Phase II Trial of Pembrolizumab (MK-3475) in Subjects With Metastatic Castration-Resistant Prostate Cancer (mCRPC) (KEYNOTE-199)
Phase: PHASE2
Conditions: Metastatic Castration-resistant Prostate Cancer
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
Phase II Trial of Pembrolizumab (MK-3475) in Subjects with 
Metastatic Castration-Resistant Prostate Cancer (mCRPC) 
(KEYNOTE-199)
12-Aug-2021
NCT02787005

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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:
Phase II Trial of Pembrolizumab (MK-3475) in Subjects with Metastatic Castration-Resistant 
Prostate Cancer (mCRPC) (KEYNOTE-199) 
IND NUMBER:  122753
EudraCT NUMBER:  2015-003644-40
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 10
SUMMARY OF CHANGES................................................................................................ 11
1.0
TRIAL SUMMARY.................................................................................................. 13
2.0
TRIAL DESIGN........................................................................................................ 14
Trial Design ........................................................................................................... 14
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es).............................................................. 17
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Rationale................................................................................................................ 20
4.2.3.1.1
Immune-related RECIST (irRECIST) .................................................. 23
4.2.3.2.1
eEuroQoL-5D (eEQ-5D) ...................................................................... 24
4.2.3.2.2
The Functional Assessment of Cancer Therapy-Prostate (FACT-P).... 24
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Benefit/Risk ........................................................................................................... 27
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
Trial Treatment(s) ................................................................................................ 33
5.2.1.2.1
Pembrolizumab ..................................................................................... 34
Randomization or Treatment Allocation............................................................ 40
Stratification.......................................................................................................... 40
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 40
Rescue Medications & Supportive Care............................................................. 42
Diet/Activity/Other Considerations..................................................................... 43
Subject Withdrawal/Discontinuation Criteria................................................... 43
Subject Replacement Strategy............................................................................. 44
Beginning and End of the Trial ........................................................................... 44
Clinical Criteria for Early Trial Termination ................................................... 44
6.0
TRIAL FLOW CHART ........................................................................................... 45
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Study Flow Chart.................................................................................................. 45
Second Course Phase (Retreatment ONLY) ...................................................... 50
7.0
TRIAL PROCEDURES ........................................................................................... 53
Trial Procedures ................................................................................................... 53
7.1.1.1.1
General Informed Consent.................................................................... 53
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 54
7.1.1.4.1
History of Prostate Cancer.................................................................... 54
7.1.1.5.1
Prior Medications.................................................................................. 54
7.1.1.5.2
Prior Treatment for Prostate Cancer ..................................................... 55
7.1.1.5.3
Concomitant Medications..................................................................... 55
7.1.1.5.4
Subsequent Anti-Cancer Therapy Status .............................................. 55
7.1.2.2.1
Full Physical Exam ............................................................................... 56
7.1.2.2.2
Directed Physical Exam........................................................................ 56
7.1.2.6.1
Initial Tumor Imaging........................................................................... 57
7.1.2.6.2
Tumor Imaging During Trial ................................................................ 58
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7.1.2.6.3
End of Treatment and Follow-up Tumor Imaging................................ 60
7.1.2.6.4
Second Course (Retreatment) Tumor Imaging..................................... 61
7.1.2.6.5
Treatment Beyond Progression............................................................. 61
7.1.3.2.1
Blood Collection for Serum MK-3475 ................................................. 66
7.1.3.2.2
Blood Collection for Anti-pembrolizumab Antibodies ........................ 67
7.1.3.2.3
Blood Collection for RNA Analyses/Plasma and Serum Biomarker 
Analyses................................................................................................ 67
7.1.3.2.4
Blood Collection for CTC..................................................................... 67
7.1.3.2.5
Blood Collection for ctDNA................................................................. 67
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 68
7.1.5.2.1
Second Course Phase (Retreatment Period) ......................................... 70
7.1.5.3.1
Survival Follow-up ............................................................................... 71
Assessing and Recording Adverse Events .......................................................... 71
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8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 78
Statistical Analysis Plan Summary ..................................................................... 78
Responsibility for Analyses/In-House Blinding ................................................. 79
Hypotheses/Estimation......................................................................................... 80
Analysis Endpoints ............................................................................................... 80
Analysis Populations............................................................................................. 82
Statistical Methods................................................................................................ 83
Interim Analysis.................................................................................................... 87
Multiplicity ............................................................................................................ 87
Sample Size and Power Calculations .................................................................. 88
Subgroup Analyses and Effect of Baseline Factors ........................................... 89
Extent of Exposure................................................................................................ 89
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 89
Investigational Product ........................................................................................ 89
Packaging and Labeling Information ................................................................. 90
Clinical Supplies Disclosure................................................................................. 90
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Storage and Handling Requirements.................................................................. 90
Discard/Destruction/Returns and Reconciliation .............................................. 91
Standard Policies................................................................................................... 91
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 91
Confidentiality....................................................................................................... 91
Compliance with Financial Disclosure Requirements....................................... 92
Compliance with Law, Audit and Debarment ................................................... 93
Compliance with Trial Registration and Results Posting Requirements........ 95
Quality Management System............................................................................... 95
Data Management................................................................................................. 95
Publications ........................................................................................................... 95
11.0
LIST OF REFERENCES......................................................................................... 97
12.0
APPENDICES......................................................................................................... 101
Merck Code of Conduct for Clinical Trials...................................................... 101
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 103
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 107
List of Abbreviations .......................................................................................... 118
ECOG Performance Status................................................................................ 121
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 .. 122
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors .............................................................. 123
Contraceptive Guidance..................................................................................... 124
13.0
SIGNATURES......................................................................................................... 125
Sponsor's Representative ................................................................................... 125
Investigator.......................................................................................................... 125
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LIST OF TABLES
    
