Clinical trial NCT03248570
Conditions: Castration Resistant Prostatic Cancer Metastatic Prostate Cancer
Sponsor: University of California, San Francisco
Start date: 2018-02-20; Completion date: 2023-09-28
Enrollment: 26 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

Detailed description:
This is a multicenter phase 2 open label study of pembrolizumab in patients with metastatic castrate resistant prostate cancer (mCRPC) with or without DNA damage repair defects.

All subjects will receive pembrolizumab 200mg intravenously (IV) every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint of the study is objective response rate (ORR) according to immune-mediated response criteria (irRC).

Arms: arm 1: Participants with mismatch repair (MMR) intact receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. If disease worsens while receiving pembrolizumab, participants may receive standard of care chemotherapy for 2-8 cycles arm 2: Participants with defective DNA repair receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. If disease worsens while receiving pembrolizumab, participants may receive standard of care chemotherapy for 2-8 cycles
Interventions: intervention 1: Pembrolizumab intervention 2: Chemotherapy
Intervention descriptions: intervention 1: All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression or unacceptable toxicity. intervention 2: At time of progression, all subjects will also have the option of receiving taxane-based chemotherapy followed by repeat pembrolizumab for those who have a clinical response to chemotherapy. Chemotherapy regimen will be at the discretion of the treating physician, and may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. carboplatin). A minimum of 4 cycles and a maximum of 8 cycles of chemotherapy will be given.

Protocol documents:
Prot_SAP_001.pdf: 
Phase 2 open label study of pembrolizumab in patients with 
metastatic castration resistant prostate cancer (mCRPC) with or 
without DNA damage repair defects
Protocol Number:  CC# 16557
Study Drug:  Pembrolizumab
Version Number: 8.0
Version Date: 05-10-2024
IND NUMBER: Exempt
SPONSOR-INVESTIGATOR:
David Oh, M.D., Ph.D.
Division of Hematology/Oncology
University of California, San Francisco
STATISTICIAN:
Li Zhang, Ph.D.
Revision History
Version 1.0
02.22.16
Version 2.0
04.13.17
Version 1.1
05.02.16
Version 3.0
05.31.17
Version 1.2
06.22.16
Version 4.0
11.02.17
Version 1.3
07.28.16
Version 5.0
06.27.18
Version 1.4
08.22.16
Version 6.0
11.25.19
Version 1.5
03.27.17
Version 7.0
03.25.21
Version 8.0
05.10.24
NCT#  03248570


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PROTOCOL SIGNATURE PAGE
Protocol No.: 16557
Version Date: 11-25-2019
Principal Investigator 
Printed Name
Signature
Date
1.
I agree to follow this protocol version as approved by the UCSF Protocol Review Committee 
(PRC), Institutional Review Board (IRB), and Data Safety Monitoring Committee (DSMC). 
2.
I will conduct the study in accordance with applicable IRB requirements, Federal regulations, 
and state and local laws to maintain the protection of the rights and welfare of study 
participants. 
3.
I certify that I, and the study staff, have received the requisite training to conduct this research 
protocol. 
4.
I have read and understand the information in the Investigators’ Brochure (or Manufacturer’s 
Brochure) regarding the risks and potential benefits. I agree to conduct the protocol in 
accordance with Good Clinical Practices (ICH-GCP), the applicable ethical principles, the 
Statement of Investigator (Form FDA 1572), and with local regulatory requirements. In 
accordance with the FDA Modernization Act, I will ensure the registration of the trial on the 
www.clinicaltrials.gov website. 
5.
I agree to maintain adequate and accurate records in accordance with IRB policies, Federal, 
state and local laws and regulations.


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TABLE OF CONTENTS
Protocol Signature Page..........................................................................................................2
Table of Contents.....................................................................................................................3
1.0
TRIAL SUMMARY ....................................................................................................7
2.0
TRIAL DESIGN ..........................................................................................................8
2.1
Trial Design..............................................................................................................8
3.0
OBJECTIVES & HYPOTHESES............................................................................10
3.1
Primary Objective & Hypothesis .........................................................................10
3.2
Secondary Objectives & Hypotheses ...................................................................10
3.3
Exploratory Objectives .........................................................................................11
4.0
BACKGROUND & RATIONALE ..........................................................................12
4.1
Background ............................................................................................................12
4.1.1
Pharmaceutical and Therapeutic Background .....................................................13
4.1.2
Preclinical and Clinical Trial Data.......................................................................14
4.2
Rationale.................................................................................................................14
4.2.1
Rationale for the Trial and Selected Subject Population .....................................14
4.2.2
Rationale for Dose Selection/Regimen/Modification..........................................15
4.2.3
Rationale for Endpoints .......................................................................................16
5.0
METHODOLOGY ....................................................................................................18
5.1
Entry Criteria ........................................................................................................18
5.1.1
Diagnosis/Condition for Entry into the Trial.......................................................18
5.1.2
Subject Inclusion Criteria ....................................................................................18
5.1.3
Subject Exclusion Criteria ...................................................................................22
5.2
Trial Treatments....................................................................................................24
5.2.1
Dose Selection/Modification ...............................................................................24
5.2.2
Timing of Dose Administration...........................................................................26
5.2.3
Trial Blinding/Masking........................................................................................26
5.3
Randomization or Treatment Allocation ............................................................26
5.4
Concomitant Medications/Vaccinations (allowed & prohibited)......................27
5.4.1
Acceptable Concomitant Medications.................................................................27


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5.4.2
Prohibited Concomitant Medications ..................................................................28
5.5
Rescue Medications & Supportive Care..............................................................29
5.5.1
Supportive Care Guidelines.................................................................................29
5.6
Diet/Activity/Other Considerations .....................................................................32
5.6.1
Diet.......................................................................................................................32
5.6.2
Contraception.......................................................................................................33
5.6.3
Use in Pregnancy .................................................................................................34
5.7
Subject Withdrawal/Discontinuation Criteria....................................................34
5.7.1
Discontinuation of Study Therapy after CR ........................................................35
5.8
Subject Replacement Strategy..............................................................................35
5.9
Stopping Rule.........................................................................................................35
5.10
Clinical Criteria for Early Trial Termination ....................................................35
6.0
TRIAL FLOW CHART............................................................................................36
7.0
TRIAL PROCEDURES ............................................................................................40
7.1
Trial Procedures ....................................................................................................40
7.1.1
Pretreatment Period..............................................................................................40
7.1.2
Treatment Period..................................................................................................41
7.1.3
Administrative Procedures...................................................................................45
7.1.4
Clinical Procedures/Assessments ........................................................................47
7.1.5
Laboratory Procedures/Assessments ...................................................................49
7.1.6
Other Procedures..................................................................................................52
7.1.7
Visit Requirements ..............................................................................................53
7.2
Assessing and Recording Adverse Events ...........................................................56
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck....................................................................................57
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck..................57
7.2.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck ..............58
7.2.4
Evaluating Adverse Events..................................................................................60
7.2.5
Sponsor Responsibility for Reporting Adverse Events .......................................64
8.0
STATISTICAL ANALYSIS PLAN .........................................................................64
8.1
Sample Size and Power Calculation.....................................................................64
8.2
Statistical Analysis Plan Summary: Primary Objective....................................65


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8.2.1
Radiographic Progression Free Survival .............................................................65
8.3
Statistical Analysis Plan Summary: Secondary Objectives...............................65
8.3.1
Progression Free Survival....................................................................................65
8.3.2
PSA Response......................................................................................................65
8.3.3
Safety and Tolerability.........................................................................................66
8.3.4
Time to Progression after Taxane-Based Chemotherapy and Repeat 
Pembrolizumab....................................................................................................66
8.4
Statistical Analysis Plan Summary: Exploratory Objectives............................66
8.4.1
Immune Infiltration..............................................................................................66
8.4.2
PD-L1 staining.....................................................................................................66
8.4.3
T Cell Receptor (TCR) Repertories.....................................................................67
8.4.4
Mutational Burden...............................................................................................67
8.4.5
Circulating Immune Cells....................................................................................67
8.4.6
DNA Damage Repair Status Concordance..........................................................67
8.4.7
Clinical Activity in Biomarker Positive Subjects................................................67
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ..................................................................................................................68
9.1
Investigational Product .........................................................................................68
9.2
Packaging and Labeling Information..................................................................68
9.3
Clinical Supplies Disclosure..................................................................................68
9.4
Storage and Handling Requirements...................................................................68
9.5
Returns and Reconciliation...................................................................................69
10.0
ADMINISTRATIVE AND REGULATORY DETAILS .......................................70
10.1
Protection of Human Subjects..............................................................................70
10.1.1 Protection from Unnecessary Harm.....................................................................70
10.1.2 Protection of Privacy ...........................................................................................70
10.2
Compliance with Financial Disclosure Requirements .......................................70
10.3
Compliance with Law, Audit and Debarment ....................................................70
10.4
Compliance with Trial Registration and Results Posting Requirements.........71
10.5
Study Management................................................................................................71
10.5.1 Pre-Study Documentation....................................................................................71


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10.5.2 Institutional Review Board Approval..................................................................71
10.5.3 Informed Consent ................................................................................................71
10.5.4 Changes in the Protocol.......................................................................................72
10.5.5 Handling and Documentation of Clinical Supplies .............................................72
10.5.6 Case Report Forms (CRFs)..................................................................................72
10.5.7 Oversight and Monitoring Plan............................................................................73
11.0
APPENDICES............................................................................................................74
11.1
Performance Status Criteria.................................................................................74
11.2
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...............75
11.3
Prostate Cancer Clinical Trials Working Group 3 (PCWG3) ..........................76
11.4
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors.................................................................77
11.5
Immune-Related Response Criteria (irRC) for Evaluation of Immune 
Therapy Activity in Solid Tumors .......................................................................78
11.6
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study.........79
12.0
ABBREVIATIONS....................................................................................................82
13.0
REFERENCES ..........................................................................................................85


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1.0 TRIAL SUMMARY
Abbreviated Title
Phase 2 pembrolizumab in mCRPC with or without DNA damage repair 
defects
Trial Phase
2
Clinical Indication
Metastatic castration resistant prostate cancer (mCRPC) after prior 
abiraterone and/or enzalutamide
Trial Type
Phase 2, non-randomized, comparative study
Type of control
- No treatment control. 
- Negative DNA damage repair defect signature as biomarker control.
Route of administration
Intravenous
Trial Blinding
No blinding.
Treatment Groups 
- Group 1: DNA damage repair proficient group
- Group 2: DNA damage repair defective group 
Patients with previously identified MSI-high tumor by PCR or IHC, or 
homozygous deletion or deleterious germline or somatic mutation(s) in 
DNA damage repair gene(s) (such as BRCA1, BRCA2 and ATM) 
identified in a CLIA-certified laboratory are allowed in Group 2.
Number of trial subjects
50 subjects total (25 subjects in each study group)
Estimated enrollment period
24 months
Estimated duration of trial
36 months
Duration of Participation
- Until progression of disease or unacceptable toxicity.
- Subjects who progress and choose to receive taxane-based 
chemotherapy (docetaxel or cabazitaxel with or without a platinum agent, 
e.g. carboplatin) for 2-8 cycles have the option to repeat pembrolizumab 
until progression of disease or unacceptable toxicity, assuming response 
to chemotherapy.
Estimated average length of 
treatment per patient
4 months (shorter for DNA damage repair proficient group; longer for 
DNA damage repair defective group)


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2.0 TRIAL DESIGN
2.1
Trial Design
This is a phase 2 open label study of pembrolizumab in patients with metastatic castrate 
resistant prostate cancer (mCRPC) with or without DNA damage repair defects. All patients 
must have received prior secondary hormonal therapy. 
At the time of screening, subjects will undergo mandatory biopsy of primary or metastatic 
tissue to determine DNA repair gene mutation and/or MSI signature status. Both tests are 
performed in a CLIA certified laboratory. MSI testing will be performed by the PCR based 
Promega assay at UCSF with a turn-around time of 1-2 weeks. 
Subjects will be assigned to one of two treatment groups: 

Group 1 (DNA damage repair proficient group):  Twenty-five subjects with MMR 
intact by having no DNA repair gene mutations by panel sequencing 

Group 2 (DNA damage repair deficient group): Twenty-five subjects with MSI-high 
and/or DNA repair gene mutations. 
o
Patients with previously identified MSI-high tumor by PCR or IHC, or 
homozygous deletion or deleterious germline or somatic mutation(s) in DNA 
damage repair gene(s) (such as BRCA1, BRCA2, and ATM) identified in a 
CLIA-certified laboratory are allowed in Group 2. 
All subjects will receive pembrolizumab 200mg IV every 3 weeks until disease progression 
or unacceptable toxicity. The primary endpoint of the study is radiographic progression-free 
survival (rPFS).
Because the DNA damage repair defective signature is anticipated to be present in only 
~20% of screened subjects, Group 1 is anticipated to complete enrollment before Group 2. 
To facilitate initial accrual, we will enroll the initial patients onto the clinical trial and begin 
treatment without having the full results of the DNA repair status available so long as Group 
1 has slots available (i.e. at least the initial 25 patients). Once Group 1 is fully enrolled (and 
DNA damage repair status verified for those subjects), DNA damage repair defective status 
must be confirmed before subjects can enroll to the remaining slots in Group 2. 
Approximately 125 subjects are anticipated to be screened to complete enrollment in both 
groups.


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Subjects who progress on pembrolizumab in either study group will have the option of 
undergoing biopsy of a metastatic site. At time of progression, all subjects will also have the 
option of receiving taxane-based chemotherapy followed by repeat pembrolizumab for those 
who have a clinical response to chemotherapy. Subjects who reinitiate pembrolizumab 
following chemotherapy will have the option of undergoing an additional biopsy of the 
metastatic site. Chemotherapy regimen will be at the discretion of the treating physician, and 
may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. carboplatin). A 
minimum of 2 cycles and a maximum of 8 cycles of chemotherapy will be given. Clinical 
response to chemotherapy is defined as PSA decrease by >50% or objective response by 
RECIST v1.1. 
Inclusion of patients onto Group 1 is important for several reasons. First, while the study 
aims to elucidate whether DNA damage repair defects could be a predictive biomarker to 
PD-1 blockade, this is the hypothesis that is being tested and it is unknown whether this is the 
case. Assessing clinical response rates in the two study groups will address this question. 
Second, a key component of the protocol is to assess whether chemotherapy “rescues” non-
responders to derive benefit from anti-PD-1 blockade, regardless of whether the tumor 
harbors DNA damage repair defects. Lastly, the clinical response to pembrolizumab in 
patients with mCRPC may be more than previously anticipated. Preliminary data from 
KEYNOTE-028 showed that 3 of 23 mCRPC patients achieved partial response (Hansen A 
et al. 2016). A phase 2 study of pembrolizumab in enzalutamide-resistant mCRPC patients 
showed that 3 of 10 patients achieved partial response, one of whom harbored MMR 
deficiency (Graff JN et al. 2016).
 


