device has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this 
association may also be true in additional cancer types (ie, triple negative breast cancer, head 
and neck, and gastric). Additional tumor or blood-derived proteins may also correlate with 
response to pembrolizumab. Therefore, tumor tissue may be participant to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
5.4.1.7.5 Other Blood Derived Biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor-derived proteins can be 
shed from tumors and released into the blood. Assays such as enzyme-linked immunosorbent 
(ELISA) measure such proteins in serum. Correlation of expression with response to 
pembrolizumab therapy may identify new approaches for predictive biomarkers in blood,
representing a major advance from today’s reliance on assessing tumor biomarkers. This 
research would serve to develop such assays for future clinical use.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time.  The 
details of future biomedical research are presented in Appendix 6.
Justification for Dose
Rationale for Pembrolizumab Dose
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the KEYTRUDA® development program, 200 mg Q3W is 
the appropriate dose of pembrolizumab across all indications and regardless of tumor type. 
As outlined below, this dose is justified by: 
•
Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W)
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•
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 pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W versus 10 mg/kg Q3W (KN001 B2, KN001 D, KN002, KN010 and KN021), 
and three studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 F2 
and KN006). All of these studies demonstrated flat dose- and exposure-response 
relationships across the doses studied representing an approximate 5 to 7.5 fold difference in 
exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the 
highest doses studied. Subsequently, flat dose-/exposure-response relationships were also 
observed in other tumor types including head and neck cancer, bladder cancer, gastric cancer 
and classical Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type. These findings are consistent with the mechanism of action of 
pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
Study Population
Male/Female participants with R/M cSCC or LA unresectable cSCC ≥18 years of age will 
be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
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Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. R/M disease cohort only – All participants must have cSCC that is either metastatic,
defined as disseminated disease, and/or unresectable disease that is not curable by 
surgery or radiation.
2. Participants must have histologically confirmed cSCC as the primary site of malignancy 
(metastatic skin involvement from another primary cancer or from an unknown primary
cancer is not permitted). 
Note: Participants for whom the primary site of squamous cell carcinoma was anogenital 
area (penis, scrotum, vulva, perianal region) are not eligible. Participants with tumors 
arising on cutaneous non-glabrous (hairbearing) lip with extension onto vermillion (dry 
red lip) may be eligible after communication and approval from the clinical director. 
Participants for whom the primary site is the nose may be eligible after communication 
and approval from the clinical director if the primary site is skin, not nasal mucosa with 
outward extension to skin.
Note: Participants who have squamous cell parotid metastases and have been treated 
previously for cSCC are permitted.
3. LA disease cohort only – Participants must be ineligible for surgical resection.
Contraindications for surgical resection:

cSCC that has recurred in the same location after 2 or more surgical procedures and 
not amenable to curative resection.

cSCC with significant local invasion that prevents total resection.

cSCC in anatomically challenging locations for which surgery is not feasible and may 
result in severe dysfunction and disfigurement (eg, nose, ear, eye resections, or limb 
amputation.
4. LA disease cohort only – Participants who received prior radiation therapy(RT) to index 
site or must be deemed to be not eligible for RT.
Contraindications (Ineligibility) for RT:

cSCC in anatomically challenging locations for which RT would be associated with 
unacceptable toxicity risk.

Patients who have previously received maximum recommended cumulative dose of 
RT at the index site for cSCC.
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5. LA disease cohort only – Participants who received prior systemic therapy for curative 
intent are eligible regardless of regimen.
6. R/M disease cohort only – Participants must have metastatic disease, defined as 
disseminated disease distant to the initial/primary site of diagnosis, and/or must have 
locally recurrent disease that has been previously treated (with either surgery or
radiotherapy) and is not curable by either surgery or radiotherapy.
Note: There is no requirement for prior chemotherapy and/or biological systemic
treatment for incurably recurrent and/or metastatic disease
Note: There is no limit to the number of prior systemic therapies that a participant may 
have received in order to meet eligibility for this trial.
7. Participants must have measurable disease based on RECIST 1.1 as assessed by the 
central imaging vendor. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
Note: The site investigator must confirm the participant has measurable disease per 
RECIST 1.1 prior to submitting to the central vendor.
8. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance 
status of 0 to 1 within 10 days prior to the start of treatment.
9. Participants must have adequate organ function as defined in the following table 
(Table 3). Specimens must be collected within 10 days prior to the start of treatment.
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil 
count (ANC)
≥ 1500 cells/µL without granulocyte colony-stimulating factor (G-
CSF) support within 2 weeks prior to the first dose of study 
treatment
Platelets
≥100 000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L. Participants are eligible if levels are 
reached after blood transfusion.
Renal
aMeasured or 
calculated creatinine 
clearance
(GFR can also be used 
in place of creatinine 
or CrCl)
≤1.5 × ULN OR ≥45 mL/min for participants with creatinine levels 
>1.5 × institutional ULN
Hepatic
bTotal bilirubin
≤1.5 × ULN OR direct bilirubin ≤ ULN for participants with total 
bilirubin levels >1.5 × ULN
AST (SGOT) and 
ALT (SGPT)
≤2.5 × ULN (≤5 x ULN for participants with liver metastases)
Coagulation
cInternational 
normalized ratio 
(INR) OR PT and 
aPTT
≤1.5 × ULN unless participant is receiving anticoagulant therapy as 
long as prothrombin time (PT) or activated partial thromboplastin 
time (aPTT) is within therapeutic range of intended use of 
anticoagulants
a Creatinine clearance should be calculated per institutional standard.
b For participants with Gilbert's disease, total bilirubin may be >1.5 × ULN; however, direct bilirubin must be 
normal.
c Partial thromboplastin time (PTT) may be performed if the local laboratory is unable to perform aPTT.
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); CrCl = creatinine clearance; GFR = glomerular 
filtration rate; ULN = upper limit of normal.
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10. Participants must have a tissue sample adequate for PD-L1 testing as determined by 
central laboratory testing prior to trial allocation. This tissue sample may be obtained
from either a newly obtained core or excisional biopsy, or a prior archival tissue 
specimen. 
Note: Participants from whom PD-L1 testing cannot be performed due to infeasibility of 
testing of the tissue sample will not be eligible.
Note: Submit an evaluable sample for analysis. If submitting unstained cut slides, freshly 
cut slides should be submitted to the testing laboratory within 14 days from when the 
slides are cut. See Section 9.7 – Pharmacodynamics for an explanation.
11. Participants must have a life expectancy of greater than 3 months.
Demographics
12. Be at least 18 years of age on the day of signing the informed consent.
Female participants:
13. Female participants of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
Note: In the event that 72 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for the participant to start receiving study 
medication.
14. A female participant is eligible to participate if she is not pregnant (see Appendix 5), not 
breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR 
b.) A WOCBP who agrees to use an adequate method of contraception as detailed in 
Appendix 5 of this protocol, during the treatment period and for at least 120 days after 
the last dose of study treatment. Note: Abstinence is acceptable if this is the usual 
lifestyle and preferred contraception for the participant. 
Informed Consent
15. The participant (or legally acceptable representative if applicable) must be willing and 
able to provide documented informed consent for the trial. The participant may also 
provide consent for Future Biomedical Research. However the participant may 
participate in the main trial without participating in Future Biomedical Research.
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Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions 
1. Participant has cSCC that can be cured with surgical resection, radiotherapy, or with a 
combination of surgery and radiotherapy.
2. Participant has any other histologic type of skin cancer other than invasive squamous cell 
carcinoma as the primary disease under study, eg, basal cell carcinoma that has not been 
definitively treated with surgery or radiation, Bowen’s disease, MCC, melanoma.
3. Participants with any prior allogeneic solid organ or bone marrow transplantations are 
excluded.
Prior/Concomitant Therapy
4. Participant 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).
5. Participant has received prior systemic anti-cancer therapy including investigational 
agents within 4 weeks prior to allocation. 
Note: Participants must have recovered from all AEs due to previously administered
therapies to ≤ Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be 
eligible.
Note: If a participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting trial treatment.
6. Participant has received prior radiotherapy within 2 weeks of start of trial treatment. 
Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted 
for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS)
disease.
7. Participant has received a live vaccine within 30 days prior to the first dose of trial drug. 
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.
Prior/Concurrent Clinical Study Experience
8. Participant is currently participating in or has participated in a trial of an investigational 
agent or has used an investigational device within 4 weeks prior to the first dose of trial 
treatment.
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Note: Participants who have entered the follow-up phase of an investigational trial may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic assessments
9. Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of trial drug.
10. Participant has a diagnosis and/or has been treated for additional malignancy within the 
past 5 years prior to allocation.
Note: Participants with basal cell carcinoma of the skin or carcinoma in situ (eg, breast 
carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are 
not excluded.
Note: Participants with low-risk early-stage prostate cancer, defined as below are not 
excluded: Stage T1c or T2a with a Gleason score ≤6 and a prostate-specific antigen 
(PSA) (≤10 ng/ml) either treated with definitive intent or untreated in active surveillance 
that has been stable for the past year prior to trial allocation.
11. Participant 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 7 days prior to 
first dose of trial treatment.
12. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
13. Participant has an active autoimmune disease that has required systemic treatment in the 
past 2 years (eg, with use of disease-modifying agents, anticoagulants, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not 
considered a form of systemic treatment and is allowed.
14. Participant has a history of (noninfectious) pneumonitis that required steroids or has 
current pneumonitis.
15. Participant has an active infection requiring systemic therapy.
16. Participant has a known history of human immunodeficiency virus (HIV) infection. 
Note: No HIV testing is required unless mandated by a local health authority.
Note: for participants enrolled from German sites, HIV testing is required as part of 
the screening procedures
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17. Participant 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 or Hepatitis C is required unless mandated by a local 
health authority. 
Note: for participants enrolled from German sites, Hepatitis B and C testing is
required as part of the screening procedures
18. Participant has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the trial, interfere with the participant's 
participation for the full duration of the trial, or is not in the best interest of the participant
to participate, in the opinion of the treating investigator.
19. Participant has a known psychiatric or substance abuse disorder that would interfere with 
the participant’s ability to cooperate with the requirements of the trial.
Other Exclusions
20. Participant is pregnant or breastfeeding or expecting to conceive or father children within 
the projected duration of the trial, starting with the screening visit through 120 days after 
the last dose of trial treatment.
Lifestyle Restrictions
There are no lifestyle restrictions.
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Caffeine, Alcohol, and Tobacco
Caffeine, alcohol and tobacco restrictions are not applicable in this study protocol. 
Activity
There are no limitations on activity during the participation of this trial.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception. For this trial, male participants will be considered to be 
of non-reproductive potential if they have azoospermia (whether due to having had a 
vasectomy or due to an underlying medical condition).
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Participants should be informed that taking the trial medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the trial. In order to participate 
in the trial, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of trial medication initiation (or 14 days prior to the 
initiation of trial medication for oral contraception) throughout the trial period up to 120 days 
after the last dose of trial medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the trial.
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from trial treatment. 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 trial 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 trial personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 9.3.6. 
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently allocated to study medication.  A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events or serious adverse events 
(SAE) meeting reporting requirements as outlined in the entry guidelines.
Participant Replacement Strategy
A participant who discontinues from trial treatment or withdraws from the trial will not be 
replaced.
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Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
The treatments to be used in this trial are outlined below in Table 4.
Table 4
Trial Treatments
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
Pembrolizumab 
(MK-3475)
200 mg
Q3W
Intravenous (IV) 
infusion
Day 1 of each 
cycle
(3 week cycles)
Experimental 
Q3W = every 3 weeks
All study treatments will be administered on an outpatient basis.
Pembrolizumab will be provided centrally by the Sponsor.
For Cycle 1, Day 1, study treatment should be given on the day of treatment allocation, but up to 3 days after 
treatment allocation/randomization is permitted. For all subsequent cycles, +/- 3 days of Day 1 are permitted.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
All supplies indicated in Table 5 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The trial site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product as per local 
guidelines unless otherwise instructed by the Sponsor.
Refer to section 9.1.8 for details regarding administration of the study treatment.
The study treatment to be used in this trial is outlined below in Table 5.
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Table 5
Study Treatment(s)
Study Treatment Name:
Pembrolizumab (MK-3475)
Dosage Formulation:
Solution for intravenous (IV) infusion
Unit Dose Strength(s):
25 mg/mL (100 mg/4 mL)
Dosage Level(s):
200 mg dose per cycle/infusion
Route of Administration:
IV infusion
Sourcing:
Provided centrally by the Sponsor
Dose Modification (Escalation/Titration/Other)
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 6.
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Table 6
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 7. 
Table 7
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 treatment
Participant may be 
premedicated 1.5h 
(± 30 minutes) prior to 
infusion of pembrolizumab
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 treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration.
For further information, please refer to the 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 patient's study record.
Second Course Phase (Retreatment) for Pembrolizumab (MK-3475)
All participants who stop study treatment with SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress 
after stopping trial treatment from the initial treatment phase. This retreatment is termed the 
Second Course Phase of this trial and is only available if the trial remains open and the 
participant meets the following conditions:
Either

