A Phase II, Open-label, Single-arm, Multicenter Study to Evaluate Efficacy and Safety of Pembrolizumab Monotherapy in Subjects With Advanced Recurrent Ovarian Cancer (KEYNOTE-100)
Phase: PHASE2
Conditions: Ovarian Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Product:  MK-3475 
1
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
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., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase II, Open-label, Single-arm, Multicenter Study to Evaluate Efficacy and Safety of 
Pembrolizumab Monotherapy in Subjects with Advanced Recurrent Ovarian Cancer
(KEYNOTE -100)
IND NUMBER:  [126,191]
EudraCT NUMBER:  [2015-003338-29]
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
2
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
Overall Trial Design ........................................................................................... 14
Trial Diagram at Individual Subject Level ......................................................... 16
Trial Diagram........................................................................................................ 17
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Exploratory Objectives......................................................................................... 19
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 20
Disease Background..................................................................................... 20
Targeting PD-1 Immune Checkpoints for Cancer Treatment...................... 22
Anti-PD-1 Antibody Pembrolizumab .......................................................... 22
Summary of Pembrolizumab Clinical Activities ................................................ 23
Rationale................................................................................................................ 25
Rationale for the Trial and Selected Subject Population .................................... 25
Rationale for Dose Selection/Regimen/Modification......................................... 26
Rationale for Endpoints ...................................................................................... 27
Efficacy Endpoints....................................................................................... 27
Immune-related RECIST (irRECIST) ......................................................... 28
Safety Endpoints.......................................................................................... 28
Planned Biomarker Research....................................................................... 29
Future Biomedical Research........................................................................ 30
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
3
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Benefit/Risk ........................................................................................................... 31
5.0
METHODOLOGY ................................................................................................... 31
Entry Criteria........................................................................................................ 31
Diagnosis/Condition for Entry into the Trial ...................................................... 31
Subject Inclusion Criteria.................................................................................... 31
Subject Exclusion Criteria .................................................................................. 34
Trial Treatment(s) ................................................................................................ 35
Dose Selection/Modification .............................................................................. 35
Dose Selection (Preparation) ....................................................................... 35
Dose Modification and Toxicity Management Guidelines for 
Pembrolizumab............................................................................................ 36
Timing of Dose Administration.......................................................................... 41
Trial Blinding/Masking....................................................................................... 42
Randomization or Treatment Allocation............................................................ 42
Stratification.......................................................................................................... 42
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 42
Acceptable Concomitant medications................................................................. 42
Prohibited Concomitant Medications.................................................................. 42
Rescue Medications & Supportive Care............................................................. 43
Supportive Care Guidelines ................................................................................ 43
Diet/Activity/Other Considerations..................................................................... 44
Diet...................................................................................................................... 44
Contraception...................................................................................................... 44
Use in Pregnancy ................................................................................................ 46
Use in Nursing Women....................................................................................... 46
Subject Withdrawal/Discontinuation Criteria................................................... 46
Discontinuation of Study Therapy after Complete Response............................. 47
Subject Replacement Strategy............................................................................. 47
Beginning and End of the Trial ........................................................................... 47
Clinical Criteria for Early Trial Termination ................................................... 48
6.0
TRIAL FLOW CHART ........................................................................................... 49
Initial Treatment Phase........................................................................................ 49
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
4
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Second Course Phase (Retreatment)................................................................... 53
7.0
TRIAL PROCEDURES ........................................................................................... 55
Trial Procedures ................................................................................................... 55
Administrative Procedures.................................................................................. 55
Informed Consent......................................................................................... 55
General Informed Consent.................................................................... 55
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 55
Inclusion/Exclusion Criteria ........................................................................ 56
Subject Identification Card .......................................................................... 56
Medical History ........................................................................................... 56
Ovarian Cancer Disease Details ........................................................... 56
Menopausal Details............................................................................... 56
Prior and Concomitant Medications Review............................................... 56
Prior Medications.................................................................................. 56
Concomitant Medications..................................................................... 57
Subsequent Anti-Cancer therapy Status....................................................... 57
Assignment of Screening Number............................................................... 57
Assignment of Treatment/Randomization Number..................................... 57
Trial Compliance (Medication/Diet/Activity/Other) ................................... 57
Clinical Procedures/Assessments........................................................................ 58
Adverse Event Monitoring........................................................................... 58
Physical Exam.............................................................................................. 58
Full Physical Exam ............................................................................... 58
Directed Physical Exam........................................................................ 58
Vital Signs.................................................................................................... 58
12-Lead Electrocardiogram ......................................................................... 59
Eastern Cooperative oncology Group Performance Status.......................... 59
Tumor Imaging and Assessment of Disease................................................ 59
Screening Tumor Imaging .................................................................... 59
Disease Assessments During Treatment Period ................................... 60
Bone Scans............................................................................................ 60
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
5
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
End of Treatment and Follow-up Tumor Imaging................................ 61
Second Course (Retreatment) Tumor Imaging..................................... 61
RECIST 1.1 Assessment of Disease..................................................... 61
irRECIST Assessment of Disease......................................................... 62
Laboratory Procedures/Assessments .................................................................. 64
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 64
Blood for Menopausal Status....................................................................... 66
Blood for Tumor Biomarker CA-125 .......................................................... 66
Pharmacokinetics/Pharmacodynamic Evaluations ...................................... 67
Blood Collection for Serum Pembrolizumab Pharmacokinetics .......... 67
Blood Collection for Anti Drug Pembrolizumab Antibodies............... 67
Tumor Tissue Collection.............................................................................. 67
Correlative Blood Collections- Samples for Correlative and Biomarker 
Analyses....................................................................................................... 68
Planned Genetic Analysis Sample Collection.............................................. 68
Future Biomedical Research Sample Collection ......................................... 68
Other Procedures................................................................................................. 68
Withdrawal/Discontinuation........................................................................ 68
Withdrawal From Future Biomedical Research ................................... 68
Blinding/Unblinding .................................................................................... 69
Calibration of Critical Equipment................................................................ 69
Visit Requirements.............................................................................................. 69
Screening...................................................................................................... 69
Treatment Cycles ......................................................................................... 70
Second Course Phase (Retreatment Period) ......................................... 70
Post-Treatment............................................................................................. 71
Discontinuation Visit............................................................................ 71
Safety Follow-up Visit.......................................................................... 71
Follow-up Visits ................................................................................... 72
Survival Follow-up ............................................................................... 72
Survival Status ............................................................................................. 72
Assessing and Recording Adverse Events .......................................................... 72
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
6
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 73
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 74
Immediate Reporting of Adverse Events to the Sponsor.................................... 74
Serious Adverse Events ............................................................................... 74
Events of Clinical Interest............................................................................ 75
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 76
Evaluating Adverse Events................................................................................. 76
Sponsor Responsibility for Reporting Adverse Events ...................................... 79
TRIAL GOVERNANCE AND OVERSIGHT................................................... 79
Scientific Advisory Committee........................................................................... 79
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 79
Statistical Analysis Plan Summary ..................................................................... 79
Responsibility for Analyses/In-House Blinding ................................................. 80
Hypotheses/Estimation ......................................................................................... 80
Analysis Endpoints ............................................................................................... 81
Efficacy Endpoints.............................................................................................. 81
Safety Endpoints ................................................................................................. 81
Analysis Populations............................................................................................. 81
Efficacy Analysis Populations ............................................................................ 81
Safety Analysis Populations ............................................................................... 82
Statistical Methods................................................................................................ 82
Statistical Methods for Efficacy Analyses .......................................................... 82
Statistical Methods for Safety Analyses ............................................................. 84
Demographic and Baseline Characteristics ........................................................ 84
Interim Analyses ................................................................................................... 84
Multiplicity ............................................................................................................ 84
Sample Size and Power Calculations .................................................................. 85
Subgroup Analyses and Effect of Baseline Factors ........................................... 86
Compliance (Medication Adherence).................................................................. 86
Extent of Exposure................................................................................................ 86
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
7
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 86
Investigational Product ........................................................................................ 86
Packaging and Labeling Information ................................................................. 87
Clinical Supplies Disclosure................................................................................. 87
Storage and Handling Requirements.................................................................. 87
Discard/Destruction/Returns and Reconciliation .............................................. 87
Standard Policies................................................................................................... 88
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 88
Confidentiality....................................................................................................... 88
Confidentiality of Data ....................................................................................... 88
Confidentiality of Subject Records..................................................................... 88
Confidentiality of Investigator Information........................................................ 88
Confidentiality of IRB/IEC Information............................................................. 89
Compliance with Financial Disclosure Requirements....................................... 89
Compliance with Law, Audit and Debarment ................................................... 89
Compliance with Trial Registration and Results Posting Requirements ........ 91
Quality Management System............................................................................... 91
Data Management................................................................................................. 92
Publications ........................................................................................................... 92
11.0
LIST OF REFERENCES......................................................................................... 94
12.0
APPENDICES........................................................................................................... 98
Merck Code of Conduct for Clinical Trials........................................................ 98
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 100
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 104
ECOG Performance Status................................................................................ 115
Common Terminology Criteria for Adverse Events ....................................... 116
Abbreviations ...................................................................................................... 117
13.0
SIGNATURES......................................................................................................... 119
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
8
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Sponsor's Representative ................................................................................... 119
Investigator.......................................................................................................... 119
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
9
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 33
Table 2
Trial Treatment ....................................................................................................... 35
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 37
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 40
Table 5
irRECIST Imaging and Treatment after First Radiologic Evidence of PD ............ 64
Table 6
Laboratory Tests ..................................................................................................... 65
Table 7
Evaluating Adverse Events..................................................................................... 77
Table 8
Analysis Strategy for Key Efficacy Endpoints....................................................... 83
Table 9
Two-sided 95% Confidence Interval of ORR in All Comer .................................. 85
Table 10 Two-sided 95% Confidence Interval for ORR in PD-L1H..................................... 86
Table 11 Product Descriptions .............................................................................................. 87
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
10
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
LIST OF FIGURES
Figure 1
Overall Study Design.......................................................................................... 17
Figure 2
Trial Diagram at Subject Level........................................................................... 17
Figure 3
Swim Lane Plot of Tumor................................................................................... 25
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
11
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-100-02
27-JAN-2020
Added standard extension study language
3475-100-01
07-DEC-2017
Expanded on cutpoint language to provide maximum 
flexibility to perform additional data analysis, updated 
language related to PK, revised guidelines for irAEs
3475-100-00
13-NOV-2015
Original protocol
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
12
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
Trial Summary
Added standard extension study 
language
To transition study into the 
pembrolizumab rollover
5.10
Beginning and End of the Trial
Added standard extension study 
language
To transition study into the 
pembrolizumab rollover
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
Multiple sections
Multiple sections
Minor typographical 
corrections
Correct minor typographical 
errors for clarity and 
consistency
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
13
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
A Phase II Study of Pembrolizumab Monotherapy in Subjects with 
Advanced Recurrent Ovarian Cancer
Trial Phase
II
Clinical Indication
Advanced recurrent ovarian cancer (ROC)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Cohort A will enroll subjects with ROC who have received 0-2 prior 
lines for treating ROC (i.e., 1-3 total prior lines counting the front line) 
and with a platinum-free interval or treatment-free interval of 3 to 12 
months based on the last regimen received.
Cohort B will enroll subject with ROC who have received 3 to 5 prior 
lines for treating ROC (i.e., 4-6 total prior lines counting the front line) 
and with a platinum-free interval or treatment-free interval ≥3 months 
based on the last regimen received.
In both cohorts, subjects will be treated with pembrolizumab 
monotherapy 200 mg every 3 weeks. 
Number of trial subjects
Approximately 325 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 48
months from the time the first subject signs the informed consent until 
the last subject’s last study-related phone call or visit, inclusive of 
overall survival (OS) follow-up period. The overall survival period 
will last for 3 years after the final subject has been enrolled.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form through the final protocol- specified 
contact.
The study includes three study periods: the Screening Period, the 
Study Treatment Period, and a Disease/ Survival Follow-up Period. 
Screening Period: The Screening procedures should be completed 
within 28 days of the planned first dose. However, certain screening 
tests such as clinical laboratory tests must be performed within a 
shorter time period of the planned first dose, as specified in the Trial 
Flow Chart in Section 6 of the protocol. 
Treatment Period: Each eligible subject will receive pembrolizumab 
monotherapy, the study treatment, at 200mg Q3W intravenously. 
Subject will continue treatment until disease progression is confirmed 
by the site per immune related Response Evaluation Criteria in Solid 
Tumors (irRECIST), unacceptable adverse event(s) (AEs), intercurrent 
illness that prevents further administration of treatment, investigator’s 
decision to withdraw the subject, noncompliance with trial treatment 
or procedures requirements or administrative reasons requiring 
cessation of treatment, or until the subject has received 35 
administrations of pembrolizumab (approximately 2 years).
Subjects
who have obtained a complete response (CR) prior to 24 months may 
stop study treatment at the discretion of his/her investigator. 
Subjects who stop trial treatment after receiving 35 administrations of 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
14
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
pembrolizumab (approximately 2 years) for reasons other than disease 
progression or intolerability, or subjects who attain a CR and stop trial 
treatment may be eligible for up to 17 additional administrations of 
pembrolizumab (approximately one year) upon experiencing disease 
progression (Section 7.1.5.2.1). The subject can be retreated only if the 
subject meets the criteria for retreatment and the trial is ongoing.
Disease/Survival Follow-up Period: After discontinuation of the study 
treatment, each subject will be followed for 30 days for AE
monitoring (serious adverse events will be collected for 90 days after 
the trial treatment or 30 days after the end of treatment if the subject 
initiates new anti-cancer therapy, whichever is earlier). After the end 
of treatment, each subject will be followed for the occurrence of AEs
and spontaneously reported pregnancy as described under Section 7.2 
of the protocol.
Imaging-based disease assessment and serum CA 125 will be 
performed every 9 weeks within the first 54 weeks, and every 12 
weeks thereafter until disease progression, death, withdrawal of 
consent or until study has achieved its primary objectives, whichever 
comes first. Subjects who discontinue study treatment for reasons 
other than disease progression, will have post-treatment follow-up for 
disease status until disease progression is confirmed by the site per 
irRECIST, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up. All subjects will be followed 
by telephone contact for OS until death, withdrawal of consent, or the 
end of the study. 
Upon study completion, participants are discontinued and may be 
enrolled in a pembrolizumab extension study.
A list of abbreviations used in this document can be found in Section 12.6.
2.0 TRIAL DESIGN
Trial Design
Overall Trial Design
This is a Phase 2, open-label, single-arm, two-cohort, multi-center study to evaluate efficacy 
and safety of pembrolizumab monotherapy 200 mg every 3 weeks (Q3W) in subjects with 
advanced epithelial ovarian cancer (EOC), fallopian tube cancer, or primary peritoneal 
cancer (will collectively refer as advanced EOC) who have demonstrated recurrent disease 
following the primary or interval cytoreductive/debulking surgery and the standard front line 
platinum–based combination therapy. The study will enroll the following 2 cohorts of 
subjects with recurrent ovarian cancer (ROC):

Cohort A will enroll ROC subjects who have received 0 to 2 prior lines for treating 
ROC (i.e., 1 to 3 total prior lines counting the front line) and must have a platinum-
free interval (PFI) or a treatment-free interval (TFI) of 3 to 12 months based on the 
last regimen received.
Randomization Ratio
N/A
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
15
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential

Cohort B will enroll ROC subjects who have received 3 to 5 prior lines for treating 
ROC (i.e., 4 to 6 total prior lines counting the front line) and must have a PFI or TFI 
≥3 months based on the last regimen received. Refer to Section 5.1.for definition of
PFI and TFI and detailed inclusion and exclusion criteria for each Cohort. The trial 
will be conducted in conformance with Good Clinical Practices (GCP).
The study has 4 primary objectives. Primary objectives (1) and (2) are designated for 
Cohort A. Primary objectives (3) and (4) are designated for Cohort B.
Primary objective (1) is to evaluate objective response rate (ORR) in the first 180 enrolled 
subjects who fulfill the eligibility criteria for Cohort A. This group is designated as 
Cohort A-All Comer group. Within Cohort A-All Comer group, a minimum of 75 subjects 
will be enrolled for the subgroup with a PFI or TFI of 3 to <6 months and the subgroup with 
a PFI or TFI of 6 to 12 months. The primary analysis of ORR will be based on the 
assessment by a central imaging vendor (BICR) per Response Evaluation Criteria in Solid 
Tumors (RECIST) version 1.1, in Section 11.0.
Primary objective (2) is to evaluate ORR in subjects who fulfill the eligibility criteria for 
Cohort A and with higher expression of program cell death-ligand protein 1 (PD-L1) in 
tumor tissue samples. It is expected that higher PD-L1 expression in tumor tissue will be 
associated with better clinical responses to pembrolizumab (refer to Section 4 for background
and rationale). In order to achieve this primary objective, a PD-L1 expression cutpoint will 
first be established with a goal to enrich the population for better clinical benefit. The 
cutpoint will be determined during the planned interim analysis using the clinical efficacy 
data and PD-L1 expression data from the first 100 enrolled Cohort A subjects. This data set 
is designated as the “training set” (refer to Section 8.7 on the approach for determining the 
PD-L1 cutpoint). In order to confirm the association of higher PD-L1 expression with 
increased clinical activity by pembrolizumab treatment, another 150 subjects who fulfill 
eligibility criteria for Cohort A will be enrolled, which is designated as the “confirmation
set”. Cohort A will therefore, enroll a total of 250 subjects. Based on the established PD-L1 
cutpoint from the training set, subjects in the confirmation set will be assigned into the 
subgroup with PD-L1 expression above or equal to the cutpoint (i.e., Cohort A PD-L1H) or 
the subgroup with PD-L1 expression below the cutpoint (i.e., Cohort A PD-L1L). Enrollment 
into Cohort A will not be interrupted for interim analysis. However, in order to ensure data 
integrity, samples from the “confirmation set” will not be assessed for PD-L1 expression 
until the cutpoint has been established and the assay has been confirmed. Based on the 
prevalence data regarding higher PD-L1 expression, the total enrollment of Cohort A may be 
increased to up to 280 to ensure a minimum of 60 subjects from the confirmation set (see 
below) will have PD-L1 expression above the expected cutpoint.
Approximately 75 subjects will be enrolled into Cohort B regardless of PD-L1 expression 
status. Primary objective (3) is to evaluate ORR in all enrolled subjects who fulfill the 
eligibility criteria for Cohort B. This group is designated as Cohort B-All Comer group. 
Primary objective (4) is to evaluate ORR in subjects enrolled into Cohort B who have tumor 
tissue PD-L1 expression above the clinical cutpoint established from the Cohort A training 
set. The population supporting primary objective (4) is designated as Cohort B PD-L1H
group. Tumor tissue samples from Cohort B will not be evaluated until a cutpoint has been 
established from Cohort A training set.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
16
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
As part of the inclusion criteria, all subjects must provide a tumor tissue sample collected 
either from a recent biopsy or prior cytoreductive surgery in order to be enrolled. Part of the 
tumor tissue sample will be submitted to a designated central laboratory for assessing PD-L1 
expression via an immunohistochemistry (IHC) assay. PD-L1 positivity is determined using 
the combined positive score, which is defined as the percent PD-L1 positive cells counting 
tumor cells, immune-infiltrating cells and cells from adjacent stroma relative to total tumor 
cells. Details will be provided in a separate document.
Clinical cut-off for interim analysis will be at least 4 months after the one-hundredth Cohort 
A subject has been enrolled to allow adequate clinical follow up. For each designated study 
population (i.e., Cohort A-All Comer, Cohort A PD-L1H, or Cohort B), the clinical cut-off for 
the final analysis of the primary endpoint ORR will be at least 8 months after the last subject 
for each population has been enrolled. The final clinical cut-off for the study (i.e., study 
completion) will be 3 years after the last subject is enrolled for final overall survival (OS)
analysis. Refer to Sections 3.2 and 3.3 for details regarding secondary and exploratory study 
objectives, and Figure 1 in Section 2.2 for illustration of the overall study design.
Trial Diagram at Individual Subject Level
This section applies to all subjects who have enrolled to the study. The study includes a 
28-day Screening Period, a Study Treatment Period and a Disease/Survival Follow-up 
Period. Subjects must have measurable disease per RECIST 1.1, as confirmed by the BICR,
and must have provided adequate tumor tissue samples in order to be eligible. After an 
eligible subject is enrolled, the subject will receive pembrolizumab monotherapy 200 mg 
Q3W via intravenous (IV) infusion until confirmed disease progression as assessed by the 
investigator, unacceptable toxicity, death, withdrawal of consent, or having received 
35 administrations (approximately 2 years) of pembrolizumab treatment without disease 
progression. In order to prevent premature study treatment discontinuation due to 
pseudoprogression, immune-related RECIST (irRECIST) will be used for confirmation of 
disease progression (refer to Section 7.1.2.6.7 for details). Decisions regarding stopping 
pembrolizumab after a confirmed complete response (CR) and guidelines on retreatment are 
detailed in Section 7.1.5.2.1.
During study treatment period, subject will have clinic visits Q3W for safety assessments and 
pembrolizumab infusion. Imaging-based disease assessments will occur every 9 weeks 
(Q9W) from study entry until Week 54 and every 12 weeks (Q12W) thereafter until disease 
progression is determined by the investigator per irRECIST, subject’s death, withdrawal of 
consent, initiation of a new anti-cancer therapy, study completion or early termination. 
Cancer antigen 125 (CA125) will be collected at baseline and at the time of each imaging 
assessment, However, CA125 should not be used by the investigator to determine disease 
progression in this study. The trial diagram at subject level is depicted in Figure 2 in 
Section 2.2.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
.
 
 
05DV3K
 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

Product:  MK-3475 
18
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In subjects with advanced ROC:
1) Objective: To evaluate clinical anti-tumor activity of pembrolizumab monotherapy 
based on ORR as assessed by BICR per RECIST 1.1 in Cohort A-All Comer group as 
defined in Section 2.1 
2) Objective: To evaluate clinical anti-tumor activity of pembrolizumab monotherapy 
based on ORR as assessed by BICR per RECIST 1.1 in Cohort A-PD-L1H subgroup,
as defined in Section 2.1, using a PD-L1 expression cutpoint established in the 
training set.
3) Objective: To evaluate clinical anti-tumor activity of pembrolizumab monotherapy 
based on ORR as assessed by BICR per RECIST 1.1 in Cohort B-All Comer group as 
defined in Section 2.1
4) Objective: To evaluate clinical anti-tumor activity of pembrolizumab monotherapy 
based on ORR as assessed by BICR per RECIST 1.1 in Cohort B PD-L1H subgroup,
as defined in Section 2.1, using a PD-L1 expression cutpoint established in the 
training set from Cohort A
The primary objectives will focus on estimation of ORR, and no formal hypothesis testing is 
planned. If the operating characteristics associated with a single biomarker cutpoint are not 
sufficiently optimized, up to 2 biomarker cutpoints may be carried forward for efficacy 
endpoint analyses (see Section 8.6.1).
Secondary Objective(s) & Hypothesis(es)
In subjects with advanced ROC: 
1) Objective: To evaluate duration of response (DOR), disease control rate (DCR) and 
progression-free survival (PFS) as assessed by BICR per RECIST 1.1 in Cohort 
A-All Comer group, Cohort A-PD-L1H subgroup, Cohort B-All Comer group, Cohort 
B-PD-L1H subgroup respectively, after treated with pembrolizumab monotherapy. 
PFS rate at 6, 12, and 18 months will also be evaluated.
2) Objective: To evaluate ORR, DOR, DCR, and PFS as assessed by investigator per 
RECIST1.1 in Cohort A-All Comer group, Cohort A-PD-L1H subgroup, Cohort B-All 
Comer group, Cohort B-PD-L1H
subgroup, respectively, after treated with 
pembrolizumab monotherapy 
3) Objective: To evaluate ORR, DOR, DCR and PFS as assessed by BICR and by 
investigator per RECIST 1.1, in Cohort A-All Comer subgroup with PFI/TFI 
≥3 to 6 months and the subgroup with PFI/TFI >6 to 12 months, respectively, after 
treated with pembrolizumab monotherapy.
4) Objective: To evaluate OS in Cohort A-All Comer group, Cohort A-PD-L1H
subgroup, Cohort A-All Comer subgroup with PFI/TFI ≥3 to 6 months and the 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
19
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
subgroup with PFI/TFI >6 to 12 months, Cohort B-All Comer group, Cohort 
B-PD-L1H subgroup, after treated with pembrolizumab monotherapy.
5) Objective: To evaluate and characterize the tolerability and safety profile of the 
entire study population and by cohorts and subgroups, respectively, after treated with 
pembrolizumab monotherapy.
No formal hypotheses will be tested for secondary objectives.
Exploratory Objectives
1) To evaluate ORR, DOR, PFS as assessed by BICR per irRECIST 1.1.
2) To evaluate ORR, DOR, PFS as assessed by investigator per Gynecologic Cancer 
InterGroup (GCIG) criteria [2].
3) To characterize tumor microenvironment for immune-related features such as 
immune-related messenger RNA expression signatures, presence of tumor-infiltrating 
lymphocytes (TILs), PD-L1/ program cell death-ligand protein 2 (PD-L2) expression; 
and to characterize genetic changes/aberrations and mutational burdens within tumor 
tissues.
4) To assess correlations of the biomarkers and the clinical activity observed in the 
overall study population and various subgroups following pembrolizumab treatment.
5) Additional translational research may include T-cell clonality, neoantigen expression, 
presence and changes in circulating tumor markers such as circulating tumor DNA, 
serum microRNA and protein changes at screening and following pembrolizumab 
treatment, and evaluation of pharmacokinetics of pembrolizumab.
6) Variation across the human genome may be analyzed for association with clinical 
efficacy and/or safety data collected in this study.
For definitions of endpoints, refer to Section 8.4.1.
4.0 BACKGROUND & RATIONALE
Background
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in vitro data, 
pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA™ (pembrolizumab) is 
indicated for the treatment of patients across a number of indications. For more details on 
specific indications refer to the Investigator Brochure.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
20
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Pharmaceutical and Therapeutic Background
Disease Background
Epidemiology and Histologic Categorization of Ovarian Cancer
Ovarian cancer is the most lethal gynecologic cancer and the fifth-leading cause of cancer 
death among women in the United States (US). In the US, the estimated number of new cases 
and deaths from ovarian cancer in 2014 was 21,980 and 14,270, respectively. Due to lack of 
tumor-specific signs and symptoms and effective screening tests for early detection, over 
70% of ovarian cancer patients are first diagnosed at advanced stages. Based on the US data 
from 2003 to 2009, at initially diagnosis, 61% had distant metastasis, 18% had regional 
disease and only 21% had localized disease. The overall 5-year survival rate of ovarian 
cancer was approximately 44% counting all stages; the 5-year survival rate in patients with 
distant metastasis was only 27% [3].
Epithelial ovarian cancer accounts for >90% of the ovarian cancer and has been recognized 
as a group of heterogeneous diseases with distinct histopathologic features, genetic 
alterations and clinical behaviors. Five main EOC subtypes have recently been designated by 
The International Federation of Gynecology and Obstetrics: high-grade serious carcinoma 
([HGSC], accounts for ~70% EOC), endometrioid carcinoma (~10% EOC), clear cell 
carcinoma (~10% EOC), mucinous carcinoma (~3% EOC), low-grade serous carcinoma (5% 
EOC), and those that are unclassifiable [4; 5]. Primary peritoneal carcinoma and fallopian 
tube carcinoma have typically been managed and studied together with EOC as they share 
similar clinic-pathologic characteristics with HGSC.
Current Standard Treatment and Area with Unmet Medical Need
The standard primary treatments for advanced EOC include primary cytoreductive/debulking
surgery followed by postoperative front line (i.e., adjuvant) systemic treatment with 
carboplatin and paclitaxel Q3W IV for 6 cycles. However, weekly paclitaxel has also been 
frequently used to replace Q3W paclitaxel. In suitable cases, postoperative chemotherapy, 
usually cisplatin plus paclitaxel, can be delivered via intraperitoneal (IP) route. In cases with 
bulky diseases that are initially non-operable, neoadjuvant therapy can be given prior to 
cytoreductive surgery (i.e., interval cytoreductive surgery) then followed by standard 
platinum/taxane-based chemotherapy [6; 7].
The goal of cytoreductive surgery is to achieve resection of all visible tumors and the goal of 
postoperative first line chemotherapy are: 1) to help achieving complete remission in those 
with residual disease, and 2) to prevent disease recurrence for those with complete tumor 
resection. However, after these primary treatments, only a small proportion of patients will 
achieve long-term disease-free and survival status. In a meta-analysis performed by du Bois 
et al [8] on data from 3 randomized trials following the standard primary treatment with 
surgery and platinum-taxane based chemotherapy (N=3126), only 24% of patients were 
recurrent free after a median follow up time of 53.9 months and the remaining 76% had 
disease recurred or progressed. The overall 5-year PFS and OS rate was 22.6% and 39.0%, 
respectively. Based on time to recurrence (TTR) since the last dose of platinum treatment, 
22% recurred 0 to 6 months, 22.5% recurred 6 to 12 months, and 31.6% recurred 
>12 months. By 12 months, the 12-month survival rate was 30.6%, 55.1%, and 66.1% in the 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
21
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
group with TTR to -6 months, TTR 6 to 12 months, and TTR >12 months, respectively; the 
24-month survival rate was 13.8%, 24.4%, and 34.9% in these 3 groups, respectively. This 
data showed an overall poor prognosis for patients with recurrent disease especially in those 
with a short TTR.
At present, ROC is considered not curable with the available choices of therapies and is an 
area of highly unmet medical need.
Selection of treatment for ROC should take into consideration several factors including:
sensitivity to first-line platinum-based therapy, as measured by PFI, prior toxicity, 
comorbidity, age, and performance status. Platinum-free interval, which is defined as the 
period from the cessation of the primary platinum-based chemotherapy to disease recurrence 
or progression, has been recognized as an important surrogate for prognosis and predicting 
response to chemotherapy. Based on PFI, ROC can be divided into the following subgroups: 
platinum-sensitive (PFI >12 months), partially platinum-sensitive (PFI of 6 to 12 months), 
platinum-resistant (PFI >1 to <6 months), and platinum-refractory (PFI ≤4 weeks or 
progression on treatment) according to the consensus achieved by the GCIG in 2010 [9].
Based on the current National Comprehensive Cancer Network and European Society for 
Medical Oncology guidelines, patients with platinum-resistant ROC can be treated with 
either single-agent chemotherapy such as gemcitabine, pegylated liposomal doxorubicin 
(PLD), weekly paclitaxel, topotecan, and docetaxel, or bevacizumab in combination with 
gemcitabine or weekly paclitaxel or topotecan. These single agents had shown similar 
clinical efficacy with a response rate around 15% to 20%, median PFS of 3 to 5 months and 
median OS of 10 to 12 months [10; 11]. Bevacizumab plus single-agent chemotherapy 
showed an improved PFS compared to single-agent chemotherapy alone (6.7 versus
3.4 months, hazard ratio [HR]: 0.48, p <0.001) and an improved response rate (27.3% versus
11.8%) via a randomized Phase 3 trial, AURELIA [12]. However, the study didn’t 
demonstrate OS benefit; and based on the Kaplan-Meier (KM) curve, less than 20% of 
subjects in the bevacizumab chemotherapy arm remained progression-free by 12 months, and 
even less in the single-agent chemotherapy arm. Platinum-resistant ROC, hence, is an area 
with high unmet medical need for novel therapies that can deliver durable clinical benefit.
Partially platinum-sensitive ROC (i.e., PFI >6 to 12 months), which used to be classified as 
part of the platinum-sensitive group, has been considered a challenging group to manage [13; 
14]. Even though the recommended treatment for partially platinum-sensitive ROC remains 
the same as those for platinum-sensitive ROC (i.e., re-treated with a platinum-containing 
doublet), the partially platinum-sensitive group has significantly reduced clinical benefit
compared to those with PFI >12 months. For example, in a review of 583 ROC patients from 
6 Phase 2-3 clinical trials by Pujade-Lauraine et. al. [15] on the impact of TFI, on clinical 
response to salvage therapy, patients with TFI of 3 to 12 months showed an ORR of 35% 
compared to an ORR of 52% in the group with TFI of 12 to 18 months. Median time to 
progression and OS in the group with TFI of 3 to 12 months was much shorter (174 days and 
393 days, respectively) compared to the group with TFI of 12 to 18 months (275 days and 
657 days, respectively). In the Phase 3 trial CALYPSO [16] that compared carboplatin plus 
PLD (CD) versus carboplatin plus paclitaxel (CP), Overall survival was significantly longer 
in subjects with TFI ≥12 months versus subjects with TFI 6 to 12 months based on 
multivariate analysis (HR = 0.5; 95% confidence interval [CI] 0.43, 0.59; p<0.001). In the 
CALYPSO trial, median PFS in the partial platinum-sensitive subpopulation was 9.4 months 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
22
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
for the CD arm and 8.8 months for the CP arm; ORR was 39% in the CD arm and 45% in the 
CP arm. However, when taking a closer look at the KM PFS curve for partial platinum-
sensitive subgroup in this study, less than 20% patients in the CP arm and a little over 20% in 
the CD arm remained progression-free at 12 months [17].
In a meta-analysis by Hanker et al [18] charterizing impact of second to sixth line of therapy 
on survival of relapsed ovarian cancer, data of n=1620 patients from 3 large randomized 
Phase 3 trials investigating primary therapy was included. The results showed that median 
PFS after the first, second, third, fourth and fifth relapse was 10.2 [95% CI 9.6 to 10.7], 
6.4 (5.9 to 7.0), 5.6 (4.8 to 6.2), 4.4 (3.7 to 4.9) and 4.1 (3.0 to 5.1) months, respectively. 
Median OS after the first, second, third, fourth and fifth relapse was 17.6 (95% CI 16.4 to 
18.6), 11.3 (10.4 to 12.9), 8.9 (7.8 to 9.9), 6.2 (5.1 to 7.7) and 5.0 (3.8 to 10.4) months, 
respectively. The overall clinical benefit greatly reduced with increased lines of therapy.
In addition to reduced clinical benefit and lack of long-lasting clinical activities from the 
existing therapies in this group, toxicities from prior or planned platinum doublets further 
limit the utility of these treatments in this subgroup [13]. Novel therapies with durable 
clinical efficacy and better safety profile are highly needed for the treatment of partially 
platinum-sensitive as well as platinum-resistant ROC.
Targeting PD-1 Immune Checkpoints for Cancer Treatment
Adaptive immune system plays a major role in controlling and eradicating cancer via a 
process called cancer immunosurveillance. Cytotoxic T lymphocytes cells (CTLs, also called 
CD8+ or effector T-cells), which are central to responses within the adaptive immunity, can 
be activated and execute cell killing function upon recognizing tumor-specific or tumor-
associated antigens presented by antigen-presenting cells [19; 20; 21].
T-cell activation is tightly controlled by co-stimulatory and co-inhibitory signals, which are 
triggered by the interactions between T-cell receptors and their ligands. The inhibitory 
pathways, also called immune checkpoints, are crucial for maintaining self-tolerance and 
minimizing collateral tissue damage in the event of immune response to pathogens. PD-1 is a 
member of the extended CD28/CTLA4 family of T-cell regulators. PD-1-mediated immune 
checkpoint plays a key role in controlling effector T-cell activities within peripheral tissues,
including tumors. Binding of PD-1 to PD-L1 and/or PD-L2 will trigger downstream 
signaling inside T-cells leading to decreased cytokine production such as IL-2 and interferon 
γ, inhibition of cell proliferation, reduced T-cell effector function and survival [19; 22; 23, 
24].
Human cancer can exploit immune checkpoint pathways to escape immunosurveillance.
Restoration of endogenous anti-cancer immunity by immune checkpoint blockade has thus
become an attractive strategy of cancer immunotherapy. The success in the clinical 
development of immune checkpoint inhibitors, in particular the PD-L1 inhibitors, has 
significantly changed the landscape of cancer treatment [20; 21; 25; 22; 26; 27].
Anti-PD-1 Antibody Pembrolizumab
Pembrolizumab (also referred to as MK-3475) is a potent and highly selective humanized 
mAb of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2. This blockade enhances functional activity of the target 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
23
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
lymphocytes to facilitate tumor regression and ultimately immune rejection. As of 
January 2015, pembrolizumab safety and clinical activities have been evaluated in 
approximately 8,000 patients across multiple tumor types via Merck-sponsored clinical trials 
and the melanoma Expanded Access Program. Pembrolizumab was generally well tolerated. 
In September 2014, pembrolizumab monotherapy received an accelerated approval by the 
Food and Drug Administration for the treatment of patients with unresectable or metastatic 
melanoma and disease progression following ipilimumab and a BRAF inhibitor if BRAF 
V600 mutation positive, with a recommended dose of 2mg/kg Q3W [28]. Refer to 
pembrolizumab clinical investigator brochure and the US label for details regarding 
pembrolizumab preclinical and clinical pharmacology studies as well as clinical safety. 
Summary of Pembrolizumab Clinical Activities
Pembrolizumab clinical activity in advanced melanoma 
In study Keynote 001 (KN001), the Phase 1 first time in human study, pembrolizumab was 
evaluated in a cohort of 135 subjects with advanced melanoma who were either treatment-
naïve (31%) or had progressed from prior ipilimumab (69%), at a dosage of 2 mg/kg Q3W, 
10 mg/kg every 2 week (Q2W), or 10 mg/kg Q3W. The study showed an ORR of 38% (95% 
CI: 25% to 44%) in the overall population. Response was durable in the majority of subjects; 
median DOR was not reached with median follow up of 11 months [29]. In an expansion 
cohort, 173 subjects with advanced melanoma who had progressed from prior ipilimumab 
were randomly assigned to receive pembrolizumab 2mg/kg Q3W or 10mg/kg Q3W. Similar 
efficacy results were observed in the 2 arms: ORR was 26% in each arm; DCR was 51% and 
50%, respectively. With a median follow-up of 8 months, 88% of responders were still 
ongoing at the clinical cut-off. Even though most responses were observed at the first scan, 
initial response could occur as late as 11 months and CR could occur as late as 16 months 
[30].
Clinical efficacy of pembrolizumab in advanced melanoma was further demonstrated via 
2 large randomized trials. In study Keynote 002 (KN002) (N=540), efficacy and safety of 
pembrolizumab 2mg/kg Q3W or 10mg/kg Q3W were compared with chemotherapy in 
subjects refractory to ipilimumab. PFS (6-months PFS rate) was significantly improved in the 
2 pembrolizumab arms compared with the chemotherapy arms. Overall response rate per 
independent review was 21% in the pembrolizumab 2 mg/kg Q3W arm, 25% in the 10 mg/kg 
Q3W arm compared to 4% in the chemotherapy arm (P<0.0001 for both comparisons). At the 
time of analysis, median DOR in the pembrolizumab arms was not reached; responses were 
ongoing in 92% and 87% of responders in the 2 pembrolizumab arms, respectively, versus 
63% in the chemotherapy arm. There was no statistically significant difference in efficacy 
parameters between the 2 pembrolizumab arms [31].
In Phase 3 Study Keynote 006 (KN006) (N=834), unresectable advanced melanoma 
population), subjects that received pembrolizumab (10mg/kg Q2W or 10mg/kg Q3W) 
showed statistically significant and clinically meaningful improvement compared to those 
that received ipilimumab in estimated 6-months PFS rate (47.3%, 46.4% and 26.5%, 
respectively), one-year OS rate (74.1%, 68.4% and 58.2%, respectively), and ORR (33.7%, 
32.9% and 11.9%, respectively). At the time of analysis, median OS was not reached in any 
treatment group. Responses were ongoing in 89.4% and 96.7% of the Q2W and Q3W 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
24
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
pembrolizumab-treated groups, respectively and in 87.9% of ipilimumab-treated patients 
after a median follow-up of 7.9 months [32].
Pembrolizumab clinical activity in advanced NSCLC
In study KN001, clinical efficacy and safety were evaluated in 495 subjects with advanced 
non-small cell lung cancer (NSCLC) after receiving pembrolizumab treatment at 2 mg/kg 
Q3W, 10mg/kg Q3W, or 10mg/kg Q2W dose, respectively. The study also evaluated the 
association between PD-L1 expression in tumor tissue samples and the clinical efficacy by 
assigning 182 subjects to the training set and 313 subjects to the validation set. In the overall 
population (N=495), ORR was 19.4% (95% CI, 16.0 to 23.2); median DOR was 
12.5 months. In the validation data set, ORR was 45.2% (95% CI, 33.5 to 57.3) in subjects 
with ≥50% of tumor cells positive for PD-L1 expression (n=73); ORR was 16.5% (95% CI, 
9.9 to 25.1) in patients with 1% to 49% tumor cells positive (n=103) and 10.7% (95% CI, 2.3
to 28.2) in patients with <1% tumor cells positive (n=28) for PD-L1 expression. This data 
indicates a potential for PD-L1 to be used as a patient enrichment biomarker for better 
clinical efficacy [33].
Pembrolizumab clinical activity in other advanced cancers
Study Keynote 012 (KN012) is an ongoing non-randomized multi-cohort Phase 1b study 
evaluated safety and clinical activities of pembrolizumab 10mg/kg Q2W in subjects with 
advanced solid tumors that have positive PD-L1 expression either in tumor cells or stroma 
cells. Most of these subjects were heavily pretreated. Subjects with advanced gastric cancer, 
head and neck cancer, urothelial track cancer and triple negative breast cancer were enrolled.  
An ORR of 31% was observed in subjects with advanced gastric cancers (N=39) [34]; an 
ORR of 27.6% (95% CI, 12.7 to 47.2%) was observed in subjects with advanced urothelial 
tract cancer (N=33) [35]; an ORR of 24.8% (95% CI, 17.3 to 33.6%) was observed in 
subjects with advanced head and neck cancer (N=132) [36]. Impressive responses have also 
been reported by Nanda, et. al., in triple negative breast cancer at the 2014 San Antonio 
Breast Cancer Symposium [37]. In all these cohorts, durable responses were observed in 
those who responded including some durable stable diseases. Higher PD-L1 expression 
seemed to associate with higher response.
Pembrolizumab clinical activity in advanced ovarian cancer
Study Keynote 028 (KN028) is an ongoing Phase 1b open-label, non-randomized 
multi-cohort study evaluating clinical activity of pembrolizumab monotherapy 10mg/kg 
Q2W in advanced solid tumors. A cohort of 26 subjects with advanced ovarian cancer that 
have failed prior chemotherapies was included. All enrolled subjects had positive PD-L1 
expression, which was defined as ≥1% of cells in tumor nests or PD-L1+ bands in stroma as 
determined by a prototype IHC assay at a central laboratory. Twenty-six ovarian cancer 
subjects were enrolled. Mean (standard deviation) age was 58.1 (7.5) years; 57.7% were 
white. 84.6% received prior therapies for recurrent/metastatic disease (38.5% received 
≥5 therapies), and 50% received prior adjuvant therapies. The best overall (confirmed) 
response was 11.5% (n=3/26, 95% CI: 2.4, 30.2); 1 subject achieved CR and 2 subjects 
experienced partial response (PR). Six out of 26 subjects (23.1%) achieved stable disease
(SD). As of clinical cut-off of 04-AUG-2015, the 3 responders and 1 subject with SD were 
still on pembrolizumab treatment without progression: 1 subject was still ongoing for
>46 weeks and 3 were still ongoing for >52 weeks. Another subject with SD showed 
 