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3.0 OBJECTIVES & HYPOTHESES
3.1
Primary Objective & Hypothesis
(1)
Objective: To compare the radiographic progression-free survival (rPFS) in mCRPC 
subjects with proficient DNA damage repair (Group 1) and defective DNA damage 
repair (Group 2), using PCWG3 criteria.
Hypothesis: mCRPC patients whose tumors have defective DNA damage repair have 
improved response to pembrolizumab compared to patients whose tumors have 
proficient DNA damage repair.
3.2
Secondary Objectives & Hypotheses
(1)
Objective: To compare rate of immune-related progression-free survival (irPFS) and 
PFS at 20 weeks and 28 weeks in both study groups, using irRC and RECIST v.1.1.
Hypothesis: Subjects whose tumors have defective DNA damage repair have longer 
irPFS and PFS than those whose tumors have proficient DNA damage repair.
(2)
Objective: To compare the proportion of subjects achieving any PSA response and 
PSA decline >50% from baseline in both study groups.
Hypothesis: A higher proportion of subjects whose tumors have defective DNA repair 
will achieve PSA response than those whose tumors have proficient DNA repair.
(3)
Objective: To assess the safety of pembrolizumab in both study groups by CTCAE 
v4.0.
Hypothesis: Pembrolizumab is well tolerated in subjects with mCRPC in both study 
groups.
(4)
Objective: To compare time to progression after taxane-based chemotherapy in 
subjects who initially progress on pembrolizumab, undergo taxane-based 
chemotherapy, followed by repeat pembrolizumab in both study groups.
Hypothesis: Taxane-based chemotherapy increases the visibility of tumor antigens 
and recaptures response to pembrolizumab in some subjects in both study groups.


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3.3
Exploratory Objectives
(1)
To assess immune infiltration and PD-L1 staining in mandatory baseline tumor tissue 
biopsy and optional progression biopsy tissues, and correlate immune infiltration and 
PD-L1 positivity to DNA damage repair signature and clinical outcomes.
(2)
To assess baseline circulating T cell receptor (TCR) repertories and changes in TCR 
repertories with treatment, and correlate baseline and turnover of repertories to DNA 
damage repair signature and clinical outcomes.
(3)
To assess tumor mutational burden (number of somatic mutations) in a subset of 
subjects in both study groups, and correlate mutational burden with DNA damage 
repair signature and clinical outcomes.
(4)
To assess changes in circulating immune cells with treatment, and correlate changes 
with DNA damage repair signature and clinical outcomes.
(5)
To assess the concordance rate of MSI status and FA/BRCA signature between paired 
baseline tumor tissue biopsy and archived primary prostate tissue, when able in a 
subset of subjects in both study groups.
(6)
To compare clinical activity among subjects in Group 2 with DNA damage repair 
defects whose tumors are: (a) MSI-high only, (b) FA/BRCA signature positive only, or 
(c) both MSI-high and FA/BRCA signature positive. 


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4.0 BACKGROUND & RATIONALE
4.1
Background
In recent years, there has been significant enthusiasm surrounding tumor immunotherapy, 
specifically with immune checkpoint antibodies targeting the immune inhibitory co-receptors 
CTLA-4 and PD-1 (Postow MA et al., 2015). However, these agents have failed to 
demonstrate significant activity in patients with advanced prostate cancer (Kwon ED et al., 
2014; Topalian SL et al., 2012). Dramatic and durable clinical responses were observed in 
approximately 10% of patients with mCRPC receiving CTLA-4 blockade (Kwek SS et al., 
2015; Fong L et al., 2009).  Furthermore, clinical responses in these trials have been shown 
to be associated with amplification of pre-existing immune responses (Kwek SS et al., 2012; 
Cha E et al., 2014).
Tumor associated mutations, which would provide a potential pool of neoantigens, have been 
shown to be associated with clinical responses to immune checkpoint inhibition. Mutational 
analysis in melanoma and NSCLC showed that greater mutational burden in the tumor is 
correlated with treatment response and survival benefit from immune checkpoint blockade 
(Snyder A et al., 2014; Rizvi NA et al., 2015). Consistent with this is the recently reported 
finding that patients with mismatch repair (MMR)-deficient metastatic carcinomas have high 
rates of somatic mutations, and have improved response and survival after PD-1 blockade 
with pembrolizumab (Le DT et al., 2015). One patient with MMR deficiency in this cohort 
had metastatic prostate cancer, and achieved complete response after treatment with 
pembrolizumab (Diaz LA et al., 2016).
Primary prostate cancers generally have a low mutational landscape (Alexandrov LB et al., 
2013), which would presumably translate to a lower number of neoantigens that can 
potentially be recognized and targeted by the immune system.  However, whole exome 
sequencing of metastatic prostate cancer indicates that the prevalence of MMR repair 
deficiency and microsatellite instability (MSI) in advanced prostate cancer can be as high as 
12% (Pritchard CC et al., 2014). Furthermore, other mutations in the DNA repair pathway, 
specifically BRCA2, BRCA1 and ATM, have been reported to occur in approximately 19% 
of patients with advanced prostate cancer (Robinson D et al., 2015). 
Recently, a 44 gene expression assay (DDRD IO) has been developed by Almac as a 
biomarker for defects in the Fanconi’s anemia (FA)/BRCA pathway, and has been shown to 
predict response to DNA-damaging chemotherapy in patients with breast cancer (Mulligan 
JM et al., 2014). Multiple genes in this signature function in immune responses, including the 
immune checkpoint targets PD-L1 and IDO1 (Mulligan JM et al., 2014). Furthermore, 
positive FA/BRCA signature is correlated with intra-tumor lymphocyte infiltration, increased 
PD-L1 expression in tumor cells and lymphocytes, as well as microsatellite instability 
(unpublished 
data), 
making 
it 
an 
attractive 
biomarker 
to 
study 
for 
cancer 
immunotherapeutics. 


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This study is designed to test the efficacy of anti-PD-1 immunotherapy in patients with 
mCRPC who had received prior secondary hormonal therapy, using mutations in DNA repair 
genes, MSI status, and/or FA/BRCA signature as predictive biomarkers. A chemotherapy 
followed by re-challenge option is included to explore the theory that chemotherapy may 
enhance and recapture responses to subsequent immune checkpoint blockade.
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475.
4.1.1
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.  
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.  


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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 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. 
More recently, Keytruda was also approved for the treatment of non-small cell lung cancer 
(NSCLC) following progression on platinum-based chemotherapy in tumors that express 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
Metastatic castration resistant prostate cancer (mCRPC) represents the most advanced form 
of prostate cancer. While treatment options exist—including androgen receptor (AR)-
targeted agents (abiraterone acetate and enzalutamide) and chemotherapy (docetaxel and 
cabazitaxel)—they are associated with significant toxicities, and resistance to these therapies 
eventually develop. 
Immunotherapy is an attractive strategy for patients with advanced prostate cancer, because it 
has the potential to lead to durable responses and is generally better tolerated. However, the 
only FDA approved immunotherapy for prostate cancer to date is sipuleucel-T, an autologous 
cellular vaccine designed to stimulate an immune response targeting PAP (prostatic acid 
phosphatase) (Kantoff PW et al., 2010). The only phase 3 randomized controlled trial of 
immune checkpoint blockade, with ipilimumab in the mCRPC patients after docetaxel, failed 
to meet its primary endpoint of overall survival (Kwon ED et al., 2014). Early phase studies 
of PD-1 blockade in advanced malignancies has not demonstrated clinical activity in 
advanced prostate cancer (Topalian SL et al., 2012). Therefore, a need exists to improve 
immunotherapeutic strategies in this patient population.
Tumors that have defective DNA repair mechanisms have higher rates of spontaneous 
mutations, translating to higher expression of neoantigens that may be recognized by the 
immune system. In this study, we hypothesize that patients with mCRPC who harbor MMR-
defective tumors and/or tumors that carry the 44-gene FA/BRCA expression signature 
(described in background) will have improved response to anti-PD-1 checkpoint blockade. 


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Half of the subjects enrolled will be selected to have intact MMR and negative FA/BRCA 
signature in their tumors, a phenotype that represents the majority of prostate cancer patients. 
The remaining subjects enrolled will be selected to harbor MSI-high and/or FA/BRCA 
signature in their tumors, which is anticipated to be present in approximately 20% of the 
target patient population. Thus we will enrich from the general mCRPC population. Patients 
with previously identified MSI-high tumor by PCR or IHC, or homozygous deletion or 
deleterious germline or somatic mutation(s) of DNA damage repair gene(s) (such as BRCA1, 
BRCA2, and ATM) identified in a CLIA-certified laboratory are allowed in the DNA damage 
repair defective group. All subjects will receive pembrolizumab. 
4.2.2
Rationale for Dose Selection/Regimen/Modification 
An open-label Phase I trial (Merck 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.  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.


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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 patient exposures 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.
4.2.3
Rationale for Endpoints
4.2.3.1 Efficacy Endpoints
Clinical efficacy endpoints for the primary and secondary objectives in the study include 
progression-free survival (rPFS, irPFS, and PFS), PSA response (any PSA decline and PSA 
decline >50% from baseline), and time to progression after taxane-based chemotherapy and 
pembrolizumab re-challenge. 


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4.2.3.2 Biomarker Research
The primary question in this study is whether MSI-high signature predict response to PD-1 
blockade in patients with mCRPC. Correlative studies will be carried out to understand 
differential effects of these DNA damage repair biomarkers on the tumor microenvironment 
and immune response, at baseline and with treatment. Exploratory analysis will include:
1. Characterization and quantification of tumor-infiltrating lymphocytes (TILs)
2. Expression of PD-L1 in tumor cells and TILs
3. Quantification of TCR repertories
4. Assessment of tumoral mutational burden  
5. Characterization of peripheral immune cell subsets


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5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
Metastatic castration resistant prostate cancer (mCRPC).
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Documented histology of adenocarcinoma of the prostate.
2. Metastatic castration resistant prostate cancer with castrate-level testosterone (<50 
ng/dL).
a.
Subjects must maintain a castrate-level testosterone during the study.
3. Disease progression defined by one or more of the following three criteria:
a.
PSA > 2.0 ng/mL and rising PSA by at least 2 consecutive measurements a 
minimum of 1-week apart.
b. Soft tissue progression as defined by RECIST v1.1 criteria (Eisenhauer EA et 
al., 2009).
c.
Bone disease progression as defined by the Prostate Cancer Clinical Trials 
Working Group 3 (PCWG3) (Scher HI et al., 2016). 
4. Have received prior secondary hormonal therapy including abiraterone, enzalutamide 
and/or apalutamide.
5. Be taking prednisone at a dose of ≤ 10mg/day, 7 days prior to starting treatment 
(C1D1).
6. Be willing and able to provide written informed consent/assent for the trial.
7. Be  18 years of age on day of signing informed consent.


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8. Patients must agree to have a tumor tissue biopsy at baseline, and there must be a 
lesion that can be biopsied with acceptable clinical risk as judged by the investigator.
a.
Patients with inconclusive DNA damage repair status testing on this baseline 
biopsy must have one of the following (per the investigator’s discretion):
i.  Sufficient archival tissue, or
ii. An additional biopsy attempt. 
b. Patients with previously identified homozygous deletion or deleterious 
germline or somatic mutation(s) in DNA damage repair gene(s) (such as 
BRCA1, BRCA2, and ATM) identified in a CLIA-certified laboratory are 
allowed in Group 2. 
i. Somatic mutation(s) in DNA damage repair gene(s) needs to be 
identified on the biopsy of a castration-resistant tumor site.
ii. Archival FFPE tissue will be requested for determination of MSI (if 
not already assessed by gene sequencing) signature status. 
1. A formalin-fixed paraffin-embedded (FFPE) tumor specimen 
in a paraffin block (preferred) or at least 10 slides containing 
unstained, freshly cut, serial sections must be available along 
with an associated pathology report before study enrollment.
iii.If archival FFPE tissue is unable to be obtained or is insufficient, 
patients will be required to undergo tumor tissue biopsy if feasible for 
determination of MSI signature status. 


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c.
Patients with germline mutation(s) in mismatch repair (MMR) gene(s) (i.e. 
Lynch syndrome), or have previously identified MSI-high tumor by PCR or 
MMR deficient tumor by IHC are also allowed in Group 2. 
i. Archival FFPE tissue will be requested for determination of FA/BRCA 
signature status.
1. A formalin-fixed paraffin-embedded (FFPE) tumor specimen 
in a paraffin block (preferred) or at least 10 slides containing 
unstained, freshly cut, serial sections must be available along 
with an associated pathology report before study enrollment. 
ii. If archival FFPE tissue is unable to be obtained or is insufficient, 
patients will be required to undergo tumor tissue biopsy if feasible for 
determination of FA/BRCA signature status. 
9. If group 1 is not filled, patients may proceed onto treatment without the completion of 
tests for DNA repair status.  Once group 1 is filled, patients cannot be enrolled onto 
the study or start treatment until DNA damage repair status is successfully determined 
for study group placement. 
a.
Patients will be replaced if they have tissues that are not evaluable for DNA 
repair mutations 
10. Patients must be willing to provide archival tissue from prior biopsy or surgery for 
prostate cancer, if available.
a.
A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin 
block (preferred) or at least 10 slides containing unstained, freshly cut, serial 
sections must be available along with an associated pathology report before 
study enrollment.  
11. Have a performance status of 0 or 1 on the ECOG Performance Scale.
12. Patients must discontinue first generation antiandrogen therapy (i.e. bicalutamide, 
flutamide, and/or nilutamide at least 4-6 weeks prior to registration with no evidence 
of PSA decline after washout.
a.
Bicalutamide: Washout period at least 6 weeks
b. Flutamide and nilutamide: Washout period at least 4 weeks


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13. Patients must discontinue therapies for mCRPC, with the exception of GnRH agent, 
for 14 days, with the exception of anti-androgens with which there may be a 
withdrawal PSA response.
a.
Prior chemotherapy is allowed if no progression of disease on chemotherapy. 
b. Prior treatment with sipuleucel-T, radium-223, or PARP inhibitor (e.g. 
olaparib) is allowed.
c.
Tissue biopsy may be performed during washout period.
14. Demonstrate adequate organ function as defined below. All screening labs should be 
performed within 28 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
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 of intended use 
of anticoagulants
aCreatinine clearance should be calculated per institutional standard.
15. Male subjects of childbearing potential must agree to use an adequate method of 
contraception as outlined in Section 5.7.2 (Contraception), starting with the first dose 
of study therapy through 120 days after the last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.


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5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Significant liver metastasis.
2. Prior taxane-based chemotherapy with progressive disease on chemotherapy.
a.
Prior docetaxel for metastatic hormone sensitive prostate cancer is allowed, if 
no progression of disease on docetaxel as defined by RECIST v1.1 and 
PCWG3.
b. Prior taxane-based chemotherapy (i.e. docetaxel or cabazitaxel with or 
without platinum agent) for mCRPC is allowed if no progression of disease on 
chemotherapy as defined by RECIST v1.1 and PCWG3.
3. 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.
4. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy 
>10mg/day or any other form of immunosuppressive therapy within 7 days prior to 
the first dose of trial treatment.
5. Has a known history of active TB (Bacillus Tuberculosis).
6. Hypersensitivity to pembrolizumab or any of its excipients.
7. 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.
8. 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.
a.
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study.
b. Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.  
9. 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 or in situ cervical cancer.


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10. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.  
11. 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 (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy < or = 10 mg of prednisone/day for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
12. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
13. Has an active infection requiring systemic therapy.
14. 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.  
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
16. Is expecting to 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.
17. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
19. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected).
20. Has received a live vaccine or live-attenuated vaccine within 30 days prior to the first 
dose of study drug.  Administration of killed vaccines is allowed.