Stopped initial treatment with trial treatment after attaining an 
investigator-determined confirmed CR based on RECIST 1.1, and
o
Was treated with at least 8 cycles of trial treatment before discontinuing 
treatment, and
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o
Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared.
OR

Had SD, PR, or CR and stopped trial treatment after completion of 35 administrations 
(approximately 2 years) of trial treatment for reasons other than disease progression 
or intolerability
AND

Experienced an investigator-determined radiographic/cutaneous disease progression 
by RECIST 1.1 after stopping initial treatment, and
o
No new anticancer treatment was administered after the last dose of trial 
treatment, and
o
The participant meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and
o
The trial is ongoing.
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
trial.
Pembrolizumab (MK-3475) Administration
Trial treatment of pembrolizumab (MK-3475) should be administered on Day 1 of each cycle 
after all procedures/assessments have been completed as detailed in Section 2 - Schedule of 
Activities. In general, the window for each visit is ± 3 days unless otherwise noted.
All trial treatments will be administered on an outpatient basis.
Pembrolizumab (MK-3475) will be administered as a 30-minute IV infusion every 3 weeks. 
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 minutes/+
10 minutes).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab (MK-3475) infusion fluid and administration of infusion solution.
Method of Treatment Assignment
Treatment allocation will occur centrally using an interactive voice response system/ 
integrated web response system (IVRS/IWRS).
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Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Blinding
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
treatment administered.
Preparation/Handling/Storage/Accountability
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments 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 treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all trial sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate.  Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
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 
treatments in accordance with the protocol and any applicable laws and regulations.
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Treatment Compliance
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record. 
Refer to Section 7.2.1 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruptions of pembrolizumab.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant.
Listed below are concomitant medications/therapies that are prohibited during the course of 
the trial:

Surgical intervention to a target lesion
Note: During study treatment surgical intervention to the disease under study is 
prohibited. This restriction applies to all skin lesions including actinic keratosis, 
target or non-target lesions. If a lesion is biopsied (not completely resected) and the 
histology is identified as different then cSCC, the case must be discussed between the 
investigator and Sponsor; if the biopsy result of a lesion biopsy confirms cSCC, this 
would be considered progressive disease leading to possible early discontinuation of
study treatment.

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol (other than denosumab for bone 
metastasis)

Chemotherapy not specified in this protocol 

Investigational agents other than pembrolizumab

Radiation therapy
Note: Radiation therapy to a symptomatic solitary nontarget lesion or to the brain 
may be allowed at the investigator’s discretion.
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
Live or live attenuated vaccines within 30 days prior to the first dose of trial treatment 
and while participating in the trial. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, 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.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be 
treated just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are 
not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE that is suspected to have an immunologic etiology. The use of physiologic doses 
of corticosteroids may be approved after consultation with the Sponsor.
Note: Use of prophylactic corticosteroids to avoid allergic reactions (eg, IV contrast 
dye or transfusions) is permitted.
Note: The use of intermittent inhaled steroids or intranasal or local injection of 
corticosteroids is permitted.
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
treatment, but continue to be followed in the trial. 
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 electronic case report form 
(eCRF) including all prescription, over-the-counter (OTC) products, herbal supplements, and 
IV medications and fluids. If changes occur during the trial 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 trial treatment 
and up to 30 days after the last dose of trial treatment should be recorded. All concomitant 
medications administered during SAEs or ECIs are to be recorded. SAEs and ECIs are
defined in Section 9.3.
Rescue Medications & 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 7.2 [Table 6]. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab,
the investigator does not need to follow the treatment guidance. Refer to Table 6 in Section 
7.2 for guidelines regarding dose modification and supportive care.
It may be necessary to perform additional procedures such as bronchoscopy, endoscopy, or
skin photography as part of evaluation of the event.
Treatment After the End of the Study
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study treatment (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
Discontinuation/Withdrawal Criteria
Discontinuation of Study Treatment
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment 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 treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 2 – Schedule of Activities 
and Section 9.10.3 – Discontinued Participants Continuing to be Monitored in the Study.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.9 – Withdrawal/Discontinuation.
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A participant must be discontinued from study treatment 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 treatment.