 
05DV3K
 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

Product:  MK-3475 
26
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
number of lines of prior treatments. Even though over 70% to 80% of patients will be in
remission following the primary treatment, majority of them will relapse within 3 years. 
Currently, there are no curative treatments available for ROC; therefore, this is an area of 
high unmet medical need. Patients with ROC can response to platinum-based or non
platinum-based therapies with varied response rate; however, the responses are mostly short-
lived, especially in the setting with a PFI/TFI within 12 months. Even though some patients 
will receive multiple lines of treatments, they will eventually develop refractory and die. 
Treatment-related toxicities can be overwhelming especially for those who receive 
combination chemotherapy therapy. In addition to extending survival and delaying
symptomatic disease progression, the goal of treatment in this setting also includes to 
improve quality of life. Novel agents that can deliver, curative or long-lasting anti-cancer 
effect with good tolerability are highly needed in this setting.
PD-1/PD-L1 immune checkpoint inhibitors like pembrolizumab have shown high anti-cancer 
activity in a wide range of solid tumors as well as hematologic malignancies. Unprecedented 
durable clinical activities have been observed in various advanced cancer indications such as 
melanoma, NSCLC, etc. Pembrolizumab has shown preliminary clinical activity in a small 
cohort of advanced ovarian cancer patients in Study KN028. Most subjects were heavily 
pretreated and became chemorefractory. Even though the observed response rate is relatively 
low (11.8%), however, 3 subjects with PR and 1 subject with stable disease were still on 
pembrolizumab treatment for >48 weeks without progressive disease (3 have passed 
52 weeks) as of 04-AUG-2015, the clinical cut-off for this dataset. Another subject with SD
progressed at 36 weeks. In a retrospective analysis, subjects with TFI of less than 3 months 
(90 days) from their last dose of anti-cancer treatment to the first dose of pembrolizumab 
(n=15) showed limited activity with 3 SDs and no responders. In the subgroup with TFI 
≥3 months (n=11), there were 3 PRs and 3 SD including one with SD for 36 weeks (see 
Figure 3).
The study will enroll 2 separate cohorts of ROC subjects based on the number of prior lines 
received for ROC. All subjects are required to have a PFI/TFI of ≥3 months based on the last 
regimen received as based on the preliminary data from study KN028, those with short 
PFI/TFI of <3 months had very limited activity compared to those with PFI/TFI of 
≥3 months. Whether this is due to higher immune suppression is unclear. In Cohort A,
approximately 250 subjects with PFI or TFI of 3 to 12 months based on their last treatment, 
regardless of their PD-L1 expression status. The clinical activities in the overall population 
(All Comer) will be evaluated. The study will also evaluate the correlation of clinical activity 
and PD-L1 expression with a goal to identify a subgroup with better clinical benefit. In order 
to achieve this primary objective, the study population is separated into 2 parts, with first 
data from the 100 subjects being used as the “training set” for determining the cutpoint; the 
remaining subjects are used as the “confirmation set” for confirming the clinical activity in 
the biomarker selected population. Cohort B will enroll approximately 75 subjects with 
multiple lines of prior treatments to evaluate clinical activity and biomarker correlation.
Rationale for Dose Selection/Regimen/Modification
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the KEYTRUDA™development program, 200 mg Q3W is the appropriate 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
27
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
dose of pembrolizumab 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 Q2W.
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications.
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred 
from 
pharmacokinetic 
[PK] 
data) 
and 
tumor 
(inferred 
from 
physiologically-based pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and NSCLC, covering different disease settings (treatment-naïve, previously 
treated, PD-L1 enriched, and all-comers) and different treatment settings (monotherapy and 
in combination with chemotherapy). Five studies compared 2 mg/kg Q3W versus 10 mg/kg 
Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 3 studies compared 
10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 B3, KN001 F2 and KN006). All of these 
studies demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-/exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These 
findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for Endpoints
Efficacy Endpoints
The study is designed as a Phase 2 single-arm study to explore clinical activities in subjects 
with platinum-resistant and partially platinum-sensitive ROC with ORR selected as the 
primary endpoint. The primary analysis of ORR will be based on the disease assessment by 
central imaging vendor per RECIST 1.1 to avoid bias. Progression-free survival and OS are 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
28
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
not appropriate as the primary endpoint for a single-arm trial. However, PFS, OS, DOR, 
DCR are included as secondary endpoints. It is worth noting that based on the available data, 
pembrolizumab has shown durable responses in several indications with long-term data such 
as melanoma and NSCLC. In addition, subjects with SD can stay in SD for an extended 
period as shown with the preliminary data of pembrolizumab in ovarian cancer (see 
Figure 3). Collectively, the study will show anti-tumor response rate as well as durability of 
response, disease control rate, PFS rate at certain time points. These can give a picture of 
overall anti-tumor activities of pembrolizumab in the selected ovarian cancer population and 
various subpopulations.
Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce anti-tumor 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 can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab.
Based on an analysis of patients with melanoma enrolled in KN001, 7% of evaluable patients 
experienced delayed or early tumor pseudoprogression.  Of note, patients who had 
progressive disease by RECIST 1.1, but not by irRECIST, had longer OS than patients with 
progressive disease by both criteria.  Additionally, the data suggest that RECIST 1.1 may 
underestimate the benefit of pembrolizumab in approximately 15% of patients. These 
findings support the need to apply a modification to RECIST 1.1 that takes into account the 
unique patterns of atypical response in immunotherapy and enable treatment beyond initial 
radiographic progression.
Immune-related RECIST (i.e., irRECIST) is RECIST 1.1 adapted to account for the unique 
tumor response seen with immuno-therapeutics as described by Nishino et al.[39]. The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1. However, Merck has implemented an adaptation related to new 
lesions, non-target and tumor burden assessment in order to confirm radiographic 
progression. irRECIST will be used by investigators to confirm disease progression and 
make treatment decisions. irRECIST will also be used for analyzing imaging based endpoint 
per assessment by central imaging vendor.
Safety Endpoints
The safety objective is to characterize the safety and tolerability of pembrolizumab in 
subjects with advanced ovarian cancer. The following safety parameters will be analyzed: 
adverse events (AEs) and serious adverse events (SAEs) graded per National Cancer Institute 
(NCI) Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0 criteria with 
time to onset/recovery, causality and outcome; changes in laboratory values, vital signs since 
baseline, treatment discontinuations and reason for discontinuation, and death and cause of 
death. Concomitant medications will be collected with time and reasons of use. These are 
routine safety parameters collected and analyzed in Phase 2/3 oncology trials. Furthermore, 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
29
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
specific immune-related adverse events (irAEs) will be collected as described in Section 
5.2.1.2.
Planned Biomarker Research
Even though PD-1 checkpoint inhibitors like pembrolizumab have shown unprecedented 
anti-cancer activities across a wide range of cancers, a good portion of patients are not 
responding to the treatments. Recent efforts have been sought to evaluate how the immune 
system functions and is regulated inside the tumor microenvironment.
Tumor PD-L1 Expression
High expression of PD-L1 was frequently found in tumor tissue samples of different cancer 
types including ovarian cancer and was often found correlated with poor prognosis or 
survival [40]. High PD-L1 expression has been associated with increased response to 
pembrolizumab treatment in advanced melanoma and NSCLC patients [32; 33] and has been 
used to enrich patient population with high response to pembrolizumab [41]. Therefore, the 
relationship between PD-L1 expression in ovarian tumor tissue and clinical activities by 
pembrolizumab will be evaluated. PD-L1 expression in tumor cells and inflammatory cells 
within pre-treatment tumor tissue samples will be characterized by IHC.
Tumor-infiltrating Lymphocytes
Tumor-infiltrating lymphocytes are frequently found inside tumor tissues indicating the 
presence of an immune response. In a pooled analysis across various cancer types for the 
presence of different TILs in tumor tissues, Presence of CD3+ TILs or CD8+ TILs was found 
to have a positive effect on survival in patients with various solid tumors including ovarian 
cancer. However, FoxP3+ TILs were not correlated with survival [42]. In a recent analysis of 
tumor tissue samples from melanoma patients treated with pembrolizumab, Tumeh et al 
found that responding patients have a much higher density of CD8+, PD-1+ and PD-L1+ 
cells at invasive margin as well as inside tumors compared to those who progress, suggesting 
that responding to PD-1 blockade requires pre-existing CD8+ T-cells that are negatively 
regulated by PD-1/PD-L1 mediated adaptive immune resistance [43]. Therefore CD8+, 
FoxP3 TILs will be evaluated using IHC for their ability to predict response to 
pembrolizumab.
Immune-related Gene Expression Profile
Gene expression profile (GEP) may be analyzed using archival tumor tissue samples from 
the enrolled ovarian cancer subjects using the NanoString platform. Association between 
GEP and response to pembrolizumab have been established using data from clinical studies 
KN012 (head and neck, bladder, gastric cancers) and KN028 (ovarian, esophageal, and other 
cancers). These signatures, which include genes from immune-regulatory pathways, may be 
tested for their association with response to pembrolizumab. The relationship between GEP 
and the probability of response may be used to identify subgroup that may have high clinical
benefit.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
30
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Circulating Protein Biomarkers
In addition to expression on the tumor tissue, PD-L1 can be shed from tumor and released 
into the blood. Enzyme-linked immunoassay can measure PD-L1 in serum and correlate this 
expression with response to pembrolizumab therapy, as well as levels of PD-L1 IHC or 
protein in the tumor. Blood would be less invasive compartment compared to tumor from 
which to measure PD-L1 protein biomarker. In addition to this specific protein biomarker, 
both tissue and blood derivatives can be subjected to proteomic profiling studies using a 
variety of platforms that could include but are not limited to immunoassay and Liquid 
chromatography/Mass Spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab therapy.
Genetic Analyses of Tumor Tissue Samples and Blood
The application of next generation sequencing of DNA isolated from tumor or blood, defines
certain tumor types at the genetic level as being ‘hypermutated’ or detects the presence of 
specific T-cell clones within the tumor microenvironment or in the peripheral blood. There is 
a potential that the hypermutated state and/or increased T-cell clonality may correlate with 
response to pembrolizumab therapy, and/or that the converse, ‘hypomutated’ state or lack of 
dominant T-cell clones may correlate with non-response.
This analysis may evaluate whether genetic mutation variation within this ovarian tumor 
population correlates with response to pembrolizumab. If genetic variation predicts efficacy 
or AEs, the data might inform optimal use of therapies in this population.
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research may evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or AEs, the data might inform optimal use of therapies in the 
patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
subjects receive the correct dose of the correct drug/vaccine at the correct time.  The details 
of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and 
Management of Specimens for Future Biomedical Research.  Additional informational 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
31
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
material for institutional review boards/ethics committees (IRBs/ERCs) and investigational 
site staff is provided in Section 12.3.
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying Investigator’s Brochure and Informed 
Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Female subjects with advanced ovarian cancer of at least 18 years of age will be enrolled in 
this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. The subject may 
also provide consent for Future Biomedical Research.  However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
2. Be 18 years of age on day of signing informed consent.
3. Have histologically confirmed epithelial ovarian cancer, fallopian tube cancer or 
primary peritoneal cancer.
4. Have received a front line platinum-based regimen (administered via either IV or IP 
route) per local standard of care or treatment guideline following the primary or 
interval debulking surgery with documented disease recurrence.
Note: Maintenance treatment following the front line treatment is permitted and 
counted together as part of the front line treatment.
5. Have fulfilled the following additional requirements regarding prior treatments for 
ROC depending on the cohort subject is to be enrolled. Each subject must have 
documented evidence of clinical response or disease stabilization to the last regimen 
received.
Cohort A: Have received 0 to 2 additional prior lines for treating ROC (or 1 to 3 total 
prior lines counting the front line) and must have a PFI of ≥3 to 12 months if the last 
regimen received is a platinum-based, or a TFI of ≥3 to 12 months if the last regimen 
received is a non-platinum-based.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
32
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Cohort B: Have received 3 to 5 additional prior lines for treating ROC (or 4 to 6 total 
prior lines counting the front line) and must have a PFI of ≥3 months if the last 
regimen received is a platinum-based, or a TFI of ≥3 months if the last regimen 
received is a non-platinum-based.
Note: PFI is defined as the time elapsed between the last dose of platinum and the 
documented evidence of disease progression per RECIST 1.1. Treatment-free interval
is defined as the time elapsed between the last dose of the regimen received and the 
documented evidence of disease progression per RECIST 1.1.
6. Have measurable disease at baseline based on RECIST 1.1 as determined by the 
central imaging vendor.
Note: Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
8. Have a life expectancy of ≥16 weeks.
9. Have provided a tumor tissue sample either collected from prior cytoreductive 
surgery or fresh newly obtained tumor tissue at screening. Formalin-fixed 
paraffin-embedded block specimens are preferred to slides. Additional samples may 
be requested if tumor tissue provided is not adequate for quality and/or quantity as 
assessed by the central laboratory.
Note 1: Tumor tissue samples from recent biopsy are preferred as it represents the 
current disease status and is much more informative for understanding the correlation 
between clinical activity and tumor microenvironment.
If available, paired tumor tissue samples from prior cytoreductive surgery and recent 
biopsy are strongly encouraged in order to understand the changes in tumor 
microenvironment during the course of the treatments. 
Note 2: For archival tumor tissue samples, block specimens are preferred than slides. 
If submitting unstained cut slides, freshly cut slides should be submitted to the testing 
laboratory within 14 days from when the slides are cut. Refer to Section 4.2.3.4 in 
protocol for an explanation.
10. Have demonstrated adequate organ function as defined in Table 1.  All screening labs 
should be performed within 10 days of treatment initiation.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
33
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L without transfusion or erythropoietin 
(EPO) dependency
Renal
Creatinine OR
Measured 
or 
calculateda
creatinine 
clearance (CrCl)
[Glomerular filtration rate (GFR) can also 
be used in place of creatinine or CrCl]
≤1.5x upper limit of normal (ULN) OR
≥30 mL/min for subject with creatinine levels >1.5x institutional 
ULN
Hepatic
Total bilirubin
≤1.5x ULN, OR 
Direct bilirubin ≤ULN for subjects with total bilirubin levels
>1.5x ULN
Aspartate aminotransferase [AST (SGOT)] 
and 
alanine 
aminotransferase 
[ALT 
(SGPT)]
≤2.5x ULN
Albumin
≥3.0 g/dL
Lactate Dehydrogenase (LDH)
<2.5x ULN
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
≤1.5x ULN 
If a subject is receiving anticoagulant therapy, PT or INR can be
>1.5x ULN as long as they are within therapeutic range of 
intended use of anticoagulants
Activated Partial Thromboplastin Time 
(aPTT) or Partial Thromboplastin Time 
(PTT)
≤1.5x ULN
If a subject is receiving anticoagulant therapy, aPTT or PTT can 
be >1.5x ULN as long they are within therapeutic range of 
intended use of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
11. Female subjects of childbearing potential must be willing to use an adequate method
of contraception as outlined in Section 5.7.2 – Contraception, for the course of the 
study through 120 days after the last dose of study medication. Note: Abstinence is 
acceptable if this is the usual lifestyle and preferred contraception for the subject.
12. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
34
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating in or has participated in a clinical study and received an 
investigational agent or used an investigational device within 4 weeks prior to the 
first dose of study treatment.
Note: Subjects who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent or device.
2. Has an active autoimmune disease that has required systemic treatment in the past 
2 years (i.e., use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency) is not considered a form of 
systemic treatment.
3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the planned first 
dose of the study. The use of physiologic doses of corticosteroids may be approved 
after consultation with the Sponsor.
4. Has had prior anti-cancer mAb, chemotherapy, targeted small molecule therapy, or 
radiation therapy within 4 weeks prior to the planned first dose of the study.
5. Has not recovered from AE to ≤Grade 1 or prior treatment level due to a previously 
administered agent.
Note:  Subjects with ≤Grade 2 neuropathy or alopecia of any grade are an exception 
to this criterion and may qualify for the study.
Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.
6. Has EOC with mucinous histology subtype.
7. Has a known additional malignancy that progressed or required active treatment
within the last 5 years. Exceptions include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin that has undergone potentially curative therapy or in situ 
cervical cancer.
8. Has known active
central nervous system metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they have stable brain metastases.
9. Has known history of, or any evidence of active, non-infectious pneumonitis.
10. Has an active infection requiring systemic therapy.
11. Has symptoms of bowel obstruction in the past 3 months.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
35
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
13. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
14. Is pregnant or breastfeeding, or expecting to conceive children within the projected 
duration of the trial, starting with the screening visit through 120 days after the last 
dose of trial treatment.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent or with 
an agent directed to another co-inhibitory T-cell receptor (e.g. CTLA-4, OX-40, 
CD137) or has participated in prior pembrolizumab trials.
16. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
17. Has known active hepatitis B (e.g., Hepatitis B surface antigen reactive) or hepatitis C 
(e.g., hepatitis C virus RNA [qualitative] is detected).
18. Has received a live vaccine within 30 days of the planned first dose of the study.
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.
Table 2
Trial Treatment
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3-
week cycle
Experimental
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
Dose selection rationale has been provided in Section 4.2.2. Details on preparation and 
administration of pembrolizumab are provided in the Pharmacy Manual.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
36
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Dose Modification and Toxicity Management Guidelines for Pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These irAEs may occur shortly after the first dose or several months after the last 
dose of pembrolizumab treatment and may affect more than 1 body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical trial 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 are provided in Table 3.
.
 
