Phase II Study of Neoadjuvant Pembrolizumab Plus Intensive Androgen Axis Blockade Prior to Prostatectomy for High Risk Localized Prostate Cancer
Phase: PHASE2
Conditions: Prostate Cancer
Sponsor: Mark Garzotto, MD

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Oregon Health & Science University 
OHSU Knight Cancer Institute 
VA Portland Health Care System 
IND:   Pending 
Sponsor:   Merck 
IRB Protocol #: 15235 
Version Date:  07/13/2017 
 
TITLE:  Phase II study of neoadjuvant pembrolizumab plus intensive androgen axis 
blockade prior to prostatectomy for high risk localized prostate cancer 
 
Coordinating Center: 
 
 
Portland VA Research Foundation 
 
Principal Investigator: 
Mark Garzotto , MD 
VA Portland Health Care System, Portland, OR 
 
 
(503) 220-8262 x 51982 
garzotto@ohsu.edu 
 
Clinical Co-Investigators: 
 
 
Tomasz Beer, MD 
Medical Oncology, OHSU, VAPORHCS 
 
Joshi Alumkal, MD 
Medical Oncology, OHSU 
 
 
 
Julie Graff, MD 
Medical Oncology, OHSU, VAPORHCS 
 
Ryan Kopp, MD 
Urologic Oncology, OHSU, VAPORHCS 
 
Correlative Science Investigator:  
 
 
George Thomas, MD 
Urologic Pathology, OHSU 
 
Statistician: 
 
Motomi Mori, PhD, MBA 
 
 
Director, Biostatistics Shared Resource, OHSU 
 
Study Coordinator:  
Wesley Stoller, MA 
OHSU, VAPORHCS 
(503) 220-8262 x 54868 
stoller@ohsu.edu 
 
Supplied Agents: 
Pembroluzimab (Keytruda®), Merck  
Enzalutamide (Xtandi®), Medivation 
 

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TABLE OF CONTENTS 
 
1.0 TRIAL SUMMARY ........................................................................................................... 5 
1.1 
OBJECTIVES ................................................................................................................ 5 
2.0 TRIAL DESIGN ................................................................................................................. 6 
2.1 Trial Design. ................................................................................................................... 6 
2.2 Trial Diagram .................................................................................................................. 6 
3.0 STUDY HYPOTHESES & OBJECTIVES ........................................................................ 6 
3.1 Objectives ....................................................................................................................... 6 
3.2 Hypotheses ...................................................................................................................... 6 
3.3 Primary Endpoint ............................................................................................................ 6 
3.4 Secondary Endpoints ...................................................................................................... 7 
3.5 Exploratory Endpoints: ................................................................................................... 7 
4.0 
BACKGROUND & RATIONALE ............................................................................... 8 
4.1 
Background ................................................................................................................ 8 
4.1.1  Pembrolizumab Pharmaceutical and Therapeutic Background .............................. 9 
4.1.2  Preclinical and Clinical Trial Data ........................................................................ 10 
4.2 Rationale ....................................................................................................................... 10 
4.2.1 Rationale for the Trial and Selected Subject Population ....................................... 10 
4.2.2 Rationale for Pembrolizumab Dose Selection/Regimen/Modification.................. 11 
4.2.3 Rationale for Endpoints ......................................................................................... 13 
5.0 METHODOLOGY ........................................................................................................... 14 
5.1 Entry Criteria ................................................................................................................ 14 
5.1.1  Diagnosis/Condition for Entry into the Trial ........................................................ 14 
5.1.2  Subject Inclusion Criteria ..................................................................................... 14 
5.1.3 Exclusion Criteria .................................................................................................. 16 
5.2 Trial Treatments ............................................................................................................ 18 
5.2.1.3  Timing of Dose Administration ......................................................................... 20 
5.3 Trial Blinding/Masking ................................................................................................. 20 
5.4 Concomitant Medications/Vaccinations (allowed & prohibited) ................................. 20 
5.4.1 Acceptable Concomitant Medications ................................................................... 21 
5.4.2 Prohibited Concomitant Medications .................................................................... 21 
5.5 
Rescue Medications & Supportive Care for Pembrolizumab .................................. 22 
5.5.1  Supportive Care Guidelines .................................................................................. 22 
5.6 Diet/Activity/Other Considerations .............................................................................. 27 

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5.6.2 
Contraception .................................................................................................... 27 
5.7 
Subject Withdrawal/Discontinuation Criteria .......................................................... 28 
5.8 
Subject Replacement Strategy .................................................................................. 29 
5.9 
Clinical Criteria for Early Trial Termination ........................................................... 29 
5.10  Duration of Treatment .............................................................................................. 29 
5.11 Duration of Follow-up .............................................................................................. 30 
6.0 STUDY FLOW CHART .................................................................................................. 30 
7.0 TRIAL PROCEDURES .................................................................................................... 31 
7.1 Trial Procedures ............................................................................................................ 31 
7.1.1  Administrative Procedures .................................................................................... 31 
7.1.2 Clinical Procedures/Assessments........................................................................... 33 
7.1.3 Laboratory Procedures/Assessments ..................................................................... 33 
7.2 Assessing and Recording Adverse Events .................................................................... 37 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ..................................................................................................... 38 
7.2.2 
Immediate Reporting of Adverse Events to the Sponsor and to Merck ........... 38 
7.2.2.1 
Serious Adverse Events ................................................................................. 38 
7.2.3 
Evaluating Adverse Events ............................................................................... 40 
7.2.4 
Sponsor Responsibility for Reporting Adverse Events .................................... 44 
8.0 
STATISTICAL CONSIDERATIONS......................................................................... 44 
8.1 Study Design ................................................................................................................. 44 
8.2 Primary and Secondary Endpoints ................................................................................ 44 
8.3 Analysis Populations ..................................................................................................... 44 
8.4 Statistical Analysis Plan ................................................................................................ 45 
8.5 Sample Size and Power ................................................................................................. 46 
8.6 Randomization Method ................................................................................................. 46 
8.7 Handling of Missing Data ............................................................................................. 46 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
 
46 
9.1 
Investigational Product ............................................................................................. 46 
9.2 
Packaging and Labeling Information ....................................................................... 47 
9.3 
Clinical Supplies Disclosure .................................................................................... 47 
9.4 
Storage and Handling Requirements ........................................................................ 47 
9.5 
Returns and Reconciliation ...................................................................................... 47 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS ............................................... 47 

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10.1 Confidentiality ............................................................................................................ 47 
10.2 Compliance with Financial Disclosure Requirements ................................................ 48 
10.3 Compliance with Law, Audit and Debarment ............................................................ 48 
10.4 Compliance with Trial Registration and Results Posting Requirements .................... 48 
10.5 Quality Management System ...................................................................................... 48 
10.6 Data Management ....................................................................................................... 48 
11 APPENDICES ................................................................................................................ 50 
11.1 ECOG Performance Status ....................................................................................... 50 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...................... 50 
11.3 The Clavien-Dindo Classification of Surgical Complications ................................... 50 
11.5 Expanded Prostate Cancer Index Composite .............................................................. 52 
11.6 BIOSPECIMEN PROCEDURES ............................................................................... 52 
11.6.1  Tissues Samples .................................................................................................. 52 
11.6.2  Serum Samples: .................................................................................................. 53 
12.0  DATA REPORTING/REGULATORY REQUIREMENTS ......................................... 53 
12.1 Data Collection and Storage ....................................................................................... 53 
12.2 Protocol Review .......................................................................................................... 54 
12.3 Informed Consent........................................................................................................ 54 
12.4 Changes to Protocol .................................................................................................... 54 
12.5 Maintenance of Records ............................................................................................. 54 
12.6 OHSU IRB Reporting of Unanticipated Problems and Adverse Events .................... 55 
12.7 OHSU Knight Cancer Institute Data and Safety Monitoring Plan ... Error! Bookmark 
not defined. 
12.8 Inclusion of Women, Minorities and Children......................................................... 55 
12.8.1 Inclusion of Women and Minorities ................................................................. 55 
12.8.2 Inclusion of Children ........................................................................................... 55 
13.0 REFERENCES ............................................................................................................... 55 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Neoadjuvant Pembrolizumab Plus Intensive Androgen 
Axis Blockade Prior to Prostatectomy 
Trial Phase 
Phase II 
Clinical Indication 
High-risk localized Prostate Cancer  
Trial Type 
Open Label, single arm 
Type of control 
Historic controls 
Route of administration 
Intravenous Pembrolizumab,  oral enzalutamide, 
subcutaneous (SQ) or intramuscular (IM) GNRH agonist  
Trial Blinding 
none 
Treatment Groups  
Single arm 
Number of trial subjects 
32 
Estimated enrollment 
period 
12 months 
Estimated duration of 
trial* 
1.5 years 
Duration of 
Participation** 
5.5 years 
Estimated average length 
of treatment per patient 
4 months 
*Duration of trial period includes enrollment and treatment period for all patients.     
** Duration of participation as the treatment period plus 5 years of follow-up 
 
 
 
 
1.1 OBJECTIVES   
Trial Concept: Intensive androgen receptor (AR) targeting has effects on prostate cancer in 
terms of lowering tumor androgen levels and inducing tissue responses, but fails to achieve 
frequent pathologic complete responses as monotherapy.   Agents which incorporate 
targeting alternative mechanisms of resistance are needed to achieve biologic responses that 
translate into meaningful and durable clinical benefits.  We propose to study the effects of 
pembrolizumab combined with intensive AR targeting prior to prostatectomy with extended 
pelvic lymph node dissection in subjects with high-risk localized prostate cancer (HRLPC). 
A strength of the neoadjuvant model is that biomarkers can be assessed by obtaining 
rigorously collected tissue specimens from the pre-and post-treatment settings.  This will 
allow for the most valid comparison of drug effectiveness.  The successful demonstration of 
efficacy and safety with this drug combination would promote widespread interest in 
carrying out trials of this regimen with surgery and radiation for intermediate and high-risk 
prostate cancers. If successful, these trials could in turn lead to changing the standard of care 
for the treatment of locally advanced prostate cancer.           
 