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 treatment.

The participant has a confirmed positive serum pregnancy test.

Confirmed radiographic disease progression outlined in Section 9.2.1.6 (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

Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 7.2

Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), 
receiving at least 2 doses of pembrolizumab beyond the date when the initial CR was 
declared. These participants may be eligible for second course treatment described in 
Section 7.2.2.

Completion of 35 treatments (approximately 2 years) with pembrolizumab

Note: The number of treatments is calculated starting with the first dose. Participants 
who stop pembrolizumab after receiving 35 doses may be eligible for retreatment if 
they progress after stopping trial treatment, provided they meet the requirements 
detailed in Section 7.2.2. Subjects may be retreated in the Second Course Phase 
(Retreatment) for up to an additional 17 cycles (approximately 1 year).
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, all visits and procedures, as outlined in the trial flowchart, should be completed.
Participants may be allowed to begin study treatment again if deemed medically appropriate.
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Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 9.1.9 – Withdrawal/Discontinuation. 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 8.3.
Lost to Follow Up
1.
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:
2.
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.
3.
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone 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 amount of missing data for the participant will be 
managed via the pre-specified statistical data handling and analysis guidelines.
Study Assessments and Procedures
1.
Study procedures and their timing are summarized in the SoA. 
2.
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
3.
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. 
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4.
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.
Administrative and General Procedures
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical trial or Future Biomedical 
Research. If there are changes to the participant’s status during the trial (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent is in place.
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the trial.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the trial. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the 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.
Specifics about the trial and the trial population are to be included in the trial informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
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Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.
Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research trial. The card will contain trial site contact information (including 
direct telephone numbers) to be used in the event of an emergency. The investigator or 
qualified designee will provide the participant with a Participant Identification Card 
immediately after the participant provides documented informed consent. At the time of 
treatment 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 health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically significant. Details regarding the 
disease for which the participant has enrolled in this trial will be recorded separately and not 
listed as medical history.
Cutaneous Squamous Cell Carcinoma
The investigator or qualified designee will obtain information regarding the participant’s 
cSCC. This information will include, but is not limited to, the presentation at primary 
diagnosis, date and stage at primary diagnosis, date of and stage at most recent recurrence, 
and location of metastases at screening (if applicable).
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Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant
within 28 days before the first dose of trial treatment. Prior treatment for other cancers will 
also be recorded as a prior medication.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.
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 treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 9.10.1. 
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by non-random assignment, and 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.
Treatment Administration
Interruptions from the protocol-specified treatment plan for greater than 12 weeks between 
pembrolizumab doses require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on participant management.
Administration of trial medication will be monitored by the investigator and/or institution 
staff. The total volume of pembrolizumab infused will be compared to the total volume 
prepared to determine compliance with each dose of pembrolizumab administered.
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Timing of Dose Administration
Not applicable.
Withdrawal/Discontinuation
Participants who discontinue study treatment prior to completion of the treatment regimen
should be encouraged to continue to be followed for all remaining study visits.
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 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3 - Adverse Events, Serious Adverse 
Events and Other Reportable Safety Events.
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial 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 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 trial data and 
results.  No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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 trial 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 
trial site.
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Efficacy Assessments
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM). Tumor imaging should be acquired by computed 
tomography (CT, strongly preferred). Magnetic resonance imaging (MRI) should be used 
when CT is contraindicated or for imaging in the brain. The same imaging technique 
regarding modality and use of contrast should be used in a participant throughout the trial to 
optimize the visualization of existing and new tumor burden. Baseline imaging should 
include head, neck, chest, abdomen, and pelvis; imaging of the affected extremities is 
required for those participants with disease in the extremities at baseline. Please refer to the 
SIM for further guidance on required imaging at scheduled assessments.
Note: imaging of the pelvis is not required after the baseline image is obtained with the 
exception of the primary involvement of the pelvis and lower extremities.
Expedited confirmation of measurable disease based on RECIST 1.1 by the central imaging 
vendor at screening will be used to determine participant eligibility. Confirmation of 
measurable disease by the central imaging vendor per RECIST 1.1 is required prior to 
participant enrollment. Although RECIST 1.1 references a maximum of 5 target lesions in 
total and 2 per organ, MSD allows a maximum of 10 target lesions in total and 5 per organ.
For participants with no RECIST 1.1 measurable disease visualized by CT or MRI, 
participants with cutaneous lesions will be considered to have RECIST 1.1 measurable 
disease when the lesion is superficial and ≥ 10 mm in diameter when assessed using calipers.
All scheduled images for all study participants from the sites will be submitted to the central 
imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at an unscheduled time point to determine disease progression, as well as imaging 
obtained for other reasons but captures radiologic progression, should be submitted to the 
central imaging vendor as well. Image submission requirements include imaging acquired at 
off-site facilities while participant is on trial.
Initial Tumor Imaging
Initial tumor imaging including any digital photography at screening must be performed 
within 28 days prior to the date of treatment allocation. The site study team must review 
screening images to confirm the participant has measurable disease per RECIST 1.1 prior to 
submitting to the central vendor. The screening images must be submitted to the central 
imaging vendor for confirmation of measurable disease per RECIST 1.1 for eligibility prior 
to randomization.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality, performed within 28 days prior to the date of 
randomization, and can be assessed by the central imaging vendor.
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Participants with previously treated brain metastases may participate provided they have 
stable brain metastases, ie, without evidence of progression by imaging [confirmed by MRI if 
MRI was used at prior imaging, or confirmed by CT imaging if CT was used at prior 
imaging] for at least 4 weeks prior to the first dose of trial treatment. Any neurologic 
symptoms must have returned to baseline and participants must have no evidence of new or 
enlarging brain metastases, and have not used steroids for brain metastases for at least 7 days
prior to trial initiation as per local site assessment. This exception does not include 
carcinomatous meningitis, as participants with carcinomatous meningitis are excluded 
regardless of clinical stability.
Tumor Imaging During the Trial
The first on-study imaging assessment should be performed at 6 weeks (42 days + 7 days) 
from the date of treatment allocation. Subsequent tumor imaging should be performed every 
6 weeks (42 days ± 7 days) or more frequently if clinically indicated through Year 1. After 
1 year, participants who remain on treatment will have imaging performed every 9 weeks 
(63 days ± 7 days). Imaging timing should follow calendar days and should not be adjusted 
for delays in cycle starts. Imaging should continue to be performed until disease progression 
(unless site principal investigator [PI] elects to continue treatment and follow irRECIST), the 
start of new anti-cancer treatment, withdrawal of consent, death, or notification by the 
Sponsor, whichever occurs first. Following first radiographic indication of disease 
progression, participant management should shift to irRECIST and disease progression 
should be confirmed at least 4 weeks after the first scan indicating PD in clinically stable 
participants. All supplemental imaging must be submitted to the central imaging vendor.
Per RECIST 1.1*, PR and CR should be confirmed by a repeat tumor imaging assessment 
obtained 4 weeks or longer from the date the response was first documented. The tumor 
imaging performed to confirm a response should be performed at the earliest 4 weeks after 
the first indication of response, or at the next scheduled scan. Participants who obtain a 
confirmation scan do not need to undergo the next scheduled tumor imaging if it is ≤4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point. *For 
participants who were deemed eligible via digital photography and who have obtained a CR,
a biopsy is required to be submitted for central pathology review to confirm CR within
30 days of initial confirmation. For participants who have obtained a CR prior to the release 
of Amendment 03, a biopsy is required within 30 days of protocol Amendment 03 approval
in their respective countries for submission to central pathology review (see Section 9.2.1.8).
Per irRECIST (Section 9.2.1.6.), disease progression should be confirmed by the site at least 
4 weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the site investigator until progression is confirmed by the site, provided they 
have met the conditions detailed in Section 9.2.1.6. Participants who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is ≤ 4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if clinically stable. 
Participants who have confirmed disease progression as assessed by the site will discontinue 
trial treatment. Exceptions are detailed in Section 9.2.1.6.
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End of Treatment and Follow-up Tumor Imaging
For participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not required and the participant should continue with the protocol specified tumor imaging 
time points. For participants who discontinue study treatment due to documented disease 
progression, this is the final required tumor imaging if the Investigator elects not to 
implement irRECIST.
In participants who discontinue trial treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 6 weeks in Year 1 or 
9 weeks after Year 1) to monitor disease status until the start of new anti-cancer treatment, 
disease progression, death, or the end of the trial, whichever occurs first.
Second Course (Retreatment) Tumor Imaging
Tumor imaging including any digital photography must be performed within 28 days prior to 
restarting treatment with pembrolizumab. Local reading (investigator assessment with site 
radiology reading) will be used to determine eligibility. Imaging should be submitted to the 
central imaging vendor for retrospective review.
Note: imaging of the pelvis is not required prior to restarting treatment with pembrolizumab 
with the exception of the primary involvement of the pelvis and lower extremities during the 
initial treatment phase.
The first on trial imaging assessment should be performed at 6 weeks (42 days + 7 days) after 
the restart of treatment. Subsequent tumor imaging should be performed every 6 weeks 
(42 days ± 7 days) or more frequently if clinically indicated.
If tumor imaging shows initial PD per RECIST 1.1, tumor assessment should be repeated 
≥4 weeks later in order to confirm PD with the option of continuing treatment while 
awaiting radiologic confirmation of progression. Participants who obtain a confirmation scan 
do not need to undergo scheduled tumor imaging if it is 4 weeks later and may wait until the 
next scheduled imaging time point if clinically stable.
Imaging should continue to be performed until disease progression, the start of new anti-
cancer treatment, withdrawal of consent, death, or notification by the Sponsor, whichever 
occurs first. Disease progression may be confirmed at least 4 weeks after the first tumor 
imaging indicating PD in clinically stable participants. Additional irRECIST details are
described in Section 9.2.1.6.
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In participants who discontinue trial treatment, tumor imaging should be performed at the 
time of treatment discontinuation (± 4 week window). If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory. In participants who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
In participants who discontinue trial treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 6 weeks (42 days ± 7 days) until either the start of a new anti-cancer treatment, disease 
progression, death, or the end of the trial, whichever occurs first.
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 trial therapy). Although RECIST 1.1 references a maximum of 5 
target lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in 
total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
irRECIST Assessment of Disease
Immune-related RECIST is RECIST 1.1 adapted as described below to account for the 
unique tumor response seen with immunotherapeutic drugs. Immune-related RECIST will be 
used by the site investigator/local radiology reviewers to confirm tumor response and 
progression, and make treatment decisions. This data will be collected in the clinical 
database.  
When feasible, participants treated with pembrolizumab should not be discontinued until 
progression is confirmed by the local site investigator/radiology assessment. 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. Participants that are 
deemed clinically unstable are not required to have repeat tumor imaging for confirmation of 
PD. Tumor flare includes any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In participants treated with pembrolizumab who have shown initial evidence of radiological 
PD by RECIST 1.1 as assessed by the site, it is at the discretion of the PI whether to continue 
a participant on trial medication until repeat imaging is obtained (using irRECIST for 
participant management) (Table 8 and Figure 2). This clinical judgment decision by the site 
investigator should be based on the participant’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data. Participants may receive trial 
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medication and the tumor assessment should be repeated ≥4 weeks later in order to confirm 
PD by irRECIST per site assessment. Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values