 
05DV3K
 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

Product:  MK-3475 
40
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hours
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g. from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
41
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Grades 3 or 4
Grade 3:
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilator
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
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. Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record.
Timing of Dose Administration
Pembrolizumab should be administered on Day 1 of each 3-week cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0). On Cycle 1 Day 1, trial treatment should begin on the day of allocation or as 
close as possible to the date on which the subject is allocated/assigned. After Cycle 1 Day 1, 
trial treatment may be administered up to 3 days before or 3 days after the scheduled Day 1 
of each cycle due to administrative reasons.
Pembrolizumab 200 mg will be administered as a 30-minute IV infusion Q3W. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible. However, 
given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
42
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Centralized interactive voice response system/integrated web response system (IVRS/IWRS) 
will be utilized. The IVRS/IWRS will be used for assignment of both the screening number 
and the randomization/treatment number of all subjects in this trial. Subjects will be assigned 
to all study therapy in an unblinded fashion.
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids. If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the eCRF.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and events of clinical interest (ECIs) as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-CR relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
43
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor (except during screening).

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, intranasal 
influenza, rabies, Bacillus Calmette–Guérin, and typhoid vaccine.

Glucocorticoids for any purpose other than to modulate symptoms from an event 
of suspected immunologic etiology or from symptomatic brain metastasis(es) 
(also during whole brain radiation therapy). The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
o
Note: Inhaled steroids are allowed for management of asthma.
o
Note:  Use of prophylactic corticosteroids to avoid allergic reactions (e.g., 
to IV contract dye) is permitted.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up phase.
Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Table 3. Where appropriate, these guidelines include the use of oral or IV treatment with 
corticosteroids, as well as additional anti-inflammatory agents if symptoms do not improve 
with administration of corticosteroids. Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or 
viral infection, which might require additional supportive care. The treatment guidelines are 
intended to be applied when the investigator determines the events to be related to 
pembrolizumab.
Note: 
If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the investigator does not need to follow the treatment guidance.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
44
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Diet/Activity/Other Considerations
Diet 
Subjects should maintain a normal diet unless modification is required to manage an AE such 
as diarrhea, nausea or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. 
Female subjects will be considered to be of non-reproductive potential if they are either:
1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women <45 years of age a high follicle-stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
OR 
2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
OR 
3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:
1) practice abstinence† from heterosexual activity; 
OR 
2) use (or have their partner use) acceptable contraception during heterosexual activity.
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
Combination method (requires use of 2 of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)

contraceptive sponge (nulliparous women only)
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
45
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently 
employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies 
and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an 
acceptable method of contraception for subjects participating in this country/region.
Subjects 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, they must adhere to the contraception requirement (described above) 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 trial therapy. 
If there is any question that a subject of childbearing potential will not reliably comply with 
the requirements for contraception, that subject should not be entered into the study.
Below are the required contraception’s for countries where the health authority requests 
compliance with the Clinical Trial Facilitation Group Guidance:
Subjects should use birth control methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly and are considered as highly effective birth control 
methods. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:
o
Oral
o
Injectable
o
Implantable
o
IUD
o
Intrauterine hormone-releasing system
o
Bilateral tubal occlusion
o
Vasectomized partner
o
Sexual abstinence
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
46
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at least 
monthly and document the subject’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 (e.g., 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.
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, subjects who are breastfeeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or discontinued from study 
therapy at the discretion of the investigator should any untoward effect occur.  In addition, a 
subject may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding discontinuation or withdrawal procedures; including specific 
details regarding withdrawal from Future Biomedical Research, are provided in Section 7.1.4 
– Other Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject is lost to follow-up.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment.

Confirmed radiographic disease progression.
Note: For unconfirmed radiographic disease progression, please see Section 7.1.2.6.2.

Unacceptable adverse experiences as described in Section 5.2.1.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw subject

The subject has a confirmed positive serum pregnancy test
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
47
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential

Noncompliance with trial treatment or procedure requirements

Completed 35 treatments (approximately 2 years) with pembrolizumab
Note: 35 treatments (approximately 2 years) are calculated from the first dose. 
Subjects who stop pembrolizumab after receiving 35 treatments may be eligible for 
retreatment if they progress after stopping study treatment if they meet the 
requirements detailed in Section 7.1.5.2.1. Subjects may be retreated in the Second 
Course Phase with up to 17 (approximately 1 year) of additional trial treatments.

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Trial Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will 
be followed for 30 days for AE monitoring (SAEs will be collected for 90 days after the end 
of treatment or 30 days after the end of treatment if the subject initiates new anti-cancer
therapy, whichever is earlier, as described in Section 7.2.3.1). Subjects who discontinue for 
reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up. After documented disease progression, each subject will be 
followed by telephone for overall survival until death, withdrawal of consent, or the end of 
the study, whichever occurs first.
Discontinuation of Study Therapy after Complete Response
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least 
2 treatments with pembrolizumab beyond the date when the initial CR was declared. Subjects 
who then experience radiographic disease progression may be eligible for up to 17 additional 
treatments (approximately 1 year) with pembrolizumab via the Second Course Phase at the 
discretion of the investigator if:

No cancer treatment was administered since the last dose of pembrolizumab

The subject meets the safety parameters listed in the Inclusion/Exclusion criteria

The trial is ongoing
Subjects will resume therapy at the same dose and schedule at the time of initial 
discontinuation. Additional details are provided in Section 7.1.5.2.1. Response or progression 
in this Second Course Phase will not count towards the ORR as the primary endpoint in this 
trial.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
48
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable. In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or other 
applicable regulatory requirements, procedure-related problems, or the number of 
discontinuations for administrative reasons is too high.
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Incidence or severity of adverse drug reaction in this and other studies indicates a 
potential health hazard
4. Planned to modify or discontinue the development of the study drug
5. In the event of Sponsor decision to no longer supply study drug, ample notification 
will be provided so that appropriate adjustments to subject treatment can be made.
 
 
05DV3K
 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

Product:  MK-3475 
51
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visitsa
Survival 
Follow-
Upb
At time of 
Discon
30 Days after 
Last Dose
Every 9 or 12 
Weeks Post-
discon
Every 
12 Weeks
or as 
directed 
by 
Sponsor
e.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to each cycle of trial treatment, and 30 days post-treatment. 
Additionally, if urine test is positive or is not evaluable, a serum test is required. Subjects must be excluded/discontinued in the event of a positive test result. Monthly 
pregnancy testing should be conducted as per  local regulations where applicable.
f.
ECOG Performance Status and Laboratory tests for screening and determining eligibility are to be performed within 10 days prior to the first dose of trial treatment.
g.
CBC with diff and Chemistry to be performed every cycle through Cycle 6 and then every other cycle thereafter.
h.
UA and thyroid function tests will be performed every other cycle.
i.
Both PK and Anti-pembrolizumab Samples: pre-dose (trough) PK and anti-pembrolizumab antibody samples will be collected at within 24 hours before infusion at Cycles 1, 
2, 4, 6, 8 and every 4 cycles thereafter.
j.
PK Samples:  additional post-dose (peak) PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. An additional single PK 
sample should be drawn at; 24 hours (± 4 hours) [Day 2], between 72 and 168 hours[Day 4-8] and 336 hours (±48 hours) [Day 15] after Cycle 1 dosing. 
k.
Sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the 
IRB/IEC does not approve of the collection of the sample for these purposes. Leftover extracted DNA will be stored for future biomedical research if the subject signs the 
ICF for FBR. 
l.
Whole blood samples for correlative studies (DNA and RNA) should be collected pre-dose on Day 1 of Cycle 1, Cycle 2, and Cycle 3, and again at treatment 
discontinuation. Whole blood for Biomarker Samples (plasma and serum) to be collected pre-dose on Day 1 of Cycle 1 only.  
m.
Blood for tumor biomarker CA-125 at screening and at the time of each tumor imaging assessment
n.
Newly obtained tissue is preferred. If a newly obtained tumor tissue sample cannot be obtained, an archived tumor tissue sample can be submitted.  Samples that are
formalin-fixed paraffin-embedded must be provided to the designated central laboratory in order to be eligible. Adequacy and quality or the archived tissue samples must be 
confirmed by the central laboratory before enrollment
o.
Screening tumor imaging will be performed within 28 days prior to the date of allocation. Confirmation of baseline measurable disease per RECIST 1.1 by the central 
imaging vendor is required prior to subject allocation. 
p.
The first on-study imaging time point will be performed at 9 weeks (63 days ± 7 days) calculated from the date of allocation during the first 54 weeks, and every 12 weeks 
(84 days ± 7 days) thereafter, or earlier if clinically indicated.
q.
In subjects who discontinue study therapy without confirmed PD by the site per irRECIST, tumor imaging should be performed at the time of treatment discontinuation (± 4 
weeks). If previous tumor imaging was obtained within 4 weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation is not 
required.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
52
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
Screening 
(Visit 1)
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety 
Follow-up
Follow Up 
Visitsa
Survival 
Follow-
Upb
At time of 
Discon
30 Days after 
Last Dose
Every 9 or 12 
Weeks Post-
discon
Every 
12 Weeks
or as 
directed 
by 
Sponsor
r.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anti-cancer therapy, 
whichever is earlier.
s.
CA-125 to be collected locally after the 3rd post treatment follow up visit.
 