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2.0 TRIAL DESIGN 
2.1 Trial Design- single arm, single-stage open label Phase II of neoadjuvant immune-
hormonal therapy in high-risk Localized prostate cancer.   
  
2.2 Trial Diagram 
 
 
 
3.0 STUDY HYPOTHESES & OBJECTIVES 
 
3.1 Objectives 
To evaluate efficacy and safety of pembrolizumab combined with intensive AR targeting 
prior to prostatectomy in subjects with high-risk localized prostate cancer (HRLPC). 
 
3.2 Hypotheses 
(1) Treatment with the pembrolizumab and intensive AR axis inhibition will result in an 
increased rate of pathologic complete responses (pCR) for high-risk localized prostate 
cancer. (2) Neoadjuvant pembrolizumab combined with intensive AR axis inhibition will 
result in long-term disease control of high-risk localized prostate cancer.    
 
3.3 Primary Endpoint 
Pathologic complete response (pCR) defined as absence of detectable malignant cells in the 

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prostatectomy specimen evaluated by standard histologic techniques.   
 
3.4 Secondary Endpoints  
1. Grade 3 or higher treatment related adverse events; 
2. Grade 2 or higher Immune-related adverse events (irAEs).  
3. pCR in patients stratified by pre-operative prostate infiltrating T-cell PD-1 
expression defined as none/low, medium, high (See section 7.3 pg 41)  
4. Biochemical complete response rate prior to surgery (i.e. PSA< 0.1 ng/mL). 
5. Incidence of surgical complications within 30 days post-surgery using Clavien-
Dindo Classification of Surgical Complications. 
 
3.5 Exploratory Endpoints:   
1. Five-year incidence of cancer directed treatment.   
2. Changes from pre- to post-treatment serum, blood and tissue markers of the 
immune response.   
3. Correlation of changes in markers of inflammatory response with clinical 
outcomes including pCR, PSA response and disease free survival.   
4. Clincal or Biochemical recurrence-free survival at five years (i.e. PSA< 0.1 
ng/mL).     
5. Changes in health related quality of life (HRQOL) measured by EPIC quality of 
life) from Week 0 vs. 16. 
6. Safety and tolerability of Pembrolizumab, defined as Pembrolizumab related 
adverse event of any grade and drug dose modification 
 
Type 
Endpoint 
Definition 
Primary 
Pathologic Complete 
Response (pCR) 
No cancer detected on path exam of 
prostatectomy specimen 
Secondary 
Grade 3+ Treatment Related 
Adverse Events (AE) 
Grade 3 or higher AE possibly related or 
related to any of three treatment drugs 
(pembrolizumab, enzalutamide, GNRH 
agonist) per CTCAE v4.03, evaluated up 
until 30 days after prostatectomy 
Secondary 
Grade 2+ Immune –related 
AE 
Grade 2 or higher immune related AE 
possibly related or related to any of three 
treatment drugs (pembrolizumab, 
enzalutamide, GNRH agonist) per 
CTCAE v4.03, evaluated up until 30 days 
after prostatectomy 
Secondary 
Biochemical Complete 
Response 
PSA < 0.1 ng/mL prior to prostectomy 
Secondary 
Incidence of Surgical 
Complications 
Clavien-Dindo Classification of Surgical 
Complications compared to historical 
department incidence rates. 
Exploratory 
Safety and tolerability of 
Pembrolizumab 
All AE’s that are related or possibily 
related to Pembrolizumab, drug 

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compliance (pharmacy record) and any 
instance of dose modification. 
Exploratory 
Five-year incidence of 
cancer directed therapy 
Time from completion of prostatectomy 
till initiation of new prostate cancer-
directed therapy during five years. Those 
who are alive and free of cancer directed 
therapy are censored at the date of last 
contact, and those who die without 
additional cancer directed therapy are 
censored at the date of death.  
Exploratory 
Compare pre- and post-
treatment markers of 
inflammatory response in 
blood and tissue 
Compare baseline to post-treatment 
markers measured just prior to 
prostatectomy (see Section 7.3 for a list of 
biomarkers to be studied).  
Exploratory 
5-year disease free survival 
Period of time from completion of 
prostatectomy till when patient has a 
cancer recurrence defined both in terms of 
clinical or biochemical (PSA) or both. 
Exploratory 
Change in HRQOL 
Intra-patient change in EPIC HRQOL 
from baseline to 16 weeks prior to 
surgery. 
 
 
 
 
 
 
 
 
 
 
.     
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
 
Use of androgen deprivation is considered standard therapy for advanced prostate cancer and 
has been intensively studied in the locally advanced prostate cancer setting.    In this trial, 
pembrolizumab will be added to two FDA-approved agents for the treatment of prostate 
cancer (i.e. enzalutamide and GNRH agonists).    
 
Pembrolizumab is a human, monoclonal antibody directed against the programmed death 
receptor (PD-1) T-cell surface marker.   It is currently indicated for the treatment of advanced 
melanoma and metastatic non-small cell lung cancer.  There are several ongoing studies of 
this drug in prostate cancer, but no data are available for locally advanced prostate cancer.   
The goal will be to combine this agent with drugs that target the androgen-receptor axis in a 
HRLPC cohort that has elected surgery as primary treatment.         
 
Enzalutamide is a potent AR inhibitor that is indicated for the treatment of metastatic 

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castration-resistant prostate cancer (See Package insert).    For this study, this drug will be 
utilized in an earlier disease state than what it is currently FDA-indicated for.    
 
GNRH agonist therapy (ie leuprolide and goserelin) is a reversible luteinizing hormone 
receptor agonist which blocks the production of luteinizing hormone and subsequently 
testosterone production.    It is indicated for advanced prostate cancer (See package inserts).    
The study population in this trial would qualify for this treatment under this general category. 
 
Since both enzalutamide and GNRH agonists are indicated for prostate cancer therapy, there 
is already a well-established rationale for use of these agents in prostate cancer.  The 
following section will focus on pembrolizumab which has only been studied in a limited 
fashion in prostate cancer.   
 
 
4.1.1 Pembrolizumab Pharmaceutical and Therapeutic Background 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells 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).  
The structure of murine PD-1 has been resolved.  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.  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.  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.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  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 .  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.  

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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.  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 melanoma (MEL).  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. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor AND platinum-refractory non-small cell lung cancer that expresses PD-L1. 
 
4.1.2  Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 Rationale 
 
4.2.1 Rationale for the Trial and Selected Subject Population 
 
High-risk Localized Prostate Cancer: an area of unmet need: Technical advances in 
surgery and radiation therapy have resulted in improved prostate cancer (PC) outcomes; 
however, disease recurrence and PC-mortality remain a high, particularly for those with 
HRLPC.1  Features predictive of adverse outcomes include Gleason grade and disease extent.   
In a randomized trial of prostatectomy vs. observation, PC-specific mortality was 5-fold 
higher for high-grade versus low-grade cancers and 14-fold higher for extracapsular disease 
vs. organ-confined disease.2  In a study by Stephenson et al., PC-mortality was 34% at 15 
years in HRLPC.3   Novel therapies that improve both systemic and local tumor control are 
urgently needed in order to reduce the burden of disease in PC. 
 
Androgen deprivation alone is inadequate in HRLPC: AR signaling is a primary means 
of tumor cell resistance in PC (Chen and Sawyers 2004).   Targeting of the AR axis has been 
established to improve the efficacy of both radiation4  and chemotherapy5  in PC.   The 
potential of intensive AR inhibition has been recently demonstrated in a series of pre-
prostatectomy studies.   For patients with intermediate- and high-risk PC, treatment with the 
androgen biosynthesis inhibitor abiraterone acetate and LHRH agonist resulted in a 7% 
pathologic complete response rate.6  Similarly, in a study using a four drug anti-AR 
combination, 1 out of 13 patients with primarily intermediate-risk disease achieved a 
pathologic complete response .7  The addition of and androgen biosynthesis inhibitor to and 
anti-androgen has recently been evaluated in the pre-operative setting.   In a pre-operative 
study of abiraterone with enzalutamide there were no pathologic CRs in 44 patients.   

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Importantly, there have been no adverse safety signals for any of these agents in the pre-
operative setting (Efstathiou ASCO 2016).  Novel combinations that work in synergy with 
AR targeting are needed to maximize the potential of these newer agents in use for PC.  
 