No decline in ECOG performance status 

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
Any participant deemed clinically unstable should be discontinued from trial treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat imaging for 
PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the local site investigator should consider all target and non-target lesions, as well as any 
incremental new lesion(s).
Disease progression will be considered to be “not confirmed” at repeat imaging if ALL of the 
following occur (as assessed by irRECIST): 

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the local site 
investigator and the participant continues to be clinically stable, treatment may continue and 
follow the regular imaging schedule. 
Disease progression will be considered to be “confirmed” at repeat imaging if ANY of the 
following occur (as assessed by irRECIST):

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
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If repeat imaging confirms PD due to any of the scenarios listed above, participants will be 
discontinued from trial therapy.
NOTE: If a participant has confirmed radiographic progression (ie, 2 scans at least 4 weeks 
apart demonstrating PD) per irRECIST, but the participant is achieving a clinically 
meaningful benefit, and there is no further increase in the tumor burden at the confirmatory 
tumor imaging, an exception to continue treatment may be considered following consultation 
with the Sponsor. In this case, if treatment is continued, tumor imaging should continue to be 
performed following the intervals as outlined in Section 2.0 and be submitted to the central 
imaging vendor.
Note: A new primary low-risk cSCC lesion is not considered as a PFS event. A new primary 
low-risk cSCC should be in an anatomically separate site to the original (Index) cSCC site. A 
new lesion(s) in close proximity (≤5 cm from the index lesion) to the index cSCC lesion site 
should be considered a recurrence unless the lesion originates from the epidermis and is 
completely contained within the dermis with epidermal connection and contains no “high 
risk” features (outlined below). Discussion with the Medical Monitor is required where there 
is uncertainty of new primary cSCC lesion vs recurrence of a lesion. If the new lesion does 
not originate from the epidermis and is confined to the dermis without epidermal connection 
or invading subcutaneous fat tissue, the lesion will be considered as “in-transit metastasis” 
and will be deemed as an event. 
For a lesion to be considered “low risk” per NCCN Guidelines [National Comprehensive 
Cancer Network 2017], the histopathology report needs to confirm the following; well or 
moderately differentiated lesion, no adenoid, adenosquamous, desmoplastic, or metaplastic 
subtypes, <2mm in thickness and no perineural, lymphatic, or vascular involvement. 
Discussion with the Sponsor is required if these criteria are not met and the investigator 
assesses the new lesion as consistent with a new primary cSCC.
Additional details about irRECIST are provided in the MSD TIP Sheet for RECIST 1.1 and 
irRECIST. 
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Table 8
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 
Repeat imaging at ≥4 
weeks at site to 
confirm PD
May continue trial 
treatment at the local site 
investigator’s discretion 
while awaiting 
confirmatory tumor 
imaging by site by 
irRECIST
Repeat imaging at≥4 
weeks to confirm PD 
per physician 
discretion only
Discontinue treatment
Repeat tumor imaging 
confirms PD by 
irRECIST at the local 
site
No additional imaging 
required
Discontinue treatment 
(exception is possible upon 
consultation with Sponsor)
No additional imaging 
required
Not applicable
Repeat tumor imaging 
shows SD, PR, or CR 
by irRECIST at the 
local site
Continue regularly 
scheduled imaging 
assessments 
Continue trial treatment at 
the local site investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart trial treatment if 
condition has improved 
and/or clinically stable per 
investigator’s discretion. 
Next tumor image should 
occur according to the 
regular imaging schedule.
CR = complete response; irRECIST = immune-related response evaluation criteria in solid tumors; PD = progressive disease; PR = partial response; RECIST = 
response evaluation criteria in solid tumors; SD = stable disease
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Figure 2
Imaging and Treatment for Clinically Stable Participants After First Radiologic 
Evidence of PD Assessed by the Site
Photography for Cutaneous Lesions
For participants without RECIST 1.1 measurable disease on CT or MRI scans, digital 
photographs documenting RECIST 1.1 measurable cutaneous lesions must be obtained if the 
cutaneous lesion is included as part of the target lesions assessment according to 
RECIST 1.1. Target cutaneous lesions are defined as superficial lesions which are ≥10 mm 
diameter as assessed using calibers. Any target skin lesion must be followed using color 
photography which includes a ruler to estimate lesion size. Specific guidance on how to 
acquire digital photographs of skin lesions will be provided in the SIM. Any malignant 
cutaneous lesion < 10 mm in diameter can be followed as non-target disease. Copies of the 
color digital photograph must be forwarded to the central imaging vendor for assessment. 
The timing for capturing cutaneous lesion photographs must follow the same schedule as the 
imaging scans. The requirements de-identifying and transmitting the digital photographs to 
the central imaging vendor are located in the SIM.
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Tumor Tissue Collection and Assessment of Disease Recurrence
For participants without RECIST 1.1 measurable disease on CT or MRI scans that were
deemed eligible by digital photography only (see Section 9.2.1.7), a tissue biopsy is required
within 30 days of investigator-determined CR and submitted for central pathology review
and confirmation of the absence of disease. For participants considered to have obtained CR 
prior to the release of Amendment 03, a biopsy is required within 30 days of Protocol 
Amendment 03 approval in their respective countries.
The study pathologists will send the representative specimens (slides) for central pathology 
review, as detailed in the Vendor Manual. The Vendor Manual will outline the standard 
guidelines for pathological evaluation of specimens. A summary note will be provided to the 
study pathologist that includes a general overview of the study.
Communication from surgeon to local pathologist should follow local practice and 
institutional guidelines. Detailed instructions for tissue collection, processing and shipment 
are provided in the Vendor Manual.
In the absence of biopsy confirmed CR, response assessment will be considered as PR; stable 
disease is not considered a response.
Quality of Life Assessments
Patient Reported Outcomes
The EuroQol EQ-5D and EORTC QLQ-C30 questionnaires will be administered by trained 
site personnel and completed electronically by participants in the following order: EuroQol
EQ-5D first, then EORTC QLQ-C30. The questionnaires should be administered prior to 
dosing at Cycle 1, Cycle 2, Cycle 3, every 2 cycles (ie, every 6 weeks) through Year 1, then 
every 3 cycles (ie., every 9 weeks) after Year 1 until End of Treatment, and at the 30-day 
Safety Follow-up Visit.
It is best practice and strongly recommended that electronic patient-reported outcomes 
(ePROs) are administered to randomized participants prior to drug administration, AE
evaluation, and disease status notification. If the participant does not complete the ePROs at a 
scheduled time point, the MISS_MODE form must be completed to capture the reason the 
assessment was not performed.
Adverse Events, Serious Adverse Events and Other Reportable Safety Events
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
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Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, 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, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
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, but before treatment allocation/randomization, must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event causes the participant to be excluded from the trial, or is the result of a 
protocol-specified intervention, including, but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days 
following cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier must be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new 
anticancer therapy  must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the sponsor or designee within the timeframes as indicated in Table 9.
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Table 9
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-
up Period
Timeframe to 
Report Event 
and Follow-up 
Information 
to SPONSOR:
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving 
placebo run-in or 
other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving 
placebo run-in or 
other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported 
– Follow to 
completion/terminat
ion; 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 DILI
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar days