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5.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 2
Table 2:  Trial Treatment1,2
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 3 
week cycle
Experimental
1.
Trial treatment should begin on the day of study group assignment or as close as possible to the date on 
which study group is allocated/assigned.
2.
Subjects who progress on pembrolizumab have the option of receiving taxane-based chemotherapy 
followed by repeat pembrolizumab for those who have a clinical response to chemotherapy. The 
patients will remain on study while receiving chemotherapy. A minimum of 2 cycles and a maximum 
of 8 cycles of chemotherapy will be given. The chemotherapy regimen will be at the discretion of the 
treating physician, and may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. 
carboplatin). Chemotherapy may be given with concurrent prednisone < 10 mg/ day. Clinical response 
to chemotherapy is defined as PSA decrease by >50% or objective response by RECIST v1.1. Subjects 
who resume pembrolizumab after achieving response to chemotherapy should taper prednisone to < 10 
mg/day prior to restarting pembrolizumab.
5.2.1
Dose Selection/Modification
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 and toxicity management for immune-related AEs associated 
with pembrolizumab
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 Table 3 below. See Section 
5.6 for supportive care guidelines, including use of corticosteroids.


Table 3: Dose Modification Guidelines for Drug-Related Adverse Events
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper.
irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold 
Pneumonitis 
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Add prophylactic antibiotics for 
opportunistic infections
  Monitor participants for signs and symptoms of 
pneumonitis
  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Diarrhea/Colitis 
Grade 2 or 3
Withhold
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Recurrent 
Grade 
3 
or 
Grade 4
Permanently 
discontinue
and ileus)
  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Grade 2 a
Withhold
  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper
AST or ALT 
Elevation 
or 
Increased 
Bilirubin
Grade 3 b or 4 c
Permanently 
discontinue
  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper
  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
T1DM 
or 
Hyperglycemia
New 
onset 
T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence 
of 
-cell failure
Withhold d
  Initiate insulin replacement therapy for 
participants with T1DM
  Administer antihyperglycemic in 
participants with hyperglycemia
  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold
Hypophysitis
Grade 3 or 4
Withhold 
or 
permanently 
discontinue d
  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated
  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 2
Continue
Hyperthyroidism
Grade 3 or 4
Withhold 
or 
permanently 
discontinue d
  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
  Monitor for signs and symptoms of thyroid 
disorders
Hypothyroidism
Grade 2, 3 or 4
Continue
  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
  Monitor for signs and symptoms of thyroid 
disorders
Grade 2
Withhold
Nephritis:
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury
Grade 3 or 4
Permanently 
discontinue
  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper
  Monitor changes of renal function
Grade 2
Withhold
Neurological 
Toxicities
Grade 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 1
Withhold
Myocarditis
Grade 2, 3 or 4
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Suspected SJS, 
TEN, 
or 
DRESS
Withhold
Exfoliative 
Dermatologic 
Conditions
Confirmed SJS, 
TEN, 
or 
DRESS
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
Persistent Grade 2 Withhold
Grade 3
Withhold 
or 
discontinue based 
on the event e 
All Other irAEs
Recurrent 
Grade 3 
or 
Grade 4 
Permanently 
discontinue
  Based on severity of AE administer 
corticosteroids
  Ensure adequate evaluation to confirm etiology 
or exclude other causes
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 


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irAEs
Toxicity 
Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
pembrolizumab may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs(vasculitis and sclerosing cholangitis).
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 PI. The reason for interruption should be documented in the 
patient's study record.


5.2.2
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. A 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 
min/+10 min).
The Pharmacy Manual contains specific instructions for the preparation of the 
pembrolizumab infusion fluid and administration of infusion solution.
5.2.3
Trial Blinding/Masking
All subjects enrolled in this study will receive pembrolizumab. Subjects will not be blinded 
to their DNA damage repair signature status given efficacy of olaparib in mCRPC patients 
with BRCA1/2, ATM, Fanconi anemia, and CHEKC2 mutations (Mateo J et al., 2015). 
5.3
Randomization or Treatment Allocation
Randomization will not be employed in this study due to the nature of the study. Subjects 
will be assigned to the appropriate study group based on DNA damage repair status (Group 1 
if DNA repair gene unmutated/MMR intact; Group 2 if MSI-high and/or DNA repair gene 
mutated). All subjects enrolled will receive pembrolizumab. Patients with previously 
identified MSI-high tumor by PCR or HIC, or homozygous deletion or deleterious somatic 
mutation(s) in DNA damage repair gene(s) (such as BRCA1, BRCA2 and ATM) identified in 
a CLIA-certified laboratory are allowed in Group 2 (Figure 1).


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Figure 1: Study schema
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 
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 ECIs as defined in Section 7.2.


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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 
o
Exception: Androgen deprivation therapy (ADT). Patients are required to 
maintain castrate-level testosterone (<50 ng/dL) with a GNRH agonist or 
antagonist +/- LHRH. Patients without history of bilateral orchiectomy are 
required to remain on ADT.  

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.  

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.  Glucocorticoids without 
significant systemic bioavailability (e.g. budesonide or joint injections) are allowed.  
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.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.


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5.5
Rescue Medications & Supportive Care
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.


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
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.

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.


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
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
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. 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475).


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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 (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.
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).
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.
5.6
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.


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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 (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Acceptable methods of contraception are:
Single method (one of the following is acceptable):

Intrauterine device (IUD) for subject’s partner

Vasectomy 

Contraceptive rod implanted into the skin for subject’s partner
 
Combination method (requires use of two of the following):

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) for subject’s partner

Cervical cap with spermicide (for subject’s partner, nulliparous women only)  

Contraceptive sponge (for subject’s partner, nulliparous women only) 

Male condom or female condom (cannot be used together)

Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection (for subject’s partner)
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 
abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
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 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study.


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5.6.3
Use in Pregnancy
If a subject impregnates his female partner, the study personnel must be informed 
immediately and the pregnancy reported to Merck and followed as described above and in 
Section 7.2.2.
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.

Confirmed radiographic disease progression
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved. See 
Section 7.1.2.2.
•
Unacceptable adverse experiences as described in Section 5.2.1.2
•
Intercurrent illness that prevents further administration of treatment
•
Investigator’s decision to withdraw the subject
•
Noncompliance with trial treatment or procedure requirements
•
The subject is lost to follow-up
•
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later.
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.7.5
•
Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.2 (Treatment Period).  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.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first.


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5.7.1 Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of 
the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule at 
the time of initial discontinuation.  Additional details are provided in Section 7.1.7.5.
5.8
Subject Replacement Strategy
All patients who receive any study therapy will be analyzed for safety and efficacy. Subjects 
who discontinue from study participation prior to receiving any study therapy may be 
replaced after discussion with the Study Monitor. Subjects who have received any dose of 
study therapy will not be replaced. Patients removed from study for unacceptable treatment 
related adverse event(s) will be followed until resolution or stabilization of all treatment 
related AEs to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever 
occurs first. However, they will not be replaced.
5.9
Stopping Rule
A stopping rule for safety will halt accrual to the study and prompt reevaluation of 
pembrolizumab dose if unacceptable treatment-related toxicity (defined as any Grade 4 
toxicity, any recurrent Grade 3 toxicity, or any Grade 3 toxicity persisting more than 4 
weeks) is observed at a frequency of ≥33% in any study group. Because pembrolizumab is 
generally well tolerated, this safety review will occur after a total of 9 subjects have been 
accrued (either study group).
5.10
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.


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6.0 TRIAL FLOW CHART
Trial Period:
Screening Phase
Treatment Cycles1
Treatment at Progression2
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Pre-screening 
(Visit 1)
Main Study 
Screening
 (Visit 2)
Pembrolizumab
Taxane-
based 
Chemo
Post-
chemotherapy 
Pembrolizumab
Discontinuation
Safety 
Follow-up3
Follow Up Visits4
Survival 
Follow-Up5
Scheduling Window (Days):
-28 to -1
Every 21 days 
+ 3 days
Every 21 
days +3 
days x 2-8
Every 21 days
 + 3 days
At time of 
Discontinuation
30 days post 
discontinuation
Every 12 weeks 
post discontinuation
Every 12 
weeks
Administrative Procedures
Pre-screening Consent6
x
Informed Consent
x
Inclusion/Exclusion Criteria
x
Demographics and Medical History
x
Prior and Concomitant Medication 
Review
x
Pembrolizumab Administration
x
x
Chemotherapy Administration7
x
Post-study anticancer therapy status
x
x
Survival Status
x
Clinical Procedures/Assessments
Review Adverse Events
x
x8
x
x
x
Full Physical Examination
x
Directed Physical Examination
x
x
x
x
x
x
Vital Signs and Weight9
x
x
x
x
x
x
x
ECOG Performance Status
x
x
x
x
x


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Trial Period:
Screening Phase
Treatment Cycles1
Treatment at Progression2
End of 
Treatment
Post-Treatment
Treatment Cycle/Title:
Pre-screening 
(Visit 1)
Main Study 
Screening
 (Visit 2)
Pembrolizumab
Taxane-
based 
Chemo
Post-
chemotherapy 
Pembrolizumab
Discontinuation
Safety 
Follow-up3
Follow Up Visits4
Survival 
Follow-Up5
Scheduling Window (Days):
-28 to -1
Every 21 days 
+ 3 days
Every 21 
days +3 
days x 2-8
Every 21 days
 + 3 days
At time of 
Discontinuation
30 days post 
discontinuation
Every 12 weeks 
post discontinuation
Every 12 
weeks
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory10
PT/INR and aPTT
x
CBC with Differential11
x
x
x
x
x
Comprehensive Serum Chemistry12 
x
x
x
x
x
Urinalysis
x
LDH
x
x
x
x
x
TSH13
x
x
x
x
x
Efficacy Measurements
Tumor Imaging
x14
x14
x14
x14
x14
x14
PSA15
x
x
x
x
x
x
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood
Newly Obtained Tissue Biopsy16
x
x
x
Mutation/MSI testing16
x
x
x
FA/BRCA signature testing16
x
x
x
Archival Tissue Collection17
x
Immunomonitoring Blood 
Collection18
x
x
x
x
x
x
x


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1.
Pembrolizumab 200mg IV every 3 weeks until confirmed progression of disease by irRC, clinical deterioration, or unacceptable toxicity. 
2.
Subjects who progress on initial pembrolizumab treatment have the option of undergoing biopsy of a metastatic site and/or receiving taxane-based 
chemotherapy for 2 to 8 cycles, if deemed fit by the investigator and subject. For site of metastatic biopsy, preferences will be given to repeat biopsy of 
metastatic bone tissue that was sampled at baseline or demonstrated radiographic progression on pembrolizumab, whenever feasible. If a bone biopsy is not 
feasible, then a soft tissue or lymph node biopsy may be performed. Repeat progression biopsy should be obtained prior to subsequent treatment. Subjects 
who respond to chemotherapy (defined as achieving objective response by RECIST v1.1 or PSA decline by >50%) have the option of repeating 
pembrolizumab, assuming adequate performance status and organ functions as specified in the inclusion criteria. Pembrolizumab should be restarted within 
30 days of the last dose of chemotherapy. Prednisone should be tapered to < 10 mg/day prior to restarting pembrolizumab. Subjects who reinitiate 
pembrolizumab following chemotherapy will have the option of undergoing an additional biopsy of the metastatic site. Additional biopsy should be 
obtained within 30 days of reinitiating pembrolizumab.
3.
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of trial treatment or before the initiation of a new 
anti-cancer treatment, whichever comes first (See Section 7.1.7.3.1).
4.
Subjects who discontinue pembrolizumab for a reason other than disease progression will move into the Follow-Up Phase and should be assessed every 12 
weeks (± 7 days) by radiologic imaging to monitor disease status.  Every effort should be made to collect information regarding disease status until the start 
of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 
7.1.7.5.  Information regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated.
5.
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the survival follow-up phase and 
should be contacted by telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first (See Section 7.1.7.4.1).
6.
Pre-screening consent for tissue biopsy for mutational sequencing and MSI testing.
7.
Subjects who progress on pembrolizumab in either study group will have the option of receiving taxane-based chemotherapy followed by repeat 
pembrolizumab for those who have a clinical response to chemotherapy. Chemotherapy should be started within 60 days of last dose of pembrolizumab. 
Chemotherapy regimen will be at the discretion of the treating physician, and may consist of docetaxel or cabazitaxel with or without a platinum agent (e.g. 
carboplatin). A minimum of 2 cycles and a maximum of 8 cycles of chemotherapy will be given. Clinical response to chemotherapy is defined as PSA 
decrease by >50% or objective response by RECIST v1.1. Chemotherapy may be given with prednisone < 10 mg/day. Prednisone should be tapered to < 10 
mg/day prior to restarting pembrolizumab.
8.
Adverse events documented during administration of chemotherapy will not be attributed to pembrolizumab, unless they are determined to be irAEs by the 
investigator.
9.
Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only.
10. Labs may be collected within a window of up to 3 days prior to each dosing of pembrolizumab. 
11. CBC includes RBC count, hemoglobin, hematocrit, WBC count with automated differential (neutrophils, lymphocytes, eosinophils, monocytes, basophils, 
and other cells), and platelet count.  A manual differential can be done if clinically indicated.  
12. Comprehensive serum chemistry includes sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, total bilirubin, 
ALT, AST, alkaline phosphatase, total protein, and albumin.
13. T3 and FT4 should be checked if TSH is outside the normal range.


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14. Radiographic evaluations and tumor measurements will be performed at screening 28 days prior to C1D1, then every 12 weeks (+/- 2 
weeks) thereafter, including the off study evaluation. During post-chemotherapy pembrolizumab, radiographic evaluation and tumor 
measurements will be performed every 12 weeks (+/- 2 weeks). Weeks are in reference to calendar week, and should not be adjusted for 
pembrolizumab dosing delays. CT chest/abdomen/pelvis with contrast and bone scan should be performed. If sodium fluoride (NaF) 
PET/CT was initially used for staging, the same bone imaging modality (i.e. NaF PET/CT) should be used throughout the study. See 
Section 7.1.4.6.
15. Subjects will check PSA at time of screening, and then every 3 weeks (+/- 1 week), including the off study evaluation. Weeks are in 
reference to calendar week, and should not be adjusted for pembrolizumab dosing delays. 
16. Subjects will undergo biopsy of any lesion (primary or metastatic) at the time of screening for mutational sequencing / MSI testing. MSI testing will be 
performed at UCSF (See Laboratory Manual). FA/BRCA expression signature will be assessed retrospectively. 
17. Archival prostate biopsy or surgical tissue will be requested if available. a. A formalin-fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block 
(preferred) or at least 10 slides containing unstained, freshly cut, serial sections must be available along with an associated pathology report before study 
enrollment.
18. Blood will be collected in four 10mL BD Sodium HeparinN (NH) 158 USP Units Plus Blood Collection Tubes (green-top) and sent to the Immune 
Monitoring Core at UCSF (See Section 7.1.5.1.2).


