A Phase 1 Randomized Clinical Study of Pembrolizumab (MK-3475) to Evaluate the Relative Bioavailability of Subcutaneous Injection Versus Intravenous Infusion in Participants With Advanced Melanoma (KEYNOTE-555)
Phase: PHASE1
Conditions: Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 1 Randomized Clinical Study of 
Pembrolizumab (MK-3475) to Evaluate the Relative 
Bioavailability of Subcutaneous Injection Versus 
Intravenous Infusion in Participants with Advanced 
Melanoma KEYNOTE-555)
NCT03665597
19-Apr-2021

PRODUCT: MK-3475 
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 1 Randomized Clinical Study of Pembrolizumab (MK-3475) to 
Evaluate the Relative Bioavailability of Subcutaneous Injection Versus Intravenous Infusion 
in Participants with Advanced Melanoma (KEYNOTE-555)
Protocol Number: 555-02
Compound Number: MK-3475
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
NA
Approval Date: 19 April 2021
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-555-02
19-APR-2021
To update the dose modification and toxicity management guidelines for 
irAEs.
3475-555-01
28-SEP-2018
To add an additional cohort of 100 participants (Cohort B) who will receive 
400 mg IV pembrolizumab Q6W from C1D1.
3475-555-00
06-JUN-2018
To estimate the relative bioavailability of an SC versus an IV dose of 
pembrolizumab, and to characterize the PK profile of pembrolizumab SC.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 02
Overall Rationale for the Amendments:
To harmonize the presentation of safety information across all FDA-approved PD-1/L1 antibody prescribing information.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
6.6.1
Immune-Related 
Events and Dose 
Modification (Withhold, 
Treat, Discontinue)
The dose modification and toxicity 
management guidelines for irAEs and 
table were updated.
The dose modification and toxicity management 
guidelines for irAEs and table were updated as requested 
by the U.S. FDA in an effort to harmonize the 
presentation of safety information across all FDA-
approved PD-1/L1 antibody prescribing information.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA)................................................................................20
1.3.1
Schedule of Activities in the Screening, Treatment, and Follow-up 
Periods..........................................................................................................20
1.3.2
Pembrolizumab PK and ADA Sampling in the Treatment Period ..............31
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.2
Background ..........................................................................................................33
2.2.1
Pharmaceutical and Therapeutic Background .............................................34
2.2.2
Pre-clinical and Clinical Studies..................................................................34
2.2.3
Ongoing Clinical Studies.............................................................................35
2.2.4
Information on Other Study-related Therapy ..............................................35
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................35
4
STUDY DESIGN............................................................................................................38
4.1
Overall Design......................................................................................................38
4.2
Scientific Rationale for Study Design.................................................................39
4.2.1
Rationale for Endpoints ...............................................................................39
4.2.1.1
Safety Endpoints................................................................................39
4.2.1.2
Pharmacokinetic Endpoints ...............................................................39
4.2.1.3
Antidrug Antibodies (ADA) ..............................................................40
4.2.1.4
Efficacy Endpoints.............................................................................40
4.3
Justification for Dose...........................................................................................42
4.4
Beginning and End of Study Definition .............................................................43
4.4.1
Clinical Criteria for Early Study Termination .............................................44
5
STUDY POPULATION ................................................................................................44
5.1
Inclusion Criteria.................................................................................................44
5.2
Exclusion Criteria................................................................................................47
5.3
Lifestyle Considerations......................................................................................49
5.3.1
Meals and Dietary Restrictions....................................................................49
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................49
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5.3.3
Activity Restrictions ....................................................................................49
5.3.4
Contraception...............................................................................................49
5.3.5
Pregnancy.....................................................................................................50
5.3.6
Use in Nursing Women................................................................................50
5.4
Screen Failures.....................................................................................................50
5.5
Participant Replacement Strategy......................................................................50
6
STUDY INTERVENTION............................................................................................51
6.1
Study Intervention(s) Administered...................................................................52
6.1.1
Medical Devices...........................................................................................53
6.2
Preparation/Handling/Storage/Accountability .................................................53
6.2.1
Dose Preparation..........................................................................................53
6.2.2
Handling, Storage, and Accountability........................................................53
6.3
Measures to Minimize Bias: Randomization and Blinding..............................54
6.3.1
Intervention Assignment..............................................................................54
6.3.2
Stratification.................................................................................................55
6.3.3
Blinding........................................................................................................55
6.4
Study Intervention Compliance..........................................................................55
6.5
Concomitant Therapy..........................................................................................55
6.5.1
Rescue Medications and Supportive Care ...................................................56
6.6
Dose Modification (Escalation/Titration/Other)...............................................57
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................57
6.7
Intervention After the End of the Study............................................................63
6.8
Clinical Supplies Disclosure................................................................................63
6.9
Standard Policies..................................................................................................63
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................64
7.1
Discontinuation of Study Intervention...............................................................64
7.2
Participant Withdrawal From the Study...........................................................65
7.3
Lost to Follow-up .................................................................................................65
8
STUDY ASSESSMENTS AND PROCEDURES........................................................66
8.1
Administrative and General Procedures ...........................................................66
8.1.1
Informed Consent.........................................................................................66
8.1.1.1
General Informed Consent.................................................................67
8.1.2
Inclusion/Exclusion Criteria ........................................................................67
8.1.3
Participant Identification Card.....................................................................67
8.1.4
Medical History ...........................................................................................67
8.1.5
Prior and Concomitant Medications Review...............................................68
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8.1.5.1
Prior Medications...............................................................................68
8.1.5.2
Concomitant Medications..................................................................68
8.1.6
Assignment of Screening Number...............................................................69
8.1.7
Assignment of Treatment/Randomization Number.....................................69
8.1.8
Study Intervention Administration ..............................................................69
8.1.8.1
Timing of Dose Administration.........................................................69
8.1.9
Discontinuation and Withdrawal .................................................................70
8.1.10
Participant Blinding/Unblinding..................................................................70
8.1.11
Domiciling ...................................................................................................70
8.1.12
Calibration of Equipment.............................................................................70
8.2
Efficacy/ Assessments ..........................................................................................71
8.2.1
Tumor Imaging and Assessment of Disease................................................71
8.2.1.1
Initial Tumor Imaging........................................................................72
8.2.1.2
Tumor Imaging During the Study......................................................72
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................73
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................73
8.2.1.5
iRECIST Assessment of Disease.......................................................74
8.3
Safety Assessments...............................................................................................76
8.3.1
Adverse Events ............................................................................................77
8.3.2
Physical Examinations.................................................................................77
8.3.2.1
Full Physical Examination.................................................................77
8.3.2.2
Directed Physical Examination..........................................................77
8.3.3
Vital Signs....................................................................................................77
8.3.4
Electrocardiograms ......................................................................................77
8.3.5
Clinical Safety Laboratory Assessments .....................................................78
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................78
8.3.5.2
Pregnancy Test...................................................................................79
8.3.6
Performance Assessments............................................................................79
8.3.6.1
Eastern Cooperative Oncology Group Performance Scale................79
8.3.7
Injection Site Signs and Symptoms Questionnaire......................................79
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................79
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................80
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......82
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...82
8.4.4
Regulatory Reporting Requirements for SAE .............................................82
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8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................82
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................83
8.4.7
Events of Clinical Interest (ECIs)................................................................83
8.4.8
Medical Device Incidents (Including Malfunctions)...................................83
8.5
Treatment of Overdose........................................................................................83
8.6
Pharmacokinetics.................................................................................................83
8.6.1
Blood Collection for Plasma for Pembrolizumab Pharmacokinetics and 
Immunogenicity ...........................................................................................84
8.6.1.1
Blood Collection for Pharmacokinetics.............................................84
8.6.1.2
Blood Collection for Anti-pembrolizumab Antibodies .....................84
8.7
Pharmacodynamics..............................................................................................84
8.8
Future Biomedical Research Sample Collection...............................................84
8.9
Planned Genetic Analysis Sample Collection....................................................84
8.10
Biomarkers ...........................................................................................................84
8.10.1
RNA Transcriptome Research .....................................................................84
8.10.2
RNA Expression Research of a Subset of RNA Species.............................84
8.10.3
Proteome Research.......................................................................................85
8.10.4
Metabolomic Research.................................................................................85
8.11
Visit Requirements...............................................................................................85
8.11.1
Screening......................................................................................................85
8.11.2
Treatment Period..........................................................................................85
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ..........86
8.11.3.1
Follow-up Visits.................................................................................86
8.11.3.2
Safety Follow-up Visit.......................................................................86
8.11.3.3
Survival Follow-up ............................................................................87
8.11.4
Survival Status .............................................................................................87
9
STATISTICAL ANALYSIS PLAN .............................................................................87
9.1
Statistical Analysis Plan Summary.....................................................................87
9.2
Responsibility for Analyses/In-house Blinding .................................................90
9.3
Hypotheses/Estimation ........................................................................................90
9.4
Analysis Endpoints...............................................................................................90
9.4.1
Pharmacokinetics Endpoints (Cohorts A and B) .........................................90
9.4.2
Safety Endpoints (Cohorts A and B) ...........................................................90
9.4.3
Efficacy Endpoints (Cohort B) ....................................................................91
9.4.3.1
Primary...............................................................................................91
9.4.3.2
Secondary...........................................................................................91
9.5
Analysis Populations............................................................................................91
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9.5.1
Pharmacokinetic Analysis Population (Cohorts A and B)...........................91
9.5.2
Safety Analysis Population (Cohorts A and B) ...........................................92
9.5.3
Efficacy Analysis Population (Cohort B) ....................................................92
9.6
Statistical Methods...............................................................................................92
9.6.1
Statistical Methods for Pharmacokinetic and Antidrug Antibodies Data 
(Cohorts A and B)........................................................................................92
9.6.2
Statistical Methods for Efficacy Analyses (Cohort B) ................................93
9.6.2.1
Objective Response Rate (ORR) .......................................................93
9.6.2.2
Progression-free Survival (PFS) ........................................................94
9.6.2.3
Overall Survival (OS) ........................................................................94
9.6.2.4
Duration of Response (DOR).............................................................95
9.6.2.5
Analysis Strategy for Key Efficacy Endpoint....................................95
9.6.3
Statistical Methods for Safety Analysis (Cohort A) ....................................96
9.6.4
Statistical Methods for Safety Analyses (Cohort B)....................................97
9.6.5
Demographics and Baseline Characteristics (Cohort B) .............................97
9.7
Interim Analyses ..................................................................................................97
9.8
Multiplicity ...........................................................................................................98
9.9
Sample Size and Power Calculations .................................................................98
9.10
Subgroup Analyses...............................................................................................98
9.11
Compliance (Medication Adherence).................................................................99
9.12
Extent of Exposure...............................................................................................99
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................100
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......100
10.1.1
Code of Conduct for Clinical Trials...........................................................100
10.1.2
Financial Disclosure...................................................................................102
10.1.3
Data Protection...........................................................................................102
10.1.3.1
Confidentiality of Data ....................................................................103
10.1.3.2
Confidentiality of Participant Records.............................................103
10.1.3.3
Confidentiality of IRB/IEC Information..........................................103
10.1.4
Committees Structure.................................................................................103
10.1.5
Publication Policy......................................................................................103
10.1.6
Compliance with Study Registration and Results Posting Requirements .104
10.1.7
Compliance with Law, Audit, and Debarment ..........................................104
10.1.8
Data Quality Assurance .............................................................................105
10.1.9
Source Documents .....................................................................................106
10.1.10
Study and Site Closure...............................................................................106
10.2
Appendix 2: Clinical Laboratory Tests............................................................107
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................109
10.3.1
Definition of AE ........................................................................................109
10.3.2
Definition of SAE ......................................................................................110
10.3.3
Additional Events Reported in the Same Manner as SAE.........................111
10.3.4
Recording AE and SAE .............................................................................112
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................114
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................116
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................117
10.5.1
Definitions..................................................................................................117
10.5.2
Contraception Requirements......................................................................118
10.5.3
Pregnancy Testing......................................................................................119
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................120
10.7
Appendix 7: Country-specific Requirements..................................................121
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................122
10.9
Appendix 9: Abbreviations ...............................................................................126
11
REFERENCES.............................................................................................................129
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LIST OF TABLES
Table 1
Schedule of Activities Cohort A................................................................20
Table 2
Schedule of Activities Cohort B ................................................................25
Table 3
Adequate Organ Function Laboratory Values ...........................................46
Table 4
Study Interventions....................................................................................52
Table 5
Sample Allocation Schedule (Cohort A) ...................................................54
Table 6
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................58
Table 7
Pembrolizumab Infusion/Injection Reaction Dose Modification and 
Treatment Guidelines.................................................................................62
Table 8
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease.......................................................................................................75
Table 9
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................81
Table 10
Censoring Rules for Analysis of Progression-free Survival......................94
Table 11
Censoring Rules for Duration of Response ...............................................95
Table 12
Analysis Strategy for Key Efficacy Endpoints..........................................96
Table 13
Analysis Strategy for Safety Parameters....................................................97
Table 14
Protocol-required Safety Laboratory Assessments..................................108
Table 15
Highly Effective Contraception Methods................................................118
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LIST OF FIGURES
Figure 1
Trial Design Diagram ................................................................................19
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by 
the Investigators.........................................................................................76
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1 Randomized Clinical Study of Pembrolizumab (MK-3475) to 
Evaluate the Relative Bioavailability of Subcutaneous Injection Versus Intravenous Infusion 
in Participants with Advanced Melanoma (KEYNOTE-555)
Short Title: Relative Bioavailability Study of Subcutaneous Injection Versus Intravenous 
Infusion of MK-3475/Pembrolizumab in Participants with Advanced Melanoma
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
Male/female participants of at least 18 years of age with advanced melanoma will be enrolled 
in this study.
Primary Objectives
Primary Endpoints
Cohort A
- To characterize the pharmacokinetic (PK) 
profile, including the absorption phase, of 
pembrolizumab following subcutaneous (SC) 
injection
- To estimate the relative bioavailability of 
pembrolizumab via SC injection
 versus 
intravenous (IV) infusion (200 mg: 
25 mg/mL)
- Pharmacokinetic parameters of 
pembrolizumab, including area under the 
curve (AUC), maximum 
concentration (Cmax), bioavailability (F), 
absorption rate (Ka), time of maximum 
concentration (Tmax), clearance (CL), and 
central volume of distribution (Vc)
Primary Objectives
Primary Endpoints
Cohort B
- To evaluate objective response rate (ORR) 
per RECIST 1.1 as assessed by blinded 
independent central review (BICR)
- Participants who have a confirmed CR or 
PR
CCI
CCI
CCI
CCI
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Secondary Objectives
Secondary Endpoints
Cohort A
- To evaluate the development of circulating 
anti-pembrolizumab antibodies (if 
applicable), following SC pembrolizumab
- Antidrug antibody levels
- To determine the safety and tolerability of 
SC pembrolizumab during the first 
3 treatment cycles based on the proportion of 
adverse events (AEs)
- Adverse events (AEs)
- Study drug discontinuations due to AEs
- To monitor the safety and tolerability of IV 
pembrolizumab during the first 3 treatment 
cycles and after Cycle 3 based on the 
proportion of AEs 
- Adverse events (AEs)
- Study drug discontinuations due to AEs
- To determine the tolerability of SC 
pembrolizumab at the injection site during 
the first 3 treatment cycles based on the 
proportion of injection site signs and 
symptoms
- Responses to an injection site signs and 
symptoms questionnaire
Secondary Objectives
Secondary Endpoints
Cohort B
- To evaluate duration of response (DOR) per 
RECIST 1.1 as assessed by BICR 
- 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 
- To evaluate progression-free survival (PFS) 
as assessed by BICR according to RECIST 
v1.1, modified to follow a maximum of 10 
target lesions and a maximum of 5 target 
lesions per organ
- PFS is the time from the first dose of study 
intervention to the first documented disease 
progression or death due to any cause, 
whichever occurs first 
- To evaluate overall survival (OS)
- OS is defined as the time from the first day 
of study treatment  to death due to any cause
- To characterize the PK profile of 
pembrolizumab following IV infusion Q6W
- Pharmacokinetic parameters of 
pembrolizumab, including AUC, Cmax, and 
Cmin
- To monitor the safety and tolerability of IV 
pembrolizumab Q6W based on the 
proportion of AEs
- Adverse events (AEs)
- Study drug discontinuations due to AEs
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Exploratory Objectives
Exploratory Endpoints
Cohort B
- To evaluate the development of circulating 
anti-pembrolizumab antibodies (if 
applicable), following IV pembrolizumab 
Q6W
- Antidrug antibody levels
Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Treatment of participants with advanced melanoma
Population
Male/female participants with advanced melanoma who are 
at least 18 years of age on the day of signing consent.
Study Type
Interventional
Intervention Model
Cross-over
This is a multi-site study.
Type of Control
Active Controlled Study
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 141 weeks from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 36 participants will be allocated/randomized in Cohort A such that 
30 evaluable participants complete the study, and approximately 100 participants will be 
allocated in Cohort B as described in Section 9.9.
Enrollment into Cohort A takes priority over Cohort B. 
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Arm
Drug
Concentration/ 
Total mg
Dose 
Frequency
Route 
of 
Admin.
Regimen/ 
Treatment 
Period
Use
Cohort A
Arm 1
Pembrolizumab
(B)
Single 
administration
SC
Cycle 1
Experimental
Pembrolizumab
(C) 25 mg/mL/ 
200 mg
Single 
administration
IV
Cycle 2
Experimental
Pembrolizumab
(A)
Single 
administration
SC
Cycle 3
Experimental
Pembrolizumab
(D) 25 mg/mL/ 
200 mg
Q3W
IV
Day 1 of 
each 
subsequent 
21-day 
cycle
Experimental
Arm 2
Pembrolizumab
(B) 
Single 
administration
SC
Cycle 1
Experimental
Pembrolizumab
(A)
Single 
administration
SC
Cycle 2
Experimental
Pembrolizumab
(C) 25 mg/mL/ 
200 mg
Single 
administration
IV
Cycle 3
Experimental
Pembrolizumab
(D) 25 mg/mL/ 
200 mg
Q3W
IV
Day 1 of 
each 
subsequent 
21-day 
cycle
Experimental
Arm 3
Pembrolizumab
(A)
Single 
administration
SC
Cycle 1
Experimental
Pembrolizumab
(B)
Single 
administration
SC
Cycle 2
Experimental
Pembrolizumab
(C) 25 mg/mL/ 
200 mg
Single 
administration
IV
Cycle 3
Experimental
Pembrolizumab
(D) 25 mg/mL/ 
200 mg
Q3W
IV
Day 1 of 
each 
subsequent 
21-day 
cycle
Experimental
CCI
CCI
CCI
CCI
CCI
CCI
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Arm 4
Pembrolizumab
(A)
Single 
administration
SC
Cycle 1
Experimental
Pembrolizumab
(C) 25 mg/mL/ 
200 mg
Single 
administration
IV
Cycle 2
Experimental
Pembrolizumab
(B)
Single 
administration
SC
Cycle 3
Experimental
Pembrolizumab
(D) 25 mg/mL/ 
200 mg
Q3W
IV
Day 1 of 
each 
subsequent 
21-day 
cycle
Experimental
Arm 5
Pembrolizumab
(C) 25 mg/mL/ 
200 mg
Single 
administration
IV
Cycle 1
Experimental
Pembrolizumab
(A)
Single 
administration
SC
Cycle 2
Experimental
Pembrolizumab
(B)
Single 
administration
SC
Cycle 3
Experimental
Pembrolizumab
(D) 25 mg/mL/ 
200 mg
Q3W
IV
Day 1 of 
each 
subsequent 
21-day 
cycle
Experimental
Arm 6
Pembrolizumab
(C) 25 mg/mL/ 
200 mg
Single 
administration
IV
Cycle 1
Experimental
Pembrolizumab
(B) 
Single 
administration
SC
Cycle 2
Experimental
Pembrolizumab
(A)
Single 
administration
SC
Cycle 3
Experimental
Pembrolizumab
(D) 25 mg/mL/ 
200 mg
Q3W
IV
Day 1 of 
each 
subsequent 
21-day 
cycle
Experimental
Cohort B
Arm 7
Pembrolizumab
25 mg/mL/ 
400 mg
Q6W
IV
Day 1 of 
each 
42-day 
cycle
Experimental
IV=intravenous; Q3W=every 3 weeks; Q6W=every 6 weeks; SC=subcutaneous.
CCI
CCI
CCI
CCI
CCI
CCI
08FNZY