PD-1 T-cell upregulation as a mechanism for cancer cell progression: Programmed death 
receptor-1 (PD-1), is a CD8+ T-cell receptor, which is suppressed as a normal part of T-cell 
regulation and prevention of autoimmunity.8   PD-1 interacts with its ligands PD-L1 and PD-
L2 or other peptides from the tumor microenvironment, resulting in the blockade of CD8+ T-
cell activation and proliferation.9 Tumor cells stimulate the expression of T-cell PD-1, 
thereby inhibiting an effective immune response.10 Pembrolizumab is a fully humanized 
monoclonal antibody, which binds to the PD-1 receptor, thus blocking the binding of 
potential ligands from tumor cells or other sources.  This agent is FDA-approved for second-
line treatment of melanoma and non-small cell lung cancer, but has not been thoroughly 
investigated in PC.  With the support of Merck this agent is presently being studied at OHSU 
(PI: J Graff) for metastatic castration-resistant prostate cancer (CRPC) patients 
(NCT02312557). 
 
PD-1 as a target for prostate cancer: Prior studies investigating the potential for immune-
based therapies in PC have shown that PD-1 is a promising target.  Prostate-infiltrating CD8+ 
T cells highly express PD-1 in PC specimens but rarely in the non-cancerous prostate 
gland.11 Up to 90% of PC infiltrating T-cells highly express the PD-1 receptor, which is 
consistent with a non-functional “exhausted” phenotype.10   The investigators concluded that 
high PD-1 expression renders the “T-cells incapable of mounting an effective anti-tumor 
immune response” possibly due to production of an inhibitory peptide derived from the H4 
histone.12 Furthermore, in patients with high Gleason scores (≥7), the effect appears to be 
systemic as peripheral blood T-cells also highly express PD-1 relative to controls.   Thus, 
inhibition of PD-1 could result in the potent anti-neoplastic effects on both local and systemic 
PC.     
 
Pembrolizumab in combination with enzalutamide -OHSU ongoing study:  In an 
ongoing Phase II single arm study of men with metastatic CRPC, Graff et al.  have shown 
promising signs of anti-PD1efficacy in this population.13  Three of  10 men treated had PSA 
reduction to <0.2 ng/mL and 2 of 10 showed partial responses.  Adverse events included 
grade 2 myositis (n=1),grade 3 hypothyroidism (n=1), and one had grade 2 hypothyroidism 
(n=1).   The study is planned for an additional 18 patients to be accrued (total = 28).    
 
4.2.2 Rationale for Pembrolizumab Dose Selection/Regimen/Modification  
 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 

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D of this protocol to test for initial tumor activity.  Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 

13 
Rationale for combination of pembrolizumab with anti-androgen therapy: Targeted 
anti-androgen therapy can have dramatic effects on the host tumor; however these agents 
usually result in relatively short term gains of several months in terms of overall survival.14   
At the cellular level these agents may induce cell death and cause the release of highly 
specific tumor antigens (a process known as “cross-priming”).15   Under the right conditions 
(such as with anti-PD-1 or PD-L1 therapy) these antigens could be taken up by antigen 
presenting cells (APCs) which could initiate an effective immune response.   Thus, there is a 
significant potential for synergistic effects between immunologic and anti-androgenic agents 
in prostate cancer. This strategy holds the potential for long-term tumor remission, a 
phenomena that has been observed in several tumors including melanoma and non-small cell 
lung cancer.  Currently, numerous trials looking at combinations of novel immunologic 
therapies in combination with established therapies such as radiation, chemotherapy and 
small molecule inhibitors are underway.16  However, to our knowledge, this approach is not 
being studied in high-risk localized prostate cancer.     
 
4.2.3 Rationale for Endpoints 
 
4.2.3.1 Efficacy Endpoints:  The primary efficacy endpoint is the elimination of all tumor 
cells as observed on standard pathologic sampling in a prostatectomy specimen.   Pathologic 
CR (pCR) is a validated endpoint in a number of solid tumor types.  In breast cancer, pCR 
correlates well with overall survival (OS).  Compared to radiographic changes, Funt and 
Chapman have proposed pCR as a “more biologically rational method of determining 
treatment effect that may be more likely to predict OS” as compared to radiographic 
changes.17  pCR has been considered an endpoint worthy of pursuit in high-risk localized 
prostate cancer where the rate of pCR is relatively low with current treatment regimens. Thus 
any significant improvement over the current baseline rate would be of great interest to the 
research community.   This endpoint will give a relatively quick readout for efficacy 
compared to long-term clinical endpoints which will require several years before it can be 
attained and may require trial randomization to make valid comparisons. Clinical and 
biochemical recurrence free survival and time to secondary treatment will also be studied as 
secondary endpoints. These will be compared to historic controls using established data from 
clinical nomograms (ie MSKCC).     
 
4.2.3.2  Safety Endpoints:  The safety of this combination will be assessed for any 
unforeseen toxicity in combination or when used in the pre-operative setting.  The hormonal 
agents have previously been given in combination prior to surgery and demonstrate no safety 
concerns.  There are no known overlapping toxicities between so the expectation is that the 
regimen will be considered safe.   Pembrolizumab plus enzalutamide is currently under study 
in patients with more advanced disease, and there are no unforeseen safety issues to date (J. 
Graff: personal communication).   Further, we will assess the changes in HRQOL before, 
during and post-treatment using EPIC.  We will assess surgical measures of safety and record 
intraoperative and post-operative metrics using standard case report forms as done previously 
by our group, the results of which are shown in table 7.18    
 
4.2.3.3  Translational Endpoints: Tissues will be examined from biopsy specimens and the 
levels of PD-1 expression will be assess by independent laboratory assessment by 

14 
immunohistochemistry (IHC).  PD-1 tissue levels will be done by independent assessment by 
Merck, who will be blinded to all clinical data.  These levels will be correlated with treatment 
response (pCR: yes vs. no).  Additional exploratory markers will be studied for treatment 
effects in both tissue and serum (see section 7.3). Dr. George Thomas (urologic pathologist, 
OHSU) will carry out remaining tissue assessments for IHC.  Serum samples will be 
evaluated for pre- and post-treatment changes to evaluate the effect of treatment on serum 
markers of the immune response (See section 7.3).  These analyses will be used to explore 
possible means of tumor resistance and immune tolerance.     
 
 
 
5.0 METHODOLOGY 
 
5.1 Entry Criteria 
 
5.1.1  Diagnosis/Condition for Entry into the Trial 
 
PATIENT POPULATION  
Potentially eligible patients will be identified by any of the study investigators in multi-
disciplinary clinics at either OHSU or the Portland VAMC. All patients will be required to 
have at least one high-risk criteria (see inclusion criteria).  For each patient the number of 
high-risk features will be recorded.      
 
5.1.2  Subject Inclusion Criteria 
 Be willing and able to provide written informed consent/assent for the trial.  
 Capability to understand and comply with the protocol and signed informed consent 
document. 
 Be  18 years of age on day of signing informed consent.   
 Have measurable disease based on RECIST 1.1.   
 Be willing to provide tissue from a newly obtained core or excisional biopsy of a 
tumor lesion.  Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit 
an archived specimen only upon agreement from the Sponsor. 
 Histologically confirmed, non-metastatic adenocarcinoma of the prostate 
 Prostatectomy with extended lymph node dissection planned as primary therapy 
 10 year or longer life expectancy based on other co-morbidities 
 Have a performance status of 0 or 1 on the ECOG Performance Scale. 
 
 
 Any one of the following three high risk features: 
 Gleason grade > 8-10 
 PSA > 20 ng/ml 
 Clinical stage T3a (resectable) 
 No evidence of lymph nodes > 2 cm in diameter on pelvic CT scan (scan only 
required in patients with a PSA > 20 ng/ml) 
 No evidence of metastases on nuclear bone scan (required on all pts) 

15 
 Tumor tissue must be provided for subsequent biomarker analyses. (PD-1 
classification not required for study enrollment) A subject must have a PD-1 
expression classification (positive, negative, or indeterminate) as determined by the 
central lab. If insufficient tumor tissue content is provided for analysis, acquisition of 
additional archived tumor tissue (block and /or slides) for the biomarker analysis is 
required. 
 No other diagnosis of malignancy (with exception of non-melanoma skin cancer or a 
malignancy diagnosed ≥5 years ago). 
 Male subjects of childbearing potential (Section 5.6.2) must agree to use an adequate 
method of contraception as outlined in Section 5.6.2- Contraception, starting with the 
first dose of study therapy through the time of surgery. Note: Abstinence is acceptable 
if this is the usual lifestyle and preferred contraception for the subject. 
 Demonstrate adequate organ function as defined in Error! Not a valid bookmark 
self-reference., all screening labs should be performed within 30 days of treatment 
initiation.   
 
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count 
(ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or 
EPO dependency (within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN 
AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time 
(PT) 
 
Activated Partial 
Thromboplastin Time (aPTT) 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 
of intended use of anticoagulants 
≤1.5 X ULN unless subject is receiving 
anticoagulant therapy 
as long as PT or PTT is within therapeutic range 

16 
of intended use of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
 
 
5.1.3 Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
 
 Has significant active medical illness, which in the opinion of the investigator would 
preclude protocol treatment (e.g. uncontrolled pulmonary, renal, or hepatic 
dysfunction, uncontrolled infection, cardiac disease). 
 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.   
 Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
 Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
 History of prolonged QT interval or congestive heart failure.   
 Prior history of seizures 
 Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.” 
 Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
 Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
 Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
 Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
o Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
o Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
 Has any other prior therapy for prostate cancer including: 
o Anti-androgen therapy including orchiectomy, LHRH therapy, anti-androgen 
therapy, abiraterone, ketoconazole, estrogen therapy (Short-term ADT 
allowed, ≤ 2 months) 
o Radiation (external beam or brachytherapy) 
o Cytotoxic chemotherapy 
o Any experimental therapy for treatment of prostate cancer.  