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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.  The study-specific assessments are detailed below (Section 7.1.1 and Section 7.1.2).  
Screening assessments must be performed within 28 days prior to the first dose of 
investigational product.  Any results falling outside of the reference ranges may be repeated 
at the discretion of the investigator. All on-study visit procedures are allowed a window of ± 
3 days unless otherwise noted.  Treatment or visit delays for public holidays or weather 
conditions do not constitute a protocol violation.
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
Pretreatment Period
7.1.1.1 Screening Assessments
The Screening procedures and assessments, except for biopsy and archival tissue collection, 
must be completed within 28 days of the Day 1 Visit. 
•
Physical examination
•
Vital signs and weight
•
Complete medical history and demographics
•
Baseline conditions assessment
•
Documentation of disease assessment
•
Performance status
•
Baseline medications taken within 28 days of Day 1
•
Sample of tumor tissue
•
Complete blood count (CBC) with differential and platelet count including
•
RBC count, hemoglobin, hematocrit, WBC count with automated differential 
(neutrophils, lymphocytes, eosinophils, monocytes, basophils, and other cells), 
and platelet count.  A manual differential can be done if clinically indicated.  
•
Blood chemistry assessment including
•
Sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose, calcium, 
total bilirubin, ALT, AST, alkaline phosphatase, total protein, and albumin


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•
Thyroid function tests: thyroid-stimulating hormone (TSH) 
•
T3 and FT4 should be checked if TSH is outside the normal range
•
Coagulation assessment, including prothrombin time, partial thromboplastin time, 
international normalized ratio (PT/PTT/INR)
•
LDH
•
PSA
•
Immune monitoring blood collection
•
Urinalysis
•
Tumor imaging 
•
CT chest/abdomen/pelvis with contrast
•
Bone scan - If sodium fluoride (NaF) PET/CT was initially used for 
staging, the same bone imaging modality (i.e. NaF PET/CT) should be 
used throughout the study
•
Biopsy of lesion at the time of screening for mutational testing and MSI testing.
•
Soft tissue or lymph node biopsies will be prioritized. If a soft tissue or lymph 
node biopsy is not feasible, then a bone biopsy may be performed.
•
Archival tissue collection, if available 
7.1.2
Treatment Period
7.1.2.1 Every 21 days
•
Directed physical examination
•
Vital signs and weight
•
Performance status
•
Evaluation of adverse events
•
CBC with differential and platelet count
•
Blood chemistry assessment 
•
Thyroid function tests
•
LDH
•
PSA - every 3 weeks (+/- 1 week), including the off study evaluation. Weeks 
are in reference to calendar week, and should not be adjusted for 
pembrolizumab dosing delays. 
•
Immune monitoring blood collection


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•
Tumor imaging - Radiographic evaluations and tumor measurements will be 
performed at screening (within 28 days prior to the first dose of 
pembrolizumab), then every 12 weeks (+/- 2 weeks) thereafter, including the 
off study evaluation. During post-chemotherapy pembrolizumab, radiographic 
evaluation and tumor measurements will be performed every 12 weeks (+/- 2 
weeks). Weeks are in reference to calendar week, and should not be adjusted 
for pembrolizumab dosing delays.
•
Pembrolizumab administration - 200mg IV every 3 weeks until confirmed 
progression of disease by irRC, clinical deterioration, or unacceptable toxicity
7.1.2.2 Optional Treatment at Progression
Subjects who progress on initial pembrolizumab treatment have the option of undergoing 
biopsy of a metastatic site and/or receiving taxane-based chemotherapy for 2 to 8 cycles, if 
deemed fit by the investigator and subject. For site of metastatic biopsy, preferences will be 
given to repeat biopsy of metastatic bone tissue that was sampled at baseline or demonstrated 
radiographic progression on pembrolizumab, whenever feasible. If a bone biopsy is not 
feasible, then a soft tissue or lymph node biopsy may be performed. Repeat progression 
biopsy should be obtained prior to subsequent treatment. The chemotherapy regimen will be 
at the discretion of the treating physician, and may consist of docetaxel or cabazitaxel with or 
without a platinum agent (e.g. carboplatin). The doses of chemotherapy may be modified at 
the discretion of the investigator as clinically indicated. Chemotherapy may be given with 
concurrent prednisone < 10mg/day. Patients will remain on study while receiving 
chemotherapy, and chemotherapy should be started within 30 days of the last dose of 
pembrolizumab. Subjects should be re-imaged every 12 weeks on chemotherapy. Subjects 
who respond to chemotherapy (defined as achieving objective response by RECIST v1.1 or 
PSA decline by >50%) have the option of repeating pembrolizumab, assuming adequate 
performance status and organ functions as specified in the inclusion criteria. Pembrolizumab 
should be restarted within 30 days of the last dose of chemotherapy. Prednisone should be 
tapered to < 10mg/day prior to restarting pembrolizumab. Subjects who reinitiate 
pembrolizumab following chemotherapy will have the option of undergoing an additional 
biopsy of the metastatic site. Additional biopsy should be obtained within 30 days of 
reinitiating pembrolizumab.


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7.1.2.2.1
Taxane-based chemotherapy - Every 21 Days (for 2-8 cycles)
•
Directed physical examination
•
Vital signs and weight
•
Performance status
•
Evaluation of adverse events
•
CBC with differential and platelet count
•
Blood chemistry assessment 
•
Thyroid function tests
•
LDH
•
PSA - every 3 weeks (+/- 1 week), including the off study evaluation. Weeks 
are in reference to calendar week, and should not be adjusted for 
pembrolizumab dosing delays. 
•
Immune monitoring blood collection
•
Tumor imaging – every 12 weeks
•
Chemotherapy administration 
7.1.2.2.2
Post-Chemotherapy Pembrolizumab - Every 21 days
•
Directed physical examination
•
Vital signs and weight
•
Performance status
•
Evaluation of adverse events
•
CBC with differential and platelet count
•
Blood chemistry assessment 
•
Thyroid function tests
•
LDH
•
PSA - every 3 weeks  
•
Immune monitoring blood collection
•
Tumor imaging – every 12 weeks
•
Pembrolizumab administration 


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7.1.2.3 End of Treatment
At time of discontinuation of study treatment:
•
Directed physical examination
•
Vital signs and weight
•
Performance status
•
Evaluation of adverse events
•
CBC with differential and platelet count
•
Blood chemistry assessment 
•
Thyroid function tests
•
LDH
•
PSA 
•
Immune monitoring blood collection
•
Tumor imaging 
7.1.2.4 Post-Treatment
7.1.2.4.1
Safety Follow-up
30 days post study treatment discontinuation:
•
Directed physical examination
•
Vital signs and weight
•
Evaluation of adverse events
•
Immune monitoring blood collection
7.1.2.4.2
Follow-up Visits
Subjects who discontinue pembrolizumab for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (± 7 days) by 
radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the subject begins retreatment with pembrolizumab 
as detailed in Section 7.1.2.2.  Information regarding post-study anti-neoplastic treatment 
will be collected if new treatment is initiated. 


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Post discontinuation, every 12 weeks:
•
Post-study anticancer therapy status 
•
Directed physical examination
•
Vital signs and weight
•
Immune monitoring blood collection
•
Tumor imaging
•
PSA
7.1.2.4.3
Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.
7.1.3
Administrative Procedures
7.1.3.1 Informed Consent
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.
7.1.3.1.1
General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.


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7.1.3.2 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. 
7.1.3.3 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 10 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.  
7.1.3.4 Prior and Concomitant Medications Review
7.1.3.4.1
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. 
7.1.3.4.2
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.
7.1.3.5 Disease Details and Treatments
7.1.3.5.1
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.3.5.2
Prior Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries.


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7.1.3.5.3
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.  Once new anti-cancer therapy has been initiated the subject 
will move into survival follow-up. 
7.1.3.6 Assignment of Screening Number
All patients who are consented will be registered in OnCore®, the UCSF Helen Diller 
Family Comprehensive Cancer Center Clinical Trial Management System (CTMS).  The 
system is password protected and meets HIPAA requirements. All patients will have a unique 
identification number. 
7.1.3.7 Assignment of Study Group Number
Patients enrolled into the study will be assigned to Group 1 or Group 2 based on DNA 
damage repair status determined by MSI and/or mutational sequencing (e.g. UCSF500, 
Foundation, Strata). Study group assignment will be documented in OnCore®.
7.1.3.8 Trial Compliance (Medication/Diet/Activity/Other)
A subject may be discontinued from the study for significant non-compliance with treatment 
or procedure requirements.
7.1.4
Clinical Procedures/Assessments
7.1.4.1 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 Appendix 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.  
7.1.4.2 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening, 


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7.1.4.3 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  
7.1.4.4 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.
7.1.4.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Appendix 11.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.  
7.1.4.6 Tumor Imaging and Assessment of Disease
Radiographic evaluations and tumor measurements will be performed at screening 
(within 28 days prior to the first dose of pembrolizumab), then every 12 weeks (+/- 
2 weeks) thereafter, including the off study evaluation. Weeks are in reference to 
calendar week, and should not be adjusted for pembrolizumab dosing delays. 
CT chest/abdomen/pelvis with contrast and bone scan should be performed. If 
sodium fluoride (NaF) PET/CT was initially used for staging, the same bone 
imaging modality (i.e. NaF PET/CT) should be used throughout the study. 
Immune-related response criteria (irRC) will be used to determine radiographic 
response of non-bone tissue on pembrolizumab. PCWG3 will be used to determine 
radiographic response of bone metastases on pembrolizumab; specifically the 
appearance of 2 or more new bone lesions will qualify as disease progression. For 
subjects who progress and go on to receive taxane-based chemotherapy,) RECIST 
v1.1 and/or PCWG3 will be used to determine radiographic response on 
chemotherapy. 
7.1.4.7 Tumor Tissue Collection and Correlative Studies Blood Sampling
Subjects will undergo tumor tissue biopsy at the time of screening for DNA repair defects. 
Assays that can be used for detecting this include: targeted mutation sequencing and MSI 
testing. Targeted mutation sequencing can include the UCSF 500 as well as commercial tests 
(e.g. Foundation, Strata). MSI testing will be performed at UCSF if the targeted mutation 
sequencing is equivocal. FA/BRCA signature testing will be performed retrospectively by 
Almac or other equivalent platform. 


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Archival tissues
Patients with previously identified DNA repair defects will have archival tumor tissue 
requested (See Section 5.1.2). A formalin-fixed paraffin-embedded (FFPE) tumor specimen 
in a paraffin block (preferred) or at least 10 slides containing unstained, freshly cut, serial 
sections must be available along with an associated pathology report before study enrollment. 
If archival FFPE tissue is unable to be obtained or is insufficient, patients will be required to 
undergo tumor tissue biopsy if feasible, for determination of DNA repair mutations, MSI 
and/or FA/BRCA signature status.
Archival prostate biopsy or surgical tissue will also be requested if available. A formalin-
fixed paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or at least 10 
slides containing unstained, freshly cut, serial sections must be available along with an 
associated pathology report before study enrollment.  
Peripheral blood immune monitoring 
Blood will be collected in four 10mL BD Sodium HeparinN (NH) 158 USP Units Plus Blood 
Collection Tubes (green-top) and sent to the Immune Monitoring Core at UCSF (See Section 
7.1.5.1.2).
7.1.5
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. Laboratory tests for hematology, chemistry, urinalysis, and others are 
specified 
in 
Table 
5.  


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Table 5:  Laboratory Tests
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 abnormal 
results are noted) 
Thyroid stimulating hormone (TSH)
Absolute Neutrophil Count
Carbon Dioxide †
Blood for correlative studies
Absolute Lymphocyte Count
  (CO2 or biocarbonate)
Calcium
Chloride
Glucose
 
Potassium  
 
Sodium
 
Total Bilirubin
 
Total protein
Creatinine
Blood Urea Nitrogen


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Laboratory tests for screening, repeat pembrolizumab after taxane-based chemotherapy, or 
entry into the Second Course Phase should be performed within 10 days prior to the first dose 
of treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing.  Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to each dose of trial treatment. 
7.1.5.1 Biomarker Determination and Correlative Studies
7.1.5.1.1
Tissue Biopsy and DNA Damage Repair Status Evaluation
MSI testing will be performed by the pathology department at UCSF. FA/BRCA signature 
testing will be performed by Almac or other equivalent platform. Sample collection, 
processing, storage and shipment instructions for tissue samples will be detailed in the 
Laboratory Manual.
7.1.5.1.2
Blood for Immunomonitoring
At the indicated time points in the trial flow chart (Section 6.0), blood will be collected in 
four 10mL BD Sodium HeparinN (NH) 158 USP Units Plus Blood Collection Tubes (green-
top) and sent to the Immune Monitoring Core at UCSF.
Immune Monitoring Core
University of California, San Francisco
.
San Francisco, CA 94143
7.1.6
Other Procedures
7.1.6.1 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.  
  Subjects who a) attain a CR or b) complete 24 months of treatment with pembrolizumab 
may discontinue treatment with the option of restarting treatment if they meet the criteria 
specified in Section 7.1.7.5.  After discontinuing treatment following assessment of CR, 
these subjects should return for a Safety Follow-up Visit and then proceed to the Follow-Up 
Period of the study (described in Section 7.1.2.4).


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7.1.6.2 Blinding/Unblinding
All subjects enrolled in this study will receive pembrolizumab. Subjects will not be blinded 
to their DNA damage repair signature status given efficacy of olaparib in mCRPC patients 
with BRCA1/2, ATM, Fanconi anemia, and CHEK2 mutations (Mateo J et al., 2015). 
7.1.7
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.7.1 Screening
7.1.7.1.1
Screening Period
During the initial accrual onto the clinical trial, patients without the full results of DNA 
repair status testing being available may be enrolled onto the clinical trial and started on 
treatment so long as there are available slots in Group 1 and so long as we have biopsy 
material to perform the testing. Once Group 1 is filled and all subjects have had their DNA 
repair status verified, the study will only enroll to Group 2. These subjects must be screened 
for DNA repair defective status before being enrolled. 
Subjects will undergo two screening visits. In the pre-screening visit (Visit 1), a pre-
screening consent for tumor tissue biopsy for mutational sequencing and MSI testing will be 
obtained. Subjects will move into the main study screening visit (Visit 2), at which time 
informed consent for the study will be obtained, and study procedures outlined in Section 7.1, 
including labs and imaging, as will be performed.
7.1.7.2 Treatment Period
During the treatment period, subjects will undergo required study procedures as indicated in 
Section 7.1. All subjects should have vital checked, a focused physical exam, adverse events 
reviewed, laboratory reviewed, and relevant imaging results reviewed before receiving the 
next planned dose of pembrolizumab. 


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7.1.7.3 Post-Treatment Visits
7.1.7.3.1
Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
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.  Subjects who are eligible for retreatment 
with pembrolizumab (as described in Section 7.1.7.5) may have up to two safety follow-up 
visits, one after the Treatment Period and one after the Second Course Phase.
7.1.7.4 Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (± 7 days) by 
radiologic imaging to monitor disease status.  Every effort should be made to collect 
information regarding disease status until the start of new anti-neoplastic therapy, disease 
progression, death, end of the study or if the subject begins retreatment with pembrolizumab 
as detailed in Section 7.1.7.5.  Information regarding post-study anti-neoplastic treatment 
will be collected if new treatment is initiated.
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.7.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.    
7.1.7.4.1
Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first. 


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7.1.7.5 Second Course Phase (Retreatment Period)
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions:

Either 
o
Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and
Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy
Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared
OR
o
Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of 
study therapy for reasons other than disease progression or intolerability
AND

Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab

Did not receive any anti-cancer treatment since the last dose of pembrolizumab

Has a performance status of 0 or 1 on the ECOG Performance Scale

Demonstrates adequate organ function as detailed in Section 5.1.2

Male subject should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.  