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Total 
Number
Cohort A: 6 Arms
Cohort B: 1 Arm
Duration of 
Participation
Each participant will participate in the study from the time the participant signs 
the Informed Consent Form through the final protocol-specified contact. 
After a screening phase of up to 28 days, each participant will be assigned to 
receive study treatment until disease progression is radiographically documented,
confirmed by the site per modified Response Evaluation Criteria in Solid Tumors 
1.1 (iRECIST) when clinically appropriate, unacceptable AEs, intercurrent illness 
that prevents further administration of treatment, investigator’s decision to 
discontinue the participant, noncompliance with study treatment or procedure 
requirements or administrative reasons requiring cessation of treatment, or until 
the participant has received 35 administrations (Cohort A) or 18 administrations 
(Cohort B) of pembrolizumab (approximately 2 years).
After the end of treatment, each participant will be followed for the occurrence of 
AEs and spontaneously reported pregnancy as described under Section 8.4.
In Cohort B participants who discontinue for reasons other than radiographic 
disease progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1, and,
when clinically appropriate, confirmed by the site per iRECIST, the start of a new 
anti-cancer treatment, withdrawal of consent, pregnancy, death, or lost to 
follow-up. All participants will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study.
Upon study completion, participants may be enrolled in a pembrolizumab 
extension study if available.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
08FNZY

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1.2
Schema
The study design is depicted in Figure 1.
Cohort A
Cohort B
Figure 1
Trial Design Diagram
Note: Cohort A: A
SC; B
 SC; C=200 mg IV in Cycle 1 to Cycle 3; and D=200 mg IV 
in Cycle 4 to Cycle 35. Cohort B: participants will receive pembrolizumab 400 mg IV Q6W. 
Abbreviations:  IV=intravenous; SC=subcutaneous. 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
08FNZY

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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities in the Screening, Treatment, and Follow-up Periods
Table 1
Schedule of Activities Cohort A
Study Period
Screening
Cohort A
Treatment Period
(Cycle = 21 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4 
(up to 35 
cycles)
At the time 
of treatment 
discon-
tinuation
Safety Follow-up
(90-day follow-up by 
phone contact only)
Treatment Day per Cycle
Day 1
Day 1
Day 1
Day 1
30 days 
after the 
last dose 
90 days 
after the 
last dose
Visit Window (Days)
-28 to -1
± 0a
± 0 a
± 0 a
± 3a
+ 7
+ 7
Individual procedure windows 
may vary
Administrative Procedures
Informed Consent
X
Written informed consent must 
be obtained prior to performing 
any protocol-specific procedures. 
Tests performed prior to consent 
as part of routine clinical 
management are acceptable if 
performed within the specified 
timeframe.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Demographics and Medical History
X
Oncology Disease Status and Prior 
Oncology Treatment History
X
Concomitant Medication
X
X
X
X
X
X
X
X
Concomitant medications will be 
collected during the 90-day safety 
follow-up if the medications are 
related to an SAE. 
Treatment Randomization
X
Dose within 3 days of 
randomization
Pembrolizumab Administration
X
X
X
X
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Study Period
Screening
Cohort A
Treatment Period
(Cycle = 21 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4 
(up to 35 
cycles)
At the time 
of treatment 
discon-
tinuation
Safety Follow-up
(90-day follow-up by 
phone contact only)
Treatment Day per Cycle
Day 1
Day 1
Day 1
Day 1
30 days 
after the 
last dose 
90 days 
after the 
last dose
Visit Window (Days)
-28 to -1
± 0a
± 0 a
± 0 a
± 3a
+ 7
+ 7
Individual procedure windows 
may vary
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
X
Baseline tumor imaging should 
be performed within 28 days of 
enrollment. First post-baseline 
assessment should be performed 
at approximately Week 12, and 
then per institutional standard of 
care. Response status will be 
assessed by the study site. 
Continue imaging until disease 
progression, discontinuation, or 
End of Treatment. 
Full Physical Examination 
X
X
X
X
For Cycles 4 to 35, directed 
physical examinations may be 
performed unless a full 
examination is deemed necessary. 
Directed Physical Examination
X
X
X
Height
X
Perform at screening only. 
Weight
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
To be measured at screening, and 
within 1 h (± 30 min) prior to 
dosing (SC and IV), and 
approximately 0.5 hours after 
pembrolizumab administration 
(SC only). Measurements include 
temperature, pulse, respiratory 
rate, and blood pressure.
ECOG Performance Status
X
ECOG will be obtained at 
screening only (within 7 days of 
the first dose). Additional ECOG 
assessments may be performed as 
clinically indicated. 
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Study Period
Screening
Cohort A
Treatment Period
(Cycle = 21 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4 
(up to 35 
cycles)
At the time 
of treatment 
discon-
tinuation
Safety Follow-up
(90-day follow-up by 
phone contact only)
Treatment Day per Cycle
Day 1
Day 1
Day 1
Day 1
30 days 
after the 
last dose 
90 days 
after the 
last dose
Visit Window (Days)
-28 to -1
± 0a
± 0 a
± 0 a
± 3a
+ 7
+ 7
Individual procedure windows 
may vary
12-Lead Electrocardiogram
X
ECG will be performed at 
screening only. Additional ECG 
assessments may be performed as 
clinically indicated.
Adverse Event Monitoring
X
All AEs that occur after the 
consent form is signed but before 
treatment allocation must be 
reported by the investigator if the 
event causes the participant to be 
excluded from the study or is the 
result of a protocol-specified 
intervention. There is to be 
continuous AE reporting from the 
time of treatment allocation.
After treatment discontinuation, 
participants will be monitored for 
AEs for 30 days and SAEs for 
90 days (30 days if the 
participant initiates new 
anticancer therapy). Participants 
with an ongoing AE at the time 
of treatment discontinuation will 
be followed until resolution, 
stabilization, the event is 
otherwise explained, or the 
participant is lost to follow-up. 
Laboratory Procedures/Assessments
CBC with Differential
X
X
X
X
X
X
X
Perform all screening clinical 
laboratory tests within 72 hours 
of treatment initiation. Perform 
all subsequent scheduled clinical 
laboratory tests within 72 hours 
Chemistry Panel
X
X
X
X
X
X
X
LDH
X
Urinalysis
X
X
X
X
X
X
X
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Study Period
Screening
Cohort A
Treatment Period
(Cycle = 21 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4 
(up to 35 
cycles)
At the time 
of treatment 
discon-
tinuation
Safety Follow-up
(90-day follow-up by 
phone contact only)
Treatment Day per Cycle
Day 1
Day 1
Day 1
Day 1
30 days 
after the 
last dose 
90 days 
after the 
last dose
Visit Window (Days)
-28 to -1
± 0a
± 0 a
± 0 a
± 3a
+ 7
+ 7
Individual procedure windows 
may vary
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
prior to treatment.
Thyroid function: To be collected 
at screening (within 28 days prior 
to treatment) and then at every 
other cycle (ie. Cycle 2, 4, 6, 
etc.). Total T4 and T3 are 
preferred over FT4 and FT3.
Pregnancy test for WOCBP only (urine or 
serum β-hCG)
X
X
Perform within 72 hours prior to 
C1D1 (if collection is done 
within this timeframe do not need 
to repeat for the C1D1). Urine 
pregnancy test to be performed as 
indicated; if test is positive or 
cannot be confirmed as negative, 
a serum pregnancy test is 
required. Additional pregnancy 
testing may be conducted if 
required by local regulations or if 
clinically indicated.
HIV/Hepatitis B and C Screen
(per site SOP)
X
To be collected at screening 
(within 28 days prior to 
treatment). Include HCV 
antibody or HCV RNA 
(qualitative) and HBsAg. HIV, 
Hepatitis B and C by history are
acceptable for exclusion, unless 
testing is required by local 
regulations. 
PK for IV and SC pembrolizumab
Xa
Xa
Xa
Xa
Cycles 1 to 4 only; refer to 
Section 1.3.2 for full details. 
Anti-pembrolizumab Antibody
Xa
Xa
Xa
Xa
Refer to Section 1.3.2 for full 
details.
08FNZY