17 
 
 Received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.   
 Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy. 
 Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.   
 Has a history of or known presence of extensive, disseminated/bilateral or Grade 3 or 
4 interstitial fibrosis or interstitial lung disease, including a history of pneumonitis, 
hypersensitivity pneumonitis, interstitial pneumonia, interstitial lung disease, 
obliterative bronchiolitis, or pulmonary fibrosis, but not including a history of prior 
radiation pneumonitis.  
 Has a known history of active TB   (Bacillus Tuberculosis) 
 Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
 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. 
 Has an active infection requiring systemic therapy. 
 Used systemic corticosteroids within 21 days.  Inhaled or topical steroids allowed.   
 Has a hypersensitivity to pembrolizumab, Enzalutamide, specific GNRH agonists or 
any of their excipients. 
 Has a gastrointestinal disorder affecting absorption 
 Subjects who received prior therapy with interferon, anti-PD-1, anti-PD-L1, anti-PD-
L2, anti-CD137, or anti-CTLA-4 antibody 
 Is currently using warfarin 
 Is using strong CYP2C8 inhibitors (e.g gemfibrozil) 
 Is using strong CYP3A4 inhibitors or inducers (e.g., itraconazole, carbamazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine)  
 Has a history of allergies (Grade 3 or above) to humanized antibodies.  
 Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
 Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
 Is unable or unwilling to abide by the study protocol or cooperate fully with the 
investigator or designee 
 Is unable to undergo research related pre-treatment biopsy are excluded as this is 
necessary to complete translational study objectives.    

18 
 
5.2 Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. In this study, 
pembrolizumab will be added to two FDA-approved drugs routinely used for the treatment of 
prostate cancer.  Surgery will be performed approximately between week 14 and 16 which 
will allow for a 2-4 week washout for pembrolizumab.  Other study medication will continue 
up until the time of surgery.       
 
Table 2:  Study drugs under investigation 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 
mg  
Q3Weeks 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Enzalutamide 
160 
mg 
Daily 
Oral 
16 weeks 
Experimental 
GNRH agonist 
therapy (ie 
leuprolide and 
goserelin)* 
 
 
 
 
 
* GNRH Agonist will be given as approved for androgen deprivation at a dose necessary to 
maintain castrate levels and equivalent to 22.5 mg of Leuprolide IM every 3 months (e.g., 
leuprolide 45 mg IM every 6 months is equivalent to leuprolide 22.5 mg IM every 3 months). 
 
5.2.1 Dose Selection/Modifications: Pembroluzimab (Keytruda®)   
 
5.2.1.1 Dose Selection:  
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.  Details on preparation and administration of pembrolizumab 
(MK-3475) are provided in the Pharmacy Manual.   
 
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per 3 below. See Section 5.5.1 
for supportive care guidelines, including use of corticosteroids. 
 
Table 3:  Dose Modification Guidelines for Drug-Related Adverse Events 
 
 

19 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus or 
Grade 3-4 hyperglycemia 
associated with evidence of beta 
cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can 
be continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidis
m  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can 
be continued while thyroid 
replacement therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or 
equal to 50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one 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; Refer to Error! Reference source not found. – Infusion Treatment Guidelines for 
further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently 
discontinue study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not 
recover to Grade 0-1 within 12 weeks of the last dose. 
 
 
 

20 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
5.2.1.3 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons.  All trial treatments will be administered on an 
outpatient basis. 
 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 
0.2 micron to 5 micron in-line or add-on filter (See Package Insert).  The drug will not co-
administer other drugs through the same infusion line. The Pharmacy Manual contains 
specific instructions for the preparation of the pembrolizumab infusion fluid and 
administration of infusion solution. 
 
5.2.2 Dose Selection/Modifications: Enzalutamide (Xtandi®)   
 
5.2.2.1 Dose Selection: The dose is derived from the prior trials that lead to the approval of 
this agent.   (See Package insert for details).  This will be self-administered as 4 capsules 
daily for a total of 160 mg per day.   
 
5.2.2.2 Dose Modification (Escalation/Titration/Other).  There are no planned dose 
modifications.   If a patient experiences toxicity thought to be attributed to the study 
drug that is Grade 3 or higher, then the medication will be withheld until resolution or 
stabilization of symptoms   
5.2.2.3 Timing of Dose Administration 
Enzalutamide will be self-administered orally on a daily basis from Day 1 of treatment until 
the day before surgery.    The dose will be 160 mg and the drug will be distributed by the 
Research Pharmacist at each treatment center.   
 
5.3  
Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, principal investigator and subject will be 
aware of the treatment administered. 
 
5.4 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 one of these or other medications 

21 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
 
5.4.1 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. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and Event of Clinical Interest ECIs as defined in Section 7.2. 
5.4.2 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  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 

22 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5 Rescue Medications & Supportive Care for Pembrolizumab 
5.5.1 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 adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous 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 the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience 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.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis,  administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 

23 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 

24 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.  
 Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Error! Reference source not found. below shows treatment guidelines for subjects 
who experience an infusion reaction associated with administration of 
pembrolizumab (MK-3475). 
Table 4 Infusion Reaction 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 infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor 
symptoms. 
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 one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
Subject may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
antipyretic). 

25 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 
(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 trial treatment 
administration. 
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: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
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. 
Subject is permanently 
discontinued from further trial 
treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
 
 
 
 
5.5 Androgen Receptor Targeting Study Drugs 
 

26 
5.5.1 Enzalutamide (Xtandi®) 
 
In this study, patients will receive daily oral doses of study drug (enzalutamide 160 mg/day), 
which will be administered as four capsules/day to be taken at or near the same time each 
day.  Any missed doses will be omitted (Extra doses are not allowed).  Enzalutamide can be 
taken with or without food.  Enzalutamide is currently FDA-approved for the treatment of 
advanced metastatic, castration resistant prostate cancer.  It has the chemical name 3-(4-
cyano-3-trifluoromethylphenyl)-1-[3-fluoro-4-(methylcarbamoyl) phenyl]-5,5-dimethyl-2-
thioxoimidazolin-4-one.   
 
In pre-clinical assays, enzalutamide has been shown to have superior efficacy to bicalutamide 
in blocking AR activation .19  Enzalutamide has been shown to inhibit bicalutamide-resistant 
prostate cancer cells through AR targeting by three distinct molecular processes which 
include blockade of testosterone binding, inhibition of DNA binding and inhibition of 
nuclear translocation.   In vitro studies have shown that enzalutamide has an 8-fold increased 
inhibition of the AR than bicalutamide.19   
 
 
Enzalutamide is FDA- approved for the treatment of metastatic CRPC.   The efficacy and 
safety of enzalutamide was initially determined in a randomized Phase III trial of 
enzalutamide versus placebo in men with metastatic CRPC who were previously treated with 
docetaxel chemotherapy.  1199 men were randomized in a 2:1 ratio to enzalutamide (n=800) 
or placebo (n=399).  Importantly all patients were maintained on their GnRH agonists 
throughout the course of the study.   At the pre-specified interim analysis when 520 events 
had occurred median survival was 18.4 mo versus 13.6 mo in the placebo arm (HR 0.63 
95%CI 0.53-0.75).  Further, in a study of 1,717 chemo-naïve patients with metastatic CRPC 
(PREVAIL), treatment with enzalutamide versus placebo resulted in a 29% reduction in 
death and an 83% reduction in radiographic progression (p<0.0001 for both endpoints).     
 
Warnings:  
Seizure:  In the randomized clinical trial, 7 of 800 (0.9%) patients treated with XTANDI 160 
mg once daily experienced a seizure. No seizures occurred in patients treated with placebo. 
Seizures occurred from 31 to 603 days after initiation of XTANDI. Patients experiencing 
seizure were permanently discontinued from therapy and all seizures resolved. There is no 
clinical trial experience re-administering XTANDI to patients who experienced seizures. 
 
Posterior Reversible Encephalopathy Syndrome (PRES):  in post approval use, there have 
been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder which 
can present with rapidly evolving symptoms including seizure, headache, lethargy, 
confusion, blindness, and other visual and neurological disturbances, with or without 
associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, 
preferably MRI. Discontinue XTANDI in patients who develop PRES. 
 
 
Dose reduction/adjustment:  Patients who experience a Grade 3 or greater toxicity that cannot 
be ameliorated by the use of adequate medical intervention should have their treatment 
interrupted until the toxicity improves to a Grade 2 or lower severity. Patients may subsequently 

27 
be re-started on study drug, including at a reduced dose (80 mg or 120 mg). There are no known 
adverse interactions with immunologic functions.  
 
Storage and labelling:   Drug should be stored in a secure location with limited access at 77°F 
(25°C), with excursions permitted to 59°F to 86°F (15°C to 30°C).  Patients will be instructed to 
store study drug at room temperature out of the reach of children. 
 