Table 1
Adequate Organ Function Laboratory Values........................................................ 31
Table 2
Trial Treatment ....................................................................................................... 34
Table 3
Dose Modification and Treatment Discontinuation Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab...................................... 35
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 38
Table 5
Imaging and Treatment after 1st Radiologic Evidence of PD................................ 60
Table 6
Laboratory Tests ..................................................................................................... 65
Table 7
Evaluating Adverse Events..................................................................................... 76
Table 8
Censoring Rules for DOR....................................................................................... 84
Table 9
Analysis Strategy for Key Efficacy Variables........................................................ 84
Table 10 Confidence Intervals for Different Observed Response Rates and Sample Size ... 88
Table 11 Product Description ................................................................................................ 90
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LIST OF FIGURES
Figure 1 Clinical Trial Design and Enrollment Plan............................................................. 17
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Original Protocol
30-MAR-2016
Amendment 01
30-AUG-2016
Updated Exclusion criteria for pneumonitis
Amendment 02
23-FEB-2017
Increase enrollment for Cohorts 1 & 2
Amendment 03
07-JUN-2017
Added Cohorts 4 & 5
Amendment 04
20-JUL-2017
Removed PK/PD blood collection and testing
Amendment 05
08-DEC-2017
Changed Exploratory Objectives, updated dose modification guidelines and 
SFU language
Amendment 06
28-OCT-2019
Added liquid formulation to product description
Amendment 07
12-AUG-2021
Added language to state that upon trial completion, subjects are discontinued 
and may be enrolled in a pembrolizumab extension study, if available.
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.10
Beginning and End of the Trial
Added language to state that 
upon trial completion, subjects 
are discontinued and may be 
enrolled in a pembrolizumab 
extension study, if available.
Subjects may be enrolled in a 
pembrolizumab extension 
study.
7.1.1.7
Assignment of 
Treatment/Randomization 
Number
Added text to state that at the 
end of the study and upon 
enrollment in an extension 
study, the participant will 
receive a new 
treatment/randomization 
number.
Subjects may be rerandomized 
into a pembrolizumab 
extension study.
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.1.2
Subject Inclusion Criteria
Contraceptive language was 
updated
Revision to align with current 
requirements 
5.1.3
Subject Exclusion Criteria
Added language regarding 
COVID-19 vaccines
Addition to clarify that any 
licensed COVID-19 vaccine 
(including for Emergency Use) 
in a particular country is 
allowed in the study as long as 
they are mRNA vaccines, 
adenoviral vaccines, or 
inactivated vaccines. 
Investigational vaccines 
(ie, those not licensed or 
approved for Emergency Use) 
are not allowed
5.5.2
Prohibited Concomitant 
Medications
5.7.2
Contraception
Section removed
Revision to remove redundancy
12.8
Contraceptive Guidance
Added new section
Addition to include the 
definition of WOCBP
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase II Trial of MK-3475 in Subjects with mCRPC 
Sponsor Product Identifiers
MK-3475
Pembrolizumab
Trial Phase
Phase II
Clinical Indication
Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)
Number of trial subjects
Approximately 370 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
36 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final protocol-specified 
contact.  
After a screening phase of up to 42 days, eligible subjects will be 
enrolled into one of 5 cohorts based on treatment history, programmed 
cell death-ligand 1 (PD-L1) status (for only Cohorts 1 and 2), and 
RECIST 1.1 measurability. Subjects with mCRPC previously treated 
with docetaxel-based chemotherapy in cohorts 1 to 3 will receive 
monotherapy with pembrolizumab. Chemotherapy-naïve subjects with 
mCRPC either having failed or showing early signs of failing on
enzalutamide treatment as defined by PCWG3 guidelines (eg, signs of 
clinical progression, increased alkaline phosphatase, prostate-specific 
antigen [PSA] increase, or positive imaging assessments) in Cohorts 4 
and 5 will receive pembrolizumab monotherapy with their current, 
stable standard of care regimen of enzalutamide. 
In all cohorts, pembrolizumab administration will occur on Day 1 of 
each 3-week dosing cycle and will continue for a maximum of 35 cycles 
(approximately 2 years) unless specific withdrawal/discontinuation 
criteria are met.
Treatment with pembrolizumab in all cohorts will continue until 
documented confirmed disease progression, unacceptable adverse events 
(AEs), intercurrent illness that prevents further administration of 
treatment, Investigator’s decision to discontinue the subject, subject 
discontinuation from the study, noncompliance with trial treatment or 
procedure 
requirements, 
subject 
receives 
35 administrations 
of 
pembrolizumab (approximately 2 years), or administrative reasons 
requiring the cessation of treatment.
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Subjects who discontinue after 35 infusions of pembrolizumab for 
reasons other than disease progression or intolerability, or who 
discontinue after attaining a complete response (and had at least 
8 administrations of pembrolizumab and at least 2 treatments beyond 
initial CR)
may be eligible for up to 17 additional infusions 
(approximately one year) after they have experienced radiographic 
disease progression.
After the end of treatment, each subject will be followed for the 
occurrence of adverse events as described under section 7.2 of the 
protocol.  Subjects who discontinue for reasons other than disease 
progression will have post-treatment follow-up for disease status until 
disease progression is confirmed by the site, initiating a non-study 
cancer treatment, withdrawing consent, or becoming lost to follow-up. 
All subjects will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study.
A list of abbreviations used in this document can be found in Section 12.4.
2.0 TRIAL DESIGN
Trial Design
This is a nonrandomized, multinational, open-label trial of pembrolizumab (MK-3475) in 
subjects with metastatic castration-resistant prostate cancer (mCRPC). The trial will be 
conducted in conformance with Good Clinical Practices.  
Approximately 370 subjects will be enrolled into one of 5 cohorts based on treatment history, 
programmed cell death-ligand 1 (PD-L1) status for Cohorts 1 and 2 only, and Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 measurability. 
PD-L1 status and 
RECIST 1.1 measurability (subjects with visceral disease) will be centrally confirmed for all 
cohorts.  All enrolled subjects will receive pembrolizumab 200 mg every 3 weeks (Q3W).  
For subjects with mCRPC previously treated with docetaxel-based chemotherapy, the 
enrollment cohorts will be: 
(Cohort 1) subjects with PD-L1 positive, RECIST 1.1-measurable disease 
(Cohort 2) subjects with PD-L1 negative, RECIST 1.1-measurable disease 
(Combined Cohorts 1 and 2, n≈200)
(Cohort 3) subjects with bone-metastases, RECIST 1.1 non-measurable (n≈50)
For chemotherapy-naïve subjects with mCRPC either having failed or showing early signs of 
failing on enzalutamide treatment as defined by PCWG3 guidelines (eg, signs of clinical 
progression, increased alkaline phosphatase, prostate-specific antigen [PSA] increase, or
positive imaging assessments) the enrollment cohorts will be:
(Cohort 4) subjects with RECIST 1.1-measurable disease (n≈80).
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(Cohort 5) subjects with bone metastases only or bone-predominant disease, 
RECIST 1.1 non-measurable (n≈40).
Subjects in Cohorts 4 and 5 will receive pembrolizumab monotherapy with their current, 
stable standard of care (SOC) regimen of enzalutamide.  Note:  subjects in Cohorts 4 and 5
may have received abiraterone prior to enzalutamide.
Bone metastases must be radiographically evident by whole body bone scintigraphy.
Participation in this trial will be dependent upon subjects supplying tumor tissue for PD-L1 
biomarker analysis from a site not previously irradiated (tumors progressing in a prior site of 
radiation are allowed for PD-L1 characterization; other exceptions may be considered after 
Sponsor consultation).
Adequacy of these specimens for PD-L1 biomarker analysis will be 
required by a central laboratory prior to enrollment for Cohorts 1 to 3.  Subjects with 
visceral/measurable lesions must provide a newly obtained biopsy or a specimen obtained 
≤12 months prior to the screening date, and an archival specimen, if available.  Candidates 
for enrollment in Cohorts 1, 2, or 4 who undergo a study-related biopsy but the tissue sample 
is determined to be inadequate will be allowed into the study if they have provided an 
adequate archival specimen.  Subjects in Cohort 3 or 5 must at least provide an archival 
specimen. Please refer to Section 7.1.2.7 for tissue sample collection requirements by cohort.
Cohorts 1 and 2 will begin enrolling irrespective of PD-L1 expression status; however, 
PD-L1 expression status will be monitored.  Combined enrollment in Cohorts 1 and 2 will be 
approximately 200 subjects and approximately 60 subjects in cohort 3. Subjects will be 
enrolled into Cohorts 3, 4, and 5 irrespective of PD-L1 status.
All subjects will undergo radiologic imaging assessments to evaluate response to treatment at 
regular intervals. On study imaging will be assessed approximately every 9 weeks for one 
year and approximately every 12 weeks thereafter.
RECIST 1.1 will be adapted per the 
consensus guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) as 
described in Section 7.1.2.6 to account for the tumor response and progression patterns seen 
in bone metastases in prostate cancer.
Adverse events (AEs) will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 (See Appendix 12.6). Treatment with 
pembrolizumab will continue until documented confirmed disease progression, unacceptable 
AEs, intercurrent illness that prevents further administration of treatment, Investigator’s 
decision to discontinue the subject, subject discontinuation from the study, noncompliance
with trial treatment or procedure requirements, subject receives 35 administrations of
pembrolizumab (approximately 2 years), or administrative reasons requiring the cessation of 
treatment. 
Subjects who attain an Investigator-determined confirmed complete response (CR) may 
receive up to 35 infusions of pembrolizumab.  Subjects who discontinue after 35 infusions 
for reasons other than disease progression or intolerability, or who discontinue after attaining 
a CR (and had at least 8 administrations of pembrolizumab and at least 2 treatments beyond 
initial CR) may be eligible for up to 17 additional infusions (approximately 1 year) of 
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pembrolizumab after they have experienced radiographic disease progression. The decision 
to retreat will be at the discretion of the Investigator only if no cancer treatment was 
administered since the last dose of pembrolizumab, the subject still meets the safety 
parameters listed in the Inclusion/Exclusion criteria, and the trial remains open (refer to 
Section 7.1.5.2. for further details). 
After the end of treatment, each subject will be followed for 30 days for AE monitoring 
(serious AEs [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 anticancer therapy, whichever is earlier). 
Subjects who discontinue treatment for reasons other than disease progression will stay on 
study and continue to undergo study-related disease assessments until disease progression, 
initiation of a non-study cancer treatment, withdrawal of consent, or becoming lost to follow-
up. All subjects will be followed by telephone contact for overall survival (OS) until death, 
withdrawal of consent or the end of the study, whichever comes first.
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.
Trial Diagram
Subjects with mCRPC with prior docetaxel and targeted endocrine therapy will concurrently
enroll in Cohorts 1, 2, and 3. Chemotherapy-naïve subjects with mCRPC either having failed 
or showing early signs of failing on enzalutamide treatment will enroll in Cohorts 4 and 5.
The trial design is depicted in Figure 1.
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Figure 1
Clinical Trial Design and Enrollment Plan
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
This study has been designed to further evaluate the signal of activity observed in 
KEYNOTE-028 (KN028) with pembrolizumab monotherapy (see Section 4.1.3) in male 
subjects at least 18 years of age with mCRPC. Objectives will be assessed by enrollment 
cohort unless otherwise specified. There will be no hypothesis testing performed in this 
study.
Primary Objective(s) & Hypothesis(es)
1) Objective: To estimate the objective response rate (ORR) by RECIST 1.1 in subjects 
with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 
combined, Cohort 1, Cohort 2, and Cohort 4.
Secondary Objective(s) & Hypothesis(es)
1) Objective: To determine the safety and tolerability of pembrolizumab for all cohorts
combined (Cohorts 1, 2, 3, 4, and 5) and by each cohort.
2) Objective: To estimate disease control rate (DCR) and radiographic progression-free 
survival (rPFS) by PCWG3-modified RECIST 1.1 assessed by central imaging 
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vendor and PSA response rate, time to PSA progression, and OS for Cohorts 1 and 2 
combined, Cohorts 1, 2, and 3 combined, Cohorts 4 and 5 combined, and by each 
cohort.
3) Objective: To estimate the duration of response (DOR) by PCWG3-modified 
RECIST 1.1 in subjects with measurable disease assessed by central imaging vendor
in Cohorts 1 and 2 combined, Cohort 1, Cohort 2, and Cohort 4.
4) Objective: To estimate the duration of response (DOR) by RECIST 1.1 in subjects 
with measurable disease assessed by central imaging vendor in Cohorts 1 and 2 
combined, Cohort 1, Cohort 2, and Cohort 4.
5) Objective: To estimate duration of PSA response, time to initiation of cytotoxic 
chemotherapy, time to new-anticancer therapy, and time to first skeletal-related event
in Cohorts 4 and 5.
Exploratory Objectives 
1) Objective: To evaluate pharmacokinetic (PK) parameters and the presence of anti-
drug antibodies (ADAs).
2) Objective: To evaluate changes in health-related quality of life assessment from 
baseline using FACT-P and to characterize utilities using EuroQoL-5D.
3) Objective: To identify molecular (including genomic, metabolic, and/or proteomic)
biomarkers that may be indicative
of clinical response/resistance, safety, 
pharmacodynamic activity and/or the mechanism of action of pembrolizumab and 
other treatments.
4) Objective: To evaluate ORR by immune-related RECIST 1.1 (irRECIST), and DCR
by PCWG3-modified irRECIST assessed by central imaging vendor.
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (previously known as MK-3475 and SCH 9000475) is a potent and highly 
selective humanized monoclonal antibody (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between the programmed cell death-1 (PD-1) receptor and its 
ligands, PD-L1 and PD-L2, without antibody-dependent cell-mediated cytotoxicity (ADCC) 
or complement-dependent cytotoxicity (CDC) activity.  Pembrolizumab is approved in the 
US for the treatment of patients with unresectable or metastatic melanoma (MEL) and 
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disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2, 3, 4, 5, 6, 7, 8, 9, 10, 11].  In particular, the presence of CD8+ 
T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells seems to correlate 
with improved prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[12, 13, 14, 15].  The structure of murine PD-1 has been resolved [16].  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM), and an 
immunoreceptor tyrosine based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ, and ZAP70 which are involved in the CD3 T-cell signaling cascade [13, 17, 18, 19, 
20].  The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins [17, 21].  PD-1 was shown to be expressed on activated lymphocytes including 
peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [22, 23].  
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T-cells as well as subsets of macrophages and dendritic cells [22, 24].  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors [13, 15, 17].  Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues [13, 15, 17].  Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-
specific T-cell expansion in subjects with MEL [25].  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention.
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Pre-clinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated antitumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
MEL, and colorectal carcinoma.  Blockade of the PD-1 pathway effectively promoted CD8+ 
T-cell infiltration into the tumor and the presence of interferon-γ (IFN-, granzyme B, and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [15, 18, 26, 27, 28].  Experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a monotherapy as well as in combination with chemotherapy in 
syngeneic mouse tumor models (refer to the IB).
In a Phase 1/2 study of 135 subjects with advanced MEL, treatment with pembrolizumab 
produced an ORR of 38% (95% CI, 25% to 44%).  Many of the responses were durable, with 
a median duration that had not been reached after a median follow-up time of 11 months 
[29].
Ongoing Clinical Trials
Subjects with PD-L1 positive mCRPC have been treated with pembrolizumab monotherapy 
in KN028.  As of 24-Jul-2015, 16 subjects with PD-L1 positive mCRPC were enrolled and 
treated with pembrolizumab monotherapy.  All had treatment with prior docetaxel and 
targeted endocrine therapy.  Three confirmed partial responses (PR) were reported for an 
ORR at that time of 19%.  The responses were durable and treatment was well tolerated.  
This study, KEYNOTE-199 (KN199), has been designed to further evaluate the signal of 
activity seen in KN028 with pembrolizumab monotherapy.  
Ongoing clinical trials are also being conducted in advanced MEL, non-small cell lung 
cancer (NSCLC), head and neck cancer, urothelial cancer, triple negative breast cancer
(TNBC), gastric cancer and hematologic malignancies. For study details please refer to the 
IB.
Rationale
Rationale for the Trial and Selected Subject Population
Prostate cancer represents the second most common malignancy diagnosed in men 
worldwide where the annual incidence has been estimated to be over 1 million and over 
300,000 deaths are expected annually [30].  In the US, approximately 1 in every 6 men will 
be diagnosed with prostate cancer in his lifetime [31].
While many men are diagnosed with locally confined disease and may be treated definitively
with radiation or surgery, men who go on to develop or are diagnosed with metastatic 
prostate cancer, an incurable entity, are typically treated first with androgen deprivation 
therapy (ADT), usually with a GnRH agonist or antagonist that results in suppression of 
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testosterone production in the testes.  This alone often succeeds in controlling disease for 
some time, years in many cases.  However, prostate cancer progresses invariably and requires 
additional systemic therapies to reestablish control of disease.  The point at which prostate 
cancer progresses in spite of ADT alone is referred to as castrate resistance, and the disease 
at this point is known as (metastatic) castrate-resistant prostate cancer (mCRPC).
A number of important systemic therapies have been developed to treat mCRPC and have 
received regulatory approval and now comprise the current therapeutic landscape.  Docetaxel 
became the first systemic therapy to improve survival for men with mCRPC in a randomized 
study with docetaxel demonstrating superior survival of median 18.9 months versus 16.5 for 
mitoxantrone [32].  Cabazitaxel, a second taxane, was studied versus mitoxantrone in 
patients after docetaxel, and it too was found to be associated with superior survival – median 
15.1 months versus 12.7 with mitoxantrone [33].  Finally, the targeted endocrine therapies
enzalutamide and abiraterone were examined in randomized clinical trials in patients with 
mCRPC before treatment with chemotherapy and found to have superior OS versus control 
therapy (placebo and prednisone, respectively) [34, 35].
Cabazitaxel can be a toxic therapy.  Deaths occurred on study due to treatment-related 
neutropenia, and mortality has been reported due to treatment-related diarrhea.  Its label 
contains a black box warning regarding risks from neutropenia and severe hypersensitivity, 
and other label warnings and precautions pertain to diarrhea, renal failure, prohibitive risk in 
elderly patients ≥ 65, and hepatic impairment.  Consequently, cabazitaxel is not well utilized 
and consensus guidelines, such as NCCN, recommend that men with mCRPC after docetaxel 
should be encouraged to participate in clinical trials.  Thus, an unmet medical need remains 
for patients after treatment in the mCRPC setting with targeted endocrine therapy and 
docetaxel.
KN199 is a nonrandomized, open-label, multinational trial of pembrolizumab (MK-3475) in 
subjects with mCRPC who are chemotherapy-naïve or have previously been treated with 
chemotherapy and has been designed to further evaluate the signal of activity observed in 
KN028. 
Participation in this trial will be dependent upon subjects’ supplying a newly obtained core or 
excisional biopsy of a tumor lesion and/or tissue from an archival tissue sample to evaluate 
for PD-L1 expression by IHC. The specimen will be evaluated at a central laboratory for 
expression status of PD-L1. Subjects with PD-L1 positive and PD-L1 negative tumors will 
be enrolled in Cohorts 1 and 2, approximately 200 combined. The prediction of response to 
anti-PD-1 therapy is based on the results from Topalian et al [36] who examined PD-L1
expression in the archival specimens of 42 of the 296 subjects treated with the PD-1 inhibitor 
nivolumab. Of those 17 subjects whose tumor cells did not stain positive for PD-L1 using a 
5% threshold of tumor cell surface expression, no objective response by RECIST 1.1 was 
observed. But among the 25 subjects whose tumor cells were considered positive for PD-L1, 
9 responded (36%). Therefore, it is hypothesized that PD-L1 expression may be a predictive 
biomarker of anti-PD-1 activity, and subjects will be allocated by PD-L1 expression in this 
study.
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An emerging body of evidence suggests that post-transcriptional modification of androgen 
receptor message RNA may mediate resistance to targeted endocrine therapy.  One such 
example appears to be by modification to androgen-receptor isoform encoded by splice 
variant 7, which lacks the androgen-binding domain [37].
Cohorts 4 and 5 will explore the efficacy of pembrolizumab in chemotherapy-naïve subjects 
with mCRPC who are receiving pre-chemotherapy enzalutamide. Bishop et al. demonstrated 
in a mouse xenograft model that enzalutamide-resistant tumors express significantly 
increased levels of tumor intrinsic PD-L1 compared to non-enzalutamide resistant tumors 
[38]. Additionally, in a small cohort of subjects, it was noted that those who progressed 
while on enzalutamide had a significantly increased number of PD-L1/2-positive dendritic 
cells in their blood compared to treatment-naïve subjects or subjects who were responding to 
enzalutamide. 
Thus, by blocking PD-L1, pembrolizumab treatment may increase the 
immune response to the enzalutamide-resistant cells that emerge in response to treatment 
with enzalutamide. 
The PSA response rate of subjects treated with enzalutamide after abiraterone may be 
modest, as judged by a retrospective study of subjects with mCRPC who received various 
prior sequences of abiraterone, docetaxel, and enzalutamide [39]. The results showed that 
the group that received enzalutamide after abiraterone (N = 79) demonstrated a 50% or 