 
05DV3K
 
 
05HR4P
05HR4P

 
 
05HR4P
05HR4P

Product:  MK-3475 
54
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Trial Period:
Treatment Cycles
End of 
Treatment
Post-treatment
Treatment Cycle/Title:
1
2
3
4
5
6
7
8 and 
Beyond
Discon
Safety Follow-
up
Follow Up 
Visitsa
Survival Follow-
Upb
At time of 
Discon
30 Days after 
Last Dose
Every 9 or 12 
Weeks Post-
discon
Every  12     
Weeks
c.
In general, the window for each visit is ± 3 days unless otherwise noted.  
d.
For women of reproductive potential, a urine or serum pregnancy test should be performed within 72 hours prior to each cycle of trial treatment and 30 days post-treatment. 
e.
Laboratory tests for determining eligibility are to be performed within 10 days prior to the first retreatment dose of pembrolizumab  
f.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  CBC and Chemistry, to be performed every cycle through Cycle 6 and then 
every other cycle thereafter. UA and Thyroid function tests to be performed every other cycle.
g.
Blood for tumor biomarker CA-125 at screening and at the time of each tumor imaging assessment.
h.
Tumor imaging should be performed within 28 days prior to restarting treatment with pembrolizumab and continue to be performed every 9 weeks (63 ± 7 days)  after the 
first dose of retreatment for the first 54 weeks and then every 12 weeks thereafter, or more frequently if clinically indicated. 
i.
Tumor imaging should be performed at the time of treatment discontinuation (i.e., date of discontinuation ± 4 week window).  If previous tumor imaging was obtained within 
4 weeks prior to the date of discontinuation, then additional tumor imaging at treatment discontinuation isn’t mandatory.
j.
SAEs will be followed through 90 days following cessation of treatment, or 30 days following cessation of treatment if the subject initiates new anti-cancer therapy, 
whichever is earlier.
k.
CA-125 to be collected locally after the third post treatment follow up visit.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
55
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’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 subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
56
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Any autoimmune disorders, 
regardless of onset, should be recorded. Disease and treatment history for ovarian cancer will 
be recorded separately (see Section 7.1.1.4.1) and not listed under medical history eCRF 
form.
Ovarian Cancer Disease Details
The investigator or qualified designee will obtain the following information regarding the 
subject’s ovarian cancer including date of and stage at initial diagnosis, prior surgery and 
radiation therapy, prior systemic anti-cancer therapy with indications (e.g. neo-adjuvant, 
adjuvant, maintenance treatment, or for relapsed disease), start/stop dates and reason for 
stopping a systemic anti-cancer regimen, time of disease progression/ recurrence following 
each systemic regimen and criteria used for evaluation of disease progression (e.g. 
RECIST 1.1 or GCIG). Sites should obtain a dated imaging and/or CA125 report 
documenting progressive disease on the most recent treatment. 
Menopausal Details
The investigator or qualified designee will obtain details regarding the subject’s menopausal 
status.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medications taken by the subject 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
57
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
within 28 days before first dose of trial medication. Prior treatment details for ovarian cancer 
will be recorded separately from prior medications (see Section 7.1.1.4.1 for details).
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2.
Subsequent Anti-Cancer therapy Status
All new anti-cancer therapy initiated after the study start must be recorded in the subsequent 
anti-cancer therapy eCRF page. If a subject initiates another anti-cancer therapy while 
receiving pembrolizumab, pembrolizumab must be discontinued and subject will move into 
Survival Follow-up Phase; if a subject initiates a new anti-cancer therapy within 30 days after 
the last dose of the trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
All subjects will be assigned a randomization number, however all subjects will receive the 
same pembrolizumab 200 mg every three weeks (Q3W) as trial treatment by non-random 
assignment in an unblinded fashion.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment for 12 weeks between pembrolizumab 
doses
require consultation between the investigator and the Sponsor and written 
documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
58
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance to each dose administered. The instructions for preparing and 
administering pembrolizumab will be provided in the Pharmacy Manual.
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE version 4.0 (see Appendix 12.5). Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.
For subjects receiving treatment with pembrolizumab, all AEs of unknown etiology 
associated with pembrolizumab exposure should be evaluated to determine if it is possibly a 
potentially immunologic etiology (irAEs); see Section 5.6. regarding the identification, 
evaluation and management of potential irAEs.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
After preliminary screening based on subjects’ medical and cancer history, candidate subjects 
will have the following assessments for evaluating baseline safety and ovarian cancer disease 
status. Safety tests include physical examination, vital signs, clinical laboratory tests (clinical 
chemistry, hematology), urinalysis, electrocardiogram (ECG) and ECOG performance status. 
Baseline safety assessments must be performed within 10 days of the planned study entry on 
Day 1 (i.e., first dose).
Physical Exam
Full Physical Exam
The investigator or clinical designee will perform a complete (full) physical exam during the 
screening period and at discontinuation of treatment as specified in the Trial Flow Chart. 
Clinically significant abnormal findings at screening should be recorded as medical history. 
New clinically significant abnormal findings at discontinuation of treatment should be 
recorded as AEs.
Directed Physical Exam
Other than the Screening and treatment discontinuation visit, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to dosing on 
Day 1 of each treatment cycle (see Trial Flow Chart). New clinically significant abnormal 
findings should be recorded as AEs.
Vital Signs
The investigator or qualified designee will assess vital signs (including temperature, pulse, 
respiratory rate, and blood pressure) and weight at screening, prior to dosing on Day 1 of 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
59
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
each treatment cycle, and at treatment discontinuation as specified in the Trial Flow Chart. 
Height will be measured at screening only.
12-Lead Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures once at 
screening. Clinically significant abnormal findings should be recorded as medical history. 
Additional time points may be performed as clinically necessary.
Eastern Cooperative oncology Group Performance Status
The investigator or qualified designee will assess ECOG status (see Appendix 12.4) at 
screening, prior to dosing on Day 1 of each treatment cycle, at treatment discontinuation, and 
at progressive disease (PD) follow-up visit as specified in the Trial Flow Chart.
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual. For this study, imaging of chest abdomen, and pelvis are 
required at Screening and at each scheduled disease assessment visit after enrollment. 
Computed tomography (CT) is the modality strongly preferred for chest. For abdomen and 
pelvis CT or magnetic resonance imaging (MRI) are both acceptable. However, the same 
imaging modality and technique, such as use of contrast should be used consistently for an 
anatomic region in a subject throughout the trial.
All scheduled images for all study subjects from the sites will be submitted to the central 
imaging vendor. In addition, additional imaging (including other modalities) that are 
obtained at an unscheduled time point to determine if the subject has progressed, as well as 
imaging obtained for other reasons but captures radiologic progression, should be submitted 
to the central vendor as well.
Screening Tumor Imaging
At Screening, imaging scans must be performed within 28 days prior to date of allocation. 
The site study team must review screening images to confirm the subject has measurable 
disease per RECIST 1.1. The screening images must be submitted to the central imaging 
vendor for confirmation of measurable disease per RECIST 1.1 for eligibility prior to 
allocation.
Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and are performed within 28 days prior to the 
date of allocation and can be assessed by the central imaging vendor.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, ie. without evidence of progression by imaging (confirmed by MRI if MRI 
was used at prior imaging, or confirmed by CT imaging if CT used at prior imaging for at 
least 4 weeks prior to the first dose of trial treatment; also, any neurologic symptoms must 
have returned to baseline), have no evidence of new or enlarging brain metastases, and have 
not used steroids for brain metastases for at least 28 days prior to trial initiation as per local 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
60
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
site assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
Disease Assessments During Treatment Period
After study start, study scheduled imaging assessments will be performed at 9 weeks 
(63 days ± 7 days) from the date of allocation up to 54 weeks. Subsequent imaging should be 
performed Q12W (84 days ± 7 days) or more frequently, if clinically indicated. Imaging 
timing should follow calendar days and should not be adjusted for delays in cycle starts or 
any dose interruptions that may occur. Imaging assessments should continue until disease 
progression per RECIST 1.1 or to confirm disease progression per irRECIST to avoid 
pseudoprogression (see Section 7.1.2.6.7 for details), the start of new anti-cancer treatment, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first. All 
supplemental imaging must be submitted to the central imaging vendor.
Per RECIST 1.1, PR and CR should be confirmed by a repeat tumor imaging assessment no 
less than 4 weeks from the date the response was first documented. Therefore, the scan for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan (9 or 12 weeks later), whichever is clinically 
indicated. Subjects will then return to regular scheduled imaging Q9W (or Q12W), starting 
with the next scheduled imaging time point. Subjects who obtain a confirmation scan do not 
need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor imaging may 
resume at the subsequent scheduled imaging time point.
Per irRECIST (section 7.1.2.6.7), disease progression should be confirmed by the site at least 
4 weeks after site-assessed first radiologic evidence of PD in clinically stable subjects. 
Subjects who have unconfirmed disease progression may continue on treatment at the 
discretion of the site investigator until progression is confirmed by the site provided they 
have met the conditions detailed in Section 7.1.2.6.7. Subjects who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point if clinically stable. 
Subjects who have confirmed disease progression as assessed by the site will discontinue the 
treatment. Exception is detailed in Section 7.1.2.6.7.
Bone Scans
Subjects with known history or new symptoms that are suggestive of osseous metastasis 
(e.g., new bone pain and/or new persistently elevated alkaline phosphatase) should obtain a 
bone scan at baseline. At follow-up, subjects with new symptoms or those suggestive of 
worsening osseous metastasis should obtain a bone scan. Additionally, plain X-ray 
evaluation should be obtained for symptomatic skeletal sites with negative bone scan 
evaluations. New osseous uptake, upon confirmation with CT or per institutional standard, 
will be assessed for progression per RECIST 1.1. Lytic/mixed lesions with soft tissue 
component may be included in the evaluation of disease burden if they meet measurability 
criteria, while blastic lesions are considered non-measurable, in accordance with 
RECIST 1.1. Note: if a bone scan is obtained that is positive for metastatic disease and the 
patient ultimately achieves a CR per RECIST 1.1; a follow-up bone scan should be obtained.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
61
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the 
same imaging schedule used while on treatment (Q9W (63 days ± 7 days) from the date of 
allocation up to 54 weeks with subsequent imaging performed Q12W (84 days ± 7 days).) to 
monitor disease status until (1) the start of new anti-cancer treatment, (2) disease progression, 
(3) death, or (4) the end of the study, whichever occurs first.
Second Course (Retreatment) Tumor Imaging
A scan must be performed within 28 days prior to restarting treatment with pembrolizumab. 
Local reading (investigator assessment with site radiology reading) will be used to determine 
eligibility. Imaging should be submitted to the central imaging vendor for retrospective 
verification.
The first on study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
after the restart of treatment up to 54 weeks. Subsequent tumor imaging should be performed 
Q12W (84 days ±7 days) or more frequently if clinically indicated.
Per RECIST 1.1, PR or CR should be confirmed by a repeat tumor imaging assessment not 
less than 4 weeks from the date the response was first documented. The tumor imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan, whichever is clinically indicated. Subjects will then 
return to regular scheduled imaging every 9 (or 12) weeks (63 or 84 days ±7 days), starting 
with the next scheduled imaging time point. Subjects who obtain a confirmation scan do not 
need to undergo scheduled tumor imaging if it is <4 weeks later and may wait until the next 
scheduled imaging time point.
Per irRECIST (Section 7.1.2.6.7) , if tumor imaging shows initial PD, tumor assessment 
should be repeated ≥4 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression. Subjects who obtain a 
confirmation scan do not need to undergo scheduled tumor imaging if it is <4 weeks later and 
may wait until the next scheduled imaging time point if clinically stable.
Imaging should continue to be performed until disease progression, the start of new 
anti-cancer treatment, withdrawal of consent, death, or notification by the Sponsor, 
whichever occurs first. Disease progression may be confirmed at least 4 weeks after the first 
tumor imaging indicating progressive disease in clinically stable subjects.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by radiologic imaging Q9W
(63 days ± 7 days) from the date of allocation up to 54 weeks; with subsequent imaging 
performed Q12W (84 days ± 7 days until (1) the start of new anti-cancer treatment, (2) 
disease progression, (3) death, or (4) the end of the study, whichever occurs first.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be applied by the sites and the central imaging vendor 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 (e.g., discontinuation of study therapy). Although 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
62
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
RECIST 1.1 references to maximum of 5 target lesions in total and 2 per organ, Merck 
allows maximum of 10 target lesions in total and 5 per organ.
irRECIST Assessment of Disease
irRECIST is RECIST 1.1 adapted as described below to account for the unique tumor 
response seen with immunotherapeutic drugs. irRECIST will be used by site 
investigator/local radiology review to assess tumor response and progression, and make 
treatment decisions. This data will be collected in the clinical database. Treatment efficacy 
based on irRECIST as assessed by central imaging vendor review will be evaluated 
retrospectively.
When feasible, subjects should not be discontinued from study treatment until progression is 
confirmed by the local site investigator/radiology assessment. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some subjects 
can have a transient tumor flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response. The following may present as tumor flare:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1, the 
investigator needs to decide whether to continue a subject on study treatment until repeat 
imaging is obtained (using irRECIST for subject management. See Table 5), which should be 
based on assessing subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. If the subject is clinically stable and can continue on study 
treatment, repeat scan should be performed ≥4 weeks later in order to confirm PD. Clinical 
stable status is defined as the following:
1) Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values
2) No decline in ECOG performance status 
3) Absence of rapid progression of disease 
4) Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention  
Any subject deemed clinically unstable should be discontinued from trial treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat imaging for 
PD confirmation.
In determining whether or not the tumor burden has increased or decreased per irRECIST, 
the investigator should consider all target and non-target lesions as well as any incremental 
new lesion(s).
Scenarios where PD is not confirmed at repeat imaging if ALL of the following occur by 
irRECIST:
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
63
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential

Target lesion sum of diameters is <20% or <5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is qualitatively stable or improved

New lesion resulting in initial PD is qualitatively stable or improved

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
If repeat imaging does not confirm PD per irRECIST as assessed by the investigator and the 
subject continues to be clinically stable, study treatment tumor imaging assessment may 
continue per study schedule.
Scenarios where PD is confirmed at repeat imaging if ANY of the following occurs by 
irRECIST:

Target lesion sum of diameters remain ≥20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, subjects will be 
discontinued from study therapy.
NOTE:  If a subject has confirmed radiographic progression (i.e., 2 scans at least 4 weeks 
apart demonstrating progressive disease) per irRECIST, but the subject is achieving a 
clinically meaningful benefit and there is no further increase in the tumor burden at the 
confirmatory tumor imaging, an exception to continue treatment may be considered
following consultation with the Sponsor. In this case, if treatment is continued, tumor 
imaging should continue to be performed following the intervals as outlined in Section 6.0 
(Trial Flowchart) and be submitted to the central imaging vendor.
Additional details about irRECIST are referenced in Merck TIP Sheet for RECIST 1 1 and 
irRECIST.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
64
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Table 5
irRECIST Imaging and Treatment after First Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1
Repeat imaging at 
>4 weeks at site to 
confirm PD
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting confirmatory 
scan by site
Repeat imaging at 
>4 weeks to confirm 
PD per physician 
discretion only
Discontinue treatment
Repeat scan confirms 
PD by irRECIST at 
the local site
No additional imaging 
required
Discontinue treatment 
(exception is possible 
upon consultation 
with Sponsor).
No additional imaging 
required
N/A
Repeat scan shows 
SD, PR or CR by 
irRECIST at the local 
site*
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the local 
site Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
Investigator’s 
discretion.  Next 
tumor imaging should 
occur according to the 
regular imaging 
schedule outlined in 
the protocol.
* SD,PR and CR for irRECIST are identical to RECIST 1.1
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
65
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
aPTTd
Platelet count
Alanine aminotransferase (ALT)
Protein
PT (INR)d
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3)e
Red 
Blood 
Cell 
Count
Bicarbonateᵇ
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Calcium
Thyroid 
stimulating 
hormone (TSH)
Absolute 
Lymphocyte Count
Chloride
FSH, estradiol f
Creatinine
Blood 
for 
correlative 
studies
Glucose
Blood for genetics
Lactate Dehydrogenase
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
Carbon 
dioxide 
(CO2
or 
bicarbonate)b
Uric acid
Ureac
Amylase
a Perform on women of childbearing potential only, 72 hours prior to Day 1 of each cycle and 30 days post 
treatment.  
b If considered standard of care in your region. If these tests are not done as part of standard of care in your 
region then these tests do not need to be performed.
c Blood Urea Nitrogen is preferred; if not available urea may be tested.
d Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  
Any subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout 
the trial.
e Total T3 is preferred; if not available free T3 may be tested.
f Blood for menopausal status is only required for some subjects as described in Section 7.1.3.2
Laboratory safety tests will be performed within 10 days prior to the first dose of trial 
treatment. After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing. Results must be reviewed by the investigator or qualified designee and found 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
66
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
to be acceptable prior to each dose of trial treatment. Blood draws for thyroid function tests 
should be done prior to dosing at the scheduled time point; however, results can be reviewed 
after dosing if not available prior to the subject’s scheduled dose after the first cycle.
Blood for Menopausal Status
Blood for evaluation of postmenopausal status (FSH and estradiol) will be evaluated if clear 
documentation of postmenopausal status in not obtained.
The menopausal status (pre- or post-menopausal) for all subjects younger than age 60 must 
be determined at screening according to the definitions below. The date of the subject’s last 
menstrual period (LMP), bilateral ovariectomy/oophorectomy status (if applicable) and, 
when indicated, serum FSH and estradiol levels, must be assessed and recorded in the 
eCRFs.
Pre-menopausal

≤12 months since LMP
OR

Biochemical evidence of pre-menopausal status according to serum FSH and estradiol 
levels and local institutional guidelines
Post-menopausal

Subject has undergone prior bilateral ovariectomy/oophorectomy
OR

>12 months since LMP and no hysterectomy, hormone replacement, estrogen 
receptor antagonist, chemotherapy or ovarian suppression at any time since LMP
OR

Biochemical evidence of post-menopausal status according to serum FSH and 
estradiol levels and local institutional guidelines.
Blood collection at screening for biochemical evidence of menopausal status (FSH and 
estradiol) will be needed if patient:
1. Is ≤60 years old, and
2. Has not had a bilateral oophorectomy, and
3. Has not had a menstrual period for at least 12 months, and
4. Had a hysterectomy or was on hormone replacement, estrogen receptor 
antagonist, chemotherapy or ovarian suppression at any time since LMP.
Blood for Tumor Biomarker CA-125
Blood for tumor biomarker CA-125 will be obtained at the time of each tumor imaging 
assessment; this blood sample will not be used for determining eligibility for study 
participation.  After the 3rd post treatment follow up visit, this sample will be collected 
locally. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
67
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Pharmacokinetics/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of anti-pembrolizumab antibodies (ADA) and PK are currently 
planned as shown in the Trial Flowchart (Section 6.1). Blood samples for PK and ADA 
collected may be stored only at this time. Further sample analysis may be performed if 
required. If ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, 
it may be reduced or discontinued.
Blood Collection for Serum Pembrolizumab Pharmacokinetics
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures manual. Pharmacokinetic samples should be drawn according to the PK 
collection schedule for subjects who receive pembrolizumab.
Blood Collection for Anti Drug Pembrolizumab Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Procedures manual. Anti-pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for subjects who receive pembrolizumab (Section 6.1).
Simultaneous PK sampling is required for interpretation of ADA analysis.
Tumor Tissue Collection
During Screening, a fresh newly-obtained tumor tissue sample or an archived tumor tissue 
sample either collected from prior cytoreductive surgery must be obtained and submitted to 
the designated central laboratory for PD-L1 status and other biomarker assessments as 
specified in Section 3.3 and Section 4.2.3.4. The samples must be of adequate amount and 
quality. Formalin-fixed paraffin-embedded tumor blocks are much preferred. If after 
agreement with the Sponsor, unstained slides are submitted, the slides should be freshly cut 
and submitted to the testing laboratory within 14 days from site slide sectioning date 
otherwise a new specimen will be requested. 
For subjects with tumor tissue samples available for different time points in the past, 
submission of a sample from each time point is strongly encouraged as this will provide us 
with good understanding of markers that may or may not change during the course of disease 
and treatment. If after agreement with the Sponsor, unstained slides are submitted, the slides 
should be freshly cut and submitted to the testing laboratory within 14 days from site slide 
sectioning date otherwise a new specimen will be requested.
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that 
would ordinarily be discarded at the end of the main study will be retained for FBR (see 
Section 4.2.3.5 for rationale). Details regarding time points for collection of tumor tissue are 
outlined in the Study Flow Chart (Section 6.1).
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
68
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Correlative Blood Collections- Samples for Correlative and Biomarker 
Analyses
Details regarding time points for blood collection to support analysis of exploratory 
biomarkers presented in Section 4.2.3.4 are outlined in the Study Flow Chart (Section 6.1).
Samples for planned, exploratory genetic analysis of DNA should be drawn unless there is a 
documented law or regulation prohibiting collection, or unless the IRB/IEC does not approve 
of the collection.
Blood for correlative biomarker studies should be collected prior to treatment at each 
specified cycle and at treatment discontinuation.
Detailed instructions for sample collection, processing and shipment are provided in the 
Procedures Manual.
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future research.