Drug interactions:  Concomitant Strong CYP2C8 Inhibitors. The concomitant use of strong 
CYP2C8 inhibitors should be avoided if possible. Patients who are on gemfibrozil and cannot 
discontinue this medication will be excluded from trial participation.    
 
5.5.2  GNRH agonist therapy (ie leuprolide and goserelin) 
 
GNRH agonist therapy is standard of care at the VAPORHCS. Dosing will be determined by 
the attending physician by considering standard therapeutic treatment regimens. GNRH 
agonists will be sourced by the VAPORHCS pharmacy; drug will not be donated by the 
manufacturer. 
 
Dose reduction/adjustment:  not reported as necessary.   
 
Storage: Goserelin Acetate: The sterile unit will be enclosed in a sealed light and moisture 
proof package. The package should be stored securely in a dry place at room temperature 
(not to exceed 25°C or 77°F). Before being opened, each package must be inspected for 
damage in which case the depot should not be used. Being sterile, the syringe should be 
removed from its package only immediately before required.  
 
Leuprolide: Store at room temperature 25°C (77°F); excursions permitted to 15-30°C (59- 
86°F) [see USP Controlled Room Temperature]. 
 
Drug interactions:  Luteinizing hormone-releasing hormone analogs may diminish the 
therapeutic effect of antidiabetic agents. No pharmacokinetic-based drug-drug interaction 
studies have been performed. Because leuprolide is a peptide that is primarily degraded by 
peptidase and not by Cytochrome P-450 enzymes and the drug is only about 46% protein 
bound, drug interactions would not be expected to occur 
 
5.6 Diet/Activity/Other Considerations 
 
5.6.1  Diet 
 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
5.6.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  For this trial, 
male subjects will be considered to be of non-reproductive potential if they have azoospermia 

28 
(whether due to having had a vasectomy or due to an underlying medical condition).   
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
from the day of study medication initiation until completion of the prostatectomy. In the 
event that surgery is not performed, then contraception should be continued up till 120 days 
after last drug study treatment.   If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
 
5.6.3 Procedure in Case of Pregnancy: 
 
If a male subject impregnates his female partner the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor and to Merck and followed 
as described above and in Section 7.2.2. 
 
The effect of enzalutamide in pregnant and lactating women is not known, and the exposure 
of a fetus or nursing infant is considered a potential risk. Enzalutamide can cause fetal harm 
when administered to a pregnant woman based on its mechanism of action. Subjects 
receiving enzalutamide are advised to use 2 acceptable methods of birth control (one of 
which must include a condom as a barrier method of contraception) starting at the time of 
screening for an enzalutamide study and continuing throughout the course of treatment and 
for at least three months after enzalutamide is discontinued. 
 
If during the conduct of the clinical trial, a male subject impregnates his partner, the subject 
should report the pregnancy to the Investigator. The Investigator should report the pregnancy 
to the Sponsor as an SAE within 24 hours of awareness of the event. The expected date of 
delivery or expected date of the end of the pregnancy, last menstruation, estimated fertility 
date, pregnancy result and neonatal data etc., should be included in this information. 
 
The Investigator should report the outcome of the pregnancy (independent of outcome, eg. 
full term delivery, pre-term delivery, spontaneous abortion, induced abortion, stillbirth, death 
of newborn, congenital anomaly [including anomaly in a miscarried fetus, etc]  in accordance 
with the same reporting procedure as for SAEs.  The date of outcome of the pregnancy, 
gestational age, date of birth and neonatal data etc., should be included in this information. 
 
5.7 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 

29 
 Unacceptable adverse experiences as described in Section 5.2.1.2 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up for up to five years.   
5.8  Subject Replacement Strategy 
The planned sample size is 30 for the trial with a plan to enroll 32 subject to account 
for subject loss.  There is no plan for subject replacement.   
5.9 
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. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 
5.10  Duration of Treatment 
 
In the absence of treatment delays due to adverse events, treatment may continue for 16 
weeks up until surgical removal of the prostate or until one of the following criteria applies: 
 

30 
o Intercurrent illness that prevents further administration of treatment, 
o Unacceptable adverse events(s), 
o Subject decides to withdraw from the study 
o General or specific changes in the subject's condition render the subject 
unacceptable for further treatment in the judgment of the investigator. 
o For any reason, at the Sponsor or Investigator’s discretion 
In the event of a delay in scheduling of surgery or intercurrent illness that delays completion 
of surgery, treatment may be continued up till a maximum of 20 weeks.   
 
5.11 
Duration of Follow-up 
 
The primary endpoint will be assessed for each patient at the end of the treatment period once 
the patient has undergone surgical removal of the prostate.  Subject will be followed for 
clinical recurrence for an additional 5 years.     Subjects removed from treatment for 
unacceptable adverse event(s) will be followed until resolution or stabilization of the adverse 
event. 
 
6.0 STUDY FLOW CHART 
 
Table 5: Schedule of 
Events. 
Pre-
recruitment 
Screening Visit 
(up to 45 days 
before treatment) 
Week 0 
Every 3 
Weeks1 
Week 16 
Week 202 
30 day post-
surgery 
Follow-up 
Eligibility Checklist 
X 
X 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
Concomitant 
Medications 
 
X 
X 
X 
 
X 
X 
Exam / Vital Signs 
 
X 
X 
X 
 
X 
 
Testosterone 
 
X 
 
 
X 
 
 
PSA 
 
X 
 
 
X 
 
 
CBC/differential 
 
X 
 
X 
X 
 
X 
Chemistry Panel 
 
X 
 
X 
X 
 
 
HRQOL 
 
X 
 
 
X 
 
X 
Thyroid Testing 
 
X3 
 
X 
X 
 
 
AE monitoring 
 
X 
X 
X 
X 
 
X 
Dispensation of 
Enzalutamide4 
 
 
X 
 
 
 
 
Administer GNRH 
 
 
X 
 
 
 
 
Administer 
Pembrolizumab 
 
 
X 
X 
 
 
 
TRUS Biopsy5 
 
X 
 
 
 
 
 
Prostatectomy with 
LND 
 
 
 
 
X 
 
 
Imaging (Bone Scan 
and/or CT/MRI)6 
X 
 
 
 
 
 
 
1For 16 weeks 
2Surgery will be within 4 weeks of completion of treatment 
3Will retest at 3 weeks after first cycle of pembrolizumab 
4Enzalutamide will be taken orally daily for 16 weeks 
5TRUS Biopsy will be done for research purposes after diagnostic biopsy.  Treatment will begin no sooner than 1 week after 
research biopsy done.  

31 
6CT or MRI performed at physician discretion, but required if PSA > 20ng/ml  
 
7.0 TRIAL PROCEDURES 
 
7.1 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 Sponsor and/or 
Merck 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. 
 
7.1.1  Administrative Procedures 
 
7.1.1.1  Informed Consent 
The Investigator or the designee must obtain documented consent from each potential subject 
prior to participating in a clinical trial. 
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 approval/favorable 
opinion in advance of use.  The subject or his 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 requirements, applicable laws and regulations and 
Sponsor requirements. 

32 
 
7.1.1.2 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.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 5 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
 
7.1.1.4.1 Prior Medications 
 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
 
7.1.1.4.2 Concomitant Medications 
 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
 
7.1.1.5 Disease Details and Treatments 
 
7.1.1.5.1 Disease Details 
 
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
 
7.1.1.5.2 Prior Treatment Details 
 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.   
 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
 
The investigator or qualified designee will review all new anti-neoplastic 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 first dose of the new therapy.   
 
7.1.1.6  Assignment of Screening Number  

33 
 
Each patient that is screened for trial participation will be assigned a study number after 
informed consent is obtained.   
 
7.1.2 Clinical Procedures/Assessments 
 
7.1.2.1 Adverse Event (AE) 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 11.2).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Physical Exam 
 
The investigator or qualified designee will perform a focused physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A physical exam should be performed during screening,  
7.1.2.3 Vital Signs 
 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
 
The investigator or qualified designee will assess ECOG status (see Section 10.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   
7.1.2.5 Tumor Tissue Collection and Correlative Studies Blood Sampling 
 
Tumor Tissue Collection and Correlative Studies Blood Sampling will be carried out as 
prescribed in the Flow Sheet of events (Section 6).  
  
7.1.3 Laboratory Procedures/Assessments 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below 
 

34 
Table 6:  Laboratory tests for hematology, chemistry, urinalysis, and others.  
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
PT (INR) 
Hemoglobin 
Alkaline phosphatase 
Glucose 
aPTT 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Total thriiodothyronine (T3) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Free tyroxine (T4) 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If dip 
abnormal)  
Thyroid stimulating hormone 
(TSH) 
Absolute Neutrophil Count 
Carbon Dioxide  
results are noted 
Blood for correlative studies 
Absolute Lymphocyte Count   (CO2 or biocarbonate) 
 
 
 
Uric Acid 
 
 
 
Calcium 
 
  
 
Chloride 
 
  
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin 
is elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
Table 5 
 
 
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 30 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to pembrolizumab dosing.  Results must be 
reviewed by the investigator or qualified designee and found to be acceptable prior to each 
dose of trial treatment.  
 