greater PSA decline in 18% of subjects. The median OS was reached only for subjects in the 
prior abiraterone plus docetaxel group and was 12.2 months. 
However, in another 
retrospective study evaluating the PSA response of enzalutamide or docetaxel treatment after 
abiraterone, the enzalutamide arm (N = 30) demonstrated a 50% or greater PSA decline in 
34% of subjects [40]. The median PFS was 4.1 months and the median PFS was 4.7 months. 
Overall survival was not described. Preliminary safety and efficacy data are available from a 
recent Phase 2 study (NCT0231255). Twenty-eight subjects with mCRPC were enrolled. 
The primary endpoint was a ≥50% PSA reduction. Early data were published in June 2016 
on the first 10 patients enrolled [41]. Three of the 10 patients enrolled and with at least 4 
months of follow-up achieved complete biochemical responses based on the primary 
endpoint. All responders continued their profound biochemical response, as well as clinical 
partial response for those with soft tissue target lesions and no sign of progression for those with 
bone metastases. These encouraging new data support a further validation as proposed for 
Cohorts 4 and 5 to better understand which patient populations respond to pembrolizumab in the 
short and long term.
Rationale for Dose Selection/Regimen/Modification
Pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg Q3W.  The initial dose 
approved by the Food and Drug Administration (FDA) for treatment of melanoma 
subjects was 2 mg/kg Q3W.  Currently, clinical trials evaluating pembrolizumab are using a 
fixed dose of 200 mg Q3W.  The use of a fixed dose is based on PK findings summarized 
below.
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The PK profile of pembrolizumab is consistent with that of other humanized mAbs, which 
typically have a low clearance and a limited volume of distribution.  A population PK model, 
which characterized the influence of body weight and other subject covariates on exposure 
using available data from 1139 subjects (from KN001 and KN002) has been performed.  The 
majority of these subjects (1077; 94.6%) had advanced melanoma.  The distribution of 
exposures from the 200 mg fixed dose were predicted to considerably overlap those obtained 
with the 2 mg/kg dose, and importantly, maintained individual subject exposures within the 
exposure range established in melanoma as associated with maximal clinical response.  This 
comparison also demonstrated that the 200 mg Q3W regimen provided no substantive 
differences in PK variability (range of the distribution of individual exposures) as seen with 
weight-based dosing.
In translating to other solid tumor indications, similarly flat exposure-response relationships 
for efficacy and safety as observed in subjects with melanoma can be expected, as the 
antitumor effect of pembrolizumab is driven through immune system activation rather than 
through a direct interaction with tumor cells, rendering it independent of the specific tumor 
type.  In addition, available PK results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures obtained at tested doses 
among tumor types.
A fixed-dose regimen is expected to simplify the dosing regimen (potentially reducing dosing 
errors), as well as be more convenient for physicians.  A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities, as well as reducing waste.
Rationale for Endpoints
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the antitumor activity of 
pembrolizumab in subjects with mCRPC previously treated with chemotherapy. Objective 
response rate will be used as the primary endpoint, and objective response will be determined 
using RECIST 1.1 by the central imaging vendor in the measurement of soft tissue disease.  
Duration of response and PFS will be determined using radiographic progression.  
Radiographic progression for soft tissue lesions will be determined using RECIST 1.1 
(Section 12.7).  Radiographic progression for bone lesions will be determined by 
radionuclide bone scan using the consensus guidelines of the PCWG3 criteria [42, 43].
Time-to-progression endpoints, including DOR, DCR, and rPFS, will be measured until 
progressive disease (PD) to be defined as the point at which there has been tumor progression 
in soft tissue lesions by RECIST 1.1 guidelines and/or tumor progression in bone lesions 
detected by radionuclide bone scan by PCWG criteria (PCWG3-modified RECIST 1.1).
4.2.3.1.1 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 antitumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
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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.  Thus, standard RECIST 1.1 
may not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab.  Based on an analysis of patients with MEL enrolled in KN001, 7% of 
evaluable patients experienced delayed or early tumor pseudoprogression.  Of note, patients 
who had PD by RECIST 1.1 but not by immune-related RECIST criteria (irRECIST) had 
longer OS than patients with PD 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 enables
treatment beyond initial radiographic progression. 
irRECIST is RECIST 1.1 adapted to account for the unique tumor response seen with 
immunotherapeutics. 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 central imaging vendor in 
support of the exploratory ORR and DCR endpoints.  Progressive disease in bone will be 
assessed using radionuclide bone scan in accord with PCWG3 criteria (PCWG3-modified 
irRECIST).
Patient Reported Outcomes
EQ-5D and FACT-P are not pure efficacy or safety endpoints because they are affected by 
both disease progression and treatment tolerability.
4.2.3.2.1 eEuroQoL-5D (eEQ-5D)
The eEQ-5D is a standardized instrument for use as a measure of health outcome.  The eEQ-
5D will provide data for use in economic models and analyses including developing health 
utilities or quality-adjusted life-years (QALYs).  The five health state dimensions in this 
instrument include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression [44].  Each dimension is rated on a three-point scale from 1 (extreme 
problem) to 3 (no problem).  The eEQ-5D also includes a graded (0 to 100) vertical visual 
analog scale on which the subject rates his or her general state of health at the time of the 
assessment. The eEQ-5D should be completed by subjects first and followed by the FACT-P.
4.2.3.2.2 The Functional Assessment of Cancer Therapy-Prostate (FACT-P)
FACT-P questionnaire is a relevant, worldwide tool used for assessing the health-related 
quality of life (HRQOL) in men with prostate cancer [45]. Developed as a disease-specific 
adjunct to the FACT measurement system, FACT-P consists of FACT-G (general) which 
contains a 27-item self-report questionnaire measuring general HRQoL in four domains 
(physical, social, emotional, and functional well-being) and 12 prostate cancer-specific items. 
FACT-P (version 4) is self–administered and requires approximately 8 to 10 minutes to 
complete.
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Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with mCRPC previously treated with docetaxel-based 
chemotherapy (Cohorts 1, 2, and 3) and in subjects with mCRPC failing or showing early 
signs of failing on current enzalutamide treatment (Cohorts 4 and 5). The primary safety 
analysis will be based on subjects who experienced toxicities as defined by CTCAE criteria 
(Appendix 12.6). 
Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received pembrolizumab, including SAEs and events of 
clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including, but not limited 
to, all AEs, SAEs, fatal AEs, and laboratory changes.
Pharmacokinetic Endpoints
Blood samples will be obtained to measure the PK of pembrolizumab for Cohorts 1 through 
3.  The pembrolizumab serum plasma maximum concentration (Cmax) and minimum 
concentration (Ctrough) at planned visits and times may be summarized.
Pharmacokinetic data may also be analyzed using nonlinear mixed effects modeling.  Based 
on PK data obtained in this study as well as PK data obtained from other studies (if 
available), a population PK analysis could be performed to characterize PK parameters 
(clearance (CL), volume of distribution (V)) and evaluate the effect of extrinsic and intrinsic 
factors to support the proposed dosing regimen.  Pharmacokinetic data may also be used to 
explore the exposure-response relationships for pembrolizumab antitumor activity/efficacy, 
as well as safety in the proposed patient population, if feasible.  The results of these analyses, 
if performed, will be reported separately.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients.  Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy as well as determinants of 
adverse events in the course of our clinical trials.  These efforts will identify novel 
predictive/pharmacodynamic biomarkers and generate information that will better guide 
single-agent and combination therapy with immuno-oncology drugs. To identify novel 
biomarkers, we will collect biospecimens (blood components, tumor material, etc.) to support 
analyses of cellular components (e.g., protein, DNA, RNA, metabolites) and other circulating
molecules. Investigations may include but are not limited to:
Germline (blood) Genetic Analyses (e.g., SNP analyses, whole exome sequencing, whole 
genome sequencing): This research will evaluate whether genetic variation within a clinical 
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trial population correlates with response to the treatment under evaluation. 
If genetic 
variation is found to predict efficacy or adverse events, the data might inform optimal use of 
therapies in the patient population. Furthermore, it is important to evaluate germline DNA 
variation across the genome in order to interpret tumor-specific DNA mutations. Finally, 
microsatellite instability (MSI) may be evaluated as this is an important biomarker for some 
cancers (i.e., colorectal cancer).
Genetic (DNA) analyses from tumor:  The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (i.e., mutations, methylation status, microsatellite instability, etc).  Key 
molecular changes of interest to immune-oncology drug development include (for example) 
the mutational burden of tumors and the clonality of T-cells in the tumor microenvironment.  
Increased mutational burden (sometimes referred to as a ‘hyper-mutated’ state) may generate 
neo-antigen presentation in the tumor microenvironment.  To conduct this type of research, it 
is important to identify tumor-specific mutations that occur across all genes in the tumor 
genome.  Thus, genome wide approaches may be used for this effort. Note that in order to 
understand tumor-specific mutations; it is necessary to compare the tumor genome with the 
germline genome.  Microsatellite instability (MSI) may also be evaluated as this is an 
important biomarker for some cancers (i.e., colorectal cancer).
Tumor and blood RNA analyses: Both genome-wide and targeted messenger RNA (mRNA) 
expression profiling and sequencing in tumor tissue and in blood may be performed to define 
gene signatures that correlate to clinical response to treatment with pembrolizumab or other 
immunotherapies.  Pembrolizumab induces a response in tumors that likely reflects an 
inflamed/ immune phenotype.  Specific immune-related gene sets (such as those capturing 
IFN-γ transcriptional pathways) may be evaluated and new signatures may be identified.  
Individual genes related to the immune system may also be evaluated (e.g., IL-10).  
MicroRNA profiling may also be pursued.
Proteomics and Immunohistochemistry (IHC) using Blood or Tumor:  Tumor and blood 
samples from this study may undergo proteomic analyses (e.g., PD-L1 IHC).  PD-L1 protein 
level in tumor sections, assessed by IHC, has been shown to correlate with response to 
pembrolizumab in patients with NSCLC, and an in-vitro diagnostic (IVD) device has been 
developed for use with pembrolizumab in NSCLC. Preliminary data indicate that this 
association may also be true in additional cancer types (i.e., TNBC, head and neck, and 
gastric). Additional tumor or blood-derived proteins may also correlate with response to 
pembrolizumab.  Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include but are not limited to immunoassays, liquid 
chromatography/mass spectrometry.  This approach could identify novel protein biomarkers 
that could aid in patient selection for pembrolizumab therapy.
Other Blood-derived Biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood.  Assays such as enzyme-linked immunoassay 
measure such proteins in serum. Correlation of expression with response to pembrolizumab 
therapy may identify new approaches for predictive biomarkers in blood, representing a 
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major advance from today’s reliance on assessing tumor biomarkers.  This research would 
serve to develop such assays for future clinical use.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens 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 
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 IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male subjects at least 18 years of age with mCRPC 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.
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3. Have histologically- or cytologically-confirmed adenocarcinoma of the prostate
without small cell histology.  Diagnosis must be stated in a pathology report and 
confirmed by the Investigator.
4. Have RECIST 1.1-measurable prostate cancer on computed tomography (CT) or 
magnetic resonance imaging (MRI) scans (Cohorts 1, 2, and 4) or detectable bone 
metastases by whole body bone scintigraphy and no RECIST 1.1-measurable tumors 
(Cohorts 3 and 5), as determined by central review. Disease must be either metastatic 
or locally confined inoperable disease that cannot be treated with definitive intent.
5. Have supplied tumor tissue from a newly obtained biopsy or provided a tumor tissue 
specimen ≤12 months prior to the screening date and an archival specimen, if 
available, from a site not previously irradiated (tumors progressing in a prior site of 
radiation are allowed for PD-L1 characterization; other exceptions may be considered 
after Sponsor consultation). Adequacy of these specimens for PD-L1 biomarker 
analysis will be required by a central laboratory prior to enrollment. Subjects in 
Cohorts 1, 2, and 4 with visceral/measurable lesions must provide a newly obtained 
biopsy performed after the last line of systemic therapy where safely available or a 
specimen obtained ≤12 months prior to the screening date and an archival specimen, 
if available. Subjects in Cohort 3 and 5 must at least provide an archival specimen.  
Note: Tumor blocks are preferred.  If submitting unstained cut slides, freshly cut slides 
should be submitted to the testing laboratory within 14 days from the date slides are cut.
For Cohorts 1, 2, and 3 only:
6. Have been treated with:
a.
At least one targeted endocrine therapy (defined as second generation 
antiandrogen therapies that include but are not limited to abiraterone acetate with 
prednisone, enzalutamide, and next generation targeted agents such as ARN-509).  
[Note: First generation antiandrogens such as flutamide, nilutamide, bicalutamide 
are not included in this group.]
b. At least one regimen/line of chemotherapy that contained docetaxel.
c.
No more than two chemotherapy regimens.
d. No more than three regimens/lines of the aforementioned treatments (having 
failed/progressed on chemotherapy and targeted endocrine therapy).
For Cohorts 4 and 5 only:
7. For chemotherapy-naïve subjects with mCRPC either having failed or showing early 
signs of failing on enzalutamide treatment as defined by PCWG3 guidelines
(eg, signs of clinical progression, increased alkaline phosphatase, PSA increase, or 
positive imaging assessments). Subjects can have failed prior abiraterone treatment 
before current enzalutamide treatment. Subjects must have had a clinically 
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meaningful response to enzalutamide treatment. Enzalutamide must have been 
initiated no less than 4 weeks prior to the first dose of trial treatment and be continued 
throughout the study.
All Cohorts:
8. Have documented prostate cancer progression within 6 months prior to screening, as 
determined by the Investigator, by means of one of the following: 
a.
PSA progression as defined by a minimum of 3 rising PSA levels with an interval 
of ≥1 week between each assessment where the PSA value at screening should be 
≥2 ng/mL.
b. Radiographic disease progression in soft tissue or bone with or without PSA 
progression 
9. Have ongoing androgen deprivation with total serum testosterone < 50 ng/dL 
(< 2.0 nM). If the subject is currently being treated with LHRH agonists (subjects 
who have not undergone an orchiectomy), this therapy must have been initiated at 
least 4 weeks prior to first dose of trial treatment.  This treatment must be continued 
throughout the study.
10. Subjects receiving bone resorptive therapy (including but
not
limited to 
bisphosphonate or RANK-L inhibitor) must have been on stable doses for ≥4 weeks
prior to first dose of trial treatment.
11. Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale (Appendix 12.5).
12. Subjects are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study 
intervention after the last dose of study intervention. The length of time required to 
continue contraception after the last dose of enzalutamide is 30 days.
Subjects must either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR
•
Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause, documented from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview), as detailed below:
•
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP (see Section 
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12.8) who is not currently pregnant.  Note: Men with a pregnant or 
breastfeeding partner must agree to remain abstinent from penile-vaginal 
intercourse or use a male condom during each episode of penile-vaginal 
penetration.
•
Contraceptive use by men should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical 
studies.  If the contraception requirements in the local label for any of the 
study interventions is more stringent than the requirements above, the local 
label requirements are to be followed.
Note: The above contraception requirements also apply to participants currently 
receiving study drugs at the time of Amendment 07.
Note: No contraception is necessary for participants who will receive
pembrolizumab monotherapy (Second Course treatment).
13. Demonstrate adequate organ function as defined in Table 1; all screening labs should
be performed within 10 days of treatment initiation.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
>1,500.0/µL
Plateletsa
≥100,000.0/µL
Hemoglobina
≥9.0 g/dL or ≥ 5.6 mmol/L
Renal
Creatinine OR
Measured 
or 
calculatedb
creatinine 
clearance
(GRF can also be used in place of creatinine 
or creatinine clearance) 
≤1.5 × upper limit of normal (ULN) OR
≥60.0 mL/min for subject with creatinine 
levels >1.5 × institutional ULN
Hepatic
Serum Total Bilirubin
≤ 1.5 × ULN OR
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 × ULN OR
≤5 × ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) or
Prothrombin Time (PT);
Partial Thromboplastin Time (PTT) or 
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
≤1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
a.
Hemoglobin and platelet requirements cannot be met by use of recent transfusion or growth factor support 
(granulocyte colony stimulating factor - GCSF or erythropoietin) within 2 weeks prior to treatment 
initiation.
b.
Creatinine clearance should be calculated per institutional standard.
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Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of
an investigational agent and received study therapy or used an investigation device
within 4 weeks of the first dose of trial treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. The use of physiologic doses of corticosteroids may be approved after
consultation with the Sponsor (replacement therapy for adrenal insufficiency is 
permitted).  
Note: Treatment with palliative prednisone such as 10 mg daily or corticosteroid 
equivalent in the manner used to treat men with prostate cancer is permitted without 
Sponsor notification.
3. Has had a prior anti-cancer mAb within 4 weeks prior to the first dose of trial 
treatment or who has not recovered (i.e., ≤Grade 1 or at baseline) from AEs due to 
mAbs administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or external beam 
radiation therapy within 4 weeks prior to the first dose of trial treatment or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously 
administered agent. Treatment with Radium-223 is allowed as long as the last dose 
has been administered no less than 4 weeks prior to the first dose.  Note: Subjects 
with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and 
may qualify for the study.
Note: If subjects received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to the first dose of trial 
treatment.
5. Has a known additional malignancy that has had progression or has required active 
treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin, and 
squamous cell carcinoma of the skin that has undergone potentially curative therapy.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate
provided they are stable (without evidence of progression by imaging for at least 
4 weeks prior to the first dose of trial treatment and any neurologic symptoms have
returned to baseline), have no evidence of new or enlarging brain metastases, and are
not using steroids for at least 7 days prior to the first dose of trial treatment. This 
exception does not include carcinomatous meningitis which is excluded regardless of 
clinical stability.
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7. Has an active autoimmune disease that has required systemic treatment in past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.
8. Has evidence of interstitial lung disease and/or a history of (non-infectious) 
pneumonitis that required steroids, or current pneumonitis.
9. Has an active infection requiring systemic therapy.
10. 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
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.
11. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
12. Has previously participated in any other pembrolizumab (MK-3475) trial, or received
prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab
or any other antibody or drug specifically targeting T-cell co-stimulation or
checkpoint pathways).
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
15. Has received a live vaccine within 30 days of planned start of study therapy.
Any licensed COVID-19 vaccine (including for Emergency use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines. Investigational vaccines (ie, those not licensed or 
approved for Emergency Use) are not allowed.
Additionally, the following apply to Cohorts 4 and 5 only:
16. Has received prior chemotherapy (e.g., docetaxel) for mCPRC.
17. Has any condition (cardiac, neurologic, absorption) other than clinically failing or 
showing early signs of failing on enzalutamide treatment that would require imminent 
discontinuation of enzalutamide treatment.
Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.
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Table 2
Trial Treatment
Study 
Treatment 
Name
Dosage 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Sourcing
Pembrolizumab
(MK-3475)
Solution for 
infusion
100 mg per 
vial
200 mg Q3W
IV infusion
Central
Abbreviations: IV = intravenous; N/A = not applicable; Q3W = every 3 weeks; QD = every day.
Trial treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
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)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously.  Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical 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, or 
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.
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Table 3
Dose Modification and Treatment Discontinuation Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced 
to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
irAEs
Toxicity grade or 
conditions (NCI 
CTCAE v4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus).

Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
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irAEs
Toxicity grade or 
conditions (NCI 
CTCAE v4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity grade or 
conditions (NCI 
CTCAE v4.0)
Action taken to 
pembrolizumab
irAE management with corticosteroid 
and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other irAEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of event.  
Events that require 
discontinuation 
include and not 
limited to:  Guillain-
Barré Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse 
Events; GI = gastrointestinal; irAE = immune-related adverse event; IV = intravenous; NCI = National Cancer Institute; T1DM = type 1 diabetes mellitus.
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis.  Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 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 hrs
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the 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 
1.5 h (±30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg PO 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
PO (or equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged 
(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 ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the 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
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; 
NCI = National Cancer Institute; NSAIDs = nonsteroidal anti-inflammatory drugs; PO = by mouth
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 CTCAE v4.0 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 subject's study record.
Timing of Dose Administration
Pembrolizumab
The first infusion should be administered on the day of treatment allocation or as close as 
possible to the date on which the subject is allocated, ie, ≤7 days.  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).  After the first cycle, trial 
treatment may be administered up to 3 days before or after the scheduled Day 1 of the cycle 
due to administrative reasons.  
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Details pertaining to the preparation and administration of pembrolizumab are provided in 
the Pharmacy Manual.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Treatment allocation will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS).  All eligible subjects will be allocated 
to receive pembrolizumab 200 mg Q3W as monotherapy. Subjects enrolled in Cohorts 4 and 
5 will remain on their current stable SOC dose of enzalutamide therapy during 
pembrolizumab monotherapy. Enzalutamide will not be supplied by the sponsor.
Stratification
All eligible subjects will be enrolled into one of the cohorts in this study based on treatment 
history, PD-L1 status for Cohorts 1 and 2 only, and RECIST 1.1 measurability.
No additional 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 case report form (CRF) 
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 CRF.  Subject may remain on anti-
coagulation therapy as long as the PT or PTT is within therapeutic range of the intended use 
of anticoagulants.
For Cohorts 4 and 5, the use of enzalutamide will be recorded on the CRF.  If dose 
modification of enzalutamide is required during the trial period, documentation of dosage 
should also be included on the CRF.
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Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

GM-CSF

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Palliative localized radiation therapy to a site of pre-existing disease may be 
permitted while on study after consultation with Sponsor.  The radiation treatment 
field may not include a target or measurable lesion by RECIST 1.1. Pre-existing
treatment with Radium-223 dichloride is allowed so long as the last dose has been 
administered no fewer than 4 weeks from the first dose of trial drug. 