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year.
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.


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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. 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.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use.
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event. 
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome.


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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. The subject is first required to provide consent 
to the main study and AEs will be captured according to guidelines for standard AE 
reporting before blood draw and fresh tumor biopsy.
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; 
220)
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor and to Merck
Although pregnancy and lactation are not considered adverse events, it is the responsibility 
of investigators or their designees to report any pregnancy or lactation in a subject’s partner 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.  
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation 
of treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 


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miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
)
7.2.3
Immediate Reporting of Adverse Events to the Sponsor and to Merck
7.2.3.1 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 an other important medical event 

Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the 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 
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/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Merck product, must be reported within 24 hours to the Sponsor and within 2 working 
days to Merck Global Safety.


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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 
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 
) at the time of submission to FDA.
7.2.3.2 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 
).
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, 
whether or not related to Merck product, must be reported within 24 hours to the Sponsor and 
within 24 hours to Merck Global Safety.


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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. 
7.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3 - Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study.
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered 
a SAE.
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. 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.


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Table 6:  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 


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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


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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 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.)


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7.2.5
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. 
Reporting to the Data and Safety Monitoring Committee
If a death occurs during the treatment phase of the study or within 30 days after the last 
administration of the study drug(s) and it is determined to be related either to the study 
drug(s) or to a study procedure, the Investigator or his/her designee must notify the DSMC 
Chair (or qualified alternate) within 1 business day of knowledge of the event.  The contact 
may be by phone or e-mail.
Reporting to UCSF Institutional Review Board
The Principal Investigator must report events meeting the UCSF IRB definition of 
“Unanticipated Problem” (UP) within 5 business days of his/her awareness of the event. 
Expedited Reporting to the Food and Drug Administration
If the study is being conducted under an IND, the Sponsor-Investigator is responsible for 
determining whether or not the suspected adverse reaction meets the criteria for expedited 
reporting in accordance with Federal Regulations (21 CFR §312.32). 
The Investigator must report in an IND safety report any suspected adverse reaction that is 
both serious and unexpected.  The Sponsor-Investigator needs to ensure that the event meets 
all three definitions: 

Suspected adverse reaction 

Unexpected 

Serious 
If the adverse event does not meet all three of the definitions, it should not be submitted as an 
expedited IND safety report.
The timeline for submitting an IND safety report to FDA is no later than 15 calendar days 
after the Investigator determines that the suspected adverse reaction qualifies for reporting 
(21 CFR 312.32(c)(1)). 
Any unexpected fatal or life-threatening suspected adverse reaction will be reported to FDA 
no later than 7 calendar days after the Investigator’s initial receipt of the information (21 
CFR 312.32(c)(2)). 
Any relevant additional information that pertains to a previously submitted IND safety report 
will be submitted to FDA as a Follow-up IND Safety Report without delay, as soon as the 
information is available (21 CFR 312.32(d)(2)). 
8.0 STATISTICAL ANALYSIS PLAN
8.1
Sample Size and Power Calculation
The primary hypothesis of the study is that subjects with defective DNA damage repair have 
increased radiographic progression free survival (rPFS) compared to subjects with proficient 
DNA damage repair. With 25 patients in each group, considering 6-month rPFS rate is 10% 


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for the subjects with proficient DNA damage repair, if 6-month rPFS rate is 45% for the 
defective DNA damage repair, we have 80% of power to claim that that subjects with 
defective DNA damage repair have increased radiographic progression free survival (rPFS) 
compared to subjects with proficient DNA damage repair at one-side alpha of 0.05.
8.2
 Statistical Analysis Plan Summary: Primary Objective
8.2.1
Radiographic Progression Free Survival
Radiographic progression free survival (rPFS) is defined as the time from the first day of 
study treatment with pembrolizumab to the date of documented radiographic tumor 
progression or death due to any cause, whichever occurs first. Radiographic tumor 
progression is defined according to the PCWG3 (Scher HI et al., 2016) guidelines. 
The point estimate of 6-month rPFS rate and its 95% confidence interval will be obtained for 
each group, and will be compared by two-sample binomial test. The median rPFS and its 
95% confidence interval will be obtained for each study group by Kaplan Meier method. Log 
rank test will be used to compare rPFS between the two study groups.
8.3
Statistical Analysis Plan Summary: Secondary Objectives
8.3.1
Progression Free Survival
Progression free survival is defined as the time from the first day of study treatment with 
pembrolizumab to the date of documented tumor progression or death due to any cause, 
whichever occurs first, as determined by irRC for irPFS and RECIST v1.1 for PFS. Subjects 
who did not progress or die will be censored on the date of their last evaluable tumor 
assessment. The point estimation and its 95% confidence interval of 20 weeks and 28 weeks 
irPFS rate and PFS rate will be obtained by study group and compared between the study 
groups by two-sample binomial test, separately. Kaplan-Meier method will be used to 
summarize PFS and irPFS; median irPFS and PFS will be estimated with 95% confidence 
interval in each study group. Log rank test will be used to compare the irPFS and PFS 
between the two groups, separately.
8.3.2
PSA Response
The proportion of subjects achieving any PSA response and PSA decline of >50% from 
baseline from the time of the first day of study treatment with pembrolizumab will be 
calculated in both study groups. The duration of PSA response related to treatment duration 
will be summarized using a radar or spider plot. The point estimate and its 95% confidence 
interval will be obtained for the proportion of PSA response separately for each study group. 
Two-sample binomial test will be used to compare the proportion of PSA response between 
the two study groups.


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8.3.3
Safety and Tolerability
All subjects will be evaluated for toxicity from the time of the first treatment with 
pembrolizumab. Adverse events occurring from the start of treatment until 30 days after the 
end of treatment will be summarized by maximum toxicity grade for each study group and by 
strata. The toxicity grade for laboratory data will be calculated using CTCAE v4.0 and the 
lab data will be summarized according to the subjects’ baseline grade and maximum grade 
for each cycle of therapy. All treatment related adverse events will be graded using NCI 
CTCAE v4.0.
8.3.4
Time to Progression after Taxane-Based Chemotherapy and Repeat 
Pembrolizumab
For subjects who undergo taxane-based chemotherapy after progression on pembrolizumab 
followed by repeat pembrolizumab after chemotherapy, time from the first chemotherapy 
treatment to disease progression will be estimated in both study groups. Disease progression 
will be defined by confirmed PSA progression on two consecutive measurements at least 2 
weeks apart, or radiographic progression by irRC. The Kaplan-Meier method will be used to 
estimate the median time to progression with 95% confidence interval by study group. Log 
rank test will be used to compare the time to progression between the two study groups.
8.4
Statistical Analysis Plan Summary: Exploratory Objectives
8.4.1
Immune Infiltration 
Immune cell subsets and localization will be assessed by immunohistochemistry (IHC) in 
baseline tissue biopsy samples as well as optional tissue biopsy samples at time of 
progression. Markers will include CD3, CD8 and FoxP3. Differences in immune cell subsets 
between study groups will be analyzed using Wilcoxon rank-sum test. For available paired 
samples, changes in immune cell subsets between baseline and progression will be analyzed 
using Wilcoxon Signed-rank test. In addition, within each study group, Wilcoxon rank-sum 
test will be used to assess whether there is a relationship between any of the immune cell 
subsets (both baseline and the change from baseline to progression) and objective response, 
PSA response, and PFS at 20 and 28 weeks, respectively.
8.4.2
PD-L1 staining
PD-L1 IHC will be performed by Qualtek (CLIA-certified) on baseline and progression 
biopsy tissues (excluding bone metastases) using Merck’s 22C3 antibody. Descriptive 
statistics will be used to summarize PD-L1 scores between study groups and individuals 
(when paired samples are available). Moreover, within each study group, Wilcoxon rank-sum 
test will be used to assess whether there is a relationship between PD-L1 score (both baseline 
and the change from baseline to progression) with objective response, PSA response, and 
PFS at 20 and 28 weeks, respectively. 


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8.4.3
T Cell Receptor (TCR) Repertories
For each subject, blood will be collected at screening, every 3 weeks during treatment, and 
every 3 months during follow-up. T cell repertoire before, during and after treatment will be 
assessed by next-generation sequencing. Besides the number of unique clonotypes and read 
depth, the TCR repertoire diversity will be assessed by Shannon diversity index and 
clonality. Repertoire overlap will be measured by Baroni-Urbani and Buser index, and 
changes in clonotypes counts between sequencing experiments will be measured using 
Morisita’s distance. The diversity index will be compared by Wilcoxon rank-sum test 
between study groups first, then within each study group. Wilcoxon rank-sum test will also 
be used to assess whether the diversity index is different between responders vs. non-
responders (defined by either objective response or PSA response), and between subjects 
who have progression at 20 and 28 weeks vs. those who have not progressed in each study 
group.
8.4.4
Mutational Burden 
Whole exome sequencing (WES) will be performed in baseline biopsy tissues in a subset of 
subjects in each study group. The average number of somatic mutations per tumor will be 
assessed by Wilcoxon rank-sum test between study groups as well as between responders vs. 
non-responders (defined by either objective response or PSA response), and between subjects 
who have progression at 20 and 28 weeks vs. those who have not progressed in each study 
group. 
8.4.5
Circulating Immune Cells
For each subject, blood will be collected at screening, every 3 weeks during treatment, and 
every 3 months during follow-up. Flow cytometry will be performed to assess changes in 
circulating immune cell subsets with treatment, including effector T cells, regulatory T cells, 
and myeloid cells. Immune cell quantification will be compared between study groups using 
Wilcoxon rank-sum test. The Wilcoxon rank-sum test will also be used to assess differences 
in immune subsets in responders vs. non-responders (defined by either objective response or 
PSA response), and between subjects who have progression at 20 and 28 weeks vs. those 
who have not progressed within each study group. Changes in immune cell subsets in 
individual subjects with treatment will be assessed using Wilcoxon Signed-rank test.
8.4.6
DNA Damage Repair Status Concordance
For subjects who have MSI and FA/BRCA signature testing performed in both baseline 
biopsy tissue as well as archival primary tissue, the agreement between MSI status and 
FA/BRCA signature status will be assessed using descriptive statistics.
8.4.7
Clinical Activity in Biomarker Positive Subjects
All subjects enrolled into Group 2 will have DNA damage repair defects by (a) MSI-high 
only, (b) FA/BRCA signature positive only, or (c) both MSI-high and FA/BRCA signature 
positive. Chi-square test will be used to examine whether there is relationship between DNA 


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damage repair defects status with objective response, PSA response rate, and PFS at 20 and 
28 weeks.
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 Merck 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
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
All subjects in the study will receive pembrolizumab. 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.
Clinical supplies may not be used for any purpose other than that stated in the protocol.


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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 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.


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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1
Protection of Human Subjects
10.1.1 Protection from Unnecessary Harm
The Sponsor-Investigator is responsible for protecting all subjects involved in human 
experimentation. This is accomplished through the IRB mechanism and the process of 
informed consent. The IRB reviews all proposed studies involving human experimentation 
and ensures that the subject’s rights and welfare are protected and that the potential benefits 
and/or the importance of the knowledge to be gained outweigh the risks to the individual. 
The IRB also reviews the informed consent document associated with each study in order to 
ensure that the consent document accurately and clearly communicates the nature of the 
research to be done and its associated risks and benefits. 
10.1.2 Protection of Privacy
Patients will be informed of the extent to which their confidential health information 
generated from this study may be used for research purposes. Following this discussion, they 
will be asked to sign the HIPAA form and informed consent documents. The original signed 
document will become part of the patient’s medical records, and each patient will receive a 
copy of the signed document. The use and disclosure of protected health information will be 
limited to the individuals described in the informed consent document.
10.2
Compliance with Financial Disclosure Requirements
For all Principal Investigators and Sub-Investigators listed on the FDA 1572, Financial 
Disclosure Forms, CVs, MD Licenses, Drug Enforcement Agency (DEA) Licenses, and Staff 
Training Documents (i.e. Collaborative Institute Training Initiative (CITI), etc.) will be 
required.
10.3
Compliance with Law, Audit and Debarment
The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will be the monitoring 
entity for this study.  The UCSF DSMC will monitor the study in accordance with the NCI-
approved Data and Safety Monitoring Plan (DSMP).  The DSMC will routinely review all 
adverse events and suspected adverse reactions considered “serious”.  The DSMC will audit 
study-related activities to ensure that the study is conducted in accordance with the protocol, 
local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP).  
Significant results of the DSMC audit will be communicated to the IRB and the appropriate 
regulatory authorities at the time of continuing review, or in an expedited fashion, as 
applicable.  See Appendix 11.5 Data and Safety Monitoring Plan for a Phase 2 or 3 
Institutional Study, for additional information.


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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
Study Management
10.5.1 Pre-Study Documentation
This study will be conducted in accordance with the ethical principles that have their origin 
in the Declaration of Helsinki as stated in 21 CFR §312.120(c)(4); consistent with GCP and 
all applicable regulatory requirements.
Before initiating this trial, the Investigator will have written and dated approval from the 
Institutional Review Board for the protocol, written informed consent form, subject 
recruitment materials, and any other written information to be provided to subjects before 
any protocol related procedures are performed on any subjects.  
The clinical investigation will not begin until either FDA has determined that the study under 
the Investigational Drug Application (IND) is allowed to proceed or the Investigator has 
received a letter from FDA stating that the study is exempt from IND requirements. 
The Investigator must comply with the applicable regulations in Title 21 of the Code of 
Federal Regulations (21 CFR §50, §54, and §312), GCP/ICH guidelines, and all applicable 
regulatory requirements.  The IRB must comply with the regulations in 21 CFR §56 and 
applicable regulatory requirements.
10.5.2 Institutional Review Board Approval
The protocol, the proposed informed consent form, and all forms of participant information 
related to the study (e.g. advertisements used to recruit participants) will be reviewed and 
approved by the UCSF IRB (UCSF Institutional Review Board).  Prior to obtaining IRB 
approval, the protocol must be approved by the Helen Diller Family Comprehensive Cancer 
Center Site Committee and by the Protocol Review Committee (PRC).  The initial protocol 
and all protocol amendments must be approved by the IRB prior to implementation.  
10.5.3 Informed Consent
All participants must be provided a consent form describing the study with sufficient 
information for each participant to make an informed decision regarding their participation.  
Participants must sign the IRB-approved informed consent form prior to participation in any 
study specific procedure.  The participant must receive a copy of the signed and dated 
consent document.  The original signed copy of the consent document must be retained in the 
medical record or research file. 