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Study Period
Screening
Cohort A
Treatment Period
(Cycle = 21 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 2
Cycle 3
Cycles ≥4 
(up to 35 
cycles)
At the time 
of treatment 
discon-
tinuation
Safety Follow-up
(90-day follow-up by 
phone contact only)
Treatment Day per Cycle
Day 1
Day 1
Day 1
Day 1
30 days 
after the 
last dose 
90 days 
after the 
last dose
Visit Window (Days)
-28 to -1
± 0a
± 0 a
± 0 a
± 3a
+ 7
+ 7
Individual procedure windows 
may vary
Injection Site Signs and Symptoms 
Questionnaire
Tolerability and injection 
difficulty will be assessed at 
Day 1 of each cycle of 
pembrolizumab administration 
(SC only), 60 minutes postdose.
aNote that visit windows do not apply to the PK and ADA sampling. 
Abbreviations:  β-hCG=beta-human chorionic gonadotropin; AE=adverse event; C=cycle; CBC=complete blood count; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; HCV=hepatitis c virus; HIV=human immunodeficiency virus; iRECIST= modified Response Evaluation Criteria in Solid Tumors; IV=intravenous; LDH=lactase 
dehydrogenase; PK=pharmacokinetics; RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE=serious adverse event; SC=subcutaneous; SOP=standard 
operating procedure; TSH=thyroid stimulating hormone; WOCBP=woman/women of childbearing potential. 
08FNZY

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Table 2
Schedule of Activities Cohort B
Study Period
Screening
Cohort B
Treatment Period
(Cycle=42 days)
Cohort B 
Treatment 
Period (Cycle= 
42 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 4
Cycles 2 to 3 and 
Cycles 5 to 18
At the time 
of treatment 
discon-
tinuation
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day per Cycle
Day 1
Day 22
Day 1
Day 22
Day 1 + Day 22
30 days 
after the 
last dose 
Every
12 weeks
Every 
12 weeks
Visit Window (Days)
-28 to -1
± 0a
± 3a
± 3a
± 3a
± 3a
+ 7
+ 7
± 7
± 7
Individual procedure windows 
may vary
Administrative Procedures
Informed Consent
X
Written informed consent must 
be obtained prior to performing 
any protocol-specific 
procedures. Tests performed 
prior to consent as part of 
routine clinical management are 
acceptable if performed within 
the specified timeframe.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Demographics and Medical 
History
X
Oncology Disease Status and 
Prior Oncology Treatment 
History
X
Concomitant Medication
X
X
X
X
X
X
X
X
Concomitant medications will 
be collected for 30 days after 
the last dose then only those 
related to an SAE/ECI. 
Treatment Randomization
X
Dose within 3 days of 
randomization
Pembrolizumab Administration
X
X
X
08FNZY

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Study Period
Screening
Cohort B
Treatment Period
(Cycle=42 days)
Cohort B 
Treatment 
Period (Cycle= 
42 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 4
Cycles 2 to 3 and 
Cycles 5 to 18
At the time 
of treatment 
discon-
tinuation
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day per Cycle
Day 1
Day 22
Day 1
Day 22
Day 1 + Day 22
30 days 
after the 
last dose 
Every
12 weeks
Every 
12 weeks
Visit Window (Days)
-28 to -1
± 0a
± 3a
± 3a
± 3a
± 3a
+ 7
+ 7
± 7
± 7
Individual procedure windows 
may vary
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, 
and iRECIST Response 
Assessment
X
X
Baseline tumor imaging should 
be performed within 28 days of 
first dose. First post-baseline 
assessment should be performed 
at approximately Week 12. 
Assessments should then be 
performed every 9 weeks (±
7 days) in Year 1 and 12 weeks 
after Year 1 calculated from day 
of first dose. Imaging should be 
performed at the time of 
treatment discontinuation (ie, 
date of discontinuation 
± 4 weeks). If previous scan was 
obtained within 4 weeks prior to 
the date of discontinuation, then 
a scan at treatment 
discontinuation does not need to 
be performed. Response status 
will be assessed by the study 
site. Continue imaging until 
disease progression, the start of 
new anti-cancer treatment, 
withdrawal of consent, or death, 
whichever occurs first. 
08FNZY

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Study Period
Screening
Cohort B
Treatment Period
(Cycle=42 days)
Cohort B 
Treatment 
Period (Cycle= 
42 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 4
Cycles 2 to 3 and 
Cycles 5 to 18
At the time 
of treatment 
discon-
tinuation
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day per Cycle
Day 1
Day 22
Day 1
Day 22
Day 1 + Day 22
30 days 
after the 
last dose 
Every
12 weeks
Every 
12 weeks
Visit Window (Days)
-28 to -1
± 0a
± 3a
± 3a
± 3a
± 3a
+ 7
+ 7
± 7
± 7
Individual procedure windows 
may vary
Survival Status
X
After investigator determined 
PD or start of new anticancer 
treatment. In addition, upon 
Sponsor request, participants 
may be contacted for survival 
status at any time during the 
course of the study.
Full Physical Examination 
X
X
X
X
For Cycles 2 to 18, directed 
physical examinations may be 
performed unless a full 
examination is deemed 
necessary.
Directed Physical Examination
X
X
X
X
Height
X
Perform at screening only. 
Weight
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Measurements include 
temperature, pulse, respiratory 
rate, and blood pressure.
ECOG Performance Status
X
X
X
X
X
X
X
X
ECOG will be obtained within 
7 days of the first dose.
12-Lead Electrocardiogram
X
ECG will be performed at 
screening only. Additional ECG 
assessments may be performed 
as clinically indicated.
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Study Period
Screening
Cohort B
Treatment Period
(Cycle=42 days)
Cohort B 
Treatment 
Period (Cycle= 
42 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 4
Cycles 2 to 3 and 
Cycles 5 to 18
At the time 
of treatment 
discon-
tinuation
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day per Cycle
Day 1
Day 22
Day 1
Day 22
Day 1 + Day 22
30 days 
after the 
last dose 
Every
12 weeks
Every 
12 weeks
Visit Window (Days)
-28 to -1
± 0a
± 3a
± 3a
± 3a
± 3a
+ 7
+ 7
± 7
± 7
Individual procedure windows 
may vary
Adverse Event Monitoring
X
All AEs that occur after the 
consent form is signed but 
before treatment allocation must 
be reported by the investigator 
if the event causes the 
participant to be excluded from 
the study or is the result of a 
protocol-specified intervention. 
There is to be continuous AE 
reporting from the time of 
treatment allocation.
After treatment discontinuation, 
participants will be monitored 
for AEs for 30 days and SAEs 
for 90 days (30 days if the 
participant initiates new 
anticancer therapy). Participants 
with an ongoing AE at the time 
of treatment discontinuation 
will be followed until 
resolution, stabilization, the 
event is otherwise explained, or 
the participant is lost to 
follow-up. 
Laboratory Procedures/Assessments
CBC with Differential
X
X
X
X
X
X
X
X
Perform screening clinical 
laboratory tests within 72 hours 
of treatment initiation. Perform 
all subsequent scheduled 
Chemistry Panel
X
X
X
X
X
X
X
X
LDH
X
Urinalysis
X
X
X
X
X
X
X
X
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Study Period
Screening
Cohort B
Treatment Period
(Cycle=42 days)
Cohort B 
Treatment 
Period (Cycle= 
42 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 4
Cycles 2 to 3 and 
Cycles 5 to 18
At the time 
of treatment 
discon-
tinuation
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day per Cycle
Day 1
Day 22
Day 1
Day 22
Day 1 + Day 22
30 days 
after the 
last dose 
Every
12 weeks
Every 
12 weeks
Visit Window (Days)
-28 to -1
± 0a
± 3a
± 3a
± 3a
± 3a
+ 7
+ 7
± 7
± 7
Individual procedure windows 
may vary
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
X
clinical laboratory tests within 
72 hours prior to treatment.
Thyroid function: To be 
collected at screening (within 
28 days prior to treatment) and 
then at every other cycle (ie. 
Cycle 2, 4, 6, etc.). Total T4 
and T3 are preferred over FT4 
and FT3.
Pregnancy test for WOCBP only 
(urine or serum β-hCG)
X
X
Perform within 72 hours prior to 
C1D1 (if collection is done 
within this timeframe do not 
need to repeat for the C1D1). 
Urine pregnancy test to be 
performed as indicated; if test is 
positive or cannot be confirmed 
as negative, a serum pregnancy 
test is required. Additional 
pregnancy testing may be 
conducted if required by local 
regulations or if clinically 
indicated.
HIV/Hepatitis B and C Screen
(per site SOP)
X
To be collected at screening 
(within 28 days prior to 
treatment). Include HCV 
antibody or HCV RNA 
(qualitative) and HBsAg. HIV, 
Hepatitis B and C by history are
acceptable for exclusion, unless 
testing is required by local 
regulations. 
08FNZY