7.1.4 Other Procedures 
 
7.1.4.1 Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events. After discontinuing treatment following assessment for CR, 
subjects should return to the site for a Safety Follow-up Visit (described in Section 7.1.5) and 
then proceed to the Follow-Up Period of the study (described in Section 7.1.6). 

35 
 
7.1.4.2 Screening 
Screening for subjects will be carried out by study personnel in clinics at both OHSU and the 
Portland VA.   Screening will be aided by a study checklist that has both inclusion and 
exclusion criteria.    
 
7.1.4.3  Screening Period 
Screening period will last no longer than 45 days from the time of enrollment until 
administration of drug therapy.    
 
7.1.4.4  Treatment Period 
The treatment period begins on day 1 of therapy and ends on the day of surgery.  Treatment 
will be planned for a total of 14 to 16 weeks.  This will allow a washout period for 
pembrolizumab of 2-4 weeks.    If in the case there is a delay of surgery due to administrative 
reasons or intercurrent disease, then treatment will be allowed to continue up until 20 weeks.  
However, if treatment is delayed due to drug toxicity, treatment with agent felt to be the 
reason for the AE will be withheld and surgery will be undertaken as soon as the patient is 
medically fit in the determination of the investigator to undergo surgery.   
 
7.1.4.5 Post-treatment visits   
Post-prostatectomy follow-up will be carried out according to institutional policy.  Typically 
the first visit is within 3 weeks of surgery.  This is followed by a second visit within 3 
months at which time a PSA is obtained.   All patients should at a minimum have a PSA done 
within three months.   Thereafter, a minimum of two PSA tests per year should be obtained, 
although more frequent monitoring per NCCN guidelines (about every 3 months) is 
recommended.   At each visit subjects will be assessed for surgical complications and these 
will be graded according to the NCI Common Terminology for Adverse Events (CTCAE), 
version 4.0 and Clavien-Dindo classification (http://www.surgicalcomplication.info/index-
2.html.)   
 
 
7.1.4.6  TRUS-guided research biopsies   
Subjects will undergo a mandatory repeat prostate biopsy which will be done for research 
purposes only.   All TRUS procedures will be carried out as previously described by the 
OHSU/VA research group who has extensive experience with this modality in the research 
setting.20  During TRUS, other metrics to be collected include prostate volume and the 
presence or absence of a hypoechoic lesion in the region of the index lesion (if present).  
Snap-frozen biopsy specimens will be obtained for future laboratory analysis as previously 
described by our group.18  A total of 10 individual samples will be taken under local 
anesthetic and cryopreserved in OCT at -80C°.     

36 
 
7.1.4.7  Radical Prostatectomy  
As a requirement of inclusion, the patient must have already selected prostatectomy with an 
extended pelvic lymph node as the primary treatment option for prostate cancer.    Thus the 
surgery is considered standard of care and not a study procedure.  Because of this, the 
surgical treatment AEs will be considered separately from the medical therapy AEs.    
Radical prostatectomy is the most common treatment for localized prostate cancer in the US.  
An in-depth understanding of anatomical considerations and inter-patient variability have 
markedly reduced the complication rate for this procedure.  The adverse event rates from 
contemporary series of patients treated with prostatectomy without neoadjuvant therapy are 
listed below. These historical data will be used as a reference for clinical outcomes on this 
trial.  In the unexpected event that for any reason the patient is deemed to no longer be a 
surgical candidate after the treatment period, the patient will be counselled about alternative 
options which would include but not be limited to primary radiotherapy.   In our two 
previous trials done for high risk prostate cancer, no patient failed to undergo surgical 
treatment for his cancer after the treatment period, so we do not expect this occurrence.18,21  
All metrics related to the surgical procedure including 30-day complication rate will be 
recorded using a uniform template.   All AE’s will be graded according to the NCI Common 
Terminology for Adverse Events (CTCAE), version 4.0 and the Clavien-Dindo Classification 
of Surgical Complications. 
 
 
 
 
7.1.5  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 60 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
Table 7: Complications from prostatectomy with node dissection 
Rate (%) 
Rectal injury  
0.3 – 2.5 
Ureteral injury 
0.2 – 1.6 
Deep venous thrombosis 
1.3 – 2.7 
Pulmonary embolus 
0.7 – 2.0 
Cardiovascular  
0.7 – 1.0 
Lymphocoele  
0.1 – 2.0 
Urinary leakage  
1.2 – 10.0 
Wound complication 
0.8 – 1.3 
Bladder neck contracture  
4.0 – 20.5 

37 
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.   
 
7.1.6 Follow-up Visits 
 
Subjects who discontinue trial treatment will remain in the study.  Subjects will be followed 
according to institutional policy regarding post-operative follow-up schema.  An initial PSA 
blood test will be done within 3 months of surgery.  Then the patients should have a 
minimum of two PSA blood tests per year.   Post-operative imaging will be done at the 
discretion of the treating physician.    
 
7.2 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. Important for this type of trial is that 
the treatment period will be separated into medical and surgical treatment periods.   Thus 
medical AEs and surgical AEs will be recorded separately.  An adverse event can therefore 
be any unfavorable 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 Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.   
 
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 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 7.2.2 and 7.2.3. The 
investigator will make every attempt to follow all subjects with non-serious adverse events 
for outcome. 
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.  

38 
 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
If a dose of Merck’s product 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 within 24 hours 
to the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
 
7.2.2 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.2.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another 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 Merck in the 
same timeframe as SAEs to meet certain local requirements. Therefore, these events 
are considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 

39 
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 and within 2 working days to Merck Global Safety 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 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 study drug 
combination, must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck 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 and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
7.2.2.2 Events of Clinical Interest 
 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
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 and within 2 working days to Merck Global Safety 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 ECI, or follow up to an ECI, 

40 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 24 hours to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck 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.  
 
7.2.3 Immediate Reporting of Adverse Events to Astellas/Medivation 
Within 24 hours of awareness of a serious adverse event, whether or not related to the study 
drug, the Investigator will complete and submit a Medwatch 3500A Form to FDA, 
containing all required information (reference 21 CFR 312.32). The Investigator will submit 
a copy of this MedWatch 3500A form to Astellas by either e-mail or fax, within the same 
timeframe. If submission of this SAE to FDA or Astellas or is not possible within 24 hours, 
the Investigator’s local drug safety contact (IRB) should be informed by phone. The SAE 
documentation, including the Medwatch 3500A Form and available source records should be 
emailed or faxed to:  
Astellas Pharma Global Development – United States  
Email: Safety-us@us.astellas.com  
Fax number: (847) 317-1241  
The following minimum information is required:  
∙ Study number/IIT regulatory identifier  
∙ Subject number, sex and age  
∙ The date of report  
∙ A description of the SAE (event, seriousness of the event)  
∙ Causal relationship to the study drug  
 
Follow-up information for the event should be sent within 7 days as necessary.  
 
7.2.3 Evaluating Adverse Events 
An investigator who is a qualified physician or designee will evaluate all adverse events 
according to the NCI Common Terminology for Adverse Events (CTCAE), version 4.0. 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. 
 
 
 

41 
 
7.3 BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Biomarker studies 
1. PD-1 – Expression of PD-1 CD8+ cells will be performed to assess the intensity of 
staining.    Groups will be ranked in none/low, intermediate and high groups.    
Clinical responses will be correlated with degree of expression.   This will be carried 
out on the clinical diagnostic biopsy and the post prostatectomy specimens.     
2. Compare pre-and post-treatment PD-1 expression comparing individual subjects pre- 
and post-treatment tumor samples.    
3. Tumor PD-L1 expression- pre- and post-treatment tumor samples will be assessed for 
expression of PD-L1.   Treatment responses will be correlated with tumor expression 
of PD-L1. PD-L1 expression will be carried out by the central lab a Merck.  To 
preserve data integrity they will be blinded to all clinical data.   
4. Exploratory biomarkers in biopsy and prostatectomy specimens.   IHC will be 
performed for CD4, CD8 and MDSC.   Markers of T-cell activation (CD27, OX-40, 
4-1BB) and T-cell exhaustion (CLTA-4, PD-1, TIM-3, LAG-3) will be studied.   
5. Serum studies – serum will be collected before and after treatment for use in future 
studies.  Candidate biomarkers would be evaluated as correlates to tissue responses.  
These include CRP, LDH, ELISPOT (INF-gamma, IL-10).  Measured at baseline, 
pre-op and post-op.   
6. Flow cytometry of blood to quantify CD4, CD8 and MDSC, markers of T-cell 
activation (CD27, OX-40, 4-1BB) and T-cell exhaustion (CLTA-4, PD-1, TIM-3, 
LAG-3).  Measured at baseline, pre-op and post-op.   

Product:  MK-3475 
42 
Protocol/Amendment No.:   
 
 
  
 
 
 
Table 8:  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 Merck 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 and to Merck within 2 working days 
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 to the Sponsor and to Merck within 2 
working days.. 
 
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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  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 Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck 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 Merck 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 
 

Product:  MK-3475 
43 
Protocol/Amendment No.:   
 
 
  
 
 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck 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 Merck 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 
MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT, 
THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 Merck 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 Merck product relationship). 
Yes, there is a reasonable possibility 
of Merck product relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  The 
AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR the AE is 
more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 

 
 
 
 
7.2.4 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.  
 