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, chickenpox, yellow fever, rabies, Bacillus 
Calmette-Guerin (BCG), and oral typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy. Investigational vaccines (ie, those not licensed or approved for 
Emergency Use) are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
AE of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
Note: Inhaled steroids for management of asthma are permitted.
Note: Use of prophylactic corticosteroids to avoid allergic reactions (e.g., to IV 
contract dye) is permitted.
Note: Treatment with palliative prednisone such as 10 mg daily or corticosteroids
equivalent in the manner used to treat men with prostate cancer is permitted.
Note: Physiologic doses of corticosteroids for adrenal insufficiency are permitted.
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Subjects who, in the assessment by the investigator and after consultation with the Sponsor, 
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 describe other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.  Subjects must 
be discontinued from the active follow-up phase if they begin a non-trial treatment for their 
underlying disease.
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 
Section 5.2.1.2, 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.  Refer to Table 3 in 
Section 5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Radiotherapy
The use of radiotherapy or surgical intervention while on study must be recorded in the trial 
database. 
Localized palliative radiation therapy to a site of pre-existing disease may be permitted while 
on study. However, if the subject develops a new lesion or a definite increase in the size of 
existing bone or visceral lesions with or without extension into the soft tissue that meets the 
criteria for disease progression according to PCWG3, treatment must be discontinued for PD
regardless of whether radiation therapy is initiated.
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Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Post Treatment.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the subject at unnecessary risk from continued 
administration of study drug.
o
The subject has a positive urine drug screen at any time during the course of the trial.
o
Documented disease progression as assessed by the investigator using PCWG3-modified 
RECIST 1.1 guidelines (Section 7.1.2.6.1 – Initial Tumor Imaging).  Two consecutive 
assessments are needed for disease progression.  Clinical deterioration will not be 
considered progression.
o
Unacceptable adverse experiences as described in Section 5.2.1.2 – Dose Modification 
(Escalation/Titration/Other) and Section 5.6.1 – Supportive Care Guidelines
o
Intercurrent illness that prevents further administration of treatment
o
Noncompliance with trial treatment or procedure requirements
o
Administrative reasons
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Cohorts 4 and 5: If subjects have to discontinue enzalutamide treatment after being enrolled 
into the study due to adverse events or toxicity attributed to enzalutamide, subjects can 
continue to receive pembrolizumab as long as they experience clinical benefit without signs 
of disease progression and tolerable safety.
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
Subjects may be allowed to begin treatment again if deemed medically appropriate.
Withdrawal from the Trial
Subjects may withdraw from the trial at any time for any reason.  If a subject withdraws from 
the trial, they will no longer receive treatment or be followed at scheduled protocol visits.
A subject must be withdrawn from the trial if:
○
The subject or subject’s legally acceptable representative withdraws consent from the 
trial.
○
The subject is lost to follow-up.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including specific details regarding withdrawal from Future Biomedical Research are 
outlined in Section 7.1.4 – Other Procedures.
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).
Upon study completion, participants are discontinued and may be enrolled in a 
pembrolizumab extension study, if available.
Clinical Criteria for Early Trial Termination
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. Plans to modify or discontinue the development of the study drug pembrolizumab.
In the event of Sponsor decision to no longer supply study drug pembrolizumab, ample 
notification will be provided so that appropriate adjustments to subject treatment can be 
made.
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6.0 TRIAL FLOW CHART
Study Flow Chart
Trial Period:
Screening 
Phase
Treatment Cyclesb
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)a
1
2 
3
4
To be repeated beyond 
8 cycles
DC
Safety 
Follow-
upc
Follow Up 
Visitsd
Survival 
Follow-Upe
5
6
7
8
Scheduling Window (Days):
-42 to -1
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days
after last 
dose
(±3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days) 
Administrative Procedures
Informed Consent
Xf
Informed Consent for FBR (optional)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
(dispense)
X 
(collect)
Demographics and Medical History
X
Prior and Concomitant Medication Review
Xg
X
X
X
X
X
X
X
X
X
Xg
Trial Treatment Administration
Xh
X
X
X
X
X
X
X
Subsequent Anticancer Therapy Status
X
X
Survival Statusi
X
Clinical Procedures/Assessments
AE/SAE Monitoring
X
X
X
X
X
X
X
X
X
X
Xj
Xj
Full Physical Examinationk
X
X
Directed Physical Examinationk
X
X
X
X
X
X
X
X
Vital Signs and Weightl
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
ECOG Performance Status
X
X
X
X
X
X
X
X
Xm
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
PT/INR and PTT/aPTT
Xn
CBC with Differentialo
Xn
X
X
X
X
X
X
X
X
Xp
Comprehensive Chemistry Panelo
Xn
X
X
X
X
X
X
X
X
Xp
Urinalysiso,q
Xn
Xq
X
X
X
X
Xp
T3, FT4 and TSHo
Xn
Xq
X
X
X
X
Xp
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Trial Period:
Screening 
Phase
Treatment Cyclesb
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)a
1
2 
3
4
To be repeated beyond 
8 cycles
DC
Safety 
Follow-
upc
Follow Up 
Visitsd
Survival 
Follow-Upe
5
6
7
8
Scheduling Window (Days):
-42 to -1
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days
after last 
dose
(±3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days) 
Total Testosteroneo
Xn
Xr
X
X
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Tumor Marker Assessment (PSA)s
X
X
X
X
X
PSA for Cohorts 4 and 5s
X
X
X
X
X
X
X
Anti-drug Antibodies (ADA)t
X
X
X
X
X
Pembrolizumab Pharmacokinetics (serum)t
Xu
X
X
X
X
Blood for CTC
Xv, w
X
Blood for AR-V7v
X
Efficacy Measurements
Tumor Imagings (CT/MRI/bone scan)
Xx
X
X
Xy
Xz
Tumor Tissue Collection/Correlative and Biomarker Studies 
Tumor Tissue Collection (Newly Obtained 
and Archival)
Xaa
Blood for Genetic Analyses
Xbb
Blood RNA Analysescc
X
X
X
X
Blood for Plasma Biomarker Analysescc
X
X
X
X
Blood for Serum Biomarker Analysescc
X
X
X
X
Blood for ctDNA (plasma)dd
X
X
X
X
Patient Reported Outcomes
EuroQol EQ-5Dee
X
X
X
X
X
X
X
FACT-Pee
X
X
X
X
X
X
X
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Trial Period:
Screening 
Phase
Treatment Cyclesb
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)a
1
2 
3
4
To be repeated beyond 
8 cycles
DC
Safety 
Follow-
upc
Follow Up 
Visitsd
Survival 
Follow-Upe
5
6
7
8
Scheduling Window (Days):
-42 to -1
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days
after last 
dose
(±3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days) 
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; AR-V7 = androgen receptor variant 7; CBC = complete blood count; 
CT = computed tomography; CTC = circulating tumor cells; ctDNA = circulating tumor cell DNA; DC = discontinuation; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; FACT-P = functional assessment of cancer therapy-prostate; FBR = future biomedical research; FT4 = free 
thyroxine; INR = international normalized ratio; MRI = magnetic resonance imaging; PSA = prostate-specific antigen; PT = prothrombin time; PTT = partial 
thromboplastin time; SAE = serious adverse event; T3 = triiodothyronine; TSH = thyroid stimulating hormone.
a.
Subjects may only be rescreened once.
b.
All treatment cycles are 3 weeks ± 3 days.
c.
If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
start of the new therapy. Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.
d.
Follow-up visits must occur using the same imaging schedule the subject was on during treatment (eg, every 9 weeks [63 days ±7 days] from the date of 
allocation or every 12 weeks [84 days ±7 days] from the date of allocation).  In subjects who discontinue study therapy without documented disease 
progression, every effort should be made to continue monitoring their disease status by radiologic imaging (CT/MRI and bone scans) and PSA according to 
the schedule that the subject was on at the time of discontinuation (eg, every 9 or 12 weeks from the date of allocation) until: 1) the start of new anti-cancer 
treatment, 2) documented disease progression, 3) death or 4) the end of the study, whichever occurs first.
e.
Survival follow-up begins 12 weeks from the time a subject experiences confirmed disease progression or starts a new anti-cancer treatment.
f.
Written consent must be obtained prior to performing any protocol specified procedures.  Results of a test performed prior to the subject signing consent are 
acceptable in lieu of new screening tests if they are a part of routine clinical management and performed within the specified timeframe.
g.
Prior medications: record all medications taken within 28 days prior to the first dose of trial treatment.  Concomitant medications: enter new medications 
started during the trial and up to 30 days after last dose of trial treatment regardless of when the safety follow-up visit occurs.  All medications related to 
reportable SAEs and events of clinical interest (ECIs) should be recorded as defined in Section 7.2.
h.
Trial treatment should begin on the day of treatment allocation or as close as possible to the date on which the subject is allocated, ie, ≤7 days.
i.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. 
Updated survival status may be requested by the Sponsor at any time during the course of the study. 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 death event previously recorded).
j.
Record all AEs (including ECIs) occurring up to 30 days after the last dose of trial treatment. SAEs must be recorded up to 90 days after the last dose of trial 
treatment or 30 days following cessation of treatment if the subject starts new anti-cancer treatment.  Treatment related SAEs must always be reported.
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Trial Period:
Screening 
Phase
Treatment Cyclesb
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)a
1
2 
3
4
To be repeated beyond 
8 cycles
DC
Safety 
Follow-
upc
Follow Up 
Visitsd
Survival 
Follow-Upe
5
6
7
8
Scheduling Window (Days):
-42 to -1
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days
after last 
dose
(±3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days) 
k.
A full physical exam will be performed at screening and at treatment discontinuation; all treatment visits will include a directed physical exam.
l.
Height will be measured at screening only.
m. Following Cycle 8, ECOG Performance Status will be performed at every other cycle (Cycles 10, 12, 14,…) and at treatment discontinuation.
n.
Laboratory procedures at screening are to be performed within 10 days prior to the first dose of trial treatment.
o.
After Cycle 1, pre-infusion laboratory procedures may be conducted up to 72 hours pre-infusion.  
p.
Unresolved abnormal lab results associated with drug-related AEs should be followed until resolution.
q.
Urinalysis and thyroid function testing are done at screening, every other cycle (Cycles 2, 4, 6,…), treatment discontinuation, and the safety follow-up visit. 
r.
Total testosterone will be done at screening, every fourth cycle (Cycles 4, 8, 12,…) and at treatment discontinuation
s.
Imaging assessments (CT/MRI and bone scans) and PSA should be performed every 9 weeks (63 days ±7 days) for the first year (through week 54), every 12 
weeks (84 days ±7 days) in the second year, at treatment discontinuation and during follow-up. The timing of these assessments should not be adjusted for 
dose delays or cycle starts. For Cohorts 4 and 5, screening PSA by central results are required prior to allocation. PSA should be performed Q3W until 
Cycle 4.
t.
Pre-infusion (trough) PK and anti-pembrolizumab antibody (ADA) samples will be collected within 24 hours before infusion at Cycles 1, 2, 4, 6, and 8.  To 
be collected from subjects in Cohorts 1 to 3 only.
u.
Post-dose (peak) PK samples will be drawn within 30 minutes after the end of infusion at Cycles 1 and 8. Additional single PK samples should be drawn at
the following time points after Cycle 1 dosing: 24 hours (±4 hours) [Day 2], between 72 and 168 hours [Day 4-8], and 336 hours (±48 hours) [Day 15].  To be 
collected from subjects in Cohorts 1 to 3 only.
v.
Blood for AR-V7 and blood for CTC can be collected up to 3 days prior to infusion at Cycle 1.  Leftover samples will be kept for future biomedical research 
if the subject signs the FBR consent. 
w.
Leftover samples may be kept for FBR if the subject signs the FBR consent.
x.
The initial tumor imaging will be performed within 28 days prior to the first dose of trial treatment.  Scans performed as part of routine clinical management 
are acceptable for use as the screening scan if they are of diagnostic quality and performed within 28 days prior to the first dose of trial treatment.  
y.
If a scan was obtained within 4 weeks prior to treatment discontinuation, then another scan at discontinuation is not mandatory.  Radiological evaluation 
should be repeated at treatment discontinuation in subjects discontinuing without confirmed disease progression (date of discontinuation ±4 weeks).
z.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by 
radiologic imaging (CT/MRI and bone scans) and PSA according to the schedule that the subject was on during study treatment (eg, every 9 weeks [63 days ± 
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Trial Period:
Screening 
Phase
Treatment Cyclesb
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Screening 
(Visit 1)a
1
2 
3
4
To be repeated beyond 
8 cycles
DC
Safety 
Follow-
upc
Follow Up 
Visitsd
Survival 
Follow-Upe
5
6
7
8
Scheduling Window (Days):
-42 to -1
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days
after last 
dose
(±3 days)
Every 9 or 
12 weeks 
(±7 days)
Every 
12 weeks
(±7 days) 
7 days] from the date of allocation or every 12 weeks [84 days ± 7 days] from the date of  allocation) until: 1) the start of new anti-cancer treatment, 2) 
documented disease progression, 3) death or 4) the end of the study, whichever occurs first.
aa. Baseline tumor tissue for biomarker analysis from an archival tissue sample and/or newly obtained core or excisional biopsy (fine needle aspirate not 
adequate) must be sent to the testing laboratory and analyzed for adequacy prior to enrollment. Refer to Section 7.1.2.7 for details on newly obtained biopsy 
and/or archival specimen requirements by cohort.
bb. This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law 
or regulation prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected 
at that site. If the sample is collected, leftover extracted DNA will be stored for FBR if the subject signs the FBR consent. If the planned genetic analysis is 
not approved, but FBR is approved and consent is given, this sample will be collected for the purpose of FBR.  
cc. Blood for RNA Analyses and Blood for Serum/Plasma Biomarker Analyses should be collected pre-infusion according to time points on the flow chart. 
Collections end at cycle 5 and should not be repeated.  Leftover samples may be kept for FBR if the subject signs the FBR consent.
dd. Blood for ctDNA can be collected up to 3 days prior to the Cycle 1 pre-infusion (if the collection coincides with a treatment cycle) every 9 weeks (63 days ±7 
days) for the first year (through week 54), every 12 weeks (84 days ±7 days) in the second year, and at treatment discontinuation.  The timing of these 
assessments should not be adjusted for dose delays or cycle starts. Leftover samples may be kept for Future Biomedical Research if the subject signs the FBR 
consent.
ee. Electronic patient reported outcomes (ePROs) should ideally be administered prior to all study procedures (EQ-5D first, followed by FACT-P). All ePROs are 
to be administered pre-infusion at Cycles 1, 2, 3, and 4 and every 3 cycles thereafter (Cycle 7, 10, 13, 16, and 19), at treatment discontinuation, and again 30 
days after last dose of trial treatment.  If the subject does not complete the ePROs at a scheduled time point, the MISS_MODE form must be completed to 
capture the reason the assessment was not performed.
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Second Course Phase (Retreatment ONLY)
Trial Period:
SECOND COURSE PHASE:  Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
1
2 
3
4
To be repeated beyond 8 cycles
DC
Safety
Follow-upb
Follow Up 
Visitsc
Survival Follow-
Upd
5
6
7
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days from 
last dose
(±3 days)
Every 9
weeks 
(±7 days)
Every 12 weeks
(±7 days)
Administrative Procedures
Eligibility Criteriae
X
Concomitant Medication Reviewf
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Subsequent Anticancer Therapy 
Status
X
X
Survival Statusg
X
Clinical Procedures/Assessments
AE/SAE Monitoring
X
X
X
X
X
X
X
X
X
Xh
Xh
Full Physical Examinationi
X
X
Directed Physical Examinationi
X
X
X
X
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
Xj
X
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory
PT/INR and PTT/aPTT
Xk
CBC with Differentiall
Xk
X
X
X
X
X
X
X
X
Xm
Comprehensive Chemistry Panell
Xk
X
X
X
X
X
X
X
X
Xm
T3, FT4 and TSHl
Xk
Xn
X
X
X
Xm
Urinalysisl
Xk
Xn
X
X
X
Xm
Total Testosteronel
Xk
Xo
X
X
Laboratory Procedures/Assessments: analysis performed by CENTRAL laboratory
Tumor Marker Assessment (PSA)p
X
X
X
X
Xc
Efficacy Measurements
Tumor Imagingp (CT/MRI/bone scan)
Xq
X
X
Xr
Xc
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Trial Period:
SECOND COURSE PHASE:  Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
1
2 
3
4
To be repeated beyond 8 cycles
DC
Safety
Follow-upb
Follow Up 
Visitsc
Survival Follow-
Upd
5
6
7
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days from 
last dose
(±3 days)
Every 9
weeks 
(±7 days)
Every 12 weeks
(±7 days)
Abbreviations: AE = adverse event; aPTT = activated partial thromboplastin time; CBC = complete blood count; CT = computed tomography; 
DC = discontinuation; ECOG = Eastern Cooperative Oncology Group; FT4 = free thyroxine; INR = international normalized ratio; MRI = magnetic 
resonance imaging; PSA = prostate-specific antigen; PT = prothrombin time; PTT = partial thromboplastin time; SAE = serious adverse event; 
T3 = triiodothyronine; TSH = thyroid stimulating hormone.
a.
All treatment cycles are 3 weeks ± 3 days.
b.
If a subject initiates a new anti-cancer therapy within 30 days after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
start of the new therapy. Once new anti-cancer therapy has been initiated the subject will move into survival follow-up.
c.
Follow-up visits must occur every 9 weeks (63 days ±7 days) from the date of last dose of study treatment.  In subjects who discontinue therapy without 
documented disease progression, every effort should be made to continue monitoring disease status by radiologic imaging (CT/MRI and bone scans) and 
PSA until: 1) the start of new anti-cancer treatment, 2) documented disease progression, 3) death or 4) the end of the study, whichever occurs first.
d.
Survival follow-up begins 12 weeks from the time a subject experiences confirmed disease progression or starts a new anti-cancer treatment.
e.
Subjects may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.
f.
Report new medications started during the trial and up to 30 days after last dose of trial treatment regardless of when the safety follow-up visit occurs.  All 
medications related to reportable SAEs and events of clinical interest (ECIs) should be recorded as defined in Section 7.2.
g.
After documented local site assessed disease progression, or the start of new anticancer treatment; contacts are approximately every 12 weeks by telephone. 
Updated survival status may be requested by the Sponsor at any time during the course of the study. 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 death event previously recorded).
h.
Record all AEs (including ECIs) occurring up to 30 days after the last dose of trial treatment. SAEs must be recorded up to 90 days after the last dose of 
trial treatment or 30 days following cessation of treatment if the subject starts new anti-cancer treatment.  Treatment related SAEs must always be reported.
i.
A full physical exam will be performed prior to subject receiving first retreatment infusion and at treatment discontinuation; all treatment visits will include 
a directed physical exam.
j.
Following Cycle 8, ECOG Performance Status will be performed at every other cycle (Cycles 10, 12, 14,…) and at treatment discontinuation.
k.
Laboratory tests are to be performed within 10 days prior to subject receiving first retreatment infusion.
l.
After Cycle 1, pre-infusion laboratory procedures may be conducted up to 72 hours pre-infusion.  
m. Unresolved abnormal lab results associated with drug-related AEs should be followed until resolution.
n.
Urinalysis and thyroid function testing are performed within 10 days prior to first retreatment infusion, every other cycle (Cycles 3, 5, 7,…), treatment 
discontinuation, and the safety follow-up visit. 
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Trial Period:
SECOND COURSE PHASE:  Treatment Cyclesa
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
1
2 
3
4
To be repeated beyond 8 cycles
DC
Safety
Follow-upb
Follow Up 
Visitsc
Survival Follow-
Upd
5
6
7
8
Scheduling Window (Days):
±3
±3
±3
±3
±3
±3
±3
At time of 
DC
30 days from 
last dose
(±3 days)
Every 9
weeks 
(±7 days)
Every 12 weeks
(±7 days)
o.
Total testosterone will be done within 10 days prior to first retreatment infusion, every fourth cycle (Cycles 4, 8, 12,…) and at treatment discontinuation. 
p.
Imaging assessments (CT/MRI and bone scans) and PSA should be performed every 9 weeks (63 days ±7 days), at treatment discontinuation and during 
follow-up. The timing of these assessments should not be adjusted for dose delays or cycle starts.
q.
Imaging assessment must be performed within 28 days prior to the subject receiving first retreatment infusion.  Scans performed as part of routine clinical 
management are acceptable if they are of diagnostic quality and performed within 28 days prior to the first dose of retreatment.  
r.
If a scan was obtained within 4 weeks prior to treatment discontinuation, then another scan at discontinuation is not mandatory.  Radiological evaluation 
should be repeated at treatment discontinuation in subjects discontinuing without confirmed disease progression (date of discontinuation ±4 weeks)
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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. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 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.
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7.1.1.1.2 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 
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. The medical 
history will include all active conditions and any conditions diagnosed within the prior 
10 years that are considered clinically significant by the Investigator.  Details pertaining to 
the subject’s prostate cancer diagnosis will be recorded separately and not listed as medical 
history.
7.1.1.4.1 History of Prostate Cancer
The investigator or qualified designee will obtain information regarding the subject’s prostate 
cancer. This information will include but is not limited to the presentation at primary 
diagnosis, date and stage at primary diagnosis, date of and stage at most recent recurrence,
and location of metastases at screening (if applicable).
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review and record prior medication taken by the 
subject within 28 days prior to the first dose of trial treatment.
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7.1.1.5.2 Prior Treatment for Prostate Cancer
The investigator or qualified designee will review and report all prior treatments to prostate 
cancer including systemic treatments, radiation, and surgeries.
7.1.1.5.3 Concomitant Medications
The investigator or qualified designee will record medications taken by the subject during the 
trial up to 30 days after the last dose of trial treatment. All medications related to reportable 
SAEs and ECIs should be recorded as defined in Section 7.2.
7.1.1.5.4 Subsequent Anti-Cancer Therapy Status
The investigator or qualified designee will review all new anti-cancer therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the 
start of the new therapy. Once new anti-cancer therapy has been initiated, the subject will
move into survival follow-up.
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. 
Upon study completion, participants are discontinued from the current study and may be 
transitioned into a pembrolizumab extension study, if available. All participants in the 
extension study will be allocated by non-random assignment and will receive a
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. This number will be 
unique from the treatment/ randomization number in the parent study.
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Trial Compliance (Medication)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between
pembrolizumab (MK-3475) 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.  
The total volume of trial treatment infused will be compared to the total volume prepared to
determine compliance with each dose administered.
The instructions for preparing and administering pembrolizumab (MK-3475) 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 experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if they are events with potential immunologic etiology.  See Section 5.6.1 
regarding the identification, evaluation, and management of AEs of a potential 
immunological etiology.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
Physical Exam
7.1.2.2.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period and at treatment discontinuation. Clinically significant abnormal findings at 
screening should be recorded as medical history.  New clinically significant abnormal 
findings at treatment discontinuation should be recorded as AEs.
7.1.2.2.2 Directed Physical Exam
The investigator or qualified designee will perform a directed physical exam, as clinically 
indicated, prior to dosing on Day 1 of each treatment cycle.  New clinically significant 
abnormal findings should be recorded as AEs.
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Vital Signs
The investigator or qualified designee will assess vital signs at screening, prior to dosing on 
Day 1 of each treatment cycle and at treatment discontinuation. 
Vital signs include 
temperature, heart rate, respiratory rate, weight and blood pressure. Height will be measured 
at screening only.
12-Lead ECG
A standard 12-lead ECG will be performed once at the screening visit using local standard 
procedures.  Clinically significant abnormal findings should be recorded as medical history. 
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG Performance Status (see 
Section 12.5) at screening and prior to dosing on Day 1 of each treatment cycle through 
Cycle 8.  After Cycle 8, ECOG Performance Status will be assessed at every other cycle 
(Cycles 10, 12, 14) and at treatment discontinuation.
Tumor Imaging and Assessment of Disease
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM).  
Tumor imaging should be acquired by CT (strongly preferred) and radionuclide bone scan.  
Magnetic resonance imaging should be used where CT is contraindicated or for imaging in 
the brain.  The same imaging technique regarding modality and use of contrast should be 
used in a subject throughout the trial to optimize the visualization of existing and new tumor 
burden. Tumor imaging by both CT (or MRI) and radionuclide bone scan is required at 
every scheduled imaging time point.
All scheduled images for all subjects must be submitted to the central imaging vendor.  
Imaging obtained at unscheduled time points must also be sent to the central imaging vendor 
if the images support new or worsening metastatic disease based on site assessment.  
Central review of baseline scans will be used to determine cohort assignment.  Local review 
of imaging will be used for subject management.  The central imaging vendor will receive 
radiologic images during the course of the study and will perform an analysis of response to 
treatment.
7.1.2.6.1 Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of first 
dose of trial treatment.  Tumor imaging by both CT (or MRI) and radionuclide bone scan is 
required at screening.
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Scans performed as part of routine clinical management are acceptable for use as the 
screening scans if they are of diagnostic quality, performed within 28 days prior to the date 
of first dose of trial treatment and can be assessed by the central imaging vendor.
Confirmation of measurable disease per RECIST 1.1 by central imaging vendor will be used 
to determine cohort assignment. Subjects with measurable disease per RECIST 1.1 will be 
enrolled in Cohorts 1, 2, and 4.  Subjects with detectable bone metastases by whole body 
bone scintigraphy and no RECIST 1.1-measurable tumors will be enrolled in Cohorts
3 and 5.
The Sponsor allows for evaluation and follow-up of up to 10 soft tissue lesions
(RECIST 1.1).   
At screening, all lesions seen by CT (or MRI) and radionuclide bone scan will be 
documented.
In determining response to treatment or progression, investigators must 
evaluate all target and non-target lesions and search for new lesions at each imaging time
point.
7.1.2.6.2 Tumor Imaging During Trial
In the first year, on study imaging assessments must be performed every 9 weeks (63 days 
±7 days) from the date of allocation for the first year (through week 54 ± 7 days). Subjects 
who remain on treatment beyond the first year will have imaging performed every 12 weeks 
(84 days ±7 days).  Imaging timing should follow calendar days from date of allocation and 
should not be adjusted for delays in cycle starts. 
Response
Per RECIST 1.1, response should be confirmed by a repeat radiographic assessment not less 
than 4 weeks from the date response was first documented.  The scan for confirmation of 
response may be performed ≥4 weeks after the first indication of response or at the next 
scheduled scan, whichever is clinically indicated. Subjects who obtain a repeat scan do not 
need to undergo the next scheduled imaging if it is <4 weeks after the confirmation scan.  
Subjects will return to their regular imaging schedule starting with the next time point.
For any subject with known brain metastases at baseline, and who achieves a CR during trial 
treatment, a follow-up brain scan is required for confirmatory assessment of CR.
Progression
Radiographic progression for soft tissue lesions will be determined according to RECIST 1.1 
(Section 12.7).  Disease progression in soft tissue lesions should be confirmed by the site
≥4 weeks after the first radiologic evidence of PD.  Subjects who have unconfirmed disease 
progression and are clinically stable may continue on treatment at the discretion of the 
investigator until progression is confirmed by the site. Subjects who obtain a repeat scan do 
not need to undergo the next scheduled imaging if it is < 4 weeks after the confirmation scan.  
Subjects will return to their regular imaging schedule starting with the next time point. 
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Subjects who have confirmed disease progression, as assessed by the site, will discontinue 
treatment.
Radiographic progression for bone lesions will be determined as described in the consensus 
guidelines of the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) [44].  
Radiographic progression of bone lesions will be defined as the appearance of ≥2 new bone 
lesions on radionuclide bone scan.  Progression in bone at the first scheduled assessment at 
Week 9, if unaccompanied by soft tissue progression, requires a second radionuclide bone 
scan ≥6 weeks later.  Progression is confirmed to have occurred at the first scheduled 
assessment if the confirmation bone scan shows ≥2 additional new lesions.  Radiographic 
bone progression after the 9 week assessment must be confirmed ≥6 weeks later, if 
unaccompanied by soft tissue progression. Progression is confirmed if the confirmation bone 
scan shows the persistence of ≥2 new bone lesions.  Subjects who have unconfirmed disease 
progression and are clinically stable may continue on treatment at the discretion of the 
investigator until progression is confirmed by the site.  Subjects who have confirmed disease 
progression, as assessed by the site, will discontinue treatment.
If a subject with confirmed radiographic progression is clinically stable or clinically 
improved, and there is no further increase in the tumor dimensions at the confirmatory scan, 
an exception may be considered to continue treatment upon consultation with the Sponsor.  
Clinically stable subjects should also have at the confirmatory scan no further increase in the 
target lesions, no unequivocal increase in non-target lesions and no additional new lesions 
develop (non-worsening PD) to continue study treatment.
Imaging should continue to be performed until documented disease progression, the start of 
new anti-cancer treatment, withdrawal of consent or death, whichever occurs first (Table 5).  
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Table 5
Imaging and Treatment after 1st Radiologic Evidence of PD
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat imaging at 
4 weeks to 
confirm PD (soft-
tissue 
progression)
Repeat bone scan
at 6 weeks to 
confirm PD (bone 
progression)
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scan
Repeat imaging at 
4 weeks to 
confirm PD if 
possible (soft-
tissue 
progression)
Repeat bone scan
at 6 weeks to 
confirm PD if 
possible (bone 
progression)
Discontinue 
treatment
Repeat scan 
confirms PD
No additional 
imaging required
Discontinue 
treatment 
(exception noted 
in Section 7.1.2.6)
No additional 
imaging required
N/A
Repeat scan 
shows SD, PR or 
CR
Continue regularly 
scheduled imaging 
assessments every
9 weeks (every 
12 weeks after
12 months)
Continue study 
treatment at the 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments every
9 weeks (every 
12 weeks after
12 months)
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per Investigator’s 
discretion
7.1.2.6.3 End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If a previous scan was obtained within 4 
weeks prior to the date of discontinuation another scan at treatment discontinuation isn’t 
mandatory. In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required 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 the subject was on during treatment (e.g. every 9 weeks [63 days 
±7 days] from the date of allocation or every 12 weeks [84 days ±7 days] from the date of  
allocation) until: 1) the start of new anti-cancer treatment, 2) disease progression, 3) death or 
4) the end of the study, whichever occurs first.
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7.1.2.6.4 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 
review.
On study imaging assessments should be performed every 9 weeks (63 days ±7 days) after 
the restart of treatment or more frequently if clinically indicated.
If tumor imaging shows initial PD (Section 7.1.2.6.), 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.
Per PCWG3, if radionuclide bone scan shows progression in bone, a radionuclide bone scan 
should be repeated ≥6 weeks later in order to confirm PD with the option of continuing 
treatment while awaiting radiologic confirmation of progression.  Subjects who obtain a 
confirmation bone scan do not need to undergo the next scheduled bone scan and may wait 
until the next scheduled 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.  
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (±4 week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation isn’t 
mandatory. 
In subjects who discontinue trial treatment due to documented disease progression, this is the 
final required tumor imaging.  In subjects who discontinue trial treatment without 
documented disease progression, every effort should be made to continue monitoring their 
disease status by radiologic imaging using the same schedule the subject was on during 
treatment (e.g. every 9 weeks from the date of allocation or every 12 weeks [63 days 
±7 days] from the date of allocation) until: 1) the start of new anti-cancer treatment, 2) 
disease progression, 3) death or 4) the end of the study, whichever occurs first.
7.1.2.6.5 Treatment Beyond Progression
When feasible, subjects should not be discontinued until progression is confirmed by the 
local site investigator/radiology assessment.  This allowance to continue treatment despite 
initial radiologic PD takes into account the observation that some subjects can have a 
transient tumor flare in the first few months after the start of immunotherapy and then 
experience subsequent disease response.  Subjects that are deemed clinically unstable are not 
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required to have repeat tumor imaging for confirmation of PD. Tumor flare includes any of 
the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing non-target lesion(s)