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Study Period
Screening
Cohort B
Treatment Period
(Cycle=42 days)
Cohort B 
Treatment 
Period (Cycle= 
42 days)
End of 
Treatment / 
Discon-
tinuation
Posttreatment Period
Notes
Treatment Cycle/Title
Screening
Cycle 1
Cycle 4
Cycles 2 to 3 and 
Cycles 5 to 18
At the time 
of treatment 
discon-
tinuation
Safety 
Follow-up
Imaging 
Follow-up
Survival 
Follow-up
Treatment Day per Cycle
Day 1
Day 22
Day 1
Day 22
Day 1 + Day 22
30 days 
after the 
last dose 
Every
12 weeks
Every 
12 weeks
Visit Window (Days)
-28 to -1
± 0a
± 3a
± 3a
± 3a
± 3a
+ 7
+ 7
± 7
± 7
Individual procedure windows 
may vary
PK for IV pembrolizumab
Xa
Xa
Xa
Xa
Refer to Section 1.3.2 for full 
details. 
Anti-pembrolizumab Antibody
Xa
Xa
Xa
Xa
Refer to Section 1.3.2 for full 
details.
aNote that visit windows do not apply to the PK and ADA sampling. 
Abbreviations:  β-hCG=beta-human chorionic gonadotropin; AE=adverse event; C=cycle; CBC=complete blood count; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology 
Group; HCV=hepatitis c virus; HIV=human immunodeficiency virus; iRECIST= modified Response Evaluation Criteria in Solid Tumors; IV=intravenous; LDH=lactase dehydrogenase; 
PK=pharmacokinetics; RECIST=Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic acid; SAE=serious adverse event; SOP=standard operating procedure; TSH=thyroid stimulating 
hormone; WOCBP=woman/women of childbearing potential. 
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1.3.2
Pembrolizumab PK and ADA Sampling in the Treatment Period
Study Period
Cohort A
Treatment Period
Cycle = 21 days
Notes
Treatment Cycle/Title
Cycles 1, 2, and/or 3, According to Arm
Cycle 4
Treatment Day per Cycle
1
1
(post-
infusion)
2
3
4
5
6
7
10
15
1
Anti-pembrolizumab Antibody 
(Arms 1 to 6)
X
X
Collect samples predose 0-4 h before 
pembrolizumab on C1D1, C2D1, C3D1, and 
C4D1. Collect with plasma samples for 
pembrolizumab PK when feasible.
Pembrolizumab (SC Dosing)
Pharmacokinetics for 
SC Pembrolizumab
X
X
X
X
X
X
X
X
X
X
Collect predose samples 0-4 h before 
pembrolizumab administration on C1D1, 
C2D1, C3D1, and C4D1. Samples collected 
on D2, D3, D4, D5, D6, D7, D10, and D15 
can be collected anytime that day.
Pembrolizumab (First Cycle of IV Dosing)
Pharmacokinetics for 
IV Pembrolizumab
X
X
X
X
X
X
X
Collect predose samples 0-4 h before 
pembrolizumab administration on C1D1, 
C2D1, C3D1, and C4D1 and at the end of 
infusion (as soon as possible, but within 
10 minutes) on C1D1, C2D1, and C3D1. 
Samples collected on D2, D5, D10, and D15 
can be collected anytime that day.
Note: If the sample day falls on a weekend or holiday and the sample cannot be drawn, an alternate sampling day will not occur. 
Abbreviations:  C=Cycle; D=Day; IV=intravenous; PK=pharmacokinetics; SC=subcutaneous.  
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Study Period
Cohort B
Treatment Period
Cycle= 42 days
Notes
Treatment Cycle/Title
1
2
4
5
Treatment Day per Cycle
1
1
(post-
infusion)
22
1
1
(post-
infusion)
22
1
1
(post-
infusion)
22
1
1
(post-
infusion)
22
Anti-pembrolizumab 
Antibody
X
X
X
X
X
X
X
X
Collect predose samples 0-4 h before 
pembrolizumab administration on 
C1D1, C2D1, C4D1, and C5D1, and 
at the end of infusion (as soon as 
possible, but within 5 minutes) on 
C1D1 and C4D1. Samples collected 
on C1D22 and C4D22 (± 6 days) can 
be collected anytime that day.
Pembrolizumab
Pharmacokinetics for 
IV Pembrolizumab
X
X
X
X
X
X
X
X
Collect predose samples 0-4 h before 
pembrolizumab administration on 
C1D1, C2D1, C4D1, and C5D1, and 
at the end of infusion (as soon as 
possible, but within 5 minutes) on 
C1D1 and C4D1. Samples collected 
on C1D22 and C4D22 (± 6 days) can 
be collected anytime that day. 
Note: If the sample day falls on a weekend or holiday and the sample cannot be drawn, an alternate sampling day will not occur. 
Abbreviations:  C=Cycle; D=Day; IV=intravenous; PK=pharmacokinetics.  
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2
INTRODUCTION
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal 
antibody (mAb) with high specificity of binding to the programmed cell death 1 (PD-1) 
receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and 
programmed cell death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab
has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab has an 
acceptable preclinical safety profile and is in clinical development as an intravenous (IV) 
immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is indicated for 
the treatment of patients across a number of indications. This study will assess the 
pharmacokinetics (PK), safety and tolerability of pembrolizumab when administered as a 
subcutaneous (SC) injection and when administered every 6 week (Q6W). Refer to the 
pembrolizumab Investigator’s Brochures (IBs) for further information.
2.1
Study Rationale
Pembrolizumab is currently indicated for the treatment of patients with melanoma, non-small 
cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma, classical Hodgkin 
lymphoma, urothelial carcinoma, microsatellite instability-high or mismatch repair deficient 
solid tumors and gastric cancer. Adult patients are currently to be treated with 
pembrolizumab at an IV dose of 200 mg every 3 weeks (Q3W). For participants in Cohort A, 
the present study is designed to estimate the relative bioavailability of a SC versus an IV dose 
of pembrolizumab, and to characterize the PK profile of pembrolizumab administered SC. 
During the first 3 treatment cycles, each participant will receive an IV infusion of 200 mg 
pembrolizumab and 2 SC injections of
pembrolizumab
 Participants are then to receive an IV infusion of 200 mg 
pembrolizumab from Cycles 4 to 35. In Cohort B, participants will receive IV infusion of 
400 mg pembrolizumab Q6W from Cycles 1 to 18. PK, efficacy, and safety data will be 
collected from these participants. Enrollment into Cohort A takes priority over Cohort B.
Participants in the study will be limited to those with a diagnosis of advanced melanoma. The 
cross-over design has been chosen to eliminate effects of interindividual variability inherent 
in a parallel-group design. The relative bioavailability of pembrolizumab will be estimated in 
this study using the SC dose
 given at 2 different concentrations/volumes) of 
pembrolizumab compared with the IV dose of pembrolizumab (200 mg). The results of this 
study will contribute to an understanding of the PK characteristics of pembrolizumab when 
administered SC. For Cohort B, results will provide preliminary PK, efficacy, and safety data 
of pembrolizumab when administered Q6W. 
Details regarding specific benefits and risks for participants in this clinical trial may be found 
in the accompanying pembrolizumab IBs and Informed Consent Form (ICF) document.
2.2
Background
Refer to the IBs/approved labeling for detailed background information on pembrolizumab.
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2.2.1
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 in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of cluster of differentiation 
(CD)8+ T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells correlates 
with improved prognosis and long-term survival in solid malignancies, such as ovarian, 
colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal 
cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, 
inducing durable objective tumor responses in cancers such as melanoma [Dudley, M. E., et 
al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic 
T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type 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, protein kinase C-
theta, and zeta-chain-associated protein kinase, 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 melanoma.
2.2.2
Pre-clinical and Clinical Studies
Pembrolizumab is approved for treatment of patients with melanoma in several countries; in 
the United States (US), European Union (EU), Australia, and New Zealand it is approved for 
the treatment of patients with advanced (unresectable or metastatic) melanoma in adults. The 
Sponsor is studying pembrolizumab for various oncology indications. Pharmacokinetic, 
efficacy, and safety data from the pembrolizumab clinical development program are 
presented in the IBs from participants with advanced melanoma, NSCLC, advanced solid 
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tumors, and hematological cancers. The observed PK profile of pembrolizumab was typical 
when compared with other IgG mAbs with a half-life of approximately 3 weeks. The overall 
response rates for pembrolizumab compared favorably to historical response rates for 
available treatments, particularly in participants who have progressed after multiple prior 
therapies. Adverse events (AEs) were generally manageable and infrequently required 
discontinuation of pembrolizumab treatment.
For more details on completed preclinical and clinical studies refer to the IBs.
2.2.3
Ongoing Clinical Studies
The Sponsor is advancing a broad and fast-growing clinical development program for 
pembrolizumab, both as a monotherapy and in combination with other therapies across more 
than 30 tumor types and enrolling more than 16,000 participants. 
For more details on ongoing clinical studies refer to the IBs.
2.2.4
Information on Other Study-related Therapy
Not applicable.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
Male/female participants of at least 18 years of age with advanced melanoma will be enrolled 
in this study.
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Objectives
Endpoints
Primary
Cohort A
•
To characterize the pharmacokinetic (PK)
profile, including the absorption phase, of 
pembrolizumab following subcutaneous 
(SC) injection
•
To estimate the relative bioavailability of 
pembrolizumab via SC injection 
versus intravenous (IV) infusion 
(200 mg: 25 mg/mL)
•
Pharmacokinetic parameters of 
pembrolizumab, including area under the 
curve (AUC), maximum 
concentration (Cmax), bioavailability (F), 
absorption rate (Ka), time of maximum 
concentration (Tmax), clearance (CL), and 
central volume of distribution (Vc)
Primary
Cohort B
•
To evaluate objective response rate 
(ORR) per RECIST 1.1 as assessed by 
blinded independent central review 
(BICR)
•
Participants who have a confirmed CR or 
PR
Secondary
Cohort A
•
To evaluate the development of 
circulating anti-pembrolizumab 
antibodies (if applicable), following SC 
pembrolizumab
•
Antidrug antibody levels
•
To determine the safety and tolerability 
of SC pembrolizumab during the first 
3 treatment cycles based on the 
proportion of adverse events (AEs)
•
Adverse events (AEs)
•
Study drug discontinuations due to AEs
•
To monitor the safety and tolerability of 
IV pembrolizumab during the first 
3 treatment cycles and after Cycle 3
based on the proportion of AEs
•
Adverse events (AEs)
•
Study drug discontinuations due to AEs
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Objectives
Endpoints
•
To determine the tolerability of SC 
pembrolizumab at the injection site
during the first 3 treatment cycles based 
on the proportion of injection site signs 
and symptoms
•
Responses to an injection site signs and 
symptoms questionnaire
Secondary
Cohort B
•
To evaluate duration of response (DOR) 
per RECIST 1.1 as assessed by BICR
•
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
•
To evaluate progression-free survival 
(PFS) as assessed by BICR according to 
RECIST v1.1, modified to follow a 
maximum of 10 target lesions and a 
maximum of 5 target lesions per organ
•
PFS is the time from the first dose of 
study intervention to the first documented 
disease progression or death due to any 
cause, whichever occurs first 
•
To evaluate overall survival (OS)
•
OS is defined as the time from the first 
day of study treatment to death due to 
any cause
•
To characterize the PK profile of 
pembrolizumab following IV infusion 
Q6W
•
Pharmacokinetic parameters of 
pembrolizumab, including AUC, Cmax, 
and Cmin
•
To monitor the safety and tolerability of 
IV pembrolizumab Q6W based on the 
proportion of AEs
•
Adverse events (AEs)
•
Study drug discontinuations due to AEs
Exploratory
Cohort B
•
To evaluate the development of 
circulating anti-pembrolizumab 
antibodies (if applicable), following IV
pembrolizumab Q6W
•
Antidrug antibody levels
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, cross-over, multicenter, open-label, bioavailability, and safety study of 
pembrolizumab in participants with advanced melanoma to be conducted in conformance 
with Good Clinical Practices (GCP). This Phase 1 study will be conducted in participants 
with unresectable or metastatic melanoma.
In Cohort A, the treatment period will continue every 21 days for up to 35 cycles
(approximately 2 years). In Cohort B, the treatment period will continue every 42 days for up 
to 18 cycles (approximately 2 years). Treatment will continue as long as participants are 
receiving benefit from treatment and have not had disease progression or met any criteria for 
study withdrawal.
In greater detail, the study consists of: 

A screening period of up to a 28-day duration to ensure that the participant is eligible 
for the study.

An intervention period of approximately 104 weeks of treatment with 
pembrolizumab. In Cohort A, this period will include 2 cycles of pembrolizumab 
administered via SC injection and 1 cycle of IV infusion over 30 minutes in a 
6-sequence cross-over design. Participants will then continue with up to 32 additional 
cycles of pembrolizumab treatment administered by IV infusion over 30 minutes 
every 3 weeks. In Cohort B, participants will receive pembrolizumab via IV infusion 
over 30 minutes Q6W for up to 18 cycles. 

A follow-up period during which participants will be monitored for AEs for 30 days 
and serious adverse events (SAEs) for 90 days (30 days if the participant initiates new 
anticancer therapy). Participants with an ongoing AE at the time of treatment 
discontinuation will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up.

In Cohort B, participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status until 
disease progression is documented radiographically per RECIST 1.1 and, when 
clinically appropriate, confirmed by the site per iRECIST, initiating a non-study 
cancer treatment, withdrawing consent, becoming lost to follow-up or the end of the 
study. All participants will be followed by telephone for overall survival in the 
Survival follow-Up period until death, participant withdrawal of consent, becoming 
lost to follow-up or the end of the study.
Upon study completion, participants may be enrolled in a pembrolizumab extension study if 
available.
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
In more than 80 countries including the US, EU, Japan, Australia, and New Zealand,
pembrolizumab is indicated for the treatment of patients with unresectable or metastatic
melanoma. All participants enrolled into this study will have a diagnosis of advanced 
melanoma. The cross-over design has been chosen to eliminate effects of interindividual 
variability inherent in a parallel-group design. The results of this study will contribute to an
understanding of the PK characteristics of pembrolizumab administered SC, and when 
administered in a Q6W dosing regimen.
4.2.1
Rationale for Endpoints
4.2.1.1
Safety Endpoints
Cohort A
A secondary objective of this study is to characterize the safety and tolerability of 
pembrolizumab when administered SC as monotherapy. The primary safety analysis will be 
based on participants who experience toxicities. Safety will be assessed by quantifying the 
toxicities and grades of toxicities experienced by participants who have received 
pembrolizumab via SC injection and IV infusion. An additional secondary objective is to 
determine the tolerability of SC pembrolizumab at the injection site during the first 
3 treatment cycles based on the proportion of injection site signs and symptoms.
Cohort B
In Cohort B, a secondary objective of this study is to characterize the safety and tolerability 
of 400 mg pembrolizumab when administered IV Q6W. 
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 adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 
[4.0].
4.2.1.2
Pharmacokinetic Endpoints
Cohort A
A primary objective of this trial is to characterize the PK profile and relative bioavailability 
of pembrolizumab following administration as a SC injection versus an IV infusion. The 
serum concentrations of these agents will serve as the primary readout for the PK, and these 
data will be used to derive PK parameters. Furthermore, the results of these analyses will be 
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used in conjunction with the safety and exploratory endpoint data to help assess future dosing 
strategies for administering pembrolizumab SC.
To evaluate pembrolizumab immunogenicity and pembrolizumab exposure after SC
administration, sample collections for analysis of antidrug antibodies (ADA) and PK are 
currently planned as shown in the SoA (Section 1.3). Blood samples will be obtained to 
measure PK of serum pembrolizumab. The pembrolizumab serum concentrations at planned 
visits and times will be summarized.
Pharmacokinetic data will also be analyzed using nonlinear mixed effects modeling. Based 
on PK data obtained in this study as well as PK data obtained from previous studies, an 
integrated population PK analysis will be performed to characterize PK parameters 
(absorption rate [Ka], bioavailability [F], clearance [CL], central volume of distribution [Vc])
of pembrolizumab following SC and IV administration.
Pharmacokinetic endpoints in this study include: 