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10.5.4 Changes in the Protocol
Once the protocol has been approved by the UCSF IRB, any changes to the protocol must be 
documented in the form of an amendment.  The amendment must be signed by the 
Investigator and approved by PRC and the IRB prior to implementation.  
If it becomes necessary to alter the protocol to eliminate an immediate hazard to patients, an 
amendment may be implemented prior to IRB approval.  In this circumstance, however, the 
Investigator must then notify the IRB in writing within five (5) working days after 
implementation.  
10.5.5 Handling and Documentation of Clinical Supplies
The UCSF Principal Investigator will maintain complete records showing the receipt, 
dispensation, return, or other disposition of all investigational drugs.  The date, quantity and 
batch or code number of the drug, and the identification of patients to whom study drug has 
been dispensed by patient number and initials will be included.  The sponsor-investigator will 
maintain written records of any disposition of the study drug.
The Principal Investigator shall not make the investigational drug available to any individuals 
other than to qualified study patients.  Furthermore, the Principal Investigator will not allow 
the investigational drug to be used in any manner other than that specified in this protocol.
10.5.6 Case Report Forms (CRFs)
The Principal Investigator and/or his/her designee, will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study.  Study 
specific Case Report Forms (CRFs) will document safety and treatment outcomes for safety 
monitoring and data analysis.  All study data will be entered into OnCore® via standardized 
CRFs in accordance with the CTMS study calendar, using single data entry with a secure 
access account.  The Clinical Research Coordinator (CRC) will complete the CRFs as soon 
as possible upon completion of the study visit; the Investigator will review and approve the 
completed CRFs. 
The information collected on CRFs shall be identical to that appearing in original source 
documents.  Source documents will be found in the patient’s medical records maintained by 
UCSF personnel.  All source documentation should be kept in separate research folders for 
each patient.
In accordance with federal regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs.  The PI will approve all 
completed CRFs to attest that the information contained on the CRFs is true and accurate. 
All source documentation and CTMS data will be available for review/monitoring by the 
UCSF DSMC and regulatory agencies.
The Principal Investigator will be responsible for ensuring the accurate capture of study data.  
At study completion, when the CRFs have been declared to be complete and accurate, the 
database will be locked.  Any changes to the data entered into the CRFs after that time can 
only be made by joint written agreement among the Principal Investigator, the Trial 
Statistician, and the Protocol Project Manager.


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10.5.7 Oversight and Monitoring Plan
See Section 10.4. The UCSF Helen Diller Family Comprehensive Cancer Center DSMC will 
be the monitoring entity for this study.  The UCSF DSMC will monitor the study in 
accordance with the NCI-approved Data and Safety Monitoring Plan (DSMP).  The DSMC 
will routinely review all adverse events and suspected adverse reactions considered 
“serious”.  The DSMC will audit study-related activities to ensure that the study is conducted 
in accordance with the protocol, local standard operating procedures, FDA regulations, and 
Good Clinical Practice (GCP).  Significant results of the DSMC audit will be communicated 
to the IRB and the appropriate regulatory authorities at the time of continuing review, or in 
an expedited fashion, as applicable.  See Appendix 11.6 Data and Safety Monitoring Plan for 
a Phase 2 or 3 Institutional Study, for additional information.


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11.0 APPENDICES
11.1
Performance Status Criteria


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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)


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11.3
Prostate Cancer Clinical Trials Working Group 3 (PCWG3)
The Prostate Cancer Clinical Trials Working Group 3 (PCWG3) guidelines* for assessment 
of radiographic progression for primary outcome measure.
As published in the Journal of Clinical Oncology
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, Antonarakis ES, Beer TM, 
Carducci MA, Chi KN, Corn PG. Trial design and objectives for castration-resistant prostate 
cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. 
Journal of Clinical Oncology. 2016 Apr 20;34(12):1402.


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11.4
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor progression for 
measurable disease. While either CT or MRI may be utilized, as per RECIST 1.1, CT is the 
preferred imaging technique in this study.
* As published in European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. 
Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47.


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11.5
Immune-Related Response Criteria (irRC) for Evaluation of Immune Therapy 
Activity in Solid Tumors
Immune-related response criteria (irRC)* will also be used in this study for assessment of 
tumor progression for measurable disease. 
* As published in Clinical Cancer Research:
J.D. Wolchok, A. Hoos, S. O’Day, J.S. Weber, O. Hamid, C. Lebbe, M. Maio, M. Binder, O. 
Bohnsack, G Nichol, R Humphrey, S.F. Hodi . Guidelines for the evaluation of immune 
therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009 
Dec;15(23): 7412-7420.


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11.6
Data and Safety Monitoring Plan for a Phase 2 or 3 Institutional Study
1.         Oversight and Monitoring Plan
The UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data and Safety 
Monitoring Committee (DSMC) is responsible for monitoring data quality and subject safety 
for all HDFCCC institutional clinical studies.  A summary of DSMC activities for this study 
includes: 

Review of patient data. 

Review of serious adverse events.

Auditing every six months (depending on study accrual).

Minimum of a yearly regulatory audit.
2.
Monitoring and Reporting Guidelines
Investigators will conduct continuous review of data and patient safety and discuss each 
patient’s treatment at monthly site committee meetings.  These discussions are documented 
in the site committee meeting minutes.  The discussion will include the number of patients, 
significant toxicities in accordance with the protocol, and observed responses.  
All institutional Phase II and III studies are designated with a moderate risk assessment (see 
Appendix H).   The data is audited twice per year with twenty percent of the patients 
monitored (or at least three patients if the calculated value is less than three).  
3.
Review and Oversight Requirements
3.1
Adverse Event Monitoring 
All Grade 3-5 Adverse Events (AEs), whether or not considered to be expected or 
unexpected and whether or not considered to be associated with the use of the study 
drug, will be entered into OnCore®, UCSF’s Clinical Trial Management System.  
Adverse Events are graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) (version 4.03) as developed and revised by the Common 
Therapy Evaluation Program (CTEP) of the National Cancer Institute.  Adverse 
events are further given an assignment of attribution or relationship to treatment or 
medical procedure.  


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Attribution categories are:
•
Definite – The adverse event is clearly related to the investigational agent(s) 
or medical procedure.
•
Probable – The adverse event is likely related to the investigational agent(s) 
or medical procedure.
•
Possible – The adverse event may be related to the investigational agent(s) or 
medical procedure.
•
Unlikely – The adverse event is doubtfully related to the investigational 
agent(s) or medical procedure.
•
Unrelated – the adverse event is clearly not related to the investigational 
agent(s) or medical procedure.
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly 
basis at the Site Committee meetings.  The Site Committee will review and discuss 
the selected toxicity, the toxicity grade, and the attribution of relationship of the 
adverse event to the administration of the study drug(s).
3.2
Serious Adverse Event Reporting 
By definition, an adverse event is defined as a serious adverse event (SAE) according 
to the following criteria:
•
Death.
•
Life-threatening (i.e. results in an immediate risk of death).
•
Requires inpatient hospitalization or prolongation of existing hospitalization,
•
Permanent or significant disability/incapacity
•
Gives rise to a congenital anomaly/birth defect, or cancer, or any experience 
that suggests a significant hazard, contraindication, side effect, or precaution 
that may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
•
Event occurring in a gene therapy study.
•
Event that changes the risk/benefit ratio of a study.
•
Any other event the Principal Investigator judges to be serious or which would 
suggest a significant hazard, contraindication, side effect, or precaution.
Serious Adverse Event reporting will be in accordance with the UCSF IRB 
Regulations and Code of Federal Regulation Title 21 Part 312.32.  The SAE will be 
reported on a Med Watch form. 
UCSF IRB website for guidance in reporting serious adverse events:
https://irb.ucsf.edu/adverse-event 
FDA website for guidance in reporting serious adverse events:
www.fda.gov/Safety/MedWatch/HowToReport/default.htm


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Med Watch forms and information:
www.fda.gov/medwatch/getforms.htm
All serious adverse events are entered into OnCore®, as well as submitted to the IRB 
(per IRB guidelines) via iMedRIS®.  The SAEs are reviewed and monitored by the 
Data and Safety Monitoring Committee on an ongoing basis and discussed at DSMC 
meetings, which take place every six weeks.  The date the SAE is sent to all required 
reporting agencies will be documented in OnCore®. 
If the SAE involves a subject death, and is determined to be possibly, probably or 
definitely related to the investigational drug or any research related procedure, the 
event must be reported to the DSMC Chair or Vice Chair within 1 business day.  
The reporting procedure is by communication via phone or in person with written 
documentation of the one-on-one communication via e-mail, with a copy of the e-
mail to the DSMC Manager.
3.3
Review of Adverse Event Rates
If an increase in the frequency of Grade 3 or 4 adverse events (above the rate reported 
in the Investigator Brochure or package insert) is noted in the study, the Principal 
Investigator will notify the DSMC at the time the increased rate is identified.  The 
report will indicate if the incidence of adverse events observed in the study is above 
the range stated in the Investigator Brochure or package insert.
If at any time the Investigator stops enrollment or stops the study due to safety issues, 
the DSMC Chair and DSMC Manager must be notified within 1 business day via e-
mail  and the IRB must be notified within 10 business days via an iRIS Reporting 
Form.
Data and Safety Monitoring Committee Contacts:
Thierry Jahan, MD
DSMC Monitors 
UCSFHDFCCCC
San Francisco, CA 94158
UCSF Helen Diller Family 
Comprehensive Cancer Center
San Francisco, CA 94143


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12.0
ABBREVIATIONS
ADT
androgen deprivation therapy
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATM
ataxia-telangiectasia mutated
BUN
blood urea nitrogen
CBC
complete blood cell (count)
CR
complete response
CRC
Clinical Research Coordinator
CRF
case report form
CRPC
castrate-resistant prostate cancer
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
DDRD
DNA damage response deficiency
DEA
Drug Enforcement Agency
DSMC
Data and Safety Monitoring Committee
DSMP
Data and Safety Monitoring Plan
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
FA
Fanconi anemia
FDA
Food and Drug Administration
FT3
free triiodothyronine
FT4
free thyroxine
GCP
Good Clinical Practice
GNRH
gonadotropin-releasing hormone
HBsAg
Hepatitis B surface antigen
HCV
hepatitis C virus
HDFCCC
Helen Diller Family Comprehensive Cancer Center
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus


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ICH
International Conference on Harmonization
IDO1
Indoleamine 2,3-Dioxygenase 1
IHC
immunohistochemistry
IND
investigational new drug application
IP
investigational product
IRB
Institutional Review Board
irPFS
immune-related progression free survival
irRC
immune-related response criteria
IV
intravenous
LDH
lactate dehydrogenase
mAb
monoclonal antibody
mCRPC
metastatic castrate resistant prostate cancer
MMR
mismatch repair
MRI
magnetic resonance imaging
MSAS
minimum sufficient adjustment sets
MSI
microsatellite instability
MSS
microsatellite stable
MTD
maximum tolerated dose
Na-F
sodium fluoride
NCI
National Cancer Institute
NSCLC
non-small cell lung cancer
OCT
over-the-counter
PAP
prostatic acid phosphatase
PCWG3
Prostate Cancer Clinical Trials Working Group 3
PD-1
programmed death 1 (PD-1)
PD-L1
programmed death-ligand 1 (PD-L1)
PD-L2
programmed death-ligand 2 (PD-L2)
PET
positron emission tomography
PFS
progression free survival
PK
pharmacokinetics
PO
Per os (by mouth, orally)
PRC
Protocol Review Committee (UCSF)
PSA
prostate specific antigen
Q2W
every 2 weeks
Q3W
every 3 weeks
RBC
red blood cell (count)
RECIST
Response Evaluation Criteria in Solid Tumors


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rPFS
Radiographic progression-free survival
Rx
treatment
SD
stable disease
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
TILs
tumor-infiltrating lymphocytes
ULN
upper limit of normal
TCR
T cell receptor
Treg
regulatory T cells
TSH
thyroid-stimulating hormone
WBC
white blood cell (count)
WES
whole exome sequencing


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13.0 REFERENCES
Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in 
human cancer. Nature 2013;500:415-21.
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N Eng J Med 2015;373:123-35.
Cha E, Klinger M, Hou Y, et al. Improved survival with T cell clonotype stability after anti-
CTLA-4 treatment in cancer patients. Sci Transl Med 2014;6:238ra70.
Diaz LA, Uram JN, Wang H, et al. Programmed death-1 blockade in mistmatch repair 
deficient cancer indepenent of tumor histology. J Clin Oncol 34, 2016 (suppl; abstr 3003).
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors: revised RECIST guideline (Version 1.1). Eur J Cancer 2009;45:228-47.
Fong L, Kwek SS, O'Brien S, et al. Potentiating endogenous antitumor immunity to prostate 
cancer through combination immunotherapy with CTLA4 blockade and GM-CSF. Cancer 
Res 2009;69:609-15.
Graff JN, Alumkal JJ, Drake CG, et al. Early evidence of anti-PD-1 activity in enzalutamide-
resistsant prostate cancer. Oncotarget 2016 July 12. Doi: 0.18632/oncotarget.10547. [Epub 
ahead of print]
Hansen A, Massard C, Ott PA, et al. Pembrolizumab for patients with advanced prostate 
adenocarcinoma: preliminary results from the KEYNOTE-028 study. Annals of Oncology 
2016; 27:243-265.
Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-
resistant prostate cancer.  N Engl J Med 2010;363:411-22.
Kwek SS, Dao V, Roy R, et al. Diversity of antigen-specific responses induced in vivo with 
CTLA-4 blockade in prostate cancer patients. J Immunol 2012;189:3759-66.
Kwek SS, Lewis J, Zhang L, et al. Pre-existing levels of CD4 T cells expressing PD-1 are 
related to overall survival in prostate cancer patients treated with ipilimumab. Cancer 
Immunol Res 2015.
Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in 
patients with metastatic castration-resistant prostate cancer that had progressed after 
docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 
trial. Lancet Oncol 2014;15:700-12.


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Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. N Engl J Med 2015;372:2509-20.
Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate 
cancer. N Engl J Med 2015;373:1697-1708.
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Adanced 
Renal-Cell Carcinoma. N Engl J Med 2015;373:1803-13.
Mulligan JM, Hill LA, Deharo S, et al. Identification and validation of an 
anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. J Natl 
Cancer Inst 2014;106:djt335.
Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. 
J Clin Oncol 2015;33:1974-82.
Pritchard CC, Morrissey C, Kumar A, et al. Complex MSH2 and MSH6 mutations in 
hypermutated microsatellite unstable advanced prostate cancer. Nat Commun 2014;5:4988.
Rizvi NA, Hellmann MD, Snyder A, et al. Cancer immunology. Mutational landscape 
determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 
2015;348:124-8.
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. N Engl J Med 2015;372:2521-32.
Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced 
prostate cancer. Cell 2015;161:1215-28.
Scher HI, Morris MJ, Stadler WM, et al. Trial design and objectives for castration-resistant 
prostate cancer: updated recommendations from the prostate cancer clinical trials working 
group 3. J Clin Oncol 2016;34:1402-18.
Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 
blockade in melanoma. N Engl J Med 2014;371:2189-99.
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-
1 antibody in cancer. N Engl J Med 2012;366:2443-54.
Wolchok JD, Hoos A, O'Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res 2009; 15:7412-
7420.