 
8.0 STATISTICAL CONSIDERATIONS 
8.1 Study Design 
 
This is a single-arm, single-stage phase II trial to evaluate efficacy and safety of pembrolizumab 
combined with intensive AR targeting prior to prostatectomy in subjects with high-risk localized 
prostate cancer (HRLPC). A total of 32 patients will be enrolled during a one-year accrual period 
at OHSU and PVAMC. All patients will have long-term follow-up of five years. 
 
8.2 Primary and Secondary Endpoints 
 
Primary and secondary endpoints are defined in Section 3.  Briefly the primary endpoint is 
pathologic complete response (pCR) defined as absence of detectable malignant cells in the 
prostatectomy specimen evaluated by standard histologic techniques. The secondary endpoints 
include: grade 3 or higher treatment related adverse events; grade 2 or higher immune-related 
adverse events (irAEs); pCR in patients stratified by pre-operative prostate infiltrating T-cell PD-
1 expression; biochemical complete response rate prior to surgery (i.e., PSA< 0.1 ng/mL) ;  
changes in EPIC health related quality of life from Week 0 vs. 16, and; incidence of surgical 
complications post-surgery using Clavien-Dindo Classification of Surgical Complications within 
30 days of surgery. Exploratory endpoints include: incidence of cancer directed treatment at five 
years; pre- vs. post-treatment changes in serum, blood and tissue markers of the immune 
response, and; correlation of changes in markers of inflammatory response with clinical 
outcomes including pCR, PSA response, biochemical recurrence free survival and Safety and 
tolerability of Pembrolizumab, defined as Pembrolizumab related adverse event of any grade and 
drug dose modification. 
 
For the purposes of this study, subjects should be evaluated for pathologic complete response to 
immuno-hormonal therapy post prostatectomy and biochemical complete response after 
immuno-hormonal therapy prior to prostatectomy. Time to biochemical recurrence is defined as 
the time from the date of surgery until the date of a confirmed PSA ≥ 0.2 ng/mL on two 
consecutive values at least a week apart. Those without the documented biochemical recurrence 
will be censored at the date of last PSA measurement. Quality of Life Assessments will be 
completed by EPIC quality of life (QOL) questionnaire throughout the course of the treatments. 
 
8.3 Analysis Populations 
 
An intent to treat (IIT) analysis set consists of all patients who consent and are enrolled in the trial 

 
 
regardless of whether they are exposed to the experimental treatment. A safety analysis set consists of all 
patients who receive at least one dose of the experimental treatment. An efficacy evaluable analysis set 
includes patients who receive at last one dose of the experimental treatment and can be assessed for an 
efficacy endpoint. An IIT analysis set will be used to report the accrual. Safety endpoints will be assessed 
using the safety analysis set, while the efficacy evaluable analysis set will be used to analyze an efficacy 
endpoint. Note that the efficacy evaluable analysis set may differ from one endpoint to another depending 
on availability of efficacy endpoint data. 
8.4 Statistical Analysis Plan 
 
8.4.1 Analysis of Primary Endpoint 
The primary endpoint is pathologic complete response (pCR) defined as absence of detectable 
malignant cells in the prostatectomy specimen evaluated by standard histologic techniques. We 
will perform a one-sided exact binomial test to determine if the pCR rate is significantly better 
than 6%, which corresponds to the historical rate of the intensive androgen axis targeting alone. 
An exact two-sided confidence interval will also be estimated and provided. 
 
8.4.2. Analysis of Secondary Endpoints 
 
AEs and irAEs will be tabulated and summarized according to the grade, attribution, and major 
organ systems according to the NCI CTCAE v4.03. A proportion of patients with the AE event, 
defined as the number of patients with the AE event divided by the total number of patients, will 
be provided, as well as the rate defined as the number of AE events divided by the total person-
days (the number of patients x the number of days). These measures will be provided for the 
entire study period, from pre-operative treatment with immune hormonal therapy and separately 
from surgical therapy post-immunohormonal therapy. Further Clavien-Dindo Classification of 
Surgical Complications will be tabulated and summarized. 
 
The proportion of patients with pCR will be presented by pre-operative prostate infiltrating T-
cell PD-1 expression status based on the median split of the expression level. Exact 95% 
confidence intervals will also be estimated and provided. The proportion of patients with 
biochemical (i.e. PSA) complete response rate at 16 weeks will be estimated along with the 95% 
exact confidence interval. Biochemical recurrence-free survival will be estimated using Kaplan-
Meier method. Generalized linear or non-linear mixed effects models will be used to analyze 
changes over time of health related quality of life measures. 
 
Patients enrolled in this trial will not have radiographically measurable disease as localized 
prostate cancer is not reliably measurable by available imaging means.  Response to treatment 
will be evaluated by measuring the blood tumor marker PSA and by examining the pathologic 
specimen at prostatectomy.  Descriptive statistics that include maximum PSA reduction on 
therapy, % of men with a PSA < 0.1 ng/ml after surgery, and others will be used.  Standard PSA 
criteria for response cannot be applied in this short-term therapy setting.  
 
 
8.4.3. Analysis of Exploratory Endpoints 
 
Time to cancer directed therapy at five years will be estimated using the cumulative incidence 

 
 
function. Those who are alive and known to be free of any cancer directed therapy and those who 
died without additional cancer directed therapy are censored at the date of last contact. 
Generalized linear or non-linear mixed effects models will be used to evaluate changes over time 
in serum, blood and tissue markers of the immune response. Logistic regression will be used to 
assess an association with markers of inflammatory response with pCR and PSA response, while 
Cox regression will be used to assess the association with biochemical recurrent free survival. 
 
8.4.4. Interim Analyses and Stopping Rules 
 
There is no formal statistical interim analysis or stopping rule planned for this trial. However, the 
Knight Cancer Institute’s Data and Safety Monitoring Committee requires regular IIT 
(investigator initiated trial) report including the information on accrual, protocol status (e.g., 
amendment, violations) and adverse events. 
8.5 Sample Size and Power 
A sample size of 30 patients is required to test the null hypothesis of 6% (the historical rate based 
on the intensive androgen axis targeting alone) vs. an alternative hypothesis of 26% (desired) 
with one-sided 3.2% significance level and 92% power using the exact binomial test. To 
accommodate potential 5% dropout and sample insufficiency, a total of 32 patients will be 
enrolled. 
 
8.6 Randomization Method 
Not applicable. No randomization will be performed for this trial. 
 
8.7 Handling of Missing Data 
Missing data will not be imputed. Whenever possible, statistical analysis methods that allow 
incomplete data (e.g., mixed effects models) will be used. In some cases, sensitivity analysis may 
be conducted under the worst and best case scenarios. 
 
 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 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 each drug manufacturer as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 

 
 
Product Name & Potency 
Dosage Form 
Enzalutamide 40 mg 
Capsule 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label text; 
random code/disclosure envelopes or lists are not provided. 
 
9.4 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. 
 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS  
 
10.1 Confidentiality  
Patient confidentiality will be protected by keeping all hard copies of subject data in a locked file 
cabinet in a locked room on a protected floor that only allows access to those with the 
appropriate badge. Any information stored on a computer will be behind the VA and firewalls. 
HIPAA procedures will also be followed through the study.    

 
 
10.2 Compliance with Financial Disclosure Requirements  
 
Funds given to investigators by Merck will be reported for public availability according to the 
Sunshine Act.  
 
10.3 Compliance with Law, Audit and Debarment  
 
This trial will be conducted in compliance with all applicable institutional, local, and federal 
regulations. This includes auditing by appropriate regulatory authorities if necessary.  
 
10.4 Compliance with Trial Registration and Results Posting Requirements  
 
 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. 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.  
 
10.5 Quality Management System  
OHSU Knight Cancer Institute, through the auditing function of the Knight Clinical Trials 
Office, is responsible for ensuring that all member investigators and affiliate investigators 
conduct clinical research studies in compliance with local IRB standards, FDA regulations and 
NIH policies and in accordance with the Data and Safety Monitoring Plan policies and 
procedures http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm  
 
Locally initiated studies will be audited by OHSU Knight CI Auditor. Newly approved studies 
may be audited anytime after enrollment has been initiated. Each OHSU Knight approved 
treatment protocol will be audited on an annual basis in accordance with the Knight Data and 
Safety Monitoring Plan. OHSU Knight CI Auditor will review OHSU patients only. VA patients 
will be audited biennially by Research Compliance Office. 
 
It is the responsibility of each participating site’s principal investigator to ensure that the study is 
conducted in compliance with local IRB standards, FDA regulations, and NIH policies. It is also 
the responsibility of each site’s principal investigator to ensure that quality assurance audits at 
their site are conducted according to their institution’s policies and procedures. The quality 
assurance audit process provides assurance that reported data accurately reflects the data in the 
primary subject record.  
 
10.6 Data Management  
 
The investigator will be responsible for developing data collection tools such as Case Report 
Forms (CRF), Study Management Tools, and a database if appropriate. Data required to meet the 
objectives of this protocol will be collected via CRF and uploaded to REDcap by the study 

 
 
coordinator. A Study-Specific Data Monitoring Plan (SsDMP) will be developed as a separate 
document for both the Lead Site and any participating Sub-sites. Risk based monitoring will be 
utilized, with remote monitoring of source documentation and protocol compliance. At the 
discretion of the investigator, monitoring or auditing in addition to that outlined in the SsDMP 
may be conducted. 