Pharmacokinetic parameters of pembrolizumab , including area under the 
curve (AUC), maximum concentration (Cmax), bioavailability (F), absorption 
rate (Ka), time of maximum concentration (Tmax), clearance (CL), and central volume 
of distribution (Vc).
Cohort B
In Cohort B, an objective of this trial is to characterize the PK profile of pembrolizumab 
following administration as an IV infusion Q6W. PK data will be analyzed after all 
participants complete Cycle 5. PK parameters will include AUC, Cmax, and Cmin. 
4.2.1.3
Antidrug Antibodies (ADA)
Formation of ADAs can potentially confound drug exposures at therapeutic doses and prime 
for subsequent infusion-related toxicity. Antidrug antibody response to pembrolizumab at the 
beginning of each of the first 4 cycles (Cohort A: Q3W pembrolizumab dosing), as well as 
Cycles 1, 2, 4, and 5 (Cohort B: Q6W pembrolizumab dosing) will be determined. Any 
impact of presence of ADAs on exposure of pembrolizumab will be explored.
4.2.1.4
Efficacy Endpoints
Cohort B
This study will use ORR based on RECIST 1.1 criteria as assessed by blinded independent 
central review (BICR) as the primary endpoint. Objective response rate is an acceptable 
measure of clinical benefit for a late stage study that demonstrates superiority of a new 
antineoplastic therapy, especially if the magnitude of the effect is large and the therapy has 
an acceptable risk/benefit profile. The use of BICR and RECIST 1.1 to assess ORR is 
typically considered acceptable by regulatory authorities. Images will be submitted to an 
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imaging CRO (iCRO) and read by independent central review blinded to treatment 
assignment to minimize bias in the response assessments. 
Overall survival (OS) is a secondary endpoint for Cohort B and has been recognized as the 
gold standard for the demonstration of superiority of a new antineoplastic therapy in 
randomized clinical studies.
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.4). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ. RECIST 1.1 will be adapted to account for the unique tumor response 
characteristics seen following treatment with pembrolizumab (Section 8.2.1.5). 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by
potentiating endogenous cancer-specific immune responses. The response patterns seen with 
such an approach may extend beyond the typical time course of responses seen with 
cytotoxic agents, and patients treated with pembrolizumab may manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Thus, 
standard RECIST 1.1 may not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab. Based on an analysis of participants with 
melanoma enrolled in KEYNOTE-001 (KN001), 7% of evaluable participants experienced
delayed or early tumor pseudo-progression. Of note, participants who had progressive 
disease (PD) by RECIST 1.1 but not by the immune-related response criteria [Wolchok, J. 
D., et al 2009] had longer overall survival than participants with PD by both criteria [Hodi, F. 
S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the benefit 
of pembrolizumab in approximately 15% of participants. These findings support the need to 
apply a modification to RECIST 1.1 that takes into account the unique patterns of atypical 
responses in immunotherapy and enables treatment beyond initial radiographic progression, 
if the participant is clinically stable. 
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by 
RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression and make treatment decisions as well as for 
exploratory efficacy analyses where specified.
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4.3
Justification for Dose
The primary purpose of Cohort A in this study is to establish the SC dose and volume for 
further clinical development. Two SC solutions have been manufactured
and will be used in Cycles 1 to 3 of this study, corresponding to a dose of 
that assumes 70% bioavailability for the SC formulation relative to IV 
(dose = 200 mg infusion given over 30 minutes in Cycles 1 to 3) [Zhao, L., et al 2013].
The planned dose of pembrolizumab for Cycle 4 onwards in this study is 200 mg IV infusion 
Q3W. Based on the totality of data generated in the Keytruda development program, 200 mg 
Q3W is the appropriate dose of pembrolizumab for adults across all indications and 
regardless of tumor type. As outlined below, this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment-naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 3 studies 
compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 and 
KN006). 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. Second, 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.
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Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
In Cohort B, participants will receive 400 mg IV pembrolizumab Q6W. A 400 mg Q6W 
dosing regimen of pembrolizumab is expected to have a similar benefit-risk profile as 
200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is currently 
approved. Specifically, the dosing regimen of 400 mg Q6W for pembrolizumab is considered 
adequate based on modeling and simulation (M&S) analyses, given the following rationale:
•
PK simulations demonstrating that in terms of pembrolizumab exposures –
o
Average concentration over the dosing interval (Cavg) (or area under the curve 
[AUC]) at 400 mg Q6W is similar to that at the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.
o
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
o
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.
•
Exposure-response (E-R) for pembrolizumab has been demonstrated to be flat across 
indications, and OS predictions in melanoma and NSCLC demonstrate that efficacy at 
400 mg Q6W is expected to be similar to that at 200 mg or 2 mg/kg Q3W, given the 
similar exposures; thus 400 mg Q6W is expected to be efficacious across indications.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
Upon study completion, participants may be enrolled in a pembrolizumab extension study if 
available.
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4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criteria specified below:

Incidence or severity of adverse drug reactions in this or other studies suggest a 
potential health hazard to participants