ICF_000.pdf: 
ICF 11-14-2022
CC#16557
PAGE 1 OF 24 
Lawrence Fong, M.D.
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
CC#16557:  Phase 2 open label study of pembrolizumab in patients with metastatic 
castration resistant prostate cancer (mCRPC) with or without DNA damage repair defects
This is a clinical trial, a type of research study.  Your research study doctor Lawrence Fong, 
M.D. or one of his associates from the UCSF Helen Diller Family Comprehensive Cancer Center
will explain the clinical trial to you.
Clinical trials include only people who choose to take part.  Please take your time to make your 
decision about participating.  You may discuss your decision with your family and friends and 
with your health care team.  If you have any questions, you may ask your research study doctor.
You are being asked to take part in this research study because you have prostate cancer that has 
progressed (worsened).
WHY IS THIS STUDY BEING DONE?
The purpose of this study is to assess how prostate cancer patients with and without DNA 
damage repair defects respond to pembrolizumab.  Tumors with DNA damage repair defects 
have more mistakes in their genes (mutations), whereas tumors with normal DNA damage repair 
have fewer mistakes. Tumors that have more mistakes in their genes may be more visible to the 
immune system. The aim of this study is to see whether tumors with DNA damage repair defects 
respond better to the immunotherapy, pembrolizumab.
Pembrolizumab has been approved for use in certain types of melanoma, lung cancer and head 
and neck cancer. However, it has not been approved for any other cancers.  The use of 
pembrolizumab for prostate cancer is experimental, which means that it has not been approved 
by the United States Food and Drug Administration (FDA).
This research study is being sponsored by Merck, the company that makes pembrolizumab, is 
supplying pembrolizumab at no cost and is providing funding to UCSF for this study. The 
National Cancer Institute (which is part of the National Institute of Health) is also providing 
funding to UCSF to conduct this study.
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?
About 50 people will take part in this research study.
IRB NUMBER: 17-22165
IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023
NCT03248570


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Lawrence Fong, M.D.
WHAT WILL HAPPEN IF I TAKE PART IN THIS RESEARCH STUDY?
DNA Damage Repair Testing
All patients enrolled in this study will receive pembrolizumab and participate in the same study 
assessments.  However, participants will be placed into one of two groups, depending on DNA 
damage repair status. The study doctor will tell you if you will be in Group 1 or Group 2. 

Group 1: Normal DNA damage repair group

Group 2: Defective DNA damage repair group
DNA damage repair status will be determined using two kinds of tests that look at different types 
of DNA damage repair in tumor tissue: the Promega Microsatellite Instability (MSI) test and a 
mutation sequencing test. If both of these tests show normal DNA damage repair, you will be in 
Group 1. If one or both of these tests show DNA damage repair defects, you will be in Group 2.

Both kinds of tests look at errors that happen during DNA-replication. If the test results 
show that the DNA only has a few of these types of errors, this indicates normal DNA 
damage repair. If the test results show a lot of these errors, it can mean that repair of 
DNA-replication errors is defective. The Promega MSI test is not approved by the FDA 
for testing your type of prostate cancer, and the use of the test in this study is 
investigational.

The mutation sequencing test (UCSF500, Foundation, or Strata) looks at your DNA to 
see what changes in your genes might cause defective DNA damage repair. UCSF500, 
Foundation, and Strata are not approved by the FDA for testing your type of prostate 
cancer, and the use of these tests in this study is investigational. 
There are expected to be more patients who are eligible for Group 1 rather than Group 2. 
Because of this, when the study first opens, participants may receive treatment before test results 
from DNA repair status are known. Whether you are in Group 1 or in Group 2, you will receive 
the same treatment. Once Group 1 is full (and all participants DNA repair status results are 
available), the DNA repair status results must be known before participants can enroll to the 
remaining slots in Group 2. The study doctor will let you know your DNA damage repair status 
and what group you are in when the test results are available.
Study Drug
Pembrolizumab will be given during a time period called a cycle.  Each cycle lasts 21 days.
Pembrolizumab will be given to you by inserting a needle into the blood vessel in your arm 
(intravenous [IV] infusion). The infusion of pembrolizumab will be delivered over 
approximately 30 minutes.  Pembrolizumab will be administered every 21 days and will continue 
until you are no longer benefiting from the drug.  
IRB NUMBER: 17-22165
IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
If your disease worsens while receiving pembrolizumab, you will have the option of having a 
biopsy of your tumor tissue, and/or receiving taxane-based chemotherapy. The chemotherapy 
regimen will be decided by your treating physician, and may consist of a taxane chemotherapy 
(docetaxel or cabazitaxel) with or without a platinum chemotherapy (such as carboplatin). You 
may receive a minimum of 2 cycles and a maximum of 8 cycles of chemotherapy. Chemotherapy 
may be given with prednisone. If you have a clinical response to chemotherapy, you may then be 
retreated with pembrolizumab immunotherapy.
BEFORE YOU BEGIN THE MAIN PART OF THE STUDY...
Screening Period
You will need to have the following exams, tests and procedures to find out if you can be in the 
main part of the research study. Most of these exams, tests or procedures are part of routine 
cancer care and may be done even if you do not join the research study. You will complete the 
following tests or procedures within 28 days unless otherwise noted below before starting the 
study drug. If you have had some of these tests or procedures recently, they may not need to be 
repeated.  This will be up to the study doctor.  The total time to complete the screening tests and 
procedures is about 6-7 hours.

Some general information about you such as race, ethnicity, age, gender will be collected

Medical history (including history of prior cancer treatment)

Physical exam, including height, weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Review of medications that you are taking, including any over-the-counter medications, 
vitamins, herbal supplements and prior treatment for your cancer

Assessment of how cancer is affecting your daily life

Urine sample for routine safety testing

Blood sample (about 4 tablespoons) for:
o
Safety tests
o
Thyroid function tests
o
PSA (Prostate-Specific Antigen test) - This is a test used to monitor your prostate 
cancer
o
LDH - This is a test to indicate whether you might have tissue damage, and if so, 
how much
o
Immune monitoring
IRB NUMBER: 17-22165
IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.

Tumor imaging by computed tomography (CT) scan and bone scan – within 14 days 
before starting the study drug
o
CT scan:  A CT scan uses special x-ray equipment to make detailed pictures of 
body tissues and organs.  For the CT scan, you may be given a "contrast material" 
(a special dye that makes it easier for doctors to see different tissues in your 
body).  The contrast material may be given orally, intravenously, or rectally (less 
likely).  Oral contrast material is given to you to drink and is used to help outline 
the stomach and intestines.  Intravenous (IV) contrast material is given to you by 
injecting the contrast material into a line which is attached to a needle in your 
arm, and is used to get clearer pictures of your body cavity.  A rectal contrast fills 
up the loops of your lower bowel so the doctors can see your tumor better.  After 
you have been given the contrast material (either by mouth, by vein, or rectum), 
you will lie flat on a table that will move you into the CT scan machine.  You will 
be asked to lie still and may be asked to hold your breath for a few seconds.  The 
CT scan is done in the radiology department and takes about half an hour.
o
Bone scan: A bone scan is a test that makes detailed images of your bones and 
any tumors on them.  Before the bone scan a radioactive substance is injected into 
your vein.  About 3 hours later you will lie on a table under a machine which will 
make an image of your bones.  The test itself will take about 1 hour, but the whole 
process takes up to 4 hours.

Tumor tissue collection for DNA damage repair testing using Promega MSI and mutation 
sequence testing.
o
You will have a tumor biopsy.

Tumor biopsy: The study doctor will obtain a small piece of tumor tissue 
using a special needle. This procedure will be done at the site where we 
can most easily get a piece of the tumor and the biopsy can involve the 
lungs, liver, bone, lymph node, skin or other. The biopsy needle will be 
inserted into tumor tissue and a small piece of the tumor will be removed. 
1 - 3 passes with this needle will be made. A CT scan may be used to help 
guide placement of the needle. This procedure takes about 30 minutes.
o
If DNA damage repair defects have been identified in a prior tumor biopsy, you 
may not need to have a biopsy at this time. We will only use the Promega MSI 
and a mutation sequencing test to look for defects that have not been found in 
prior testing. If your tumor has previously been tested for MSI status, the 
Promega MSI test will not need to be done for this study.

You will be asked to provide leftover tumor tissue from a prior biopsy or 
surgery for this testing. If no leftover tissue is available, you will have a 
tumor biopsy as described above, as long as it is safe to do so.
DURING THE MAIN PART OF THE STUDY...
If the exams, tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will have the procedures listed below.
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Lawrence Fong, M.D.
Pembrolizumab Cycles – Every 21 Days
You will have the following exams, tests, and procedures at each clinic visit every 21 days. Each 
of the visits will take about 2 - 3 hours, but may take up to 6 hours, depending on the tests and 
procedures you have done. 

Physical exam, including weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Assessment of how cancer is affecting your daily life

Review of side effects you may be experiencing

Blood sample (about 4 - 6 tablespoons) for:
o
Safety tests
o
Thyroid function tests
o
LDH – This is a test to indicate whether you might have tissue damage, and if so, 
how much
o
PSA – This is a test used to monitor your prostate cancer
o
Immune monitoring 

Tumor imaging (CT scan and bone scan) – every 12 weeks

Pembrolizumab infusion
Optional Chemotherapy Cycles – Every 21 Days (for 2-8 cycles)
If your disease worsens while receiving pembrolizumab, you will have the option of having a 
biopsy of your tumor tissue and/or receiving standard of care taxane-based chemotherapy 
(docetaxel or cabazitaxel) with or without a platinum chemotherapy (such as carboplatin).  You 
can receive a minimum of 2 cycles and a maximum of 8 cycles of chemotherapy, and it may be 
given with prednisone. 
If you move onto this chemotherapy regimen, you will have the following tests exams, tests and 
procedures at each clinic visit every 21 days (for 2 to 8 cycles). Each of the visits will take about 
2 - 3 hours, but may take up to 6 hours, depending on the tests and procedures you have done. 

Physical exam, including weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Assessment of how cancer is affecting your daily life

Review of side effects you may be experiencing

Blood sample (about 4 - 6 tablespoons) for:
o
Safety tests
o
Thyroid function tests
o
LDH
o
PSA
o
Immune monitoring

Tumor imaging – every 12 weeks

Chemotherapy infusion
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IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
Optional Pembrolizumab Cycles – Every 21 Days
If you respond well to the chemotherapy, you will have the option of resuming pembrolizumab. 
If that is the case, you will have the following exams, tests, and procedures at each clinic visit 
every 21 days. Each of the visits will take about 2 - 3 hours, but may take up to 6 hours, 
depending on the tests and procedures you have done. You will also have the option of 
undergoing an additional biopsy of your tumor tissue.

Physical exam, including weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Assessment of how cancer is affecting your daily life

Review of side effects you may be experiencing

Blood sample (about 4 - 6 tablespoons) for:
o
Safety tests
o
Thyroid function tests
o
LDH
o
PSA
o
Immune monitoring

Tumor imaging – every 12 weeks

Pembrolizumab infusion
WHEN YOU ARE FINISHED RECEIVING THE STUDY DRUG…
End of Treatment Visit
At the time that you discontinue the study drug, you will have the following exams, tests, or 
procedures. They may not need to be repeated if you recently had them done. This visit may take 
about 2-3 hours.

Physical exam, including weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Assessment of how cancer is affecting your daily life

Review of side effects you may be experiencing

Blood sample (about 4 - 6 tablespoons) for:
o
Safety tests
o
Thyroid function tests
o
LDH
o
PSA
o
Immune monitoring

Tumor imaging 
IRB NUMBER: 17-22165
IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
Safety Follow-up Visit
You will be asked to return to the clinic within 30 days of the last dose of study drug.  During 
this visit, you will have the following exams, tests or procedures. This visit will take about 2 
hours. 

Physical exam, including weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Review of side effects you may be experiencing

Blood sample (about 2 tablespoons) for immune monitoring
Follow-Up
If you discontinue pembrolizumab for a reason other than disease progression, the following 
assessments will be performed every 12 weeks until either the study ends, your disease 
progresses, you start a new anti-cancer therapy, or death.  These visits will take about 3-4 hours.

Physical exam, including weight

Vital signs (temperature, breathing rate, blood pressure, and pulse)

Anti-cancer therapy status

Blood sample (about 4 - 6 tablespoons) for:
o
PSA 
o
Immune monitoring

Tumor imaging
If your disease worsens or you start a new anti-cancer therapy, you will be contacted by 
telephone every 12 weeks to check your health status until death, withdrawal of consent, or the 
end of the study, whichever occurs first.  
Study location: All research study procedures will be done at UCSF Helen Diller Family 
Comprehensive Cancer Center.
HOW LONG WILL I BE IN THE STUDY?
You can continue receiving pembrolizumab as long as you respond to the study drug. However, 
if your disease worsens while receiving pembrolizumab, you will have the option of receiving 
taxane-based chemotherapy followed by pembrolizumab for those who have a clinical response 
to chemotherapy. The chemotherapy will be decided by your treating physician after discussion 
with you, and may consist of docetaxel or cabazitaxel with or without a platinum agent such as 
carboplatin. The length of time you are on the study will depend upon how you are feeling, how 
well you tolerate pembrolizumab and whether your disease responds to the study drug.
 
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IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
CAN I STOP BEING IN THE STUDY?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. The study doctor will tell you how to stop your participation safely. It is 
important to tell the study doctor if you are thinking about stopping so any risks from the study 
drugs can be evaluated by your doctor. Another reason to tell your doctor that you are thinking 
about stopping is to discuss what follow-up care and testing could be most helpful for you.
The study doctor may stop you from taking part in this study at any time if he believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
WHAT SIDE EFFECTS OR RISKS CAN I EXPECT FROM BEING IN THE STUDY?
You may have side effects while on the study.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious. 
Your health care team may give you medicines to help lessen side effects.  Many side effects go 
away soon after you stop taking the study drug.  In some cases, side effects can be serious, long 
lasting, or may never go away.  There also is a risk of death.
You should talk to your study doctor about any side effects that you experience while taking part 
in the study. 
Risks of Pembrolizumab (Keytruda)
Receiving pembrolizumab as a single drug may not be effective in treating your cancer. There is 
a risk that your cancer may get worse while receiving pembrolizumab.
Pembrolizumab works by helping your immune system to fight your cancer. However, 
pembrolizumab can also cause your immune system to attack normal organs and tissues in your 
body and can affect the way they work, which can result in side effects. These side effects may 
be serious (i.e., causing hospitalization or be life-threatening), may result in death, and/or may 
occur after you stop taking pembrolizumab. These side effects can affect more than one of your 
normal organs and tissues at the same time.
Very common side effects (some may be serious) seen in 20% or more of patients treated 
with pembrolizumab include the following:

Itching of the skin 

Loose or watery stools

Cough
Common side effects (some may be serious) seen in 5% to less than 20% of patients treated 
with pembrolizumab include the following:

Joint pain
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IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.