Leftover tumor tissue
Other Procedures
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. Subjects who a) attain a CR or b) complete 35 trial treatments 
(approximately 2 years) of treatment with pembrolizumab may discontinue treatment with 
the option of restarting treatment if they meet the criteria specified in Section 7.1.5.2.1. After 
discontinuing treatment following assessment of CR or of the 35 trial treatments, these 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5.3.2) 
and then proceed to the Follow-up Period of the study (described in Section 7.1.5.3.3).
Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
69
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
subject's specimens will be removed from the biorepository and be destroyed.  A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for satisfaction of entry criteria and trial 
assessments and routine safety evaluation of subjects

Imaging equipment – as required for study objectives

Drug administration equipment –
as required for storage, preparation and 
administration(infusion) of pembrolizumab
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual and Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
Screening
Written consent for the main study must be obtained prior to performing any protocol 
specific procedure including the mandatory newly obtained (fresh) tumor biopsy that is 
required for eligibility. Potential subjects will be evaluated to determine that they fulfill the 
entry requirements as set forth in Section 5.1. Visit requirements are outlined in Section 6.0 
(Trial Flow Chart). Results of a test performed prior to the subject signing consent as part of 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
70
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
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 trial treatment 
except for the following:

Laboratory tests and evaluation of ECOG status are to be performed within 10 days 
prior to the first dose of trial treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment. If urine pregnancy results cannot be
confirmed as negative, a serum pregnancy test will be required (performed by the 
local study site laboratory).

Initial tumor imaging must be performed within 28 days of the first dose of study.
Screening procedures may be repeated after consultation with the Sponsor. Subjects may be 
rescreened after initially failing to meet the inclusion/exclusion criteria. Results from 
assessments performed during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the inclusion/exclusion 
criteria is met.
Treatment Cycles
Visit requirements are outlined in Section 6.0 (Trial Flow Chart). Specific procedure-related 
details are provided above in Section 7.1 (Trial Procedures).
Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab with SD or better may be eligible for up to 17 additional 
trial treatments (approximately 1 year) if they progress after stopping study treatment. This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and

Was treated for at least 24 weeks with pembrolizumab before 
discontinuing therapy

Received at least two treatments with pembrolizumab beyond the date 
when the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 35 trial 
treatments ( approximately 2 years) for reasons other than disease progression 
or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression
or clinical progression after stopping their initial treatment with pembrolizumab. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
71
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Subjects being considered for second course retreatment after experiencing clinical 
progression may only be enrolled in second course after consulation with the 
Sponsor.

Did not receive any anti-cancer treatment since the last dose of pembrolizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 5.1.2

Female subject of childbearing potential must have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.  

Female subject of childbearing potential (Section 5.7.1) should be willing to use an 
adequate method of contraception as outlined in Section 5.7.1- Contraception, for the 
retreatment period 
of the study through 120 days after the last dose of study 
medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Pembrolizumab will be administered for up to an
additional 17 trial treatments (approximately 1 year).
Visit requirements are outlined in Section 6.0 (Trial Flow Chart).
Post-Treatment
Discontinuation Visit
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up Visit, procedures do not need to be repeated. 
Visit requirements are outlined in Section 6.0 (Trial Flow Chart). Specific procedure-related 
details are provided above in Section 7.1 (Trial Procedures). Additional details regarding 
subject withdrawal and discontinuation are presented in Section 5.8.
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-up Visit should be recorded. 
Subjects with an AE of Grade >1 will be followed until the resolution of the AE to Grade 0
to 1 or until the beginning of a new anti-cancer therapy, whichever occurs first. Serious 
adverse events that occur within 90 days of the end of treatment or before initiation of a new 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
72
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
anti-cancer treatment should also be followed and recorded regardless of causality. Beyond 
90 days, only SAE and ECIs that are considered related to trial treatment should be reported.
Subjects who are eligible for retreatment with pembrolizumab (as described in 
Section 7.1.5.2.1) may have up to 2 safety follow-up visits, 1 after the Treatment Period and 
1 after the Second Course Phase.
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-up Phase and should be assessed per study schedule to monitor disease 
status. The Sponsor may request survival status to be assessed at additional time points 
during the course of the study (not to exceed approximately 12 weeks). Every effort should 
be made to collect information regarding disease status until the start of new anti-cancer 
therapy, disease progression, death, end of trial (or if the subject begins retreatment with 
pembrolizumab as detailed in Section 7.1). Information regarding post-trial anti-cancer
treatment will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 5.2.3 will move from the Follow-up Phase to the Second Course Phase when they 
experience disease progression. Details are provided in the Trial Flow Chart (Section 6) for 
retreatment with pembrolizumab.
Survival Follow-up
Subjects who experience confirmed disease progression or start a new anti-cancer therapy, 
will move into the Survival Follow-up Phase and should be contacted by telephone 
approximately Q12W to assess for survival status until death, withdrawal of consent, or the 
end of the trial, whichever occurs first.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to, but not limited to, an external 
Data Monitoring Committee review, interim and/or final analysis. Upon Sponsor notification, 
all participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding participants 
that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
73
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose  of 1000 mg or greater (≥5 times the indicated dose). No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
74
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator. All reported pregnancies  must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 7 for additional details regarding each of the above criteria.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
75
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the safety follow-up period 
specified in the paragraph above, or at any time outside of the time period specified in the 
previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
76
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outline in this section will not be reported to the Sponsor as outlined in 
Section 7.2.3 (Immediate Reporting of Adverse Events to the Sponsor).
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as an SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
77
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Table 7
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
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
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
78
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
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; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject 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 trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
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
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
79
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
TRIAL GOVERNANCE AND OVERSIGHT
Scientific Advisory Committee
This trial was developed in collaboration with a Scientific Advisory Committee (SAC).  The 
SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with 
respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific 
publications.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, but prior to any unblinding/final database lock, changes made to primary 
and/or key secondary hypotheses, or the statistical methods related to those hypotheses, then 
the protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or 
other non-confirmatory analyses made after the protocol has been finalized, but prior to final 
database lock, will be documented in the supplemental Statistical Analysis Plan SAP (sSAP)
and referenced in the Clinical Study Report (CSR) for the study. Post-hoc exploratory 
analyses will be clearly identified in the CSR. The sSAP will also document the detailed 
biomarker analysis strategy including determination of the PD-L1H cut-off selection .
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2 through 8.12.
Study Design Overview
A Phase 2, open-label, single-arm, two-cohort, multi-center trial of 
pembrolizumab monotherapy in subjects with advanced ovarian 
cancer who have demonstrated recurrent disease following the front 
line treatment and received up to 5 lines of treatments for ROC. 
Treatment Assignment
Cohort A will enroll subjects with ROC who have received 0 to 
2 prior lines for treating ROC (i.e., 1 to 3 total prior lines counting the 
front line) and with a platinum-free interval or treatment-free interval 
of 3 to 12 months based on the last regimen received.
Cohort B will enroll subject with ROC who have received 3 to 5 prior 
lines for treating ROC (i.e., 4 to 6 total prior lines counting the front 
line) and with a platinum-free interval or treatment-free interval 
≥3 months based on the last regimen received.
In both cohorts, subjects will be treated with pembrolizumab 
monotherapy 200 mg Q3W as trial treatment by non-randomized 
assignment in an unblinded fashion. 
Analysis Populations
Efficacy: Full Analysis Set (FAS)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR by RECIST 1.1 per BICR review
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
80
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Key Secondary Endpoints

DOR, DCR, PFS, per RECIST 1.1 as assessed by BICR

ORR, DOR, DCR, PFS per RECIST 1.1 as assessed by 
investigator 

OS

Proportions of PFS at 6, 12 and 18 months and proportions of 
survival at 6, 12, 18, and 24 months
Statistical Methods for Key 
Efficacy Analyses
The primary objectives will be evaluated by the point estimate and
95% confidence interval for the ORR in the Cohort A-All Comer 
Population and Cohort A PD-L1H subgroup, respectively, using an 
exact binomial distribution. ORR will be evaluated similarly in the 
Cohort B-All Comer group and Cohort B PD-L1H subgroup, 
respectively. 
Statistical Methods for Key 
Safety Analyses
Summary statistics, and 95% CI for the incidence rate of Grade 2 or 
higher adverse events with an immune etiology and the incidence rate 
of Grade 4/5 AEs.
Interim Analyses
An interim analysis is planned at 4 months after the first 100 subjects
have been enrolled in Cohort A, which will be used as the training set. 
IA will evaluate clinical activity and the correlation of PD-L1 in 
tumor tissue samples in the training set to facilitate the PD-L1 
expression cut-off selection. 
Multiplicity
No multiplicity adjustment has been planned.
Sample Size and Power 
Cohort A-All Comer group include the first 180 enrolled subjects 
fulfilling the eligibility of Cohort A. A minimum of 75 subjects will 
be enrolled for the subgroup with a PFI/TFI of 3 to <6 months and the 
subgroup with a PFI/TFI of 6 to 12 months. The first 100 enrolled 
Cohort A subjects will be used as the training set for determining a 
PD-L1 expression cut point. The additional 150 enrolled Cohort A 
subjects will be in the confirmation set, therefore, the study will enroll 
approximately 250 Cohort A subjects regardless of the PD-L1 status.
The exact number of subjects enrolled in the confirmation set will 
depend on the prevalence of the PD-L1H as determined by the 
biomarker analysis. Approximately 75 subjects will be enrolled in 
Cohort B.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
clinical biostatistics department of the Sponsor. This trial is being conducted as an open-label 
non-randomized single-arm clinical trial (i.e., subjects, investigators, and Sponsor personnel 
will be aware of subject treatment assignments after each subject is enrolled and treatment is 
assigned). The study team at the Sponsor consisting of clinical, statistical, statistical 
programming, and data management personnel will be blinded to subject-level PD-L1 
biomarker results. An unblinded Sponsor biomarker statistician will have access to the 
subject-level PD-L1 results for the purpose of data review and biomarker correlation 
analysis. The unblinded Sponsor biomarker statistician will have no other responsibilities 
associated with the study.
Hypotheses/Estimation
Objectives of the study are stated in Section 3.0.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
81
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
The primary efficacy endpoint is ORR, defined as the proportion of subjects in the analysis 
population who have CR or PR at any time during the study using RECIST 1.1 criteria 
assessed by the blinded central imaging vendor review.
Secondary efficacy endpoints include:

RECIST 1.1 ORR by investigator review.

Duration of response, defined as the time from first response to disease progression in
subjects who achieve a PR or better, based on assessments by the central imaging 
vendor per RECIST 1.1.

Progression-free survival, defined as the time from first dose of study medication to 
the first documented disease progression per RECIST 1.1 based on assessments by 
the central imaging vendor or death due to any cause, whichever occurs first.

Overall survival, defined as the time from first dose of study medication to death due 
to any cause.

Proportions of PFS at 6, 12 and 18 months and proportions of survival at 6, 12, 18 
and 24 months.

Disease Control Rate, defined as the percentage of subjects who have achieved 
confirmed CR or PR or have demonstrated SD for at least 24 weeks prior to any 
evidence of progression, based on assessments by the central imaging vendor per 
RECIST 1.1.
Overall response rate, DOR, PFS per irRECIST 1.1 by the central imaging vendor, and 
restricted mean survival time estimate of PFS over time are the exploratory efficacy 
endpoints.
Safety Endpoints
Safety measurements are as described in Section 7.2.
The primary safety endpoints are AEs graded using CTCAE v4.0 criteria. Safety will be 
assessed by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab, including SAEs and ECIs. Other safety endpoints include laboratory safety 
assessments, ECOG performance status, vital signs, reasons for treatment discontinuation, 
dose interruptions or reductions, and physical examinations.
Analysis Populations
Efficacy Analysis Populations
Cohort A
The Full Analysis Set (FAS) population for All Comers, which consists of 180 first enrolled
subjects in Cohort A who receive at least 1 dose of study treatment and with measurable 
disease at baseline, will serve as the primary population for the analyses of efficacy data for 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
82
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Cohort A All Comers. The FAS population for PD-L1H subgroup in Cohort A, which 
includes the subjects in the confirmation set above the PD-L1 cut-off, will be used for the 
analyses of efficacy data for PD-L1H subjects in Cohort A. Supportive analyses of efficacy 
will be conducted in the All Subjects as Treated (ASaT) population, defined as all enrolled
subjects in all comers or PD-L1H in the confirmation set respectively who receive at least 
1 dose of study medication (not applicable if there is no difference with the FAS population).
Cohort B
The FAS population consists of all subjects in Cohort B who receive at least 1 dose of study 
treatment and with measurable disease at baseline. The FAS population for PD-L1H subgroup 
in Cohort B, which includes the subjects in Cohort B above the PD-L1 cut-off, will be used 
for the analyses of efficacy data for PD-L1H subjects in Cohort B.
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data. 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.
Details on the approach to handling missing data for safety analyses are provided in 
Section 8.6 (Statistical Methods).
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP.
Data from the training set (first 100 subjects in Cohort A) will be evaluated for biomarker 
analysis and cut point determination. The analysis of confirmation set (150 subjects in Cohort 
A) will focus on verifying the response rate above the cut point is consistent with predictions 
made based on the training set data used to set the cut point via the interim analysis. Results 
for the cut point will be considered confirmed in a direction that supports the proposition of 
enrichment provided the observed response rate in the confirmation set for subjects above the 
selected cut point is greater than or equal to the 20th percentile of its posterior predictive 
distribution as determined using the training set at the time the cut point is set. In other 
words, consistency of effect is defined as not belonging to the lower 20% of the training set’s 
predictions for enrichment associated with use of the cut point.
Efficacy will be evaluated in the All Comer group and the PD-L1H subgroup for Cohort A 
and B respectively. For the primary efficacy endpoint, the ORR based on RECIST 1.1 by the 
blinded central imaging vendor review, the point estimate, and 95% CI (as determined by the 
upper and lower 97.5% one-sided confidence bounds) will be provided using an exact 
binomial distribution. Subjects without response data will be counted as non-responders. 
Secondary efficacy evaluations of ORR based on RECIST 1.1 by investigator review, and
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
83
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
ORR based on modified RECIST 1.1 by blinded central imaging vendor review will also be 
conducted using the same methodology as for the primary efficacy analysis.
Duration of response by blinded central imaging vendor review and investigator review will 
be summarized using KM method in all responders.
For PFS and OS, KM curves, median estimates, and survival at 6, 12 and 18 months based on 
the KM curves (95% CI is based on Greenwood's formula) will be provided as appropriate. 
Subjects without efficacy evaluation data or without survival data will be censored at Day 1.
The DCR will be summarized at the end of the trial. The restricted Mean Survival Time
estimate of PFS and OS will also be calculated and plotted over time.
An outline of the key efficacy analysis strategy is presented in Table 8.
Table 8
Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Method
Analysis 
Population
Missing Data 
Approach

ORR by BICR per 
RECIST1.1 

ORR by investigator 
assessment per RECIST1.1
Exact 
test 
of 
binomial 
parameter; 95% CI†
FAS‡/ASaT
Subjects with missing
data 
are 
considered
non-responders

DOR
by 
BICR
per 
RECIST1.1 

DOR 
by 
investigator 
assessment per RECIST1.1 
Summary statistics using
KM method 
All 
responders
Non-responders 
are
excluded in analysis

PFS 
by 
BICR
and 
investigator assessment per 
RECIST 1.1OS

Proportion of subjects with 
PFS at 6, 12 and 18
months; 
Proportion 
of 
survival at 6, 12, 18, and 
24 months
Summary statistics using
KM method
FAS‡/ASaT
Censored 
at 
last
assessment