Development of new lesion(s)
In subjects who have shown initial evidence of radiological PD by RECIST 1.1, it is at the 
discretion of the PI whether to continue a subject on study treatment until repeat imaging is 
obtained.  This clinical judgment decision by the site investigator should be based on the 
subject’s overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.
Subjects who are clinically stable may continue receiving study therapy 
until PD is confirmed by repeat imaging assessments.  Progression in soft tissue lesions 
should be confirmed by the site ≥4 weeks after the first radiologic evidence of PD. 
Progression in bone should be confirmed by the site ≥6 weeks after the first radiologic 
evidence of PD. Clinical stability 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, the local site 
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: 

Target lesion sum of diameters is <20 % or <5 mm absolute increase compared to 
nadir

Non-target disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new non-target lesion progression since last evaluation
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If repeat imaging does not confirm PD as assessed by the local site investigator and the 
subject continues to be clinically stable, treatment may continue and follow the regular 
imaging schedule. 
Scenarios where PD is confirmed at repeat imaging if ANY of the following occur:

Target lesion sum of diameters remains ≥20% and at least 5 mm absolute increase 
compared to nadir

Non-target disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation

Additional new non-target lesion progression since last evaluation
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 PD), 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 Study Flowchart and be submitted to the 
central imaging vendor.
Tumor Tissue Collection
Participation in this trial will be dependent upon subjects’ supplying tumor tissue for PD-L1 
biomarker analysis from a site not previously irradiated (tumors progressing in a prior site of 
radiation are allowed for PD-L1 characterization; other exceptions may be considered after 
Sponsor consultation). Adequacy of these specimens for PD-L1 biomarker analysis will be 
required by a central laboratory prior to enrollment. 
Subjects in Cohorts 1, 2, or 4 with visceral/measurable lesions must provide a newly obtained 
biopsy where safely available and an archival specimen, if available.  Candidates for 
enrollment into Cohort 1, 2, or 4 who undergo a study-related biopsy but the tissue sample is 
determined to be inadequate will be allowed onto the study if they have provided an adequate 
archival specimen.  Subjects in Cohorts 3 and 5 must at least provide an archival specimen.  
Subjects whose tumor tissue is adequate for PD-L1 testing but indeterminate will be 
considered to have prostate cancer that is non-PD-L1 positive.
The newly obtained biopsy tissue sample may be one that was obtained at any time prior to 
enrollment, as long as the subject has not received any intervening systemic therapy from the 
time the tissue was collected until the subject enrolls in the study.
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Submission of FFPE tumor tissue blocks are preferred; if submitting unstained slides, 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.
Neither the archival tissue sample nor newly obtained biopsy (obtained ≤12 months prior to 
screening date) is required to have been obtained within 42 days of enrollment.  Subjects 
must sign the main study consent prior to submitting existing tissue samples and/or 
undergoing a new biopsy.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Procedures Manual.
Tumor Marker Assessment (PSA)
The initial Prostate-Specific Antigen (PSA) biomarker assessment at screening must be 
performed within 28 days prior to the date of allocation/Cycle 1.  
In the first year (through week 54), on study PSA biomarker assessments must be performed 
every 9 weeks (63 days ±7 days) from the date of allocation. After one year, subjects who 
remain on treatment will have PSA performed every 12 weeks (84 days ±7 days).  PSA
timing should follow calendar days from the date of allocation and should not be adjusted for 
delays in cycle starts.
In Cohorts 4 and 5, screening PSA by central results are required during the screening period 
as part of eligibility and should be drawn and sent to the central lab to ensure the result is 
available in time for allocation. PSA biomarker assessment must occur every 3 weeks (± 3 
days) from the date of allocation/Cycle 1 while the subject is on trial treatment (at weeks 3 
and 9) up to cycle 4 (week 12) then follow the imaging schedule as described above. PSA 
timing should follow calendar days from the date of allocation and should not be adjusted for 
delays in cycle starts.
In subjects who discontinue trial treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by PSA biomarker 
assessments using the same schedule the subject was on during treatment (e.g. every 9 weeks 
[63 days ±7 days from the date of allocation] or every 12 weeks [84 days ±7 days from the 
date of  allocation]) until: 1) the start of new anti-cancer treatment, 2) disease progression, 
3) death or 4) the end of the study, whichever occurs first.
Patient Reported Outcomes (PROs)
The EQ-5D and FACT-P questionnaires should be completed electronically by subjects in 
the following order: EQ-5D first, then FACT-P. The questionnaires should be administered at 
Cycles 1, 2, 3, and 4 and every 3 cycles thereafter (Cycles 7, 10, 13, 16, and 19), at treatment 
discontinuation, and again 30 days after the last dose of trial treatment.
It is a best practice and strongly recommended that ePROs are administered to randomized 
subjects prior to drug administration, adverse event evaluation, and disease status 
notification.  If the subject does not complete either of the ePRO questionnaires, the reason 
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the assessment was not performed must be captured in the appropriate study electronic case 
report form.  
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.
Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Platelet Count
Alanine 
Aminotransferase (ALT)
Protein
PT (INR)
WBC (Total and 
Differential)
Aspartate 
Aminotransferase (AST)
Specific Gravity PTT / aPTT
Red Blood Cell Count Lactate Dehydrogenase 
(LDH)
Microscopic 
Examb
(If abnormal 
results are 
noted)
Total Triiodothyronine 
(T3)c
Absolute Neutrophil 
Count
Carbon Dioxidea
(CO2 or bicarbonate)
Free Thyroxine (FT4)
Absolute Lymphocyte 
Count
Uric Acid
Thyroid Stimulating 
Hormone (TSH)
Calcium
Blood for Genetic 
Analysis
Chloride
Blood for Correlative 
Studies
Glucose
Total Testosterone
Phosphorus
Prostate-Specific 
Antigen (PSA)
Potassium  
Sodium
Magnesium
Total Bilirubin
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Hematology
Chemistry
Urinalysis
Other
Direct Bilirubin (If total 
bilirubin is elevated 
above the upper limit of 
normal)
Total protein
Blood Urea Nitrogen
(BUN) is preferred but 
Urea can be used if 
BUN not available
Creatinined
Alkaline Phosphatase
Albumin
a.
If considered standard of care in your region.
b.
Institutional standards are acceptable.
c.
Free T3 may be performed in place of Total T3 per local standards
d.
GFR (measured or calculated) or CrCl can be used in place of creatinine.
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  
After Cycle 1, pre-dose laboratory procedures may be conducted up to 72 hours prior to 
dosing.  Results of scheduled laboratory tests must be reviewed by the investigator or 
qualified designee and found to be acceptable prior to each dose of trial treatment. Any 
results found to be clinically unacceptable may be repeated.
There may be instances when sites are unable to obtain the thyroid function testing results 
prior to scheduled dosing. After Cycle 1, review of thyroid function test (T3, FT4, and TSH)
results after dosing is acceptable.
Pharmacokinetic/Pharmacodynamic Evaluations
To evaluate the immunogenicity and exposure of pembrolizumab in this indication, sample 
collections for analysis of ADAs and PK are currently planned as shown in the Trial 
Flowchart (Section 6.1) for Cohorts 1 to 3 only. Blood samples for PK and ADA collected 
may be stored at this time. Further 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. 
7.1.3.2.1 Blood Collection for Serum MK-3475
PK serum samples must be drawn within 24 hours before infusion at Cycles 1, 2, 4, 6 and 8.
Post-dose PK serum samples will be drawn within 30 minutes after the end of infusion at 
Cycles 1 and 8. Additional single PK samples should be drawn at the following time points 
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after Cycle 1: 24 hours (±4 hours) [Day 2], between 72 and 168 hours [Day 4-8], and 
336 hours (±48 hours) [Day 15].
Sample collection, storage and shipment instructions will be in the Procedures Manual.
7.1.3.2.2 Blood Collection for Anti-pembrolizumab Antibodies
Pre-dose anti-pembrolizumab antibody (ADA) samples must be drawn at the same time 
points as the pre-dose PK serum samples, as simultaneous PK sampling is required for 
interpretation of ADA analysis.
Sample collection, storage and shipment instructions will be in the Procedures Manual.
7.1.3.2.3 Blood Collection for RNA Analyses/Plasma and Serum Biomarker Analyses
Blood for RNA analyses, blood for plasma biomarker analyses and blood for serum 
biomarker analyses must be collected pre-dose at Cycles 1, 2, and 5 and at treatment 
discontinuation. Leftover samples may be kept for future biomedical research if the subject 
signs the FBR consent.
Sample collection, storage and shipment instructions will be in the Procedures Manual.
7.1.3.2.4 Blood Collection for CTC
Blood for CTC will be collected at Cycle 1 and at treatment discontinuation. Leftover 
samples may be kept for future biomedical research if the subject signs the FBR consent.
Sample collection, storage and shipment instructions will be in the Procedures Manual.
7.1.3.2.5 Blood Collection for ctDNA
Blood for ctDNA will be collected at Cycle 1, pre-infusion (if the collection coincides with a 
treatment cycle) every 9 weeks for the first year (through week 54) (63 days ±7 days), every 
12 weeks in the second year, and at treatment discontinuation.  The timing of these 
assessments should not be adjusted for dose delays or cycle starts. Leftover samples may be 
kept for future biomedical research if the subject signs the FBR consent.
Sample collection, storage and shipment instructions will be 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:
DNA for future research.
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
Leftover archival tumor tissue or leftover newly obtained biopsy sample 

Leftover RNA

Leftover Plasma and Serum from biomarker analyses

Leftover Blood for CTC and Blood for ctDNA

Leftover Blood for AR-V7
Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the End-of-Treatment 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.
7.1.4.1.1 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 
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.
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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 inclusion labs and trial assessments

Imaging equipment- as required for trial objectives

Infusion equipment- as required for administering drug product.
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
Approximately 42 days prior to enrollment, 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.  
After providing main study consent subjects will be assigned a screening number.  Subjects 
must sign the main study consent prior to submitting existing tissue samples and/or 
undergoing a new biopsy. Requirements pertaining to submission of tissue samples are found 
in Section 7.1.2.7.
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame.  
Screening procedures are to be completed within 42 days prior to the first dose of trial 
treatment.  The following procedures need to be performed within the specified time frames:

Laboratory tests within 10 days prior to the first dose of trial treatment (unless 
otherwise noted in the protocol).

ECOG within 10 days prior to the date of treatment allocation.

Baseline imaging assessments by CT (or MRI) and bone scan within 28 days prior to 
the first dose of trial treatment.