of learning of 
event
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Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE
1.
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 treatment under clinical investigation are met. 
2.
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All Adverse Events will be reported to regulatory authorities, IRB/IECs 
and investigators in accordance with all applicable global laws and regulations, i.e., 
per ICH Topic E6 (R1) Guidelines for Good Clinical Practice.
3.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
4.
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Progression of the cancer under study is not considered a reportable event. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
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Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee), including the pregnancy of a male participant's 
female partner, that occurs during the trial are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events).  If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1.
an overdose of Sponsor's product, as defined in Section 9.4 – Treatment of 
Overdose, that is not associated with clinical symptoms or abnormal 
laboratory results.
2.
an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying 
etiology. The trial site guidance for assessment and follow up of these criteria 
can be found in the Investigator Trial File Binder (or equivalent).
It may also be appropriate to conduct additional evaluation for an underlying etiology in the 
setting of abnormalities of liver blood tests including AST, ALT, bilirubin, and alkaline 
phosphatase that do not meet the criteria noted above. In these cases, the decision to proceed 
with additional evaluation will be made through consultation between the study investigators 
and the Sponsor Clinical Director. However, abnormalities of liver blood tests that do not 
meet the criteria noted above are not ECIs for this trial.
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Treatment of Overdose
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab (MK-3475) by ≥1000 mg (5 times the dose) and as any dose >20%
over the prescribed dose for the standard treatments. No specific information is available on 
the treatment of overdose of pembrolizumab (MK-3475). In the event of overdose, 
pembrolizumab (MK-3475) should be discontinued and the participant should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated.
Safety
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
The investigator or qualified designee will perform a complete physical exam during the
Screening Period. Clinically significant abnormal findings should be recorded as medical
history. The time points for full physical exams are described in Section 2. After the first 
dose of trial treatment, new clinically significant abnormal findings should be recorded as 
AEs.
For cycles that do not require a full physical exam as defined in Section 2, the investigator or
qualified designee will perform a directed physical exam prior to the administration of the 
trial treatment. New clinically significant abnormal findings should be recorded as AEs. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
Vital Signs
Prior to dosing vital signs will be measured after 5 minutes rest and will include temperature,
systolic and diastolic blood pressure, weight, height (screening only), and pulse.
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures once at screening. Clinically significant abnormal findings should be recorded as 
medical history. Additional time points may be performed as clinically necessary.
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. 
1.
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
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underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
2.
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
3.
If laboratory values from non-protocol 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).
4.
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 14 days after the last dose of study 
treatment, 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 trial are 
provided below and Appendix 2. The total amount of blood/tissue to be drawn/collected over 
the course of the trial (from pretrial to post-trial visits), including approximate blood/tissue 
volumes drawn/collected by visit and by sample type per participant can be found in the Trial 
Manual. Refer to the Schedule of Activities (Section 2) for the timing of laboratory 
assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment. (If the screening labs are collected outside 10 days from treatment allocation 
then the Day 1 screening labs will be collected and reviewed before the start of trial 
treatment). Participants eligible for trial retreatment should have imaging performed within 
21 days and laboratory tests performed within 10 days prior to the first dose of trial treatment 
in the Second Course Phase. After Cycle 1, in both the Initial Treatment Phase and the 
Second Course Phase, predose laboratory safety tests can be conducted up to 72 hours prior 
to dosing unless otherwise noted on the flow charts. Urinalysis is only required at the 
screening visit. During the Second Course Phase thyroid laboratory assessments will 
continue to be collected every other cycle after Cycle 5.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Unresolved abnormal 
laboratory values that are drug-related AEs should be followed until resolution. Laboratory 
tests do not need to be repeated after the end of treatment if laboratory results are within the 
normal range. 
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
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Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of the initial trial 
treatment, EOT and 30 days post-treatment. If a urine test is positive or not evaluable, a 
serum test will be required. Participants must be excluded from participation in the event of a 
positive result during screening. In the event of a positive or borderline-positive test result
during the study, the participant must be taken off treatment but continue to be followed (See 
Appendix 5). 
Note: for participants enrolled from German sites, monthly pregnancy testing is required 
while on study therapy.
Performance Assessments
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status (Table 10) at screening, prior 
to the administration of each dose of trial treatment, at all on treatment visits, and during the 
follow-up period as specified in the Schedule of Activities (Section 2).
Table 10
Eastern Cooperative Oncology Group Performance Status
Grade
Eastern Cooperative Oncology Group Performance Status
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light sedentary nature, eg, light house work, 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: [Oken, M. M., et al 1982]
http://www.ecog-acrin.org/resources/ecog-performance-status
Pharmacokinetics
To evaluate the exposure of pembrolizumab in this indication, PK sample collections are 
currently planned as shown in the Schedule of Activities (Section 2). Blood samples for PK 
collected may only be stored. Further analysis may be performed if required. If ongoing PK 
sampling is deemed to be unnecessary by the Sponsor, it may be reduced or discontinued.
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Blood Collection for PK
PK sampling of pembrolizumab will be obtained from all participants. All predose (trough) 
PK samples should be drawn within 24 hours before infusion of pembrolizumab at Cycles 1, 
2, 4, 6, 8 and every 4 cycles thereafter, until discontinuation of study drug (or until the 
participant starts new anti-cancer therapy). Post-dose peak PK samples will be drawn within 
30 minutes after the end of pembrolizumab infusion at Cycle 1.
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Procedures Manual. 
Pharmacodynamics
Tumor Tissue Collection
Tissue for biomarker analysis should be obtained from an archival tissue sample or newly 
obtained core or excisional biopsy of a tumor lesion not previously irradiated. An archived 
tumor tissue sample must be <5 years old. This tissue should come from the site of 
metastasis, if available. Informed consent for the study must be taken prior to collection of a 
fresh biopsy. If the participant provides documented informed consent for Future Biomedical 
Research, any leftover tissue that would ordinarily be discarded at the end of the main study 
will be retained for Future Biomedical Research. Details regarding time points for collection 
of tumor tissue are outlined in the SoA – Section 2. Include a copy of the local pathology 
report with the tissue for biomarker analysis.
For a tumor biopsy to be considered newly obtained (fresh biopsy) the sample from a core or 
excisional biopsy must be obtained from the subject during the screening period.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Procedures Manual.
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover samples listed in Section 9.9
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA (Section 2):

Blood for genetic analysis

Blood for RNA analyses

Blood for plasma biomarker analyses
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
Blood for serum biomarker analyses 