 
 
11 APPENDICES 
11.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair. 
 
11.2  Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
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) 
 
11.3 The Clavien-Dindo Classification of Surgical 
Complications  (http://www.surgicalcomplication.info/index-2.html) 
Full Scale 
 
Contracted Form 
Grades 
Definition 
Grades 
Definition 
Grade  I: 
Any deviation from the 
normal postoperative 
course without the need 
for pharmacological 
treatment or surgical, 
endoscopic and 
radiological 
interventions. 
 
Grade  I: 
Same as for Full Scale 
Allowed therapeutic 
regimens are: drugs as 

 
 
antiemetics, 
antipyretics, analgetics, 
diuretics and 
electrolytes and 
physiotherapy. This 
grade also includes 
wound infections 
opened at the bedside. 
 
Grade  II: 
Requiring 
pharmacological 
treatment with drugs 
other than such allowed 
for grade I 
complications. 
Blood transfusions and 
total parenteral nutrition 
are also included. 
 
Grade  II: Same as for Full Scale 
 
Grade  III: Requiring surgical, 
endoscopic or 
radiological 
intervention 
 
Grade  III: 
 
Grades IIIa & IIIb 
    Grade 
III-a: 
intervention not under 
general anesthesia 
    Grade 
III-b: 
intervention under 
general anesthesia 
 
Grade IV: 
Life-threatening 
complication (including 
CNS complications)‡ 
requiring IC/ICU-
management 
 
Grade IV: Grades IVa & IVb 
    Grade 
IV-a: 
single organ 
dysfunction (including 
dialysis) 
    Grade 
IV-b: 
multi organ dysfunction 
 
Grade V: 
Death of a patient 
 
Grade V: Same as for Full Scale 
Suffix 'd': 
If the patients suffers 
from a complication at 
the time of 
discharge,  the 
 
 
 

 
 
suffix  “d”  (for 
‘disability’) is added to 
the respective grade of 
complication. This label 
indicates the need for a 
follow-up to fully 
evaluate the 
complication. 
  
‡ brain hemorrhage, ischemic stroke, subarrachnoidal bleeding,but excluding transient ischemic attacks (TIA);IC: 
Intermediate care; ICU: Intensive care unit. 
  
 
11.5 Expanded Prostate Cancer Index Composite (http://urologyhealthteam.com/epic.pdf) 
 
11.6 BIOSPECIMEN PROCEDURES 
 
11.6.1  Tissues Samples 
 
Tissue Snap Freezing (Biopsy Samples) 
 
1. Label 1” cardboard squares with pencil (previously cut up from old backs of notebooks) with 
patient initials, patient id, and sample location 
2. Pour Pentane solution over 4-5 pieces of dry ice or about ¾ cup of shaved dry ice until the 
cup is boiling and has enough liquid to cover the samples 
3. Place drop of Cryomatrix on cardboard square (be sure that there aren’t any trapped air 
bubbles) 
4. Lay sample in Cryomatrix and cover with another drop of solution 
5. Drop into pentane/dry ice solution (can remain in this solution for as long as need be as long 
as the solution is still boiling) 
6. Store at –80 C in labeled 50 ml tubes 
 
Accessories: 
 
o 10- 1 in2 cardboard pieces (can be cut out of the back of paper pads) 
o Needles and syringes (to transfer biopsy samples from biopsy needle to cardboard) 
o Small plastic beaker 
o Pentane Solution (2 Methyl butane (Isobutane) – EM Science MXO760-1) 
o Cryomatrix (Frozen Specimen Embedding Medium – Shandon 6769006) 
o Tweezers (to transfer cardboard out of pentane/dry ice) 
o 50 ml plastic tube 
 
 

 
 
Tissue Snap Freezing (Surgical Samples) 
 
Using preoperative biopsy results and gross impression as guides, suspicious areas will be 
subjected to frozen section evaluation until several areas (6 or more mm in greatest dimension) 
are confirmed as tumor.  Samples are divided in half and one is sent for frozen section and the 
other cryopreserved.  Then bank both the frozen section residual tumor along with the reserved 
fresh tissue from the same locale.  Tissues are then placed in small cryovials and topped off with 
isopentane.    From those areas tissues will be frozen in OCT compound for storage at –80 
degrees C.  The goal will be to preserve at least three confirmed frozen tumor blocks and at least 
two frozen blocks of normal prostate from each case.   Once everything is frozen (2 tumor and 1 
non-tumor, both frozen section residual and reserved fresh tissue for a total of 6 vials) then pack 
the 6 cryo-tubes in a larger tube and place on dry ice until placed in -80C.   
 
 
 
Assuming in the typical case, five frozen tissue samples are collected, they will be labeled 
accordingly as follows:  Study and case number and “FS TUMOR A” (the block from which the 
frozen section examination was performed); “NON-FS TUMOR B”—when the diagnosis is 
based on gross impression—and so forth.  The confirmed normal prostate tissue will be labeled 
with Study and case number and “FS NL D” for example, reflecting frozen section confirmation 
of normalcy with presumptive non-frozen normal tissue also collected and similarly labeled. 
 
Storage:  Frozen specimens excluding the Tumor Bank tissue will be stored in the Garzotto 
laboratory (VA Bldg 103:F218).  Two H&E stained slides will be generated as frozen sections; 
one will remain with the permanent sections slides in the surgical pathology laboratory and the 
other will be stored in the research laboratory. 
 
As per protocol, a record mapping the physical location (preferably using terms right/left and 
anterior/posterior and mid/apical/bladder neck) will be made. The frozen samples should not 
include marginal tissue or otherwise compromise the histologic study of the specimen. 
 
 
11.6.2  Serum Samples: 
 
Venipuncture at specified time-points will be performed to fill two 10 cc Red Top tubes.  Blood 
will be spun down at approximately 1000 rpm for 10 minutes and serum extracted off the top and 
aliquoted in a new 1.5 ml Eppendorf tubes until all available serum extracted.   Serum will then 
be frozen down at -80C.    
 
 
 
12.0  DATA REPORTING/REGULATORY REQUIREMENTS 
 
12.1 Data Collection and Storage 
 

 
 
The following data forms will be used as requested: consent form, eligibility checklist, patient 
data form, medical history form, physical exam form, screening visit form (including all baseline 
data as outlined), study drug diary, adverse event report form, and concomitant medication form. 
Record maintenance will be upheld by the study coordinator.  Data accumulated from this study 
will be forwarded either by completed source documents and/or sent via the networked OCI 
database to the OHSU Cancer Institute Data Manager on a monthly or as applicable basis unless 
otherwise informed.  The Guardian of records will be:   
 
 
 
 
 
 
Wesley Stoller, MA 
                                                            Clinical Research Coordinator 
Portland VA Medical Center 
3710 SW US Veterans Hospital Rd. 
Mailcode:  P3HSR&D 
Portland, OR  97239 
Telephone (503) 220-8262 x-57758 
Fax (503) 721-1479 
      
 
 
12.2 Protocol Review 
 
The protocol and informed consent form for this study must be reviewed and approved in writing 
by the OHSU Knight Cancer Institute (CI) Clinical Research Review Committee (CRRC) and 
the appropriate Institutional Review Board (IRB) prior to any subject being consented on this 
study.   
 
12.3 Informed Consent 
 
Written informed consent will be obtained from all subjects, or the legally authorized  
representative of the subject, participating in this trial, as stated in the Informed Consent section 
of the case of Federal Regulations, Title 21, Part 50.  Documentation of the consent process and 
a copy of the signed consent shall be maintained in the subject’s medical record.  
12.4 Changes to Protocol  
 
Any modification of this protocol must be documented in the form of a protocol revision   
or amendment signed by the principal investigator and approved by the CRRC and IRB,   
before the revision or amendment may be implemented.  The only circumstance in which  
the amendment may be initiated without regulatory approval is for a change necessary to   
eliminate an apparent and immediate hazard to the subject.  In that event, the investigator  
must notify the CRRC and IRB in writing within 10 working days after the implementation. 
Investigators holding the IND must notify FDA of substantive changes to the protocol.  
12.5 Maintenance of Records 
 
If the investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution, another investigator, or to 
OHSU Knight Cancer Institute Clinical Trials Office.  Records must be maintained according to 
sponsor or FDA and VA requirements.  

 
 
12.6 OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in 
Section 7.0 (Adverse Events: List and Reporting Requirements). 
12.8 
Inclusion of Women, Minorities and Children 
12.8.1 Inclusion of Women and Minorities 
No OHSU Cancer Institute or PVAMC study will focus on any particular racial or ethnic subset. 
No subject will be excluded from the study on the basis of racial or ethnic origin. Ethnic 
distribution should be similar to Oregon’s ethnic distribution, though African Americans may be 
overrepresented and Asians underrepresented because prostate cancer is more common in 
African Americans and less common in Asians when compared to the average risk.  Minority 
volunteers will be recruited for this study from the general population and since prostate cancer 
only affects men, women will not be included in this study.   
 
                  
12.8.2 Inclusion of Children 
This protocol does not include children for the following reason: children are not affected by 
prostate cancer.  
  
 
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