Prostate-Specific Antigen (PSA) tumor marker assessment within 28 days prior to the 
date of allocation.  
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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.
The subject identification card will be updated with the screening number.
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
7.1.5.2.1 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab (MK-3475) with SD or better may be eligible for up to 
17 additional infusions of pembrolizumab (MK-3475) therapy if they progress after stopping 
MK-3475.  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 (MK-3475) after attaining an 
investigator-determined confirmed CR according to RECIST 1.1

Was treated for at least 8 administrations with pembrolizumab 
(MK-3475) before discontinuing therapy

Received at least two treatments with pembrolizumab (MK-3475)
beyond the date when the initial CR was declared
OR
o
Subject had SD, PR or CR and stopped study treatment after completion of 
35 administrations (approximately 2 years) of pembrolizumab (MK-3475)
treatment for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab (MK-3475)

Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
(MK-3475)

Has a performance status of 0, 1, or 2 on the ECOG Performance Scale

Demonstrate adequate organ function as detailed in Section 5.1.2

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.
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Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab (MK-3475).  Treatment will be administered for up to 17 additional 
administrations of pembrolizumab (approximately one year).
Visit requirements are outlined in Section 6.1 – Trial Flow Chart. 
Post-Treatment
Subjects will be required to return to clinic approximately 30 days after the last dose of trial 
drug for the post-treatment visit.  If the post-treatment visit occurs less than 30 days after the 
last dose of trial drug, a subsequent follow-up phone call should be made at 30 days post the 
last dose of trial drug to determine if any adverse events have occurred since the post-trial 
clinic visit.
7.1.5.3.1 Survival Follow-up
Subjects who experience confirmed disease progression or start a new anticancer therapy, 
will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the trial, whichever occurs first.  The Sponsor may request survival 
status be assessed at additional time points during the course of the study.  For example, 
these additional time points may be requested prior to an efficacy interim analysis and/or 
final analysis.  All subjects who are not known to have died prior to the request for these 
additional survival status time points will be contacted at that time.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor.  For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.  Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
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 
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.
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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 Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
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 for pembrolizumab defined as any dose greater than 1000 mg or greater. 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.
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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 
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), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time 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 of subjects 
and female partners of male subjects 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. 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;
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●
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.
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 specified 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, 
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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. 
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 outlined in this section will not be reported to the Sponsor as described 
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 a 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.
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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
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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.)
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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.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after 
the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analysis, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study. A separate PK analysis plan, as well as biomarker analysis plan, will be 
provided. Post hoc exploratory analyses will be clearly identified in the CSR. The PRO 
analysis plan will also be included in the sSAP.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.11.  
Study Design Overview
Phase II Trial of Pembrolizumab (MK-3475) in Subjects with mCRPC 
Treatment Assignment
This is a single-arm, open-label study. All subjects will receive 
pembrolizumab 200 mg administered intravenously (IV) every 3 weeks 
(Q3W).  
Analysis Populations
Efficacy: The All Subjects as Treated (ASaT) population will serve as 
the primary population for the analysis of efficacy data in this study.
The ASaT population consists of all allocated subjects who received at 
least one dose of study treatment.
The analysis population for ORR consists of all subjects with 
measurable disease at baseline in ASaT. 
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
Cohorts 1, 2, and 4: Objective response rate (ORR) per RECIST 1.1 
assessed by central imaging vendor 
Secondary Endpoints
Duration of response (DOR) per RECIST 1.1 and PCWG3-modified 
RECIST 1.1, disease control rate (DCR), radiographic progression-free 
survival (rPFS) where progressive disease (PD) in bone metastases will 
be determined by radionuclide bone scan using PCWG3 criteria and PD 
for all other tumors will be determined using by RECIST 1.1 by central 
imaging vendor, PSA response rate, time to PSA progression, overall 
survival (OS)
Cohorts 4 and 5 only: duration of PSA response, time to initiation of 
cytotoxic chemotherapy, time to new-anticancer therapy, time to first 
skeletal-related event
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Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
For ORR: the point estimate and 95% CI will be calculated using an 
exact method based on binomial distribution (Clopper-Pearson method)
Statistical Methods for Key 
Safety Analyses
Count and percentage of AEs will be provided. 
Interim Analyses
The interim analysis is summarized below.  Details are provided in 
Section 8.7. 
Timing: To be performed about 27 weeks after the first 100 subjects
with RECIST 1.1-measurable disease (Cohorts 1 and 2) and all subjects 
in Cohort 3 have been enrolled. 
Scope of analyses: ORR, DOR and safety will be evaluated 
Multiplicity
There will be no hypothesis testing performed in this study. For the 
primary and secondary objectives in this Phase II study, no adjustment 
to control for Type I error is planned. 
Sample Size and Power 
The planned sample size is approximately 370 including:
Cohorts 1-3: subjects with mCRPC previously treated with docetaxel-
based chemotherapy; Cohort 1 includes subjects with PD-L1 positive, 
RECIST 1.1-measurable disease and Cohort 2 includes subjects with 
PD-L1 negative, RECIST 1.1-measurable disease (n≈200 in Cohorts 1 
and 2 combined); Cohort 3 includes subjects with bone-metastases, 
RECIST 1.1 non-measurable (n≈50)
Cohorts 4 and 5: subjects who are on pre-chemotherapy enzalutamide 
treatment and failing or showing early signs of failing enzalutamide 
treatment
Cohort 4: subjects with RECISIT 1.1-measurable disease (n≈80)
Cohort 5: subjects bone metastases only or bone-predominant disease, 
RECIST 1.1 non-measurable (n≈40)  
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 is an open-label trial; therefore, the Sponsor, investigators, and subjects will know the 
treatment administered. 
Association between biomarker status and clinical response/resistance will be explored. The 
subjects-level biomarker results will be masked in the database to the study team, including 
clinical, statistical, statistical programming, and data management personnel throughout the 
study period until database lock for the primary study report. Access to the biomarker 
subject-level results will be limited to an unblinded Sponsor clinical scientist, unblinded 
Sponsor data management personnel, unblinded Sponsor statistician, and unblinded Sponsor 
statistical programmer who will be responsible for biomarker data review and analysis. 
Analyses related to biomarker scores will be conducted by a sponsor unblinded statistician.
Unblinded analyses related to biomarker scores will be limited to biomarker score vs 
outcome at the interim analysis and conducted by a sponsor unblinded biomarker statistician.
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Hypotheses/Estimation
This trial is being conducted as an open-label study. There is no randomization in the study. 
Objectives and associated estimations of the study are stated in Section 3.
Analysis Endpoints
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Primary

Objective Response Rate (ORR) – per RECIST 1.1 assessed by central imaging 
vendor
Proportion of subjects in the analysis population who have complete response (CR) or partial 
response (PR) where responses are determined by RECIST 1.1 assessed by central imaging 
vendor.
Secondary

Duration of Response (DOR) – per PCWG3-modified RECIST 1.1 assessed by 
central imaging vendor
For subjects who demonstrated CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until progressive disease (PD) assessed by central imaging where PD 
will be determined by radionuclide bone scan using RECIST 1.1/PCWG3 criteria and PD for 
all other tumors will be determined using RECIST 1.1 or death due to any cause, whichever 
occurs first.

Duration of Response (DOR) – per RECIST 1.1 assessed by central imaging vendor
For subjects who demonstrated CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until progressive disease (PD) assessed by central imaging using 
RECIST 1.1 or death due to any cause, whichever occurs first.

Disease Control Rate (DCR) – per PCWG3-modified RECIST 1.1 assessed by 
central imaging vendor
Proportion of subjects in the analysis population who have CR or PR or stable disease (SD) 
for at least 6 months, by central imaging vendor where PD in bone-only tumors will be 
determined by radionuclide bone scan using PCWG3 criteria and PD for all other tumors will 
be determined using RECIST 1.1.

PSA Response Rate
Proportion of subjects in the analysis population who have PSA response defined as at least
50% decline from baseline measured twice at least 3 weeks apart.
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
Time to PSA Progression
Time to PSA progression is defined as the time from first day of study treatment to the date 
of PSA progression. Subjects without PSA progression will be censored at the last PSA 
assessment date. PSA progression is defined as the date that an increase of 25% or more and 
an absolute increase of 2 ng/mL or more from the nadir are documented. For subjects who 
have a decline in PSA during treatment, PSA progression must be confirmed by a second 
value 3 or more weeks later increased with respect to the nadir PSA.

Radiographic progression-free survival (rPFS) – per PCWG3-modified RECIST 1.1 
assessed by central imaging vendor
Progression-free-survival (rPFS) is defined as the time from first day of study treatment to 
the documented disease progression by central imaging vendor where PD in bone-only 
tumors will be determined by radionuclide bone scan using PCWG3 criteria and PD for all 
other tumors will be determined using RECIST 1.1 or death due to any cause, whichever 
occurs first.

Overall Survival (OS)
Overall survival (OS) is defined as the time from first day of study treatment to the time of 
death.

Duration of PSA response (Cohorts 4 and 5 only)
Duration of PSA response is defined as the time from PSA response, when the PSA value 
first declines by at least 50% of the baseline (must be confirmed by a second value), to the 
date of PSA progression at which there is an increase of 25% or more from the nadir PSA, 
provided the absolute increase from the nadir PDA is at least 2 ng/mL.  

Time to initiation of cytotoxic chemotherapy (Cohorts 4 and 5 only)
Time to initiation of cytotoxic chemotherapy is defined as the time from first day of study 
treatment to the time of initiation of cytotoxic chemotherapy for prostate cancer. 

Time to new-anticancer therapy (Cohorts 4 and 5 only) 
Time to new-anticancer therapy is defined as the time from first day of study treatment to the 
time of new-anticancer therapy for prostate cancer

Time to first skeletal-related event (Cohorts 4 and 5 only) 
Time to initiation of first skeletal-related event is defined as the time from first day of study 
treatment to the first skeletal-related event, which is defined as radiation therapy or surgery 
to bone, pathologic bone fracture, spinal cord compression, or change or antineoplastic 
therapy to treat bone pain. See Section 8.6.1 for censoring rules.
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Safety Endpoints
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with mCRPC. The primary safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE 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).
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
attribution to study treatment, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs will be analyzed including but 
not limited to all AEs, SAEs, fatal AEs, and laboratory changes.
Analysis Populations  
Subjects will be entered into the trial when they are assigned an allocation number by the 
IVRS/IWRS.
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will serve as the primary population for the 
analysis of efficacy data in this study. The ASaT population consists of all allocated subjects 
who received at least one dose of study treatment.
The analysis of DCR, PSA response rate, time to PSA progression, time to initiation of 
cytotoxic chemotherapy, time to new-anticancer therapy, time to first skeletal-related event, 
rPFS, and OS will be based on the ASaT population.  
The analysis of ORR will be based on all subjects with measurable disease at baseline in the 
ASaT population. 
The analysis of DOR will be based on all responders with measurable disease at baseline in 
the ASaT population.
The analysis of duration of PSA response will be based on all PSA responders with at least 
50% decline from baseline measured twice at least 3 weeks apart. The primary analysis will 
comprise all subjects with measurable PSA at baseline; the secondary analysis will comprise 
all subjects with elevated PSA at baseline as a sensitivity analysis.
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all allocated subjects who received at least one 
dose of study treatment. 
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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.
Biomarker Discovery Population
The biomarker discovery population consists of the first 100 subjects with RECIST1.1-
measurable disease in Cohorts 1 and 2 who are clinically evaluable, which is defined as any 
subjects who received at least one dose of study drug and had at least 3 post-baseline scans, 
or discontinued due to radiographic/clinical progression or death before reaching Week 27. 
The biomarker discovery population will be used in this study for the evaluation of the 
association between biomarker score and clinical efficacy and subsequently to determine a 
biomarker cut-point (if applicable and necessary). The biomarker discovery population will 
be excluded from any subsequent validation analyses for any biomarker selected population, 
if applicable. These subjects will still be included in the general efficacy analyses for 
combined cohorts and by each cohort irrespective of biomarker status. 
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 8.6.2. In addition, 
separate SAPs will describe the analysis of Pharmacokinetic (PK) data described in Section 
7.1.3.2 and a biomarker analysis plan.
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory objectives will be described in the supplemental 
SAP.
For ORR, DCR and PSA response rate, the point estimate and 95% confidence interval will 
be provided using the exact binomial method proposed by Clopper and Pearson (1934). 
Subjects in the analysis population without response data will be counted as non-responder.
For rPFS, DOR, time to PSA progression, duration of PSA response, time to initiation of 
cytotoxic chemotherapy, time to new-anticancer therapy, time to first skeletal-related event, 
and OS, Kaplan-Meier (KM) curves and median estimates from the KM curves will be 
provided as appropriate.
Censoring rules for DOR are summarized in Table 8. 
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Table 8
Censoring Rules for DOR
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new anti-
cancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new anti-
cancer therapy initiated
Last adequate disease assessment before 
new anti-cancer therapy initiated
Censor
(non-event)
Death or progression after ≥2 missed 
adequate disease assessments
Last adequate disease assessment prior to 
the after ≥2 missed adequate disease 
assessments
Censor
(non-event)
Death or progression after ≤1 missed 
adequate disease assessments
PD or death
End of response
(Event)
Subjects are considered to have an ongoing response if censored, alive, have not progressed, have not started a new anti-
cancer therapy and have not been determined to be lost to follow-up 
Table 9 summarizes the key efficacy analyses.
Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data 
Approach
ORR per RECIST 1.1 assessed 
by central imaging vendor
Exact method based on 
binomial 
distribution 
(Clopper-Pearson
method)
Subjects with measurable 
disease at baseline in ASaT 
in all below populations

Cohorts 1 and 2

Cohort 1

Cohort 2

Cohort 4
Subjects with missing 
data are considered 
non-responders
DOR per RECSIT 1.1 and per 
PCWG3-modified RECIST 1.1 
assessed by central imaging 
vendor
Summary 
statistics 
using 
Kaplan-Meier 
method
Responders with measurable 
disease at baseline in ASaT 
in all below populations

Cohorts 1 and 2

Cohort 1 

Cohort 2

Cohort 4
Details are provided 
in a separate table
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Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data 
Approach
DCR
per 
PCWG3-modified
RECIST 1.1 assessed by central 
imaging vendor
Exact method based on 
binomial 
distribution 
(Clopper-Pearson 
method)
ASaT 

Cohorts 1+2+3

Cohorts 1+2

Cohorts 4+5

Each Cohort
Subjects with missing 
data are considered 
disease 
not 
under 
control
PSA Response Rate
Exact method based on 
binomial 
distribution 
(Clopper-Pearson 
method)
ASaT 

Cohorts 1+2+3

Cohorts 1+2

Cohorts 4+5

Each Cohort
Subjects with missing 
data are considered 
non-responders
Time to PSA Progression
Summary 
statistic 
using 
Kaplan-Meier 
method
ASaT 

Cohorts 1+2+3

Cohorts 1+2

Cohorts 4+5

Each Cohort
Censored 
at 
last 
assessment date
Radiographic PFS per PCWG3-
modified RECIST 1.1 assessed 
by central imaging vendor
Summary 
statistics 
using 
Kaplan-Meier 
method
ASaT 

Cohorts 1+2+3

Cohorts 1+2

Cohorts 4+5

Each Cohort
Censored 
at 
last 
assessment date
OS
Summary 
statistics 
using 
Kaplan-Meier 
method
ASaT 

Cohorts 1+2+3

Cohorts 1+2

Cohorts 4+5

Each Cohort
Censored at last date 
known alive
Duration of PSA response
Summary 
statistics 
using 
Kaplan-Meier 
method
PSA responders in 

Cohorts 4 and 5

Cohort 4

Cohort 5
Censored 
at 
last 
assessment date if no 
new 
anti-cancer 
therapy initiated or 
last adequate disease 
assessment 
before 
new 
anti-cancer 
therapy initiated
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Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis Population
Missing Data 
Approach
Time to initiation of cytotoxic 
chemotherapy 
Summary 
statistics 
using 
Kaplan-Meier 
method
ASaT in 

Cohorts 4 and 5

Cohort 4

Cohort 5
Censored at last date 
known alive
Time to new-anticancer therapy
Summary 
statistics 
using 
Kaplan-Meier 
method
ASaT in 

Cohorts 4 and 5

Cohort 4

Cohort 5
Censored at last date 
known alive
Time to first skeletal-related 
event 
Summary 
statistics 
using 
Kaplan-Meier 
method
ASaT in 