Plans to modify or discontinue the development of the study drug

Poor adherence to protocol and regulatory requirements

Quality or quantity of data recording is inaccurate or incomplete

Ample notification will be provided in the event of Sponsor decision to no longer 
supply pembrolizumab.
5
STUDY POPULATION
Male/female participants with advanced melanoma of at least 18 years of age on the day of 
signing informed consent will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have histologically or cytologically confirmed diagnosis of advanced melanoma
2. Have unresectable Stage III or Stage IV melanoma, as per American Joint Committee 
on Cancer (AJCC) staging system not amenable to local therapy.
3. Have been untreated for advanced or metastatic disease except as follows:
a.
BRAF V600 mutant melanoma may have received standard of care targeted 
therapy (eg, BRAF/MEK inhibitor, alone or in combination) and be eligible for 
this study
Note: Targeted therapy is not required for eligibility.
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b. Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed 
at least 4 weeks before randomization and all related AEs have either returned to 
baseline or stabilized (resolution of toxic effect(s) of the most recent prior therapy 
to Grade 1 or less [except alopecia]). If subject received major surgery or 
radiation therapy of >30 Gy, they must have recovered from the toxicity and/or 
complications from the intervention.
Demographics
Female Participants
4. A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least 1 of the following conditions applies: A WOCBP who 
agrees to follow the contraceptive guidance in Appendix 5 during the treatment period 
and for at least 120 days. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
Informed Consent
5. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study.
6. Have measurable disease per RECIST 1.1 as assessed by BICR. Lesions situated in a 
previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
Additional Categories
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
8. Have adequate organ function as defined in the following table (Table 3). Specimens 
must be collected within 72 hours prior to the start of study intervention.
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Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine 
or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
1Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
2Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory 
value requirements should be adapted according to local regulations and guidelines for the 
administration of specific chemotherapies.
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; 
ULN=upper limit of normal.
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5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization or treatment allocation (see Appendix 5). If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
Note:  In the event that 72 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for subject to start receiving study medication.
Prior/Concomitant Therapy
2. Has received prior systemic treatment for unresectable or metastatic melanoma (except 
as noted in inclusion criteria #3).
3. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, OX-40 and
CD137) or any other antibody or drug specifically targeting checkpoint pathways other 
than anti-CTLA-4 which is permitted in the adjuvant setting.
4. Has received prior radiotherapy within 2 weeks of start of study 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.
5. Has received a live vaccine within 30 days prior to the first dose of study drug. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, 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
6. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study 
may participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
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Diagnostic Assessments
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.
8. Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging 
(note that the repeat imaging should be performed during study screening), clinically 
stable and without requirement of steroid treatment for at least 14 days prior to first 
dose of study intervention.
10. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
11. Has ocular melanoma.
12. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
13. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.
14. Has an active infection requiring systemic therapy.
15. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
16. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or  known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
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17. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
18. Has a known psychiatric or substance abuse disorder that would interfere with 
cooperating with the requirements of the study.
Other Exclusions 
19. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
20. Has had an allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
There are no restrictions on caffeine, alcohol, or tobacco.
5.3.3
Activity Restrictions
There are no restrictions.
5.3.4
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of study 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 study.
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5.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention. The site will contact 
the participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 8.4.
5.3.6
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.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
5.5
Participant Replacement Strategy
Cohort A
If a participant discontinues from study intervention OR withdraws from the study prior to 
completing Cycle 3, a replacement participant may be enrolled if deemed appropriate by the 
investigator and Sponsor. The replacement participant will be assigned a unique 
treatment/randomization number. The replacement participant will be allocated to the same 
treatment arm as the participant who is being replaced. The study site should contact the 
Sponsor for the replacement participant’s treatment/randomization number.
Cohort B
In Cohort B, if a participant discontinues from study intervention OR withdraws from the 
study, they will not be replaced. 
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study intervention[s] provided by the Sponsor) will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies. Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 4.
Table 4
Study Interventions
Arm 
Name
Arm Type
Interven-
tion 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
All Arms 
in Cohort 
A
Experimental
MK-3475
Biological
Sterile 
Solution for 
IV Infusion
25 mg/mL
200 mg
IV Infusion
Every 3 weeks
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
All Arms 
in Cohort 
A
Experimental
MK-3475
Biological
Sterile 
Solution for 
SC Injection
SC Injection
Every 3 weeks
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
All Arms 
in Cohort 
A
Experimental
MK-3475
Biological
Sterile 
Solution for 
SC Injection
SC Injection
Every 3 weeks
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
Cohort B
Experimental
MK-3475
Biological
Sterile 
Solution for 
IV Infusion
25 mg/mL
400 mg
IV Infusion
Every 6 weeks
Experi
mental
IMP
Provided 
centrally 
by 
Sponsor
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) are based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
Abbreviations:  IV=intravenous; SC=subcutaneous.
CCI
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
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and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Enrollment into Cohort A takes priority over Cohort B.
Cohort A
No Interactive Voice Recognition System (IVRS) will be used in Cohort A. Participants will 
be assigned randomly according to a computer-generated allocation schedule, and will be 
assigned uniformly to 1 of 6 treatment arms (Table 5). 
A sample allocation schedule for the treatment plan of this study in Cohort A is provided in
Table 5. 
Table 5
Sample Allocation Schedule (Cohort A)
Treatment Arm
Cycle 1
Cycle 2
Cycle 3
Cycles 4-35
1 (N=5)
B
C
A
D
2 (N=5)
B
A
C
D
3 (N=5)
A
B
C
D
4 (N=5)
A
C
B
D
5 (N=5)
C
A
B
D
6 (N=5)
C
B
A
D
Note: A
 SC; B
 SC; C=200 mg IV; D=200 mg IV. 
Abbreviations:  IV=intravenous; SC=subcutaneous. 
CCI
CCI
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Cohort B
In Cohort B, all participants will receive 400 mg IV pembrolizumab Q6W. Study treatment 
will be allocated via IVRS.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Administration of study medication will be witnessed by the investigator and/or study staff. 
The total volume of study medication infused or injected will be compared with the total 
volume prepared to determine compliance with each dose administered.
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed.  
If there is a clinical indication for any medication or vaccination specifically prohibited, 
discontinuation from study therapy or vaccination may be required. The investigator should 
discuss any questions regarding this with the Sponsor's Clinical Director. The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the participant's 
primary physician. However, the decision to continue the participant on study intervention 
requires the mutual agreement of the investigator, the Sponsor, and the participant.
Participants are prohibited from receiving the following therapies during the screening and 
treatment periods of this study:
•
Immunotherapy not specified in this protocol
•
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol
•
Investigational agents not specified in this protocol. Radiation therapy (radiotherapy for 
symptom management is allowed)
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•
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 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.
•
Glucocorticoids other than to modulate symptoms from an immune-mediated AE. 
Chronic systemic replacement doses of steroids and non-systemic steroids including 
inhaled steroids, topical steroids, intra-nasal steroids, intra-articular, and ophthalmic 
steroids are allowed that is suspected to have an immunologic etiology. The use of 
physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
There are no prohibited therapies after Post-Treatment Safety follow-up visit. 
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the treatment 
period.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids. 
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 30 days after the last dose of study intervention 
should be recorded for SAEs and events of clinical interest (ECIs) as defined in Section 
8.4.7.
6.5.1
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6, 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.
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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
6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 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
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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
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
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
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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
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/Injection Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion/injection-reactions including 
severe hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or 
shortly after drug infusion/injection and generally resolve completely within 24 hours of 
completion of infusion/injection. Dose modification and toxicity management guidelines on 
pembrolizumab associated infusion/injection reaction are provided in Table 7.
Table 7
Pembrolizumab Infusion/Injection 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 1.5 h (±30 
minutes) prior to 
infusion/injection of _____ 
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 participant's study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (pembrolizumab, 200 mg IV, 400 mg IV,
and
SC) is included on the dispensed study medication label text; random 
code/disclosure envelopes or lists are not provided.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention prior to completion of the protocol-specified treatment 
period will still continue to participate in the study as specified in Section 1.3 and 
Section 8.11.3.
Participants may discontinue study intervention at any time for any reason or be dropped 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
The participant interrupts study intervention administration for more than 12 consecutive 
weeks or has 3 cumulative missed doses unless Sponsor approval to continue.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Radiographic disease progression outlined in Section 8.11 (exception if the Sponsor 
approves treatment continuation following confirmed PD per iRECIST)
•
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
•
Unacceptable adverse experiences as described in Section 8.4.
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•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue treatment.
•
Recurrent Grade 2 pneumonitis
•
Completion of 35 treatments (Cohort A) or 18 treatments (Cohort B) (approximately 2 
years) with pembrolizumab
For participants who are discontinued from study intervention all applicable discontinuation 
activities will be performed according to Section 1.3 (Schedule of Activities) and 
Section 8.1.9.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, are outlined in Section 8.1.9. The procedures to be performed should a participant 
repeatedly fail to return for scheduled visits and/or if the study site is unable to contact the 
participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel responsibilities 
will be documented in the Investigator Trial File Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the study
is outlined in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study. If there are changes to the 
participant’s status during the study (eg, health or age of majority requirements), the 
investigator or medically qualified designee must ensure the appropriate consent is in place.
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8.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides written informed consent. At the time of intervention
allocation/randomization, site personnel will add the intervention/randomization number to 
the participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
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10 years that the investigator considers to be clinically significant. Any cancer other than the 
cancer under study will be recorded as medical history even if diagnosed greater than 
10 years prior to enrollment. Details regarding the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as medical history.
The investigator or qualified designee will obtain historic and current details of the 
participant’s cancer under study. This information will include, but is not limited to, date of 
diagnosis, stage, histology, locations of primary lesions and location of metastases if 
applicable.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting study intervention. Treatment for the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as a prior 
medication.
The investigator or qualified designee will review and record all treatments for the cancer
under study including systemic and local treatment, vaccinations, radiation, and surgeries.
Additional information collected on these treatments will include, but is not limited to, dates 
of administration, reason for discontinuation, best response, and date of progression after 
each treatment as applicable.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety follow-up visit.
The investigator or qualified designee will review and record all new anti-cancer treatments
for the cancer under study initiated after the participant discontinued from study treatment. 
Additional information collected on these treatments will include, but is not limited to, dates 
of administration, reason for discontinuation, best response, and date of progression after 
each treatment as applicable.
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8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization/allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Specific details on the screening/rescreening visit 
requirements are provided in Section 8.11.1.
The procedures for obtaining a screening number from the Sponsor are outlined in the 
procedure manual.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated 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.
The procedures for obtaining a randomization number from the Sponsor are outlined in the 
procedure manual.
8.1.8
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
Study treatment should begin within 3 days of randomization/allocation.
8.1.8.1
Timing of Dose Administration
Study treatment with pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the SoA (Section 1.3.1). All
study treatments will be administered on an outpatient basis.
The Pharmacy Manual contains specific instructions for pembrolizumab storage, 
reconstitution, preparation of the infusion fluid, and administration. Note that the SC dose of 
 is approximate (A:
 B: 
).
CCI
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Cohort A
Study treatment with pembrolizumab will be administered on the scheduled treatment day for 
Day 1 of Cycles 1, 2, and 3 (note: Cycle 1 dose should be administered within 3 days of 
randomization). For Cycles 4 and beyond, study treatment with pembrolizumab may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle (eg, due to 
administrative reasons).
Pembrolizumab will be administered as a dose of either 200 mg using a 30-minute IV 
infusion or 
injected SC. Sites should make every effort to target infusion timing to be 
as close to 30 minutes as possible. However, given the variability of infusion pumps from 
site to site, a window of −5 minutes and +10 minutes is permitted (ie, infusion time is 
30 minutes −5 min/+10 min).
Cohort B
Study treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle (eg, due to administrative reasons) after Cycle 1. Dosing for 
Cycle 1 should be within 3 days of randomization. Pembrolizumab will be administered as a 
400 mg dose using a 30-minute IV infusion. Sites should make every effort to target infusion 
timing to be as close to 30 minutes as possible. However, given the variability of infusion 
pumps from site to site, a window of −5 minutes and +10 minutes is permitted (ie, infusion 
time is 30 minutes −5 min/+10 min). 
8.1.9
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
that are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
Domiciling
Not applicable.
8.1.12
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
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calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/ Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Cohort A and B
Tumor assessments will include all known or suspected disease sites. Imaging may include 
chest, abdomen, and pelvis computed tomography (CT) or magnetic resonance imaging 
(MRI) at baseline and when disease progression or brain metastases are suspected. Tumor 
imaging is strongly preferred to be acquired by CT. For chest, abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. For the brain, MRI is the strongly preferred imaging 
modality.
The same imaging modality technique (ideally the same scanner, and consistent use of 
contrast) should be used in a participant throughout the study. Consistent use of imaging 
techniques will help to optimize the reproducibility of the assessment of existing and new 
tumor burden, and to improve the accuracy of the assessment of response or progression. 
Note: for the purposes of assessing tumor imaging, the term “investigator” refers to the local 
investigator at the site and/or the radiological reviewer at the site or at an offsite facility.
All scheduled images for all study participants will be reviewed by the investigator for 
disease progression. In addition, images (including those obtained via other modalities) that 
are obtained at an unscheduled time point to determine disease progression (as well as 
imaging obtained for other reasons, but that capture radiologic progression based on 
investigator assessment), should also be filed at the study site. Note: for the purposes of 
assessing tumor imaging, the term “investigator” refers to the local investigator at the site 
and/or the radiological reviewer at the site or at an offsite facility.
Cohort B
Confirmation of measurable disease based on RECIST 1.1 by BICR at Screening will be 
used to determine participant eligibility. Confirmation by the BICR that the participant’s 
imaging shows at least 1 lesion that is appropriate for selection as a target lesion per 
RECIST 1.1 is required prior to participant allocation.
All scheduled imaging for all study participants will be submitted to the iCRO. In addition, 
imaging that is obtained at an unscheduled time point, for any reason (including suspicion of 
progression or other clinical reason), should also be submitted to the iCRO if it shows 
progression, or if it is used to support a response assessment. All imaging acquired within the 
protocol-specified window (± 7 days) of time around a scheduled imaging visit can be 
classified as pertaining to that visit. 
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8.2.1.1
Initial Tumor Imaging
Cohort A
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization. Any imaging obtained after Cycle 1 Day 1 of treatment cannot be included in 
the screening assessment. The site study team must review screening images to confirm the 
participant has measurable disease per RECIST 1.1. Tumor imaging performed as part of 
routine clinical management is acceptable for use as screening tumor imaging if it is of 
diagnostic quality and performed within 28 days prior to the date of randomization. 
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
Cohort B
Initial tumor imaging at Screening must be performed within 28 days prior to the date of first 
dose. Any imaging obtained after Cycle 1 Day 1 of treatment cannot be included in the 
screening assessment. The site study team must review screening images to confirm the 
participant has measurable disease per RECIST 1.1. The screening images must be submitted 
to the iCRO for confirmation of measurable disease per RECIST 1.1 for eligibility prior to 
allocation.
If brain imaging is performed to document the stability of existing metastases, MRI should 
be used if possible. If MRI is medically contraindicated, CT with contrast is an acceptable 
alternative.
8.2.1.2
Tumor Imaging During the Study
Imaging timing should follow calendar days and should not be adjusted for delays in cycle 
starts. Imaging should continue to be performed until disease progression is identified by the 
investigator and (unless the investigator elects to continue treatment and follow iRECIST), 
the start of new anticancer treatment, withdrawal of consent, or death, or notification by the 
Sponsor, whichever occurs first. 
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Per modified iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 
4 to 8 weeks after first radiologic evidence of progressive disease (PD) in clinically stable 
participants. Participants who have unconfirmed disease progression may continue on 
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treatment at the discretion of the investigator until progression is confirmed by the site, 
provided they have met the conditions detailed in Section 8.2.1.5. Participants who receive 
confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is less 
than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time 
point, if clinically stable. Participants who have confirmed disease progression by iRECIST, 
as assessed by the site, will discontinue study treatment. Exceptions are detailed in 
Section 8.2.1.5.
Cohort A
The first on-study imaging assessment should be performed at approximately 12 weeks from 
the date of randomization. Subsequent tumor imaging should be performed per the 
institutional standard of care.
Cohort B
The first on-study imaging assessment should be performed at 12 weeks (84 days ± 7 days]) 
from the date of first dose. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ± 7 days) or more frequently if clinically indicated. After 52 weeks (365 days 
±7 days), participants who remain on treatment will have imaging performed every 12 weeks 
(84 days ± 7 days). All supplemental imaging must be submitted to the iCRO.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (± 4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants in Cohort B who discontinue study intervention without documented disease 
progression, every effort should be made to continue monitoring disease status by tumor 
imaging every 12 weeks until the start of a new anticancer treatment, disease progression, 
pregnancy, death, withdrawal of consent, or the end of the study, whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used (by BICR for Cohort B) as the primary measure for assessment of 
tumor response, date of disease progression, and as a basis for all protocol guidelines related 
to disease status (eg, discontinuation of study intervention). Although RECIST 1.1 references 
a maximum of 5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 
target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of 
tumor burden.
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8.2.1.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
the time when site-assessed first radiologic evidence of PD, and is not required to have repeat 
tumor imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR (Cohort B).
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in 
Section 8.2.1.2 and submitted to the iCRO (Cohort B).
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 8 and illustrated as a flowchart in Figure 2.
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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 per 
investigator 
assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD
May continue 
study treatment at 
the assessment of 
the investigator 
and after the 
participant’s 
consent
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue 
study intervention 
at the 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
confirms PD (iCPD) 
by iRECIST per 
investigator 
assessment.
No additional 
imaging 
required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator 
assessment.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
Abbreviations:  iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; 
iPR=iRECIST confirmed partial response; iRECIST=modified Response Evaluation Criteria in Solid 
Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; iUPD=iRECIST unconfirmed 
progressive disease; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 
1.1; VOP=verification of progression
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigators
Abbreviations:  iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1
Note: Imaging submission to iCRO is only applicable to Cohort B. 
8.3
Safety Assessments
Safety assessments will include the collection of AEs and SAEs, monitoring of vital signs
and laboratory assessments (including pregnancy tests), performance of electrocardiograms 
(ECGs) and physical examinations, and verification of concurrent medications. 
Every effort should be made to ensure that the protocol required tests and procedures are 
completed as presented in the SoA.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Adverse Events
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the SoA (Section 1.3) and more frequently if clinically 
indicated. Assessment of AEs will include, but is not limited to, the type, incidence, severity 
(graded by the National Cancer Institute Common Terminology Criteria for Adverse Events 
[NCI CTCAE] Version 4.0), timing, seriousness, and relatedness to study drug. Adverse 
events that occur during the study, including baseline signs and symptoms, will be recorded 
on the AE case report form (CRF) page.
8.3.2
Physical Examinations
8.3.2.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
8.3.2.2
Directed Physical Examination
For cycles that do not require a full physical exam as defined in Section 1.3, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study intervention. New clinically significant abnormal findings should 
be recorded as AEs.
8.3.3
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to each 
pembrolizumab administration, after SC pembrolizumab administration, and during the 
follow-up period as specified in the SoA (Section 1.3).
Vital signs will be measured in a semi-supine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, respiratory rate, pulse rate, and weight.
Height will be collected at screening only.
8.3.4
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA in Section 1.3. Clinically significant abnormal findings at 
Screening should be recorded as medical history. Additional ECG(s) should be performed on 
study when clinically necessary. Clinically significant findings seen on the follow-up ECGs 
should be recorded as AEs.
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8.3.5
Clinical Safety Laboratory Assessments
•
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Study 
Procedures Manual. Refer to the SoA (Section 1.3) for the timing of laboratory assessments.
8.3.5.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 72 hours prior to the first dose of 
study intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. After Cycle 1, predose laboratory safety tests can be 
conducted up to 72 hours prior to dosing unless otherwise noted on the SoA (Section 1.3). 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study intervention. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
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Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within normal range.
8.3.5.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours or the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation.
8.3.6
Performance Assessments
8.3.6.1
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 8) at screening
(Cohort A and Cohort B). For Cohort A, repeat ECOG should be performed on-study only if 
clinically necessary. For Cohort B, ECOG should be performed every visit as specified in the 
SoA (Section 1.3).
8.3.7
Injection Site Signs and Symptoms Questionnaire
Participants will complete the injection site signs and symptoms questionnaire after SC 
injection of pembrolizumab during the first 3 treatment cycles in Cohort A as specified in the 
SoA (Section 1.3). The questionnaire should be completed 60 minutes after the SC injection. 
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE unless it results in 
hospitalization or death as described in Section 8.4.6 and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
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The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure.
•
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation 
of study intervention if the participant initiates new anticancer therapy, whichever is 
earlier, must be reported by the investigator.
•
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study intervention, or 
30 days following cessation of study intervention if the participant initiates new 
anticancer therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 9.
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Table 9
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
Specified 
Follow-up Period
Reporting Time Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Non-Serious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if: 
drug-/vaccine-related.
(Follow ongoing to 
outcome)
Within 
24 hours of 
learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- due to 
intervention
- causes 
exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 
24 hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- Potential drug-
induced liver 
injury (DILI)
- Require 
regulatory 
reporting
Not required
Within 
24 hours of 
learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar 
days of 
learning of 
event
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee), including the pregnancy of a male participant’s female 
partner, that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Progression of the cancer under study is not considered a reportable event unless it results in 
hospitalization or death.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1.
An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.
2.
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that must trigger 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.4.8
Medical Device Incidents (Including Malfunctions)
Not applicable. 
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
To evaluate pembrolizumab immunogenicity and pembrolizumab exposure after MK-3475
SC administration (Cohort A ), and Q6W dosing (Cohort B), sample collections for analysis 
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of ADAs and PK are currently planned as shown in the SoA (Section 1.3). Blood samples 
will be obtained to measure PK of serum pembrolizumab. The pembrolizumab serum 
concentration at planned visits and times will be summarized. 
8.6.1
Blood Collection for Plasma for Pembrolizumab Pharmacokinetics and 
Immunogenicity
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the procedures/laboratory manual.
8.6.1.1
Blood Collection for Pharmacokinetics
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the procedure/laboratory manual. Pharmacokinetic samples should be drawn according to the 
PK collection schedule for all participants. 
8.6.1.2
Blood Collection for Anti-pembrolizumab Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the procedure manual. Anti-pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for all participants (Section 1.3). 
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.9
Planned Genetic Analysis Sample Collection
Planned genetic analysis samples will not be evaluated in this study.
8.10
Biomarkers
Biomarkers are not evaluated in this study.
8.10.1
RNA Transcriptome Research 
Not applicable. 
8.10.2
RNA Expression Research of a Subset of RNA Species 
Not applicable. 
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8.10.3
Proteome Research 
Not applicable. 
8.10.4
Metabolomic Research 
Not applicable. 
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine 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 
study intervention except for the following:
•
Laboratory tests are to be performed within 72 hours prior to the first dose of study 
intervention. An exception is hepatitis and thyroid testing which may be done up to 28 
days prior to the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
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8.11.3
Discontinued Participants Continuing to be Monitored in the Study
The End of Treatment visit should occur at the time study treatment is discontinued for any 
reason. Visit requirements are outlined in the SoA (Section 1.3).
If the End of Treatment visit occurs 30 days from the last dose of study treatment, at the time 
of the mandatory Safety follow-up visit, the End of Treatment visit procedures and any 
additional safety follow up procedures should be performed.
8.11.3.1
Follow-up Visits
Cohort B
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks ([84] days ± 7 days) 
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 
study.
8.11.3.2
Safety Follow-up Visit
Participants will be required to return to the clinic for the Safety follow-up visit 
approximately 30 days after the last dose of study treatment or before initiating a new 
anticancer therapy, whichever occurs first. If the Safety follow-up visit occurs less than 
30 days after the last dose of study treatment, a subsequent follow up phone call should be 
made 30 calendar days after the last dose of study treatment to determine if any AEs occurred 
since the last study visit.
After treatment discontinuation, participants will be monitored for AEs for 30 calendar days 
and SAEs for 90 calendar days after the last administration of the investigational product 
(30 calendar days if the participant initiates new anticancer therapy). Participants with an 
ongoing AE at the time of treatment discontinuation will be followed until resolution, 
stabilization, the event is otherwise explained, or the participant is lost to follow-up.
If the End of Treatment visit occurs 30 days from the last dose of study treatment, at the time 
of the mandatory Safety follow-up visit, the End of Treatment visit procedures and any 
additional safety follow up procedures should be performed.
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8.11.3.3
Survival Follow-up
Cohort A
Survival follow-up will not be collected for participants in Cohort A.
Cohort B
Participants who experience confirmed disease progression or start a new anticancer therapy,
will move into the Survival follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.
8.11.4 Survival Status
Cohort A
Collection of survival status will not be required for Cohort A.
Cohort B
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 interim 
and/or final analysis. Upon Sponsor notification, all participants who do not/will not have a 
scheduled study visit or study contact during the Sponsor defined time period will be 
contacted for their survival status (excluding participants that have a previously recorded 
death event in the collection tool). 
9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategies and procedures for the primary,
secondary, and exploratory analyses of the study.
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Post hoc exploratory analyses will be clearly identified in the 
Clinical Study Report (CSR).
Full details are in the Statistical Analysis Plan, Section 9.2 through Section 9.12.
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Study Design Overview
Phase 1, relative bioavailability, cross-over study of 
pembrolizumab administered via IV infusion or 
SC injection in participants with advanced melanoma
(Cohort A) and of IV pembrolizumab Q6W dosing 
(Cohort B).
Treatment Assignment
In Cohort A, participants will be randomized to 1 of 
6 treatment arms and will receive 1 IV infusion and 2 SC 
injections over the first 3 cycles, followed by IV infusion of 
pembrolizumab for up to 35 cycles.
In Cohort B, participants will receive IV infusion of 
pembrolizumab Q6W for up to 18 cycles. 
Enrollment into Cohort A takes priority over Cohort B.
Analysis Populations
Cohort A:
PK (Primary): Per-Protocol (PP)
Safety (Secondary): All-Participants-as-Treated (APaT) 
Cohort B:
Efficacy (Primary): Full Analysis Set (FAS)
PK (Secondary): Per-Protocol (PP)
Safety (Secondary): All-Participants-as-Treated (APaT) 
Primary Endpoint(s)
Cohort A: Pharmacokinetic parameters of 
pembrolizumab, including area under the curve (AUC), 
maximum concentration (Cmax), bioavailability (F), 
absorption rate (Ka), time of maximum 
concentration (Tmax), clearance (CL), and central volume of 
distribution (Vc) 
Cohort B:  ORR per RECIST 1.1. by BICR
Secondary Endpoints
Cohort A:

Circulating antidrug antibody levels

Adverse events (AEs)

Discontinuing study treatment due to an AE

Responses to the injection site signs and symptoms 
questionnaire
Cohort B:

DOR per RECIST 1.1 by BICR

PFS per RECIST 1.1 by BICR
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
OS

Adverse events (AEs)

Pharmacokinetics: Pharmacokinetic parameters of 
pembrolizumab, including AUC, Cmax, and Cmin after 
administration of 400 mg Q6W pembrolizumab
Exploratory
Cohort B

Circulating antidrug antibody levels
Statistical Methods for 
Pharmacokinetic 
Analyses
Cohort A: The relative bioavailability of pembrolizumab 
via SC injection will be estimated using AUC comparing 
with that via IV infusion. The log-transformed AUC of 
pembrolizumab will be analyzed with a linear mixed effects 
model with fixed effects terms for treatment and cycle. Point 
estimates for Geometric Mean Ratio (GMR, SC 
versus IV, SC
versus IV) and their 90% 
confidence intervals (CIs) will also be calculated.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints 
as appropriate.
Statistical Methods for 
Efficacy Analyses
Cohort B:  Estimation of ORR; Estimation of DOR, PFS 
and OS using the Kaplan-Meier method.
Interim Analyses
No interim analysis is planned. Two PK analyses will be 
conducted during the study. The first PK analysis will occur 
when at least 30 participants have completed the first 
3 cycles of this study in Cohort A. The second PK analysis 
will occur after Cycle 5 in Cohort B. 
Multiplicity
No multiplicity adjustment is planned for this Phase 1 
research design.  
Sample Size and Power There is no hypothesis testing. For Cohort A, assuming the 
true GMR of AUC between SC injection and IV infusion is 
1.0, with 30 completers the 90% CI of the GMR will be 
(0.90, 1.11). For Cohort B, assuming the observed ORR is 
what is expected with pembrolizumab 200 mg Q3W for 
35 cycles (~35%), 100 subjects will assure a 95% CI for the 
true ORR of approximately (25%, 45%).  
Abbreviations: BICR=blinded independent central review; DOR=duration of response; 
ORR=objective response rate; OS=overall survival; PFS=progression-free survival; 
RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1
CCI
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9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study is open-label; participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned. 
Allocation to treatment in Cohort A will be randomized. There will be direct treatment 
assignment for Cohort B. 
9.3
Hypotheses/Estimation
Objectives of the study are outlined in Section 3.0. No hypotheses are being tested in this 
study.
9.4
Analysis Endpoints
9.4.1
Pharmacokinetics Endpoints (Cohorts A and B)
Pharmacokinetic endpoints are PK parameters of pembrolizumab after IV (200 mg Q3W) 
and SC administration including area under the curve (AUC), maximum 
concentration (Cmax), bioavailability (F), absorption rate (Ka), time of maximum 
concentration (Tmax), clearance (CL), and central volume of distribution (Vc). PK endpoints 
also include AUC, Cmax, and Cmin after IV infusion 400 mg Q6W. 
In addition, the development of circulating anti-pembrolizumab antibodies (if applicable) 
will be evaluated following IV 200 mg Q3W and SC administration, as well as IV 400 mg 
Q6W pembrolizumab administration. 
9.4.2
Safety Endpoints (Cohorts A and B)
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs, as well as the injection site signs and symptoms 
questionnaire.
A description of safety measures is provided in Section 8.3 and Section 8.4.
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9.4.3
Efficacy Endpoints (Cohort B)
9.4.3.1
Primary
Objective Response Rate (ORR) per RECIST 1.1 assessed by BICR
Objective Response is defined as a best overall response of CR or PR. The details of the 
ORR analysis plan can be found in Section 9.6.1.1.
9.4.3.2
Secondary
Duration of Response (DOR) per RECIST 1.1 assessed by BICR
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. See Section 9.6.1.4 for definition of censoring.
Progression-free Survival (PFS) per RECIST 1.1 assessed by BICR
PFS is defined as the time from the first day of study treatment to the first documented 
disease progression or death due to any cause, whichever occurs first. See Section 9.6.1.2 for 
definition of censoring.
Overall Survival (OS)
OS is defined as the time from the first day of study treatment  to death due to any cause. 
Participants without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
9.5
Analysis Populations
9.5.1
Pharmacokinetic Analysis Population (Cohorts A and B) 
The Per-Protocol (PP) population will be used for the analysis of PK data in this study. The 
PP population consists of the subset of participants who complied with the protocol 
sufficiently to ensure that their data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance includes such considerations as 
exposure to treatment, availability of measurements, and the absence of major protocol 
violations. Any participants or data values excluded from the analyses will be identified, 
along with the reasons for exclusion, in the CSR. At the end of the study, all participants who 
were compliant with the study procedures and have available data from at least 1 treatment 
will be included in the PP analysis dataset.
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9.5.2
Safety Analysis Population (Cohorts A and B)
The All-Participants-as-Treated (APaT) population will be used for the analysis of safety 
data in this study, including injection site signs and symptoms. The APaT population consists 
of all participants who received at least 1 dose of study treatment. In case of treatment 
administration errors, participants will be analyzed according to the treatment they actually 
received.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.3
Efficacy Analysis Population (Cohort B) 
The APaT population will serve as the primary population for the analysis of efficacy data in 
this study. 
9.6
Statistical Methods
9.6.1
Statistical Methods for Pharmacokinetic and Antidrug Antibodies Data
(Cohorts A and B)
Cohort A
Primary/final PK analysis will be conducted when at least 30 participants have completed the 
first 3 cycles of this study. Along with the safety data, the PK analysis will be used for 
programmatic decision making purposes. The study will not be discontinued regardless of the 
outcome of the PK analysis.
The relative bioavailability of pembrolizumab via SC injection will be estimated using AUC 
comparing with that via IV infusion. The log-transformed AUC of pembrolizumab will be 
analyzed with a linear mixed effects model with fixed effects terms for treatment and cycle. 
An unstructured covariance matrix will be used to allow for unequal treatment variances and 
to model the correlation between different treatment measurements within the same subject 
via the REPEATED statement in SAS PROC MIXED. Kenward and Roger's method will be 
used to calculate the denominator degrees of freedom for the fixed effects (DDFM=KR). If 
the model fails to converge, a simpler covariances structure, such as 
heterogeneous-compound symmetry, will be used.
If the concentration of pembrolizumab observed in the pre-dose sample of Treatment Cycle 2 
or Cycle 3 is <5% of the Cmax observed in the same cycle, this level of carry-over can be 
considered negligible and no correction is needed. However, if the concentration observed in 
the pre-dose samples is ≥5% of the Cmax observed in the same cycle, all concentrations in that 
cycle will be adjusted (assuming linear PK) for the impact of the carry-over as specified by 
the equation below. If carry-over adjustment is necessary in any given cycle, the adjustment 
will be made for all subjects with quantifiable predose concentrations before 
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non-compartmental PK analysis for AUC and statistical model fitting. In addition, a reduced 
model may be explored to fit the Treatment Cycle 1 data only. In this model treatment will be 
included as a factor. The key covariates will also be considered. 
Cadj = Corig – CPD * e-(Ke)(t)
Where:
Cadj = carry-over-adjusted concentration
Corig = observed concentration
CPD = original predose concentration 
Ke = slope of terminal phase (elimination constant lambda z in Phoenix) of the previous 
cycle
t = time of Corig compared to predose
Back-transformed Geometric Mean of AUC as well as its 95% CI will be calculated by 
treatment. Point estimates for Geometric Mean Ratio (GMR, SC 
 versus IV, 
SC
 versus IV) and their 90% confidence intervals (CIs) will also be calculated. 
Other PK parameters including Ka, Cmax, CL, and Vc will be analyzed in a similar fashion. 
Antidrug antibodies data will be summarized by treatment and visit. Relationship between 
the presence/absence of positivity for ADA and PK of pembrolizumab will be explored.
Cohorts A and B
Individual values will be listed for each PK parameter by treatment, and the following 
(nonmodel-based) descriptive statistics will be provided: N (number of subjects with 
nonmissing data), arithmetic mean, standard deviation, arithmetic percent coefficient of 
variation (CV) (calculated as 100 x standard deviation/arithmetic mean), median, minimum, 
maximum, geometric mean, and geometric percent CV (calculated as 100 x sqrt(exp(s2) - 1), 
where s2 is the observed variance on the natural log-scale).
9.6.2
Statistical Methods for Efficacy Analyses (Cohort B)
This section describes the statistical methods that address the primary and secondary 
objectives. 
9.6.2.1
Objective Response Rate (ORR)
ORR will be calculated as the ratio of the number of participants reported to have achieved a 
confirmed CR or PR verified by BICR, divided by the number of participants included in 
APaT population. Participants in the APaT analysis population without ORR assessments 
will be counted as non-responders.
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A 95% exact binomial CI (based on method Clopper and Pearson,1934) will be calculated for 
the true ORR. 
9.6.2.2
Progression-free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS distribution. 
95% CIs for the median PFS and PFS point estimates at various follow-up times from first 
day of study treatment will be calculated.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. The true date of PD will be approximated by the date of the first assessment at 
which PD is objectively documented based on RECIST 1.1 by BICR. Death is always 
considered as a PFS event. Participants who do not experience a PFS event will be censored 
at the last disease assessment.
For the analysis of PFS, if the events (PD or death) are immediately after more than one 
missed disease assessment, the data are censored at the last disease assessment prior to 
missing visits. Also, data after new anticancer therapy are censored at the last disease 
assessment prior to the initiation of new anticancer therapy. The censoring rule is
summarized in Table 10. If a participant meets multiple criteria for censoring, the censoring 
criterion that occurs earliest will be applied.
Table 10
Censoring Rules for Analysis of Progression-free Survival
Situation
Date of Progression or Censoring
PD or death documented after ≤1 missed 
disease assessment, and before new 
anticancer therapy, if any
Progressed at date of documented PD or death
PD or death documented immediately after 
≥2 consecutive missed disease assessments 
or after new anticancer therapy, if any
Censored at last disease assessment prior to the earlier date of  
≥2 consecutive missed disease assessment and new 
anticancer therapy, if any
No PD and no death; and new anticancer 
treatment is not initiated
Censored at last disease assessment 
No PD and no death; new anticancer 
treatment is initiated
Censored at last disease assessment before new anticancer 
treatment 
Abbreviations: PD=progressive disease; PFS=progression-free survival
9.6.2.3
Overall Survival (OS)
The non-parametric Kaplan-Meier method will be used to estimate the OS distribution. 
95% CIs for the median OS and OS point estimates at various follow-up times from first day 
of study treatment will be calculated.
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9.6.2.4
Duration of Response (DOR)
DOR will be summarized descriptively using the non-parametric Kaplan-Meier method. 
Only the subset of participants who show a CR or PR will be included in this analysis.
Censoring rules for DOR are summarized in Table 11.
Table 11
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anti-cancer therapy 
initiated
Censor
(non-event)
Death or progression immediately 
after ≥ 2 consecutive missed 
disease assessments or after new 
anti-cancer therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥ 2 missed 
adequate disease assessments and 
new anti-cancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 
missed disease assessments and 
before new anti-cancer therapy, if 
any
Progressive disease or death
End of response
(Event)
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.  
DOR = duration of response
9.6.2.5
Analysis Strategy for Key Efficacy Endpoint
Table 12 summarizes the primary analysis approach for key efficacy endpoints.
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Table 12
Analysis Strategy for Key Efficacy Endpoints
Endpoint 
Statistical Methoda
Analysis 
Population
Missing Data Approach
Primary Endpoints
ORR per RECIST 1.1 by 
BICR 
Exact method based
on binomial
distribution
(Clopper-Pearson
method)
APaT
Participants without
assessments are 
considered 
non-responders and 
conservatively included in 
the denominator
Key Secondary Endpoint
PFS per RECIST 1.1 by 
BICR
Summary statistics
using Kaplan-Meier
method
APaT
Primary censoring rule
Sensitivity analysis 1
Sensitivity analysis 2
(More details are 
provided in Table 10,
Censoring Rules
for Primary and 
Sensitivity Analyses of 
PFS)
OS
Summary statistics
using Kaplan-Meier
method
APaT
Censored at the last 
known alive date
DOR per RECIST 1.1 by 
BICR
Summary statistics
using Kaplan-Meier
method
APaT
Non-responders are
excluded from analysis.
Responders are
censored according to
the censoring rules
listed in Table 11.
a Statistical models are described in further detail in the text.
Abbreviations: APaT=All Participants as Treated; BICR=blinded independent central review; DOR=duration of 
response; ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST=Response 
Evaluation Criteria in Solid Tumors
9.6.3
Statistical Methods for Safety Analysis (Cohort A)
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, and physical examinations.
Cycles 1 through 3
The counts and frequency of AEs including injection site reaction AEs will be summarized 
by treatment and by sequence. In addition, AEs will be summarized based on Treatment 
Cycle 1 data only as well. Laboratory tests, vital signs, and other safety endpoints will be 
summarized as appropriate. 
Descriptive summary statistics will be provided for the injection site signs and symptoms 
questionnaire data by treatment. 
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Post Cycle 3
Adverse events collected from Cycle 4 to the end of the study will reported. 
9.6.4
Statistical Methods for Safety Analyses (Cohort B)
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences and laboratory parameters. 
The broad AE categories consisting of the percentage of participants with any AE, a 
drug-related AE, a serious AE, an AE which is both drug-related and serious, and who 
discontinued due to an AE will be summarized via point estimates with 95% CIs (Table 13).
Table 13
Analysis Strategy for Safety Parameters
Safety Endpoint
Within 
Group 
95% CI 
Descriptive Statistics
Any AE
X
X
Any Serious AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs 
X
Change from Baseline Results (Labs, Vital Signs)
X
Note: 95% CIs will be calculated using the Clopper Pearson method
X  = results will be provided
Abbreviations: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change
For continuous measures such as changes from baseline in laboratory parameters, summary 
statistics for baseline, on-treatment, and change from baseline values will be provided in 
table format.
9.6.5
Demographics and Baseline Characteristics (Cohort B)
The number and percentage of subjects screened, allocated, the primary reasons for screening
failure, and the primary reasons for discontinuation will be displayed. Demographic variables 
(e.g., age, gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized either by descriptive statistics or categorical tables 
for all enrolled subjects.
9.7
Interim Analyses
No interim analysis is planned. 
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9.8
Multiplicity
No multiplicity adjustment is planned for this study. 
9.9
Sample Size and Power Calculations
Cohort A
The overall sample size for this Phase 1 study is expected to be up to approximately 
30 to 36 participants. Assuming that the within-subject standard deviation of pembrolizumab
AUC in melanoma patients following subcutaneous administration is the same as it is
following IV administration (which is 0.25 on log scale based on previous pembrolizumab
studies) and assuming the true GMR of AUC between SC injection and IV infusion is 1.0, 
with 30 completers the 90% CI of GMR will be (0.90, 1.11).
A between-subject comparison will also be provided based on Treatment Cycle 1 data only. 
The between-subject standard deviation of pembrolizumab AUC in melanoma patients 
following IV administration is 0.30 on log scale based on previous pembrolizumab studies. 
Assuming the between-subject standard deviation following SC administration is 0.50 on log 
scale based on published SC PK data for other mAbs [Dirks, N. L. 2010], when the true 
GMR of AUC between SC injection and IV infusion is 1.0, with 10 completers in each 
treatment (30 in total), the 90% CI of GMR will be (0.72, 1.38).
Cohort B
Approximately 100 participants will be enrolled in Cohort B. The ORR for the dose and 
schedule to be used in Cohort B is expected to be similar to that seen with pembrolizumab, 
200 mg Q3Ws 35 cycles (~ 35%). If the observed ORR for the 100 subjects was 35%, a 95% 
CI for the true ORR based on the method of Clopper and Pearson (1934) would be (25.7%, 
45.2%).
9.10
Subgroup Analyses
Cohort A
There will be no subgroup analyses conducted for Cohort A.
Cohort B
To determine whether the response rate is consistent across various subgroups, the estimate 
of the response rate (with a nominal 95% CI) for the primary endpoint will be estimated 
within each category of the following classification variables:

Age category (< 65 vs. ≥65 years)

Sex (female vs. male)
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
Race (white vs. non-white)

Disease stage (III vs. IVM1a vs. IVM1b vs. IVM1c)

Brain metastasis (yes vs. no)

ECOG status (0 vs. 1)

PD-L1 status (positive vs. negative [includes indeterminate])

BRAF wild type versus BRAF mutant (no prior treatment) versus BRAF mutant
(prior treatment)

LDH (≤ ULN vs. > ULN but < 2X ULN vs. ≥ 2X ULN)
A Forest plot will be produced, which provides the estimated point estimates and CIs for the 
treatment effect across the categories of subgroups listed above.
Any specified subgroups that have less than 10 participants will be excluded from analysis. 
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, 
efficacy, and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. 
Alternatively, MSD may conduct outcomes research trials, trials to assess or validate various endpoint 
measures, or trials to determine patient preferences, etc.
The design (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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are investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and 
ethics review committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review 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 (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Not applicable. 
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.  
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); and all applicable federal, state and local laws, 
rules and regulations relating to the conduct of the clinical study. The Code of Conduct, a 
collection of goals and considerations that govern the ethical and scientific conduct of 
clinical investigations sponsored by MSD, is provided in this appendix under the Code of 
Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
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Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 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.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 14 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
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Table 14
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
Blood Urea 
Nitrogen (BUN)
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)
Albumin
Bicarbonate
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose 
Calcium
Alkaline 
phosphatase
TSH
Total T3 (or free 
T3)
Total T4 (or free 
T4)a
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte esterase] by 
dipstick
Microscopic examination (if blood or protein is abnormal)
Other Screening 
Tests
Follicle-stimulating hormone and estradiol (as needed in women of nonchildbearing 
potential only)
[Serum or urine] [alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) if applicable]
[Serum or urine] β-human chorionic gonadotropin (β-hCG) pregnancy test (as needed for 
WOCBP)
[Serology [(HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody)] [or specify other tests] [if applicable] 
NOTES:
aT3 and T4 are preferred; if not available, free T3 and free T4 may be tested. 
Abbreviations:  β-hCG=β-human chorionic gonadotropin; ALT=alanine transaminase; AST=aspartate 
transaminase; BUN=blood urea nitrogen; HBsAg=hepatitis B surface antigen; HIV=human immunodeficiency 
virus; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; 
SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic pyruvic transaminase; TSH=thyroid 
stimulating hormone; WBC=white blood cell; WOCBP=woman/women of childbearing potential. 
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, 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 intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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Worsening of signs and symptoms of malignancy during the study should be reported as an 
AE in the appropriate section of the CRF. Disease progression assessed by measurement of 
malignant lesions on radiographs or other methods should not be reported as an AE, unless 
the event results in hospitalization or death.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.7 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose
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10.3.4
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of causality
Did the Sponsor’s product cause the AE?
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s 
product and the AE; the greater the correlation with the components and their respective 
elements (in number and/or intensity), the more likely the Sponsor’s product caused the AE:
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Exposure:  Is there evidence that the participant was actually exposed to the Sponsor’s 
product such as: reliable history, acceptable compliance assessment (pill count, diary, etc.), 
expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course:  Did the AE follow in a reasonable temporal sequence from administration of 
the Sponsor’s product? Is the time of onset of the AE compatible with a drug-induced effect 
(applies to studies with investigational medicinal product)?
Likely Cause:  Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors.
Dechallenge:  Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?

If yes, did the AE resolve or improve?

If yes, this is a positive dechallenge.

If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Sponsor’s product; (3) the study is 
a single-dose drug study; or (4) Sponsor’s product(s) is/are only used 1 time.)
Rechallenge:  Was the participant re-exposed to the Sponsor’s product in this study?

If yes, did the AE recur or worsen?

If yes, this is a positive rechallenge.

If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent 
disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s product(s) is/are used 
only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
Consistency with study intervention profile:  Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).

Yes, there is a reasonable possibility of Sponsor’s product relationship:
There is evidence of exposure to the Sponsor’s product. The temporal sequence of the AE 
onset relative to the administration of the Sponsor’s product is reasonable. The AE is more 
likely explained by the Sponsor’s product than by another cause.

No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor’s product OR temporal sequence of the AE onset 
relative to administration of the Sponsor’s product is not reasonable OR the AE is more 
likely explained by another
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
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•
Reference Section 8.4.1  for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Not Applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
•
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the nonhormonal highly effective contraception methods if they wish to continue their 
HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
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 15
during the protocol-defined time frame in Section 6.1.
Table 15
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependenta
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraceptionb
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraceptionb
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implantb
●
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 lower than perfect-use failure rates (i.e. when used consistently and 
correctly). 
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation. 
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10.5.3
Pregnancy Testing
Women of childbearing potential should only be included after a negative highly sensitive 
urine or serum pregnancy test.
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points 
specified in the Schedule of Activities, and as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not applicable.
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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging 4 to 8 weeks later is obtained (using iRECIST for 
participant management (see Table 7 and Figure 2). This decision by the investigator should 
be based on the participant’s overall clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR (Cohort B).
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
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•
Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
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•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the iCRO (Cohort B).
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.
•
New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
β-HCG
beta-human chorionic gonadotropin
ADA
antidrug antibodies
AE
adverse event 
AJCC
American Joint Committee on Cancer
ALT
alanine transaminase
APaT
All Patients as Treated
AST
aspartate transaminase
AUC
area under the curve
BCG
Bacillus Calmette-Guérin
BICR
Blinded Independent Central Review
C
Cycle
Cavg
average concentration
CBC
complete blood count
CD
cluster of differentiation
CI
confidence interval
CL
clearance
Cmax
maximum concentration
Cmin
minimum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
case report form 
CRO
Contract Research Organization
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CV
coefficient of variation
D
Day
DILI
drug-induced liver injury
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
EMA
European Medicines Agency
E-R
exposure-response
EU
European Union
F
Bioavailability
FAS
Full Analysis Set
FDAAA
Food and Drug Administration Amendments Act
FSH
Follicle-stimulating hormone 
GCP
Good Clinical Practice 
GI
gastrointestinal
GMR
geometric mean ratio
HBsAg
hepatitis B surface antigen
HCV
hepatitis c virus
HIV
human immunodeficiency virus
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Abbreviation
Expanded Term
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
ICMJE
International Committee of Medical Journal Editors
iCPD
confirmed radiographic progression
iCR
iRECIST complete response
iCRO
Imaging Contract Research Organization
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG
immunoglobulin G
IMP
investigational medicinal product
INR
international normalized ratio
iPR
iRECIST confirmed partial response
irAE
immune related adverse event
IRB
Institutional Review Board 
iRECIST
modified Response Evaluation Criteria in Solid Tumors
iSD
iRECIST stable disease
iUPD
iRECIST unconfirmed progressive disease
IV
intravenous
Ka
absorption rate
LDH
lactase dehydrogenase
M&S
Modelling and Simulation
mAB
monoclonal antibody
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NIMP
non-investigational medicinal product
NSAE
non-serious adverse event
NSAID
non-steroidal anti-inflammatory
NSCLC
non-small cell lung carcinoma
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based pharmacokinetics
PD
Progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression free survival
PK
pharmacokinetic
PO
oral
PP
Per Protocol
PR
partial response
pRBC
packed red blood cell
PT
partial thromboplastin
PTT
partial thromboplastin time
Q2W
every 2 weeks
Q3W
every 3 weeks
Q6W
every 6 weeks
RBC
red blood cell
RNA
ribonucleic acid
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Abbreviation
Expanded Term
SAE
serious adverse event 
SC
subcutaneous
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
SLAB
Supplemental laboratory procedures
SoA
schedule of activities
SOP
Standard Operating Procedure
SUSAR
suspected unexpected serious adverse reaction
TMDD
target-mediated drug disposition
TSH
thyroid-stimulating hormone
Tmax
time of maximum concentration
ULN
upper limit of normal
US
United States
V
volume of distribution
Vc
central volume of distribution
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
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11
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