Tumor tissue
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. Procedures Manual Samples should be collected 
for planned analysis of associations between genetic variants in germline/tumor DNA and 
drug response. If a documented law or regulation prohibits (or local IRB/Independent Ethics 
Committee [IEC] does not approve) sample collection for these purposes, then such samples 
should not be collected at the corresponding sites. Leftover DNA extracted from planned 
genetic analysis samples will be stored for future biomedical research only if participant 
provides documented informed consent for Future Biomedical Research.
Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Within 28 days prior to treatment allocation/randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 6.0 Visit 
requirements are outlined in the SoA (Section 2). Screening procedures may be repeated after 
consultation with the Sponsor.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the protocol SoA, including consent review. 
Rescreen procedures cannot be conducted the day prior to treatment allocation/randomization 
if there are Day -1 procedures planned per protocol.
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of trial treatment except for the following:

Evaluation of ECOG is to be performed within 10 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of trial treatment. If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test will be required 
(performed by the local trial site laboratory).
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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.
Treatment Period Visits
Visit requirements are outlined in the Section 2 – Schedule of Activities. Specific procedure-
related details are provided in Section 9.1
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment for a reason other than disease progression will 
be considered as on study and should continue with regularly scheduled assessments 
including collecting participant information on the start of new anticancer therapy, disease 
progression, and death.
Post-treatment Visit
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.
Participants who are eligible for retreatment with pembrolizumab may have up to 2 Safety 
Follow-up Visits, 1 after the Initial Treatment Period and 1 after the Second Course 
Treatment.
Follow-up Visits
Participants who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-up phase and should be assessed every 6 weeks (Q6W) in Year 1 and 
every 9 weeks (Q9W) after Year 1 to monitor disease status. Every effort should be made to 
collect information regarding disease status until the start of new anti-cancer therapy, disease 
progression, death, end of trial (or if the participant begins retreatment with pembrolizumab 
as detailed in [Section 7.2]). Information regarding post-trial anti-cancer treatment will be 
collected if new treatment is initiated.
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 7 will move from the Follow-up Phase to the Second Course Phase when 
they experience disease progression. Details are provided in the Schedule of Activities 
(Section 2) for retreatment with pembrolizumab.
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Survival Follow-up Assessments
Participants who experience confirmed disease progression or start a new anti-cancer 
therapy, will move into the Survival Follow-up Phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the trial, whichever occurs first. 
Post-Study
Participants will be required to return to clinic approximately 30 days after the last dose of 
study treatment for the post-trial visit. If the post-trial visit occurs less than 30 days after the
last dose of study treatment, a subsequent follow-up phone call should be made at 30 days 
post the last dose of study treatment to determine if any AEs have occurred since the post-
trial clinic visit.
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).
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 hypotheses, or the 
statistical methods related to those hypotheses, 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. A separate PK analysis plan as well as biomarker analysis 
plan will be provided. Post-hoc exploratory analyses will be clearly identified in the CSR. 
The PRO analysis plan will also be included in the sSAP.
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Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 10.2-10.12. 
Study Design Overview
Phase 2 trial of pembrolizumab in R/M cSCC or LA 
unresectable cSCC (KEYNOTE-629)
Treatment Assignment
Single-arm, open-label
Analysis Populations
Efficacy: All Participants as Treated (APaT)
Safety: All Participants as Treated (APaT)
Primary Endpoint(s)
ORR per RECIST 1.1 assessed by BICR
Secondary Endpoints
1. DOR per RECIST 1.1 assessed by BICR
2. DCR per RECIST 1.1 assessed by BICR
3. PFS per RECIST 1.1 assessed by BICR
4. OS
Statistical Methods for Key 
Efficacy Analyses
The estimate of the ORR, along with its 95% CI based on 
the Clopper-Pearson method [Clopper, C. J. and Pearson, E. 
S. 1934], will be provided.
Statistical Methods for Key 
Safety Analyses
Counts, percentages and the corresponding 95% 
confidence intervals (CIs) of participants with AEs will 
be provided
Interim Analyses
Periodic data monitoring will be performed by the sponsor. 
Multiplicity
No multiplicity adjustment will be applied.
Sample Size and Power 
The planned sample size is up to approximately 100
participants with R/M cSCC and 50 participants with LA
unresectable cSCC. Section 10.9 provides the precision of 
the ORR estimates.
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 trial is being conducted as a non-randomized, 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.
The clinical biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.
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Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
The definitions of ORR, DOR, DCR, and PFS below apply to the endpoints based on 
RECIST 1.1 as well as the endpoints based on irRECIST. Per RECIST 1.1, PR and CR 
should be confirmed by a repeat tumor imaging assessment obtained 4 weeks or longer from 
the date the response was first documented. 
Objective Response Rate (ORR): proportion of participants in the analysis population who 
have CR or PR.
Duration of Response (DOR): for participants who demonstrate 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.
Disease Control Rate (DCR): DCR is defined as the proportion of participants in the analysis 
population who have CR or PR or SD for at least 12 weeks.
Progression-free Survival (PFS): time from the date of the first dose of study medication to 
the first documented disease progression or death due to any cause.
Overall Survival (OS): time from the date of the first dose of study medication to death due 
to any cause.
Safety Endpoints
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to study treatment, time of onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. Adverse events will be analyzed 
including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Consider 
referring to Section 5.4.1.5 and Section 9.5 for the initial description of safety measures.
Analysis Populations
Efficacy Analysis Population
The All Participants as Treated (APaT) population will be used for the analysis of ORR, 
DCR, PFS, and OS. The APaT population consists of all allocated participants who received 
at least one dose of study treatment.
The analysis population for DOR consists of all responders.
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Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT
population consists of all allocated participants who received at least one dose of study 
treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the supplemental 
SAP. Analyses will be performed by cohort (R/M cSCC participants versus LA unresectable 
cSCC participants).
Statistical Methods for Primary Efficacy Endpoint
The primary endpoint is ORR per RECIST 1.1 assessed by BICR. The point estimate and 
95% CI will be provided using exact binomial method proposed by Clopper and Pearson
(1934) [Clopper, C. J. and Pearson, E. S. 1934]. Participants in the primary analysis 
population (APaT) without ORR data will be counted as non-responders.
Statistical Methods for Secondary Efficacy Endpoints
Duration of Response (DOR)
For DOR, Kaplan-Meier (KM) curves and median estimates from the KM curves will be 
provided. Censoring rules for DOR are summarized in Table 11. 
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
have not initiated new anti-cancer treatment, have not been determined to be lost to follow-
up, and have had a disease assessment within approximately 5 months of the data cutoff date 
are considered ongoing responders at the time of analysis. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied.
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Table 11
Censoring Rules for DOR
Situation
Date of progression or censoring
Outcome
No progression or death, no new anti-cancer 
therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression or death, new anti-cancer 
therapy initiated
Last adequate assessment before new 
anti-cancer therapy initiated
Censor 
(non-event)
Death or progression after ≥ 2 
consecutive missed adequate disease 
assessments or after new anti-cancer 
therapy, if any
Earlier date of last adequate 
assessment prior to ≥ 2 missed 
adequate disease assessments and new 
anti-cancer therapy, if any
Censor 
(non-event)
Death or progression after ≤1 missed 
adequate disease assessments and before 
new anti-cancer therapy, if any
Death or progression
End of response 
(event)
NOTE: Participants are considered to have an ongoing response if censored, alive, have not progressed, have not started a 
new anti-cancer therapy, and have not been determined to be lost to follow-up.
Disease Control Rate (DCR)
The same method used to analyze ORR will be used to analyze DCR.
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve. Since 
disease progression is assessed periodically, progressive disease (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 date of the first assessment at which PD is objectively documented per 
RECIST 1.1 by BICR. Death is always considered as a confirmed PD event. Subjects who do 
not experience a PFS event will be censored at the last disease assessment. 
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the OS curve. 
Summary of Efficacy Analysis Methods
The efficacy endpoints, analysis population, and statistical methods (including missing data 
handling) that will be employed for the efficacy analyses are presented in Table 12.
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Table 12
Summary of Analysis Strategy for Efficacy Endpoints
Endpoint
Statistical Method
Analysis Population
Missing data approach
Primary Endpoint
ORR

RECIST 1.1, BICR
Exact method based 
on binomial 
distribution
APaT
Participants with missing data 
are considered non-responders
Secondary Endpoints
DOR