Rash

Fever

Back pain

Pain in your belly

Loss of skin color

Not enough thyroid hormone, so you may feel tired, gain weight, feel cold, or have 
infrequent or hard stools (hypothyroidism)

Low levels of salt in the blood that may cause you to feel tired, feel confused, have a 
headache, have muscle cramps, and/or feel sick to your stomach (hyponatremia)
Uncommon side effects (some may be serious) seen in 1% to less than 5% of patients treated 
with pembrolizumab include the following:

Inflammation of the lungs, so you may feel short of breath and cough (pneumonitis)

Too much thyroid hormone, so you may feel anxious, feel angry, have trouble sleeping, 
feel weak, tremble, sweat, feel tired, have loose and watery stools (hyperthyroidism)

Infusion reaction, where you may feel dizzy or faint, feel flushed, get a rash, have a fever, 
feel short of breath, experience a decrease in your blood pressure at the time of receiving 
your infusion (IV) or just after, or have pain at the site of infusion

Inflammation of the bowels/gut, which may cause severe pain in your belly with loose or 
watery stools, and black, tarry, sticky stools or stools with blood or mucus (colitis)

Inflammation of the skin so you may have peeling of the skin, itchiness, and/or skin 
redness. The skin inflammation (i.e., peeling, itching and redness) could also be widespread 
throughout your body. More severe skin reactions may involve the inside of your mouth, 
the surface of your eye and genital areas, and/or may cause the top layer of your skin to 
peel from all over your body which can cause severe infection (Severe skin reactions, 
including Stevens-Johnson syndromeor toxic epidermal necrolysis)
Rare side effects (some may be serious) seen in less than 1% of patients treated with 
pembrolizumab include the following:

Inflammation of the nerves that may cause pain, weakness, or tingling in your hands and 
feet, and may spread to your legs, arms, and upper body, leading to severe muscle weakness 
and possible temporary paralysis (Guillain-Barré syndrome)

Inflammation of the muscles, so you may feel weak or have pain in your muscles (myositis)

Inflammation of the pancreas (a gland in your abdomen that controls sugar levels), so you 
may have severe pain in the top part of your belly that may move to your back, feel sick to 
your stomach, and have vomiting that gets worse when you eat (pancreatitis)

Inflammation of the eye, so you may have eye redness, blurred vision, sensitivity to light, 
eye pain, see floaters, or have headaches (uveitis)
IRB NUMBER: 17-22165
IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.

Inflammation of the liver that may make you feel sick to your stomach and vomit, feel like 
not eating, feel tired, have a mild fever, a pain in the right side of your belly, yellow eyes 
and skin, and dark urine (hepatitis)

Inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick 
to your stomach or have headaches, changes in your behavior, double vision, few to no 
menstrual cycles, weakness, vomiting and dizziness, or fainting (hypophysitis)

Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which 
could cause tiredness, weight loss, muscle weakness, feeling faint, having joint, muscle, 
and bellyaches, nausea, vomiting, loose or watery stools, fever, salt craving, and sometimes 
darkening of the skin like a suntan (adrenal insufficiency)

Type 1 diabetes, a condition that can cause too much sugar in your blood, feeling thirstier 
than usual, frequent urination, and weight loss. You are likely to need regular insulin shots 

Inflammation of the kidney, so you may pass less urine or have cloudy or bloody urine, 
swelling, and low back pain (nephritis)

Inflammation of the middle layer of your heart wall that may cause your heart to have 
difficulty pumping blood throughout your body, which can cause chest pain, shortness of 
breath, and swelling of the legs. You may experience a fast or irregular heartbeat that may 
cause dizziness or fainting (myocarditis)

Inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This 
condition may lead to change in your heart rate, blood pressure, body temperature, and the 
rate at which food is converted into energy (thyroiditis)

A condition that may make you feel weak and tired and may cause drooping of the eyelids, 
blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and 
legs, or difficulty breathing (myasthenic syndrome/myasthenia gravis including 
exacerbation)

The formation of small clusters of immune cells (called granulomas) in parts of your body 
such as your lymph nodes, eyes, skin, or lungs (sarcoidosis)

Inflammation of the brain with confusion and fever. This may also include: disorientation, 
memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, 
weakness or loss of movement in some parts of your body, and loss of consciousness 
(encephalitis)

Inflammation of the spinal cord with pain, numbness, tingling, or weakness in the arms or 
legs, bladder or bowel problems including needing to urinate more frequently, urinary 
incontinence, difficulty urinating, and constipation (myelitis)

Inflammation of the blood vessels (vasculitis). Symptoms will depend on the particular 
blood vessels that are involved in the inflammatory process, for example; if it is your 
skin, you may get a rash. If your nerves are not getting enough blood, you could have 
numbness and weakness. You may also experience fever, weight loss, and fatigue.

Low levels of parathyroid hormone (a hormone made by 4 tiny glands in your neck) 
which may result in low blood calcium and cause muscle cramps or spasms; fatigue or 
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IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
weakness; numbness, tingling or burning in your fingertips, toes or lips 
(hypoparathyroidism)
Additionally, since pembrolizumab was approved (for melanoma) in September 2014, the 
following side effects have been reported by people receiving pembrolizumab. These side effects 
were voluntarily reported from a group of people of unknown size. It is not possible to estimate 
the frequency of these side effects:

Inflammation of the joints which may include joint pain, stiffness and/or swelling (arthritis)

Severe responses of the immune system that cause the body to attack its own blood cells, 
spleen, liver, lymph nodes, skin and brain. This may include fever, rash, inflammation of 
the liver, yellowing of the skin, an enlarged liver and spleen, low blood counts, and 
enlarged lymph nodes. The nervous system may also be affected and cause confusion, 
seizures, and even coma (hemophagocytic lymphohistiocytosis)

Changes in eyesight, eye pain, whitish patches on the skin and hearing loss (Vogt-
Koyanagi-Harada syndrome)

Inflammation and scarring of the bile ducts (tubes that carry digestive fluid that is made in 
the liver).  This can cause symptoms similar to those seen with inflammation of the liver 
(hepatitis) such as pain in the right side of your belly, yellow eyes and skin, feeling tired, 
and itching (sclerosing cholangitis).

Inflammation or swelling of the nerve fibers of the eye which send visual information from 
your eye to your brain. This health condition often has a sudden onset of vision loss, loss 
of color vision, pain when moving your eyes, and/or loss of peripheral vision. It may affect 
one or both eyes at the same time (optic neuritis).
Also, the following side effects might be noticed during your treatment with pembrolizumab:
If you have had a solid organ transplant (for example, if you have received a kidney or heart 
transplant), you may experience rejection of the transplanted organ. Your doctor will monitor 
you and should tell you what signs and symptoms you should report depending on the type of 
organ transplant that you have had.
If you have had an allogeneic stem cell transplant (a procedure in which a person receives blood-
forming stem cells from a donor), you may experience graft versus host disease (GvHD), which 
may include diarrhea, skin rashes, and liver damage, after receiving pembrolizumab. Sometimes 
this condition can lead to death.
Risks of Docetaxel
Like all medicines, docetaxel can cause side effects, although not everybody gets them.
The severity and frequency of side effects may vary depending on whether docetaxel is given 
alone or in combination with other anti-cancer medicines.  Side effects that might be noticed 
during your treatment are listed below.
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IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
Very common side effects seen in 
more than 10% of patients:
Common side effects seen 
in 1% to 10% of patients: 
Uncommon and rare side 
effects seen in less than 1% 
of patients:
Side effects 
where the 
frequency is 
unknown:

Infection 

Decrease in the number of red 
and/or white blood cells or 
platelets (your doctor will 
check this) 

Fever 

Allergic reactions as described 
above 

Loss of appetite 

Inability to sleep 

Feeling of numbness, or pins 
and needles 

Headache 

Reduced sensation to touch 

Increased tear formation 

Swelling under the skin 

Bleeding from the nose 

Runny nose, inflammation of 
the nose and throat 

Cough 

Chest pain 

Change in sense of taste 

Shortness of breath/difficulty 
in breathing 

Sores in your mouth (including 
tongue and/or lips and/or 
cheeks) 

Diarrhea 

Feeling and/or being sick 

Constipation 

Abdominal pain 

Indigestion 

Loss of hair 

Redness and swelling of the 
palms of your hands or soles 
of your feet which may cause 
your skin to peel (this may 
also occur on your arms, face 
or body) 

Change in the color of your 
nails, which may detach 

Muscle aches or pain 

Back pain or bone pain 

Change or absence of 
menstrual period 

Swelling of the hands, feet or 
legs 

Feeling of weakness 

Fungal infection in the 
mouth 

Inflammation of the 
skin 

Dry mouth 

Dizziness 

Headache 

Dehydration 

Conjunctivitis 

Impaired hearing 

Difficulty or pain when 
swallowing 

Irregular heart beat 

High or low blood 
pressure (your doctor 
will check this) 

Heart failure 

Heartburn 

Bleeding 

Raised liver enzymes

Fainting 

Inflammation of the vein 

Inflammation of the 
colon, small intestine or 
perforation of the large 
intestine 

Fits or temporary loss of 
consciousness 

Hearing loss 

Heart attack 

Blood clots 

Pneumonia 

Inflammation and /or 
fluid on the lungs which 
may cause you to cough, 
with or without frothy 
phlegm 

Intestinal blockage 
causing abdominal pain 

Skin redness at the site 
of previous radiation 
therapy  

Acute myeloid leukemia.  
Your doctor will do 
blood tests to check for 
this. 

Temporary visual 
disturbances e.g. flashes, 
flashing lights, reduced 
vision 

Inflammation of the liver 

Skin redness and/or 
blisters

Blurred 
vision due to 
swelling of 
the retina 
within the eye 
(cystoid 
macular 
edema)

Decrease of 
sodium in 
your blood
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IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.
Very common side effects seen in 
more than 10% of patients:
Common side effects seen 
in 1% to 10% of patients: 
Uncommon and rare side 
effects seen in less than 1% 
of patients:
Side effects 
where the 
frequency is 
unknown:

Tiredness or flu-like 
symptoms 

Weight gain 

Weight loss 
Risks of Cabazitaxel
Like all medicines, cabazitaxel can cause side effects, although not everybody gets them.
Very common side effects seen in 
more than 10% of patients:
Common side effects seen in 1% to 
10% of patients: 
Other reported risks

Decrease in the number of red 
blood cells (anemia) or white 
blood cells 

Decrease in the number of 
platelets (risk of bleeding) 

Loss of appetite (anorexia)

Alteration in sense of taste

Shortness of breath

Cough

Stomach upsets including nausea

Vomiting

Diarrhea

Constipation

Abdominal pain

Short term hair loss (in most 
cases normal hair growth should 
return)

Back pain

Joint pain

Blood in the urine

Fatigue

Weakness

Fever

Urinary tract infection

Lack of white blood cells 
associated with fever

Dehydration

Weakness of the arms and legs

Feeling of numbness, tingling, 
burning or decreased sensations 
in hands and feet

Dizziness

Headache

Decrease in blood pressure

Uncomfortable feeling in the 
stomach or belching after eating

Stomach pain

Cardiac rhythm 
alterations (mainly bradycardia 
and tachycardia)

Hemorrhoids

Gastro-esophageal reflux disease 
(heartburn)

Muscle pain

Pain when passing urine

Kidney disease

Sores in the mouth

Hypersensitivity
Loss of blood and perforation of your 
stomach and intestines (gastrointestinal 
hemorrhage and perforation, 
obstruction of the intestine due to 
paralysis of the intestinal muscles 
(ileus), and intestinal tissue death 
(entercolitis) leading to death, have 
been reported.  Risk may be increased 
with neutropenia (decrease of white 
blood cells), age, steroid use, 
concomitant use of nonsteroidal anti-
inflammatory drugs, anti-platelet 
therapy or anti-coagulants, and patients 
with prior history of pelvic 
radiotherapy, intestinal adhesions, 
ulceration and gastrointestinal bleeding.
Risks of Carboplatin
Like all medicines, carboplatin can cause side effects, although not everybody gets them.
Very common side effects 
(experienced in more than 20% of 
patients):
Common side effects (experienced 
in 6-20% of patients):
Less common side effects 
(experienced in less than 5% of 
patients):
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IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023


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Lawrence Fong, M.D.

Lowered white blood cell count 
(leukopenia)

Lowered red blood cell count 
(anemia)

Lowered platelets 
(thrombocytopenia)

Low levels of a certain type of 
white blood cell known as a 
neutrophil (neutropenia)

Damage to nerves causing 
numbness in the hands and/or 
feet

Nausea and/or vomiting

Loss of appetite

Change in liver function 
without symptoms

Pain

Low levels of electrolytes 
(magnesium, calcium, 
potassium, sodium)

Hair Loss

Weakness, loss of strength

Kidney damage

Allergic reaction

Hearing loss

Infection

Cardiovascular disorders

Bleeding

Diarrhea

Constipation

Altered taste

Mouth sores, sometimes 
making it difficult or 
painful to swallow

Respiratory disorders

Serious allergic reaction 
(anaphylaxis), which could 
be life-threatening with 
hives, wheezing,

Cough, dizziness, chills, 
rash, trouble breathing, 
chest or throat tightness, 
swelling in your

Face or hands, fever, 
itching, and low blood 
pressure.

Heart failure, blood clot, 
stroke

Kidney failure
OTHER RISKS RELATED TO THIS STUDY INCLUDE:
Blood drawing (venipuncture) risks:  Drawing blood may cause temporary discomfort from 
the needle stick, bruising, and rarely, infection.
Infusion risks: As with most intravenous products, you may experience pain, irritation, swelling 
or bruising, or a slight chance of infection at the site where the intravenous catheter (small tube) 
is inserted into your vein. These side effects may also be observed at the site where blood is 
drawn for laboratory tests.
Radiation:  This research study involves exposure to radiation. Some of this radiation exposure 
may be for research purposes only, and is not necessary for your medical care. This amount of 
radiation may involve a low, lifetime risk of cancer. However, we believe that this risk is not 
clinically relevant given your overall medical condition. If you have any questions regarding the 
use of radiation or the risks involved, please consult your study doctor.
CT scan risks:  CT scans involve the risks of radiation (see above).  In addition, if contrast 
material (iodine dye) is used, there is a slight risk of developing an allergic reaction, from mild 
(itching, rash) to severe (difficulty breathing, shock, or rarely, death).  The contrast material may 
also cause kidney problems, especially if you are dehydrated or have poor kidney function.  The 
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research study doctors will ask you about any allergies or related conditions before the 
procedure.  If you have any of these problems, you may not be allowed to have a CT scan.
Having a CT scan may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for 
a long time.  If contrast material is used, you may feel discomfort when it is injected. You may 
feel warm and flushed and get a metallic taste in your mouth. Rarely, the contrast material may 
cause nausea, vomiting or a headache. 
Bone Scan: The bone scan involves exposure to radiation. The bone scan involves an injection, 
in a vein in your arm, of a radiotracer (radioactive compound that localizes in the bone).  As with 
all injections, it may feel like a small sting and there may be possible bruising at the injection 
site. You may become uncomfortable lying still for the duration of the examination.  See 
Radiation Risks.
Tissue biopsy: The biopsy has small but serious risks. While we make every effort to minimize 
the pain related to the procedure, the procedure is usually uncomfortable and sometimes painful. 
Wherever the biopsy is done in your body, it can lead to bleeding in that area, damage of organs 
near where the biopsy is done, or infection. While it is uncommon, sometimes bleeding or pain 
from the biopsy will require you to stay overnight in the hospital or require you to go to the 
operating room to control any bleeding. We check your laboratory values before the biopsy to 
make sure that the procedure is as safe as possible and to minimize your chance of having a 
complication. Additionally, if the biopsy involves the lungs, it can cause the lungs to deflate and 
if this occurs, you might require treatment to correct this.  We try to take as little tissue as 
possible when we do the biopsy, and this means that sometimes the biopsy procedure can be 
unsuccessful and require a repeat biopsy to get enough tissue. Other potential risks will be 
described to you and discussed with you by doctors who conduct these biopsies.
Reproductive risks:  There may be risks if your partner is pregnant or trying to become 
pregnant.  If your partner is able to have a baby, you and your partner must avoid having sex 
(abstinence) or use reliable birth control methods during the study and from your first day of 
receiving study drug throughout the study period up to 120 days after your last dose of study 
drug.
The following birth control methods are allowed during the study:
Use of two (2) of the following in combination:

Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

Condom (male or