DCR 
by 
BICR
and 
investigator assessment per 
RECIST 1.1
Exact test of binomial 
parameter; 95% CI†
FAS‡/ASaT
Subjects with missing
data 
are 
considered
non-responders
†95% CI is determined by the upper and lower 97.5% one-sided confidence bounds.
‡Primary population for efficacy analyses
The strategy to address multiplicity issues with regard to multiple endpoints and interim 
analyses is described in Section 8.7 (Interim Analyses) and in Section 8.8 (Multiplicity).
The association between biomarker values and ORR will be investigated via logistic 
regression using one-sided tests on the regression coefficient. Cut-off evaluation and 
selection will involve a review of how the positive predictive value (PPV, response rate in 
those above a cut-off) and negative predictive value (NPV, response rate in those below the 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
84
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
cut-off) vary with putative cut-offs. A cut-off that maintains high NPV (e.g., above 90%) 
while achieving meaningful enrichment of response and largely capturing patients showing 
durable clinical benefit is ideal. The profiles of PPV, NPV, and the percentage of patients 
above a given cut-off along with intervals quantifying the uncertainty in those profiles will be 
estimated as a function of potential cut-offs. Receiver operating characteristic curve analysis 
will also be used to understand the sensitivity and specificity profile and examine cut-offs 
that might be suggested based on the ROC curve and their appropriateness with regard to 
PPV and NPV. If the operating characteristics associated with a single biomarker cutpoint are 
not sufficiently optimized, up to 2 biomarker cutpoints may be carried forward for efficacy 
endpoint analyses (i.e., a biomarker positive cutpoint and a biomarker high positive cutpoint),
as has been implemented in other tumor types within the pembrolizumab program (e.g., 
bladder cancer) [44]. Details of the biomarker analysis strategy will be documented in the 
sSAP.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. Summary statistics (e.g., counts, percentage, mean, 
standard deviation) will be provided for the safety endpoints as appropriate. The 95% CI for 
the incidence rate of Grade 2 or higher AEs with an immune etiology (irAEs) and the 
incidence rate of Grade 4/5 AEs will be provided as appropriate. The All Comer group and 
the PD-L1H subgroup will be summarized separately for Cohort A and Cohort B.
Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs. No statistical 
hypothesis tests will be performed on these characteristics. The number and percentage of 
subjects screened, enrolled, primary reasons for screening failure, and 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. The All Comer group and the PD-L1H subgroup 
will be summarized separately for Cohort A and Cohort B.
Interim Analyses
An interim analysis will be performed after 100 subjects in Cohort A have been enrolled and 
followed up for at least 4 months to determine a PD-L1 expression cutpoint based on PD-L1 
biomarker and tumor response data. The results of this analysis will be presented to the study 
team without unblinding anyone to individual results. The efficacy data from the interim 
analysis may facilitate further interactions with regulatory agencies.
Multiplicity
The primary objectives for ORR per RECIST 1.1 in All Comer Population and PD-L1H
subgroup for Cohort A and Cohort B will be assessed by point estimate and 95% CI. There 
are no formal hypotheses and no adjustments for multiplicity are planned. Evaluation of 
objectives should be interpreted with caution due to the potential for an increase in the false 
positive rate.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
85
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Sample Size and Power Calculations
Based on the preliminary data of pembrolizumab in ovarian cancer patients as described in 
Section 4.1.2, we expect an ORR of approximately 25% for the All Comer population. These 
responding subjects expect to have durable responses. In addition we expect additional 
subjects will have durable SD. We expect in a PD-L1 enriched population, ORR may reach 
to above 35% with durable response in majority of the subjects.
Table 9 shows the two-sided 95% CI of ORR for different observed response rates based on 
different sample size in the All Comer group for Cohort A or Cohort B.
Table 9
Two-sided 95% Confidence Interval of ORR in All Comer 
Sample Size
Observed ORR
95% CI of ORR (%)
75
17%
(9.3, 27.4)
25%
(15.7, 36.3)
30%
(20.0, 41.7)
35%
(24.3, 46.9)
100
17%
(10.2, 25.8)
25%
(16.9, 34.7)
30%
(21.2, 40.0)
35%
(25.7, 45.2)
180
17%
(12.0, 23.5)
25%
(18.9, 32.0)
30%
(23.4, 37.3)
35%
(28.1, 42.4)
250
17%
(12.7, 22.5)
25%
(20.0, 31.1)
30%
(24.4, 36.1)
35%
(29.3, 41.5)
For the PD-L1H subgroup, if the prevalence of PD-L1H is about 40%, there will be 
approximately 60 PD-L1H subjects if there are 150 all comer subjects in the confirmation set, 
and approximately 30 PD-L1H subjects if there are 75 all comer subjects in Cohort B.
Table 10 shows the two-sided 95% CI of ORR with 30 and 60 subjects for different response 
rates. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
86
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Table 10
Two-sided 95% Confidence Interval for ORR in PD-L1H
Sample Size
Observed ORR
95% CI of ORR (%)
30
25%
(12.2, 45.9)
30%
(14.7, 49.4)
35%
(17.3, 52.8)
40%
(22.7, 59.4)
60
25%
(14.7, 37.9)
30%
(18.9, 43.2)
35%
(23.1, 48.4)
40%
(27.6, 53.5)
The sample size for the training set (n=100), was selected to achieve adequate precision on 
the PPV and NPV profiles as a function of putative cut-offs. 
Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and/or plotted 
within each category of the following classification variables:

Age category (<65 and ≥65 years)

Race (Asian , non-Asian)

Platinum 
sensitivity 
(platinum-resistant 
recurrent,
partial 
platinum-sensitive 
recurrent)

ECOG Performance Status (0,1)

Histology (high-grade serous, endometroid, clear cell, and other)
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study agent infusions/injections; and 2) missing an infusion/injection. Numbers and 
percentages of subjects and infusion/injection visits with any deviation in these measures will 
be reported for the ASaT population.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
87
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 11
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional 
Information
Pembrolizumab 
50 mg/vial
Lyophilized powder for 
injection
Provided centrally by the 
Sponsor
Pembrolizumab 
25mg/mL
Solution for infusion
Provided centrally by the 
Sponsor
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
All supplies will be provided open label. Pembrolizumab will be provided as non-kitted 
single vials.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
88
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
89
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
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.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
90
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
91
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
92
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
93
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
94
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
11.0 LIST OF REFERENCES
1.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST Guidelines (Version 1.1). EJC 2009;45:228-247.
2.
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. 
Definitions for response and progression in ovarian cancer clinical trials incorporating 
RECIST 1.1 and CA125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J 
Gynecol Cancer, 2011;Feb;21(2):419-23.
3.
Siegel R., Ma J, Zou Z, and Jemal A. Cancer statistics, 2014. CA Cancer J Clin, 
2014;64(1): p. 9-29.
4.
Gilks CB, and Prat J. Ovarian carcinoma pathology and genetics: recent advances. 
Hum Pathol. 2009; Sep;40(9):1213-23.
5.
Prat J. FIGO Committee on Gynecologic Oncology. Staging classification for cancer of 
the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet. 2014 Jan;124(1):1-5.
6.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in 
Oncology: ovarain cancer including fallopian tube cancer and primary peritoneal 
cancer: version 3.2014. Fort Washington PA: National Comprehensive Cancer 
Network (NCCN), 2014.
7.
Ledermann, JA, et al. Newly diagnosed and relapsed epithelial ovarian carcinoma: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol, 
2013;Oct;24 (Suppl 6): vi24-32.
8.
duBois A, Russe A, Pujade Lauraine E, Harter P, Ray-Coquard I, and Pfisterer J. Role 
of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a 
combined exploratory analysis of 3 prospectively randomized phase 3 multicenter 
trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe 
Ovarialkarzinom (AGO-OVAR) and the Groupe d'Investigateurs Nationaux Pour les 
Etudes des Cancers de l'Ovaire (GINECO). Cancer. 2009 Mar 15;115(6): 1234-44.
9.
Friedlander M, et al. Clinical trials in recurrent ovarian cancer. Int J Gynecol Cancer. 
2011 May;21(4):771-5.
10.
Naumann RW, and Coleman RL. Management Strategies for recurrent platinum-
resistant ovarian cancer.  Aclis Data Information BV Drugs 2011;71(11):1397-1412.
11.
Coleman RL, Monk BJ, Sood AK, Herzog TJ. Latest research and treatment of 
advanced-stage epithelial ovarian cancer. Cat Rev Clin Oncol. 2013 Apr;10(4):211-
224.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
95
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
12.
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. 
Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian 
cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;May 
1;32(13):1302-8. Erratum in: J Clin Oncol. 2014 Dec 10;32(35):4025.
13.
Gabra H. Introduction to managing patients with recurrent ovarian cancer. EJC Suppl. 
2014 Dec;12(2):2-6.
14.
Kaye SB. Management of partially platinum-sensitive relapsed ovarian cancer. EJC 
Suppl. 2008;6:16-21.
15.
Pujade-Lauraine E, Paraiso D, Cure H, Germann N, Lortholary A, Luca V, et al. 
Predicting the effectiveness of chemotherapy (Cx) in patients with recurrent ovarian 
cancer (ROC): a GINECO study [abstract]. Abstracts of the 38th Annual Meeting of 
the American Society of Clinical Oncology; 2002 May 18-21;ASCO;2002:208a.
16.
Wagner U, Marth C, Largillier R, Kaern J, Brown C, Heywood M, et al. Final overall 
survival results of phase III GCIG CALYPSO trila of pegylated liposomal doxorubicin 
and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer 
patients. Br J  Cancer. 2012 Aug 7;107(4):588-91.
17.
Gladieff L, Ferrero A, De Rauglaudre G, Brown C, et al. Carboplatin and pegykated 
liposomal doorubicin versus carboplatin and paclitaxel and partially platinum-
sensitive ovarian cancer patients: results from a subset analysis of the CALYPSO phase 
III trial.  Ann Oncol 2012;23:1185-1189. 
18.
Hanker LC, Loibl S, Burchardi N, Pfisterer J, Meier W, Pujade-Lauraine E,et al. The 
impact of second to sixth line therapy on survival of relapsed ovarian cancer after 
primary taxane/platinum-based therapy. Ann Oncol. 2012;Oct;23(10):2605-12 .
19.
Finn, O.J. Molecular origins of cancer: cancer immunology. N Engl J Med. 2008;Jun 
19;358(250:2704-15). 
20.
Schreiber RD, Old LJ, and Smyth MJ. Cancer immunoediting: integrating immunity's 
roles in cancer suppression and promotion. Science, 2011 Mar 25;331(6024):1565-70.  
21.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural inate and adaptive 
immunity to cancer. Annu Rev Immunol. 2011;29:235-71. 
22.
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev 
Cancer, 2012;12:252-264. 
23.
Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition.  
Nat Rev Immunol. 2013 Apr;13(4):227-42. Erratum in: Nat Rev Immunol. 2013 
Jul;13(7):542. 
24.
Pedoeem, A., Azoulay-Alfaguter I, et al., Programmed death-1 pathway in cancer and 
autoimmunity. Clin Immunol, 2014;153(1):145-52. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
96
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
25.
Mellman I, Coukos G, and Dranoff G. Canceer immunotherapy comes of age. Nature 
2011;480:480-489. 
26.
Topalian SL, Drake CG, and Pardoll DM. Targeting the PD-1/B7-H1(PD-L1) pathway 
to activate anti-tumor immunity. Curr Opin Immunol 2012;24:207-212. 
27.
Postow, MA, Callahan MK, and Wolchok JD. Immune checkpoint blockade in cancer 
therapy. J Clin Oncol, 2015; 33:1-9. 
28.
U.S. Prescribing Information: KEYTRUDA (pembrolizumab) for injection, for 
intravenous use: 2014. 
29.
Hamid O, Robert C, DAud A, Hodi FS, HWU WJ, Kefford R, et al. SAfety and tumor 
responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. 2013 Jul 11; 
369(2):134-44
30.
Robert C, Ribas A, Walchak JD, et al. Anti-programmed-death-receptor-1 treatment 
with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised 
dose-comparison cohort of a phase 1 trial. Lancet, 2014. 384(9948): 1109-17. 
31.
Ribas A, Puzanov I, Dummer R, Schadendorf F, et al. Pembrolizumab versus 
investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-
002): A randomised, controlled, phase 2 trial. Lancet Oncol 2015: 16:908-18.  
32.
Robert C, Schacter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced 
melanoma. N Eng J Med. 2015 Apr 19: [Epub ahead of print]. 
33.
Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, et al. 
Pembrolizumab for the Treatment of Non-Small-Cell Lung Cancer. N Eng J Med. 2015 
Apr 19. [Epub ahead of print]. 
34.
Muro K, Bang Y, Shankaran V, Geva R, Catenacci DVT,  Gupta S, et al.  A phase 1b 
Study of pembrolizumab (pembro; mk-3475) in patients (pts) with advanced gastric 
cancer [abstract]. Ann Oncol. 2014;25( Suppl 5):v1-v41. Abstract no.LBA15V.
35.
Plimack ER, Bellmunt J, Gupta S, Berger R, Montgomery RB, Heath K, et al.  
Pembrolizumab (MK-3475) ) for advanced urothelial cancer: Updated results and 
biomarker analysis from KEYNOTE-012 [abstract]. Abstracts of the 2015 ASCO 
Annual Meeting; 2015 May 29 to June 2; Chicago, IL. American Society of Clinical 
Oncology(ASCO);2015. 
36.
Seiwert TY, Burtness B, Weiss J, Gluck I, Eder JP, Pai SI, et al.  Safety A phase Ib 
study of MK-3475 in patients with human papillomavirus (HPV)-associated and non-
HPV–associated head and neck (H/N) cancer. [abstract]. J Clin Oncol. 2014;32(15) 
Suppl 20:6011. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
97
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
37.
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. A phase 1b study of 
pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer.  
San Antonio Breast Cancer Symposium 2014; abstract S1-09.  
38.
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, et al.  
Safety Survival, durable tumor remission and long-term safety in patients with 
advanced melanoma receiving nivolumab. J Clin Oncol. 2014 Apr 1;32(10):1020-30. 
39.
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, and Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements.  Clin Cancer Res. 2013 
Jul 15;19(14):3936-43. 
40.
Zou W, and Chen L. Inhibitory B7-family molecules in the tumour microenvironment.
Nat Rev Immunology 2008;8:467-477. 
41.
Johnson DB, Rioth MJ, and Horn L.  Immune checkpoint inhibitors in NSCLC. Current 
Treatment Options in Oncology(2014) 15:658-669. 
42.
Gooden MJM, de Bock GH, Leffers N, et al. The prognostic influence of tumour-
infiltrating lymphocytes in cancer: a systematic review with meta-analysis. Br J Cancer, 
2011. 105(1): 93-103. 
43.
Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by 
inhibiting adaptive immune resistance. Nature 2014;515:145-152
44.
Balar Arjun V, Castellano David, et al. First-line pembrolizumab in cisplatin-ineligible 
patients with locally advanced and unresectable or metastatic urothelial cancer 
(KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncology (2017) 
The Lancet Web September 26, 2017; 1-9
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
98
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
12.0
APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
99
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
100
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.8 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
101
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
A template of each trial site’s approved informed consent will be stored in the
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
102
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
103
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
through appropriate mechanisms (e.g., scientific publications and/or presentations).
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For FBR, risks to the subject have been minimized. No additional risks to the subject 
have been identified as no additional specimens are being collected for FBR (i.e., only 
leftover samples are being retained). 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
104
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
105
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
106
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
107
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
108
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
109
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
110
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
111
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
112
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
113
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
114
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
115
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
116
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Common Terminology Criteria for Adverse Events
The descriptions and grading scales found in the revised NCI CTCAE v4.0 will be utilized 
for AE reporting. (http://ctep.cancer.gov/reporting/ctc.html).
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
117
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Abbreviations
Abbreviation/Term
Definition
AE
adverse event
ADA
anti-drug antibodies
ASaT
All Subjects as Treated
BICR
Blinded Independent Central Review
CA 125
cancer antigen 125
CD
carboplatin plus pegylated liposomal doxorubicin
CI
confidence interval
CP
carboplatin plus paclitaxel
CR
complete response
CSR
clinical study report
CT
computed tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLs
cytotoxic t lymphocytes cells
CTLA-4
cytotoxic t-lymphocyte-associated antigen-4
DCR
disease control rate
DOR
duration of response
ECG
electrocardiogram
ECI
events of clinical interest
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
eCRFs
electronic case report forms
EOC
epithelial ovarian cancer
ERC
Ethics Review Committee
FAS
Full Analysis Set
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FSH
follicle-stimulating hormone
GCIG
Gynecologic Cancer InterGroup
GCP
Good Clinical Practice
GEP
gene-expression profile
HGSC
high-grade serous carcinoma
HIV
human immunodeficiency virus
HR
hazard ratio
ICH
International Conference for Harmonization
IgG4
immunoglobulin g4
IHC
immunohistochemistry
IP
intraperitoneal
irAEs
immune-related adverse events
irRECIST
Immune-related Response Evaluation Criteria in Solid Tumors
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
KM
Kaplan-Meier
KN
KEYNOTE
LMP
last menstrual period
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
118
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
Abbreviation/Term
Definition
mAb
monoclonal antibody
MRI
magnetic resonance imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NCI
National Cancer Institute
NPV
negative predictive value
NSCLC
non-small cell lung cancer
ORR
overall response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based pharmacokinetic
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
program cell death-ligand protein 1
PD-L2
program cell death-ligand protein 2
PFI
platinum-free interval
PFS
progression-free survival
PK
pharmacokinetic
PLD
pegylated liposomal doxorubicin
PPV
positive predictive value
PR
partial response
Q2W
every 2 weeks
Q3W
every 3 weeks
Q9W
every 9 weeks
Q12W
every 12 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
ROC
recurrent ovarian cancer
SAC
Scientific Advisory Committee
SAE
serious adverse events
SD
stable disease
sSAP
supplemental Statistical Analysis Plan
TFI
treatment-free interval
TILs
tumor-infiltrating lymphocytes
TTR
time to recurrence
ULN
upper limit of normal
 
 
05DV3K
 
 
05HR4P
05HR4P

Product:  MK-3475 
119
Protocol/Amendment No.: 100-02 
MK-3475-100-02 Final Protocol
27-Jan-2020
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
05DV3K
 