RECIST 1.1, BICR
Summary statistics 
using Kaplan-Meier 
method
Responders in APaT
population
Censored at last assessment 
date
DCR

RECIST 1.1, BICR
Exact method based 
on binomial 
distribution
APaT
Participants with missing data 
are considered as disease not 
under control
PFS

RECIST 1.1, BICR
Summary statistics 
using Kaplan-Meier 
method
APaT
Censored at last assessment 
date
OS
Summary statistics 
using Kaplan-Meier 
method
APaT
Censored at last date the 
participant was known to be 
alive 
APaT = All Participants as Treated; BICR = Blinded independent central review; DCR = Disease control rate; 
DOR = Duration of response; ORR = Overall response rate; OS = overall survival; PFS = Progression-free 
survival; RECIST = Response Evaluation Criteria In Solid Tumors.
NOTE: Analyses per irRECIST are considered supportive.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. Counts, percentages, and the corresponding 95% CIs of 
participants with AEs will be provided. Analyses will be performed by cohort (R/M cSCC 
participants versus LA unresectable cSCC participants).
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of participants screened, allocated, the primary reasons for 
screening failure, and the primary reason for discontinuation will be displayed. Demographic 
variables (such as age and gender) and baseline characteristics will be summarized either by 
descriptive statistics or categorical tables.
Interim Analyses
Periodic data monitoring will be performed by the sponsor. The timing of interim analyses 
and the final analysis will be documented in the sSAP. The sSAP will also be updated as the 
trial evolves. Participants will continue to be followed after the final analysis until the overall 
trial ends.
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Multiplicity
No multiplicity adjustment will be applied.
Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
In this study, up to approximately 100 participants with R/M cSCC and 50 participants with 
LA unresectable cSCC will be allocated to receive pembrolizumab 200 mg Q3W. With 
expected ORR to be at least 30% for R/M cSCC participants, the study has >95% power to 
have the lower bound of the 95% CI >15%. Table 13 shows the two-sided 95% CI for ORR 
with 100 R/M cSCC participants for different objective response rates. With expected ORR 
to be at least 40% for LA unresectable cSCC participants, the study has 84.4% power to have 
the lower bound of the 95% CI >20%. Table 14 shows the two-sided 95% CI for ORR with 
50 LA unresectable cSCC participants for different objective response rates. The calculations 
are based on the exact binomial method by Clopper and Pearson (1934) [Clopper, C. J. and 
Pearson, E. S. 1934].
Table 13
Two-sided 95% CI for ORR with 100 R/M cSCC Participants
Number of 
Responders
ORR Estimate (%)
95% CI† of 
ORR (%)
Probability that Lower 
Bound of 95% CI > 15%
20
20
(12.7, 29.2)
26.1%
25
25
(16.9, 34.7)
71.4%
30
30
(21.2, 40.0)\
95.2%
35
35
(25.7, 45.2)
99.7%
40
40
(30.3, 50.3)
>99.9%
45
45
(35.0, 55.3)
>99.9%
50
50
(39.8, 60.2)
>99.9%
55
55
(44.7, 65.0)
>99.9%
60
60
(49.7, 69.7)
>99.9%
†  Based on the two-tailed exact CI of a binomial proportion (Clopper and Pearson, 1934).
CI = Confidence interval; cSCC=cutaneous squamous cell carcinoma; ORR = Objective response rate. CI = 
Confidence interval; R/M=recurrent/metastatic
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Table 14
Two-sided 95% CI for ORR with 50 LA Unresectable cSCC Participants
Number of 
Responders
ORR Estimate 
(%)
95% CI† of 
ORR (%)
Probability that Lower 
Bound of 95% CI > 20%
20
40
(26.4, 54.8)
84.4%
23
46
(31.8, 60.7)
96.9%
25
50
(35.5, 64.5)
99.2%
28
56
(41.3, 70.0)
>99.9%
30
60
(45.2, 73.6)
>99.9%
33
66
(51.2, 78.8)
>99.9%
35
70
(55.4, 82.1)
>99.9%
†  Based on the two-tailed exact CI of a binomial proportion (Clopper and Pearson, 1934).
CI = Confidence interval; cSCC=cutaneous squamous cell carcinoma; LA=locally advanced; ORR = Objective 
response rate.
Sample Size and Power for Safety Analyses
The estimate of and the 95% CI for the percentage of participants experiencing AEs given 
various hypothetical observed number of participants experiencing AEs are provided in 
Table 15 for 100 R/M cSCC participants and in Table 16 for 50 LA unresectable cSCC 
participants. These calculations are based on the exact binomial method by Clopper and 
Pearson (1934) [Clopper, C. J. and Pearson, E. S. 1934].
Table 15
Estimate of and 95% CI for Incidence of Participants Experiencing AEs With 100
R/M cSCC Participants
Hypothetical Number of 
Participants With AEs
Estimate of 
Incidence (%)
95% CI† (%)
70
70
(60.0, 78.8)
75
75
(65.3, 83.1)
80
80
(70.8, 87.3)
85
85
(76.5, 91.4)
90
90
(82.4, 95.1)
95
95
(88.7, 98.4)
† Based on the two-tailed exact CI of a binomial proportion (Clopper and Pearson, 1934).
AE=adverse event; cSCC=cutaneous squamous cell carcinoma; CI=confidence interval; 
R/M=recurrent/metastatic.
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Table 16
Estimate of and 95% CI for Incidence of Participants Experiencing AEs With 50 
LA Unresectable cSCC Participants 
Hypothetical Number of 
Participants With AEs
Estimate of 
Incidence (%)
95% CI† (%)
35
70
(55.4, 82.1)
38
75
(61.8, 86.9)
40
80
(66.3, 90.0)
43
85
(73.3, 94.2)
45
90
(78.2, 96.7)
48
95
(86.3, 99.5)
† Based on the two-tailed exact confidence interval of a binomial proportion (Clopper and Pearson, 1934).
AE=adverse event; cSCC=cutaneous squamous cell carcinoma; CI=confidence interval; LA=locally advanced.
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the treatment effect (with a nominal 95% CI) for the primary endpoint will be 
estimated and plotted within each category of the following classification variables: 

Age category (<65 versus ≥65 years)

Sex (female versus male)

Race (white versus all others)