Cohorts 4 and 5

Cohort 4

Cohort 5
Censored at last date 
known alive
Statistical Methods for Safety Analyses
Safety will be summarized for the overall safety population for Cohorts 1, 2, and 3 in the 
post-chemotherapy population and overall safety for Cohorts 4 and 5 in the pre-
chemotherapy population. If there is no difference among individual patient populations, an 
overall analysis will be performed. 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests, and vital signs. Count and percentage of AE will 
be provided. 
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate. The summary statistics of count and percentage will be 
provided for the incidence rate of any AE, any serious AE, any Grade 3-5 AE, any drug-
related AE, any serious and drug-related AE, any Grade 3-5 and drug-related AE, dose 
interrupted due to AE, discontinuation due to AE, any immune-related AE (irAE), death and 
specific AEs.
The summary statistics of mean and standard deviation will be provided for change from 
Baseline Results (Labs and Vital Signs) within each treatment cycle. The summary statistics 
of count and percentage will be provided for laboratory worsening from Baseline in terms of 
CTCAE grades.
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Statistical Methods for Biomarker Analyses 
The evaluation of a general positive association between biomarker score and ORR/DCR will 
be investigated via standard logistic regression as well as generalized additive models. The 
profiles of PPV (positive predictive value), NPV (negative predictive value), and the 
percentage of subjects above a given cut-off, along with intervals quantifying the uncertainty 
in those profiles, will be estimated as a function of potential cut-offs. A biomarker cut-off 
that maintains high NPV (e.g., near or above 90%) while achieving meaningful enrichment 
of response and largely capturing subjects showing durable clinical benefit is sought. 
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. 
Summaries of Baseline Characteristics, Demographics, and Other Analyses
The number and percentage of subjects screened, enrolled, the primary reasons for screening 
failure, and the primary reason for discontinuation will be displayed.  Demographic 
variables, baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
Interim Analysis
Efficacy and safety data will be monitored over time in this single-arm, open-label, multi-
cohort study.    
One interim analysis will be conducted in the first 100 subjects with RECIST 1.1-measurable 
disease by RECIST 1.1 (Cohort 1 and Cohort 2) and all subjects in Cohort 3 at about 
27 weeks after the completion of enrollment of all these subjects.  Other analyses at the 
interim analysis will include DOR and safety.
A biomarker analysis is planned at the time of the interim analysis where a subset of subjects 
(the biomarker discovery population, about 100 subjects from Cohorts 1 and 2, see Section 
8.5.3 for details) will be used to explore the association between the biomarker score and 
clinical efficacy/resistance and also to determine the biomarker cut-point. More subjects may 
be allocated to the biomarker discovery population, if necessary.
The final analysis of ORR in the population with measurable disease by RECIST 1.1 will be 
performed after all subjects have been enrolled and all subjects have accumulated mature 
data and had adequate follow-up.  All other analyses, including safety, DOR, DCR, PSA 
response, time to PSA progression, rPFS, and OS will be analyzed at this time.
Multiplicity
There will be no hypothesis testing performed in this study. For the primary and secondary 
objectives in this Phase II study, no adjustment to control for Type I error is planned.  
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Sample Size and Power Calculations
The primary objective of this study is to estimate ORR in Cohorts 1 and 2 combined, Cohort 
1, Cohort 2, and Cohort 4. The planned sample size is approximately 370 with about
200 subjects in Cohorts 1 and 2, 50 subjects in Cohort 3, 80 subjects in Cohort 4, and 
40 subjects in Cohort 5. With a sample size of 200, 100, and 80, the confidence intervals for 
an observed response rate of 10%, 15%, 20%, 25% and 30% are listed below for 95% 
confidence level (Table 10). In addition, about 50 subjects with bone-predominant disease at 
baseline for Cohort 3 will be enrolled. 
Table 10
Confidence Intervals for Different Observed Response Rates and Sample Size
Sample Size
Number of Subjects 
with a response
Observed 
Response 
Rate
95% CI
95% CI
Width
200
20
10%
(6.2%, 15.0%)
8.8%
200
30
15%
(10.4%, 20.7%)
10.4%
200
40
20%
(14.7%, 26.2%)
11.5%
200
50
25%
(19.2%, 31.6%)
12.4%
200
60
30%
(23.7%, 36.9%)
13.1%
100
10
10%
(4.9%, 17.6%)
12.7%
100
15
15%
(8.6%, 23.5%)
14.9%
100
20
20%
(12.7%, 29.2%)
16.5%
100
25
25%
(16.9%, 34.7%)
17.8%
100
30
30%
(21.2%, 40.0%)
18.7%
80
8
10%
(4.4%, 18.8 %)
14.3%
80
12
15%
(8.0%, 24.7 %)
16.7%
80
16
20%
(11.9%, 30.4 %)
18.6%
80
20
25%
(16.0%, 35.9 %)
19.9%
80
24
30%
(20.3%, 41.3 %)
21.0%
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Subgroup Analyses and Effect of Baseline Factors
For the primary objective ORR, subgroup analyses to be performed include but may not be 
limited to following subgroups based on 

Age (<65 years, ≥65 years)

Race

PD-L1 expression level (positive, negative),

And biomarker status as appropriate

RECIST-measurability (yes, no)
Categories of subgroup may be subject to change according to actual data. Categories with 
few than 5 subjects might not be considered or might be combined into other categories.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
the study medication infusion. Summary statistics will be provided on Extent of Exposure for 
ASaT population.
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 
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.
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Table 11
Product Description
Product Name & 
Potency
Dosage Form
Source/Additional Information
Pembrolizumab 
(MK-3475) 50 mg
Lyophilized powder for 
IV infusion
Provided centrally by the Sponsor.
Pembrolizumab 
(MK-3475) 100 mg/4 mL 
(25 mg/mL)
Solution for IV infusion
Provided centrally by the Sponsor
All supplies indicated in Table 11 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 11 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label pembrolizumab (MK-3475), supplied either as vials 
containing 50 mg of lyophilized powder, or as kits containing 2 vials of solution for infusion.
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.
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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 
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.
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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;
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 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 
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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.
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, 
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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.
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.
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Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. 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 
FDAAA or the EMA clinical trials directive 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 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
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 
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 
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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 
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.
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11.0 LIST OF REFERENCES
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3. Al-Shibli KI, Donnem T, Al-Saad S, et al. Prognostic effect of epithelial and stromal 
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4. Deschoolmeester V, Baay M, Van Marck E, et al. Tumor infiltrating lymphocytes: an 
intriguing player in the survival of colorectal cancer patients. BMC Immunol. 
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5. Galon J, Costes A, Sanchez-Cabo F, et al. Type, density, and location of immune cells 
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6. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
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7. Nobili C, Degrate L, Caprotti R, et al. Prolonged survival of a patient affected by 
pancreatic adenocarcinoma with massive lymphocyte and dendritic cell infiltration after 
interleukin-2 immunotherapy. Report of a case. Tumor. 2008;94(3):426-30.
8. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol. 2010;37 (Suppl 1):48-53.
9. Hillen F, Baeten CIM, van de Winkel A, et al. Leukocyte infiltration and tumor cell 
plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer 
Immunol Immunother. 2008;57(1):97-106.
10. Lee HE, Chae SW, Lee YJ, et al. Prognostic implications of type and density of tumour-
infiltrating lymphocytes in gastric cancer. Br J Cancer. 2008;99(10):1704-11.
11. Leffers N, Gooden MJM, de Jong RA, et al. Prognostic significance of tumor-infiltrating 
T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. 
Cancer Immunol Immunother. 2009;58(3):449-59.
12. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800.
13. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nat
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14. Brown JA, Dorfman DM, Ma F-R, et al. Blockade of programmed death-1 ligands on 
dendritic cells enhances T cell activation and cytokine production. J Immunol. 
2003;170(3):1257-66.
15. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Ann Rev Immunol. 
2005;23:515-48.
16. Zhang X, Schwartz J-CD, Guo X, et al. Structural and functional analysis of the 
costimulatory receptor programmed death-1. Immunity 2004;20(3):337-47.
17. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42.
18. Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-
mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 
2 to phosphotyrosine. Proc Natl Acad Sci U S A. 2001;20(24):13866-71.
19. Sheppard KA, Fitz LI, Lee JM, et al. PD-1 inhibits T-cell receptor induced 
phosphorylation of ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. 
FEBS Lett. 2004;574(1-3):37-41.
20. Chemnitz JM, Parry RV, Nichols KE, et al. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
human T cell stimulation, but only ligation prevents T cell activation. J Immunol. 
2004;173(2):945-54.
21. Parry RV, Chemnitz JM, Frauwirth KA, et al. CTLA-4 and PD-1 receptors inhibit T-cell 
activation by distinct mechanisms. Mol Cell Biol. 2005;25(21):9543-53.
22. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface 
of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8:765-72.
23. Nishimura H, Agata Y, Kawasaki A, et al. Developmentally-regulated expression of the 
PD-1 protein on the surface of double-negatibe (CD4– CD8–) thymocytes. Int Immunol. 
1996;8:773-80.
24. Nishimura H, Honjo T, Minato N. Facilitation of β selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med. 2000;191(5):891-7.
25. Fourcade J, Kudela P, Sun Z, et al.PD-1 is a regulator of NY-ESO-1-specific CD8+ T 
cell expansion in melanoma patients. J Immunol. 2009;182:5240-9.
26. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following 
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-57.
27. Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous 
CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-703.
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28. Ölcher M, Braun M, Friedrichs N, et al. Foxp3+ cell infiltration and granzyme 
B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant chemotherapy-treated 
ovarian carcinoma. Cancer Immunol Immunother. 2010;59(6):909-19.
29. Hamid O, Robert C, Daud A, et. al. Safety and tumor responses with lambrolizumab 
(anti-PD 1) in melanoma. N Engl J Med. 2013;369(2):134-44.
30. Humphrey, WHO, 2014.
31. Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics 2011: the impact of eliminating 
socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin.
2011. 2011;61(4):212-36.
32. Tannock I, de Witt R, Berry W, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502-12.
33. de Bono J, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone 
for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a 
randomised open-label trial. Lancet. 2010;376(9747):1147-54.
34. Ryan CJ, Smith M, de Bono JS, et al. Abiraterone in metastatic prostate cancer without 
previous chemotherapy. N Engl J Med. 2013;368(2):138-48.
35. Beer TM, Armstrong A, Rathkopf D, et al. Enzalutamide in metastatic prostate cancer 
before chemotherapy. N Engl J Med. 2014;371(5):424-33.
36. Topalian S, Hodi FS, Brahmer JR, et al.  Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443-54.
37. Antonarakis E, Lu C, Wang H, et al.  AR-V7 and resistance to enzalutamide and 
arbiterone in prostate cancer. N Engl J Med. 2014;371(11):1028-38.
38. Bishop JL, Sio A, Angeles A, Roberts M, Azad A, Chi K, et al. PD-L1 is highly 
expressed in enzalutamide resistant prostate cancer. Oncotarget. 2014;6:234-242.
39. Cheng HH, Gulati RR, Nadal R, Twardowski P, Vaishampayan UN, Agarwal N, et al. 
Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is 
affected by prior treatment with abiraterone and/or docetaxel. Prostate Cancer and 
Prostatic Disease. 2015 18, 122–127.
40. Suzman D, Luber B, Schweizer M, Nadal R, Antonarakis E. Clinical activity of 
enzalutamideversusdocetaxel in men with castration-resistant prostate cancer progressing 
afterabiraterone. The Prostate. 2014;74:1278-1285.
41. Graff J, Alumkal J, Drake C, Thomas G, Redmond W, Farhad, et al. Early evidence of 
anti-PD-1 activity in enzalutamide-resistant prostate cancer. Oncotarget. 2016;1-8.
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42. Scher HI, Halabi S, Tannock I, et al. Design and end points of clinical trials for patients 
with progressive prostate cancer and castrate levels of testosterone: recommendations of 
the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26(7):1148-59.
43. Scher H, Morris M, Stadler W, et al. Trial design and objectives for castration-resistant 
prostate cancer: updated recommendations from the prostate cancer clinical trials 
working group 3. J Clin Oncol. 2016;34(12):1402-18.
44. Esper P, Mo F, Chodak G, et al. Measuring quality of life in men with prostate cancer 
using the functional assessments of cancer therapy prostate instrument. Urol. 
1997;50(6):920-8.
45. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
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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. 
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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."
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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 7.1.3.3 – 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 
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signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of subject 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.
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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 
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.
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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 
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 future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address 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
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
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List of Abbreviations
Abbreviation/Term
Definition
AE
Adverse Event
ADA
Anti-Drug Antibodies
ADCC
Antibody-dependent Cell-mediated Cytotoxicity
ADT
Androgen deprivation therapy
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AR-V7
Androgen-receptor isoform encoded by splice variant 7
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
BCG
Bacillus-Calmette Guerin (vaccine)
BOR
Best Overall Response
C1D1
Cycle 1 day 1
Cmax
Maximum concentration
Ctrough
Minimum concentration
CAC
Clinical Adjudication Committee
CBC
Complete Blood Count
CDC
Complement-dependent Cytotoxicity
CFR
Code of Federal Regulations
CI
Confidence Interval
CL
Clearance
CNS
Central Nervous System
CPS
Combined Positive Score
CR
Complete Response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTA
Clinical trial assay
CTC
circulating tumor cell assay 
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
dL
Deciliter
DCR
Disease Control Rate
DKA
Diabetic Ketoacidosis
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
EBMT
European Group for Blood and Marrow Transplantation 
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
ELISA
Enzyme-linked Immunoassay 
ERC
Ethics Review Committee
EU
European Union
FACT-P
Functional Assessment of Cancer Therapy-Prostate
FAS
Full Analysis Set
FBR
Future Biomedical Research 
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation/Term
Definition
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin fixed and paraffin embedded 
FSH
Follicle Stimulating Hormone
g
Gram
GCP
Good Clinical Practice
GCSF
Granulocyte Colony Stimulating Factor
GI
Gastrointestinal
GM-CSF
Granulocyte Macrophage - Colony Stimulating Factor
HCB
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
hr
Hour
HRQOL
health-related quality of life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
INR
International Normalized Ratio
irRECIST
immune-related RECIST
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
IV
Intravenous
IVRS
Integrated Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
LDH
Lactate Dehydrogenase
LHRH
Luteinizing-Hormone-Releasing Hormone
LOCF
Last Observation Carried Forward
mAb
Monoclonal antibody
mCRPC
Metastatic Castration-resistant Prostate Cancer
mcL
Microliters
MedDRA
Medical Dictionary for Regulatory Activities
MEL
Melanoma 
mg
Milligram
mL
Milliliter
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic acid
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MSI
Microsatellite instability
MTD
Maximum Tolerated Dose
NA or N/A
Not Applicable
NCI
National Cancer Institute
NK
Natural Killer
NPV
Negative predictive value
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-small Cell Lung Cancer
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-the-Counter
PCWG3
Prostate Cancer Working Group 
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Abbreviation/Term
Definition
PD
Progressive Disease
PD-1
Programmed Cell Death 1 Receptor
PD-L1
Programmed Cell Death Ligand 1 Receptor
PD-L2
Programmed Cell Death Ligand 2 Receptor
PFS
Progression Free Survival
PI
Principal Investigator
PIN
Personal Identification Number
PK
Pharmacokinetic
PO
Oral Administration
PPV
Positive predictive value
PR
Partial Response
PRES
Posterior reversible encephalopathy syndrome
PRO
Patient reported outcome
PSA
Prostate-specific Antigen
PT
Prothrombin Time
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
QALY
Quality-adjusted life-years 
QoL
Quality of Life
RNA
Ribonucleic Acid
rPFS
Radiographic Progression Free Survival
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
T3
Total Thyroidothyronine
T4
Free Tyroxine
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
US
United States
V
Volume
Variable-type
V-type
WBC
White Blood Cell
WOCBP
Woman/women of childbearing potential
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ECOG Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
*Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
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Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
The descriptions and grading scales found in the revised NCI Common Terminology Criteria
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting.
(http://ctep.cancer.gov/reporting/ctc.html).
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique
in this study.
* As published in the European Journal of Cancer [41].
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Contraceptive Guidance
Definition
Women of Childbearing Potential (WOCBP) Nonparticipant Only
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):

Women in the following categories are not considered WOCBP:
-
Premenarchal
-
Premenopausal female with 1 of the following:
-
Hysterectomy
-
Bilateral salpingectomy
-
Bilateral oophorectomy
-
Permanent infertility due to an alternate medical cause other than the above (eg, 
Mullerian agenesis, androgen insensitivity.
-
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.
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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 – TRIAL PROCEDURES (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
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