 
05HR4P
05HR4P

MK-3475
PAGE 1
P100
Supplemental Statistical Analysis Plan (sSAP)
MK 3475-P100
Supplemental Statistical Analysis Plan (sSAP)
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 2
P100
Supplemental Statistical Analysis Plan (sSAP)
TABLE OF CONTENTS
TABLE OF CONTENTS......................................................................................2
1. INTRODUCTION ..........................................................................................3
2. SUMMARY OF CHANGES..........................................................................3
3. ANALYTICAL AND METHODOLOGICAL DETAILS.............................4
3.1 Statistical Analysis Plan Summary...........................................................4
3.2 Responsibility for Analyses/In-House Blinding.......................................5
3.3 Hypotheses/Estimation .............................................................................5
3.4 Analysis Endpoints ...................................................................................5
3.4.1
Efficacy Endpoints..............................................................................5
3.4.2
Safety Endpoints.................................................................................6
3.5 Analysis Populations.................................................................................6
3.5.1
Efficacy Analysis Populations ............................................................6
3.5.2
Safety Analysis Populations ...............................................................7
3.6 Statistical Methods....................................................................................7
3.6.1
Statistical Methods for Efficacy Analyses..........................................7
3.6.2
Statistical Methods for Safety Analyses ...........................................10
3.6.3
Demographic and Baseline Characteristics ......................................10
3.7 Interim Analysis......................................................................................10
3.8 Multiplicity .............................................................................................10
3.9 Sample Size and Power Calculations......................................................11
3.10
Subgroup Analyses and Effect of Baseline Factors..........................12
3.11
Extent of Exposure............................................................................12
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 3
P100
Supplemental Statistical Analysis Plan (sSAP)
1.
INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization.    
2.
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
3.1
Statistical Analysis Plan 
Summary
Population 
of 
primary 
efficacy analysis changed to
All 
Subjects 
as 
Treated 
(ASaT).
Per 
FDA 
requirement.
3.1
Statistical Analysis Plan 
Summary
Delete 95% CI for safety 
analysis.
For 
single 
arm 
study, 95% CI for 
AE incidence rate is 
not required.
3.4.1
Efficacy Endpoints
Reorganized.
To 
align 
with 
protocol section 3 
Objectives.
8.4.1
Efficacy Endpoints
Updated definition of PFS
Editorial update
3.6.1
Statistical Methods for 
Efficacy Analysis
Censoring rules for DOR and 
PFS added.
To provide more 
details 
about 
censoring rule.
3.6.1
Statistical Methods for 
Efficacy Analysis
Added information regarding 
data cutpoint
To 
provide 
maximum 
flexibility 
to 
perform additional 
data analysis
3.11
Compliance
Section deleted.
Per new alignment.
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 4
P100
Supplemental Statistical Analysis Plan (sSAP)
3.
ANALYTICAL AND METHODOLOGICAL DETAILS
3.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Sections 3.2-3.12.
Study Design Overview
A Phase II, open-label,  single arm, two-cohort, multi-center trial of 
pembrolizumab monotherapy in subjects with advanced ovarian cancer who 
have demonstrated recurrent disease following the front line treatment and 
received up to 5 lines of treatments for ROC. 
Treatment Assignment
Cohort A will enroll subjects with ROC who have received 0-2 prior lines for 
treating ROC (i.e., 1-3 total prior lines counting the front line) and with a 
platinum-free interval or treatment-free interval of 3 to 12 months based on 
the last regimen received.
Cohort B will enroll subject with ROC who have received 3 to 5 prior lines 
for treating ROC (i.e., 4-6 total prior lines counting the front line) and with a 
platinum-free interval or treatment-free interval ≥3 months based on the last 
regimen received.
In both cohorts, subjects will be treated with pembrolizumab monotherapy 200 
mg every 3 weeks (Q3W) as trial treatment by non-randomized assignment in 
an unblinded fashion.
Analysis Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
ORR by RECIST 1.1 per BICR review
Key Secondary Endpoints

DOR, DCR, PFS per RECIST 1.1 as assessed by BICR

OS
Statistical 
Methods 
for 
Key 
Efficacy Analyses
The primary objectives will be evaluated by the point estimate and 95% 
confidence interval for the ORR in the Cohort A-All Comer Population and 
Cohort A PD-L1H subgroup, respectively, using an exact binomial distribution. 
ORR will be evaluated similarly in the Cohort B-All Comer group and Cohort B
PD-L1H subgroup, respectively. 
Statistical Methods for Key Safety 
Analyses
Summary statistics for the incidence rate of Grade 2 or higher adverse events 
with an immune etiology and the incidence rate of Grade 4/5 AEs. 
Interim Analyses
An interim analysis is planned at 4 months after the first 100 subjects have been
enrolled in Cohort A, which will be used as the training set. IA will evaluate 
clinical activity and the correlation of PD-L1 in tumor tissue samples in the 
training set to facilitate the PD-L1 expression cutoff selection.  
Multiplicity
No multiplicity adjustment has been planned.
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 5
P100
Supplemental Statistical Analysis Plan (sSAP)
Sample Size and Power 
Cohort A-All Comer group include all enrolled subjects of Cohort A. A 
minimum of 75 subjects will be enrolled for the subgroup with a PFI/TFI of 3-
<6 months and a minimum of 75 subjects will be enrolled for the subgroup with 
a PFI/TFI of 6 to 12 months. The first 100 enrolled Cohort A subjects will be 
used as the training set for determining a PD-L1 expression cut point. The 
additional 150 enrolled Cohort A subjects will be in the confirmation set, 
therefore, the study will enroll approximately 250 Cohort A subjects regardless 
of the PD-L1 status. The exact number of subjects enrolled in the confirmation 
set will depend on the prevalence of the PD-L1H as determined by the biomarker
analysis. Approximately 75 subjects will be enrolled in Cohort B.
3.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
clinical biostatistics department of the SPONSOR. This trial is being conducted as an open-label 
non-randomized single-arm clinical trial, i.e., subjects, investigators, and SPONSOR personnel 
will be aware of subject treatment assignments after each subject is enrolled and treatment is 
assigned. The study team at the Sponsor consisting of clinical, statistical, statistical programming 
and data management personnel, will be blinded to subject-level PD-L1 biomarker results. An 
unblinded Sponsor biomarker statistician will have access to the subject-level PD-L1 results for 
the purpose of data review and biomarker correlation analysis. The unblinded SPONSOR 
biomarker statistician will have no other responsibilities associated with the study. 
3.3
Hypotheses/Estimation
Objectives of the study are stated in Section 3.0 of the protocol.
3.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
3.4.1
Efficacy Endpoints
Primary 

Objective response rate (ORR) - per RECIST 1.1 assessed by BICR
Objective Response Rate (ORR), defined as the proportion of subjects in the analysis population 
who have confirmed complete response (CR) or partial response (PR) at any time during the 
study.
Secondary 

Duration of Response (DOR) - per RECIST 1.1 assessed by BICR and by 
investigator
Duration of response (DOR), defined as the time from first documented evidence of response to 
disease progression in subjects who achieve a confirmed PR or CR.
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 6
P100
Supplemental Statistical Analysis Plan (sSAP)

Progression-free Survival (PFS) - per RECIST 1.1 assessed by BICR and by 
investigator
Progression-free survival (PFS), 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.  

Overall survival (OS)
Overall survival (OS), defined as the time from the first day of study treatment to death due to 
any cause.

Disease Control Rate (DCR) - per RECIST 1.1 assessed by BICR
Disease Control Rate (DCR), defined as the percentage of subjects who have achieved confirmed 
CR or PR or have demonstrated SD for at least 24 weeks prior to any evidence of progression.
Exploratory

Progression-free survival (PFS) – irRECIST assessed by BICR
Progression-free-survival (PFS) is defined as the time from first day of study treatment to the 
first confirmed disease progression or death due to any cause, whichever occurs first.  
ORR and DOR per irRECIST by BICR are also the exploratory efficacy endpoints.
3.4.2
Safety Endpoints
Safety measurements are as described in Section 4.2.3.2 of the protocol.
The primary safety endpoints are AEs graded using CTCAE (Version 4.0 or above) criteria. 
Safety will be assessed by quantifying the toxicities and grades experienced by subjects who 
have received pembrolizumab, including serious adverse events (SAEs) and events of clinical 
interest (ECIs). Other safety endpoints include laboratory safety assessments, vital signs, reasons 
for treatment discontinuation, dose interruptions or reductions, and physical examinations.
3.5
Analysis Populations
3.5.1
Efficacy Analysis Populations
Cohort A
The all subjects as treated (ASaT) in Cohort A who receive at least one dose of study treatment, 
will serve as the primary population for the analyses of efficacy data for Cohort A All Comers. 
The all subjects as treated (ASaT) population for PD-L1H subgroup in Cohort A, which includes 
the subjects in the confirmation set above the PD-L1 cut-off, will be used for the analyses of 
efficacy data for PD-L1H subjects in Cohort A
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 7
P100
Supplemental Statistical Analysis Plan (sSAP)
Cohort B
The all subjects as treated (ASaT) population consists of all subjects in Cohort B who receive at 
least one dose of study treatment. The all subjects as treated (ASaT) population for PD-L1H
subgroup in Cohort B, which includes the subjects in Cohort B above the PD-L1 cut-off, will be 
used for the analyses of efficacy data for PD-L1H subjects in Cohort B.
3.5.2
Safety Analysis Populations
The all subjects as treated (ASaT) population will be used for the analysis of safety data. At least 
one laboratory or vital sign measurement obtained subsequent to at least one dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess change 
from baseline, a baseline measurement is also required. 
3.6
Statistical Methods
3.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary objectives.  
Data from the training set (first 100 subjects in Cohort A) will be evaluated for biomarker 
analysis and cut point determination. Subjects who did not meet Treatment-free 
Interval/Platinum-free Interval inclusion criteria for Cohort A would be excluded from the cut 
point determination analysis.
Efficacy will be evaluated in the All Comer group and the PD-L1H subgroup for Cohort A and B 
respectively.  For the primary efficacy endpoint, the ORR based on RECIST 1.1 by the BICR, 
the point estimate, and 95% confidence interval (as determined by the upper and lower 97.5% 
one-sided confidence bounds) will be provided using an exact binomial distribution. Secondary 
efficacy evaluations of ORR based on RECIST 1.1 by investigator review, DCR based on 
RECIST 1.1 by the BICR and ORR based on irRECIST by BICR will also be conducted using 
the same methodology as for the primary efficacy analysis. Subjects without response data will 
be counted as non-responders and disease not controlled.
Duration of response by BICR and investigator review will be summarized using Kaplan-Meier 
method in all responders. 
For PFS and OS, Kaplan-Meier (KM) curves, median estimates, and survival at 6, 12 and 18 
months based on the KM curves (95% CI is based on Greenwood's formula) will be provided as 
appropriate. Subjects without efficacy evaluation data or without survival data will be censored 
at Day 1. The restricted Mean Survival Time estimate of PFS and OS will also be calculated and 
plotted over time. Censoring rules for DOR and PFS are summarized in Table 1 and Table 2
respectively.
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 8
P100
Supplemental Statistical Analysis Plan (sSAP)
Table 1 Censoring Rules for Analyses of DOR
Situation
Date of progression or censoring
Outcome
No progression nor death, no new anti-cancer 
therapy initiated
Last adequate assessment
Censor 
(non-event)
No progression nor death, new anti-cancer 
therapy initiated
Last adequate assessment before new 
anti-cancer therapy initiated
Censor 
(non-event)
Death or progression after ≥ 2 
consecutive missed adequate disease 
assessments
Last adequate assessment prior to ≥ 
2 missed adequate disease assessments
Censor 
(non-event)
Death or  progression after ≤1 missed 
adequate disease assessments
Death or progression
End of response 
(Event)
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response. 
Table 2 Censoring Rules for Analyses of PFS
Situation
Date of progression or censoring
No PD and no death; new anticancer treatment is not initiated
Censored at last disease assessment
No PD and no death; new anticancer treatment is initiated
Censored at last disease assessment before 
new anticancer treatment
PD or death documented after ≤ 1 missed disease assessment
Progressed at date of documented PD or 
death
PD or death documented after ≥ 2 missed disease assessments
Progressed at date of documented PD or 
death
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 9
P100
Supplemental Statistical Analysis Plan (sSAP)
An outline of the key efficacy analysis strategy is presented in Table 3.
Table 3  Analysis Strategy for Key Efficacy Endpoints
Endpoint
Statistical Method
Analysis 
Population
Missing 
Data 
Approach

ORR 
by 
BICR
per 
RECIST1.1 

ORR 
by 
investigator 
assessment 
per 
RECIST1.1
Exact test of binomial 
parameter; 95% CI†
ASaT
Subjects with missing
data are considered
non-responders

DOR
by 
BICR
per 
RECIST1.1 

DOR 
by 
investigator 
assessment
per 
RECIST1.1 
Summary statistics using
Kaplan-Meier method 
All 
responders
Refer to Table 1

PFS 
by 
BICR
and 
investigator assessment 
per RECIST 1.1
Summary statistics using
Kaplan-Meier method
ASaT
Refer to Table 2

DCR 
by 
BICR
and 
investigator assessment 
per RECIST 1.1
Exact test of binomial
parameter; 95% CI†
ASaT
Subjects with missing
data are considered
disease not controlled 

OS
Summary statistics using 
Kaplan-Meier method
ASaT
Censored 
at 
last 
known alive date
†95% confidence interval is determined by the upper and lower 97.5% one-sided confidence 
bounds.
The strategy to address multiplicity issues with regard to multiple endpoints and interim analyses 
is described in Section 3.7, Interim Analyses and in Section 3.8, Multiplicity.
The evaluation of a general positive association between CPS and BOR will be investigated via 
standard logistic regression as well as generalized additive models. The potential for a cut -off 
greater than CPS 1% to define a PD-L1 positive population with good clinical utility will depend 
on the strength of evidence in the observed association, as well as a detailed evaluation of the 
relative improvement in clinical utility with higher cut-offs. This evaluation involves a review of 
the positive predictive value (PPV, response rate in those above a cut-off), sensitivity (proportion 
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 10
P100
Supplemental Statistical Analysis Plan (sSAP)
above the cutoff among responders), negative predictive value (NPV, non-response rate in those 
below the cut-off), specificity (proportion below the cutoff among non-responders), and fraction 
of PD-L1 positive patients (prevalence) as functions of increasing cut-offs.  A clinically useful 
PD-L1 positive cut-off should maintain high NPV (e.g. near or above 90%) while achieving a 
meaningful enrichment of response, and largely capturing patients showing durable clinical 
benefit is sought. A receiver operating characteristic curve, and graphical illustrations will be 
utilized to assess the performance of a binary classifier and to understand the sensitivity and 
specificity profile in the context of PPV and NPV. Analyses will also be performed on PFS and 
OS, as appropriate, examining associations using cox proportional hazards models and KM 
estimates with graphical illustrations.  CPS ranges for any promising cut-offs will also have to be 
gauged in the context of practical implementation and interpretation by pathologists in clinical 
practice.
The associations between clinical response and other biomarkers, e.g., immune-related mRNA 
expression signatures and somatic mutational load, will be evaluated similarly.
3.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Summary statistics (counts, 
percentage, mean, standard deviation, etc.) will be provided for the safety endpoints as 
appropriate.
3.6.3
Demographic and Baseline Characteristics
Baseline characteristics will be assessed by the use of tables and/or graphs. No statistical 
hypothesis tests will be performed on these characteristics. The number and percentage of 
subjects screened, enrolled, primary reasons for screening failure, and 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.  The All Comer group and the PD-L1H subgroup will 
be summarized separately for Cohort A and Cohort B.
3.7
Interim Analysis
An interim analysis will be performed after 100 subjects in Cohort A have been enrolled and 
followed up for at least 4 months to determine a PD-L1 expression cutpoint based on PD-L1 
biomarker and tumor response data. The results of this analysis will be presented to the study 
team without unblinding anyone to biomarker results for any individuals. The efficacy data from 
the interim analysis may facilitate further interactions with regulatory agencies.
3.8
Multiplicity
The primary objectives for ORR per RECIST 1.1 in All Comer Population and PD-L1H subgroup 
for Cohort A and Cohort B will be assessed by point estimate and 95% confidence interval. 
There are no formal hypotheses and no adjustments for multiplicity are planned. Evaluation of 
objectives should be interpreted with caution due to the potential for an increase in the false 
positive rate.
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 11
P100
Supplemental Statistical Analysis Plan (sSAP)
3.9
Sample Size and Power Calculations
Based on the preliminary data of pembrolizumab in ovarian cancer patients as described in 
Section 4.1.2 of the protocol, we expect an ORR of approximately 25% for the All Comer
population. These responding subjects expect to have durable responses. In addition we expect 
additional subjects will have durable stable disease. We expect in a PD-L1 enriched population, 
ORR may reach to above 35% with durable response in majority of the subjects. 
Table 4 shows the two-sided 95% confidence interval of ORR for different observed response 
rates based on different sample size in the All Comer group for Cohort A or Cohort B.
Table 4 Two-sided 95% Confidence Interval of ORR in All Comer  
Sample Size
Observed ORR
95% CI of ORR (%)
75
17%
(9.3, 27.4)
25%
(15.7, 36.3)
30%
(20.0, 41.7)
35%
(24.3, 46.9)
100
17%
(10.2, 25.8)
25%
(16.9, 34.7)
30%
(21.2, 40.0)
35%
(25.7, 45.2)
180
17%
(12.0, 23.5)
25%
(18.9, 32.0)
30%
(23.4, 37.3)
35%
(28.1, 42.4)
250
17%
(12.7, 22.5)
25%
(20.0, 31.1)
30%
(24.4, 36.1)
35%
(29.3, 41.5)
 
 
04X3P2
 
 
05JFXD
05JFXD

MK-3475
PAGE 12
P100
Supplemental Statistical Analysis Plan (sSAP)
For the PD-L1H subgroup, if the prevalence of PD-L1H is about 40%, there will be approximately 
60 PD-L1H subjects if there are 150 all comer subjects in the confirmation set, and approximately 
30 PD-L1H subjects if there are 75 all comer subjects in Cohort B. Table 5 shows the two-sided 
95% CI of ORR with 30 and 60 subjects for different response rates. 
The sample size for the training set (n=100), was selected to achieve adequate precision on the 
PPV and NPV profiles as a function of putative cut-offs. 
Table 5  Two-sided 95% Confidence Interval for ORR in PD-L1H
Sample Size
Observed ORR
95% CI of ORR (%)
30
25%
(12.2, 45.9)
30%
(14.7, 49.4)
35%
(17.3, 52.8)
40%
(22.7, 59.4)
60
25%
(14.7, 37.9)
30%
(18.9, 43.2)
35%
(23.1, 48.4)
40%
(27.6, 53.5)
3.10
Subgroup Analyses and Effect of Baseline Factors
The estimate of the treatment effect for the primary endpoint will be estimated and/or plotted 
within each category of the following classification variables: 

Age category (<65 , ≥65 years)

Race (Asian , non-Asian)

Platinum sensitivity (platinum resistant recurrent, partial platinum sensitive recurrent)

ECOG Performance Status (0,1)

Histology (high-grade serous, mucinous, endometroid, clear cell, and other)
3.11
Extent of Exposure
The extent of exposure will be summarized as number of cycles in which the subject receives the 
study medication infusion. 
 
 
04X3P2
 
 
05JFXD
05JFXD