Region (North America versus European Union versus Rest of the World)
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
Extent of Exposure for a participant is defined as the number of cycles in which the 
participant receives the study medication infusion. Summary statistics will be provided on 
extent of exposure for the APaT population.
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activity of pembrolizumab for treatment of 
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Oncol. 2016 May 27. [Epub ahead of print].
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Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation/Term
Definition
2L
Second line
ADA
Anti-drug antibody
ADL
Activities of daily living
AE
Adverse event
ALT
alanine aminotransferase
AMA
American Medical Association
ANC
absolute neutrophil count
APaT
All Participants as Treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
β-HCG
beta human chorionic gonadotropin
BCC
Basal cell carcinoma
BCG
Bacillus Calmette-Guérin
BICR
Blinded independent central review
BUN
blood urea nitrogen
CAC
Clinical Adjudication Committee
CD3ζ
CD3 zeta
CFR
Code of Federal Regulations 
CI
confidence interval
cHL
classical Hodgkin lymphoma
CNS
Central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease caused by severe acute respiratory 
syndrome coronavirus 2
CR
complete response
CrCl
Calculated creatinine clearance
CRF
case report form
cSCC
Cutaneous squamous cell carcinoma
CSR
Clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
cytotoxic T-lymphocyte-associated antigen-4
CTR
Clinical Trials Register
DCR
Disease control rate
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid
DOR
duration of response
ECI
Event of clinical interest
ECG
electrocardiogram
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Abbreviation/Term
Definition
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
electronic data capture
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EORTC
European Organization for Research and Treatment of 
Cancer
EoT
End of Treatment
ePRO
electronic patient-reported outcome
ERC
Ethics Review Committee
ERCs
European Research Councils
EU
European Union
EuroQol
European Quality of Life
EV
Epidermodysplasia verruciformis
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FNA
fine needle aspirate
FSH
Follicle stimulating hormone
FT4
free thyroxine
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HNSCC
Head and neck squamous cell carcinoma
HPV
human papillomavirus
HRT
Hormonal replacement therapy
IB
Investigator’s Brochure
IA(s)
interim analysis(ses)
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgV
Ig-variable–type
IHC
immunohistochemistry
INR
international normalized ratio
irAE
immune-related adverse event
IRB
Institutional Review Board
irRECIST
immune-related RECIST
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
intravenous
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Abbreviation/Term
Definition
IVD
In vitro diagnostic
IVRS
interactive voice response system
IWRS
integrated web response system
KM
Kaplan-Meier
LA
locally advanced
mAb
monoclonal antibody
MCC
Merkel cell carcinoma
MCPyV
Merkel cell polyomavirus
MRI
magnetic resonance imaging
mRNA
Messenger RNA
NCI
National Cancer Institute
NSAID
nonsteroidal anti-inflammatory drug
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PCL
Protocol Clarification Letter
PD
progressive disease
PD-1
Programmed Cell Death 1 
PD-L1
Programmed Death Ligand 1
PD-L2
Programmed Death Ligand 2
PFS
progression-free survival
PI
Principal investigator
PK
pharmacokinetic
PKCθ
Protein kinase C-theta
PR
partial response
PRO
Patient reported outcome
PSA
Prostate-specific antigen
PT
prothrombin time
PTT
partial thromboplastin time
Q3W
every 3 weeks
Q6W
Every 6 weeks
Q12W
Every 12 weeks
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
R/M
Recurrent and/or metastatic
RNA
ribonucleic acid
RT
radiation therapy
SAC
Scientific Advisory Committee
SAE
serious adverse event
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SIM
Site Imaging Manual
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Abbreviation/Term
Definition
SNP
Single nucleotic polymorphism
SoA
Schedule of Activities
sSAP
Supplemental Statistical Analysis Plan
SUSAR
Suspected unexpected serious adverse reactions
Treg
Regulatory T-cell
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
TIL
tumor-infiltrating lymphocyte
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
UV
Ultraviolet
WBC
white blood cell
WOCB
Woman of childbearing potential
ZAP70
Zeta-chain–associated protein kinase
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Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 17 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6.1 and 6.2 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 17
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count 
RBC indices:
MCV
MCH
WBC count with 
differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC count
Hemoglobin 
Hematocrit
Coagulationa
(screening)
PT (INR)
aPTTb
Chemistry
Blood Urea 
Nitrogen 
(BUN)c
Potassium
Aspartate 
aminotransferase
(AST)/Serum 
glutamic-oxaloacetic 
transaminase (SGOT)
Total bilirubin (and 
direct bilirubin, if total 
bilirubin is elevated 
above the upper limit 
of normal)
Carbon 
dioxide or 
bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
aminotransferase
(ALT)/Serum 
glutamic-pyruvic 
transaminase (SGPT)
Total protein
Glucose 
(nonfasting)
Calcium
Alkaline phosphatase
Ureac
Routine 
urinalysisd

Specific gravity

Glucose, protein, blood (by dipstick)

Microscopic examination (if blood or protein is abnormal)
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Laboratory 
Assessments
Parameters
Other 
screening tests

Follicle-stimulating hormone and estradiol (as needed in women of non-
childbearing potential only)

Total T3 or free T3, FT4, and TSHe

Serum or urine beta-human chorionic gonadotropin (β-HCG) pregnancy test 
(as needed for women of childbearing potential)

HIV/HBV/HCV Serology
aPTT = activated partial thromboplastin time; FT4 = free thyroxine; INR = international normalized ratio; 
MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; PT = prothrombin time; RBC = 
red blood cell; T3 = total triiodothyronine; TSH = thyroid stimulating hormone; WBC = white blood cell.
a Any participant receiving anticoagulant therapy should have coagulation tests monitored closely 
throughout the trial.
b PTT may be performed if the local laboratory is unable to perform aPTT.
c Blood Urea Nitrogen is preferred; if not available, urea may be tested.
d Urinalysis required at screening only
e   If the local laboratory is unable to perform these tests, the site should submit the sample to the central 
laboratory for testing.  
  NOTE: Additional details are provided in the Procedures Manual.
Investigators must document their review of each laboratory safety report.
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Appendix 3: Study Governance Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
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3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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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 and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the
protocol, agree to support these ethical and scientific standards.
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.
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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 which 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.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/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 trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of 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 trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the participant 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form 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 trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission.  This allows the sponsor to protect 
proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  MSD, as Sponsor of this trial, 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 trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.  
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Compliance With Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all 
applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the MSD Code of Conduct for Clinical Trials.
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The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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. 
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
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 
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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, 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. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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 trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
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 treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the sponsor for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are 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 treatment 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 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, 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). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 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 9.3.5 for protocol specific exceptions
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 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation.  (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event).  A pre-existing condition is a clinical condition 
that is diagnosed prior to the use of a MSD product and is documented in the patient’s
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one 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.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
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 Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by the Sponsor. In this case, all participant identifiers, with the exception of 
the participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
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Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology Criteria 
for Adverse Events (CTCAE), version [4.0]. Any AE which changes CTCAE grade 
over the course of a given episode will have each change of grade recorded on the AE
CFRs/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 adverse event?
●
The determination of the likelihood that the Sponsor's product caused the adverse 
event will be provided by an investigator who is a qualified physician.  The 
investigator’s signed/dated initials on the source document or worksheet that supports 
the causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done.  This initialed document must be retained for the required 
regulatory time frame.  The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test 
product and the adverse event based upon the available information
●
The following components are to be used to assess the relationship between 
the Sponsor's product and the AE; the greater the correlation with the 
components and their respective elements (in number and/or intensity), the more 
likely the Sponsor's product caused the adverse event:
●
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 trials with investigational 
medicinal product)?
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●
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 trial is a single-dose drug trial); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death 
or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF 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 INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the case report forms /worksheets
by an investigator who is a qualified physician according to his/her best clinical 
judgment, including consideration of the above elements.
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●
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 one of the criteria used when determining regulatory 
reporting requirements
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.
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and Other Reportable Safety Event Reporting to Sponsor via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information 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 electronic data collection 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 electronic data collection 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 Trial File Binder (or 
equivalent).
SAE Reporting to the Sponsor via Paper CRF
●
If the electronic data collection 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 Trial File Binder (or equivalent).
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal 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 non-hormonal 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.
Highly Effective Contraception Requirements
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 18
during the protocol-defined time frame in Section 6.1. 
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Table 18
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b
●
Intrauterine hormone-releasing system (IUS)
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner 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. 
●
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 treatment. 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.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and 
correctly). If a contraceptive method listed is restricted by local regulations/guidelines, then it does not 
qualify as an acceptable method of contraception for participants participating at sites in this 
country/region.
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
Note: The following are not acceptable methods of contraception:

Periodic abstinence (calendar, sympothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhea method (LAM). 

Male condom with cap, diaphragm, or sponge with spermicide.

Male and female condom should not be used together (due to risk of failure with friction).
  
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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 at EOT and 
30 days, after the last dose of study treatment and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
Monthly pregnancy testing should be conducted as per local regulations where applicable.
Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
the end of relevant systemic exposure.
Note: for participants enrolled from German sites, monthly pregnancy testing is required 
while on study therapy.
Female participants of childbearing/reproductive potential must have a negative urine or 
serum pregnancy test within 72 hours prior to randomization. If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
Note, in the event that 72 hours have elapsed between the screening pregnancy test and the 
first dose of study treatment, another pregnancy test (urine or serum) must be performed and 
must be negative in order for participant to start receiving study medication.
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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 Research3,4
The specimens consented and/or collected in this trial as outlined in Section 9.8 – Future 
Biomedical Research Sample Collection will be used in various experiments to 
understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
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3. Summary of Procedures for Future Biomedical Research3,4
a.
Participants for Enrollment
All participants enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
trial visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the participants on the visit designated in 
the trial flow chart.  If delayed, present consent at next possible Participant Visit.  
Consent forms signed by the participant will be kept at the clinical trial site under 
secure storage for regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for Future Biomedical Research will be 
captured in the electronic Case Report Forms (eCRFs). Any specimens for which 
such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the participant is having blood drawn for other trial purposes.
4. Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
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identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the trial site.  No personal identifiers will 
appear on the specimen tube.  
5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices.  Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in Future Biomedical Research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial. If 
medical records for the main trial 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 main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research trial data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main trial are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens3,4
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
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Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3,4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3,4
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 Population3,4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research3,4
For future biomedical research, risks to the participant have been minimized. No 
additional risks to the participant have been identified as no additional specimens are 
being collected for Future Biomedical Research (i.e., only leftover samples are being 
retained).
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
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12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA AND SAMPLE CODING CATEGORIES - E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. Understanding the Intent, Scope and 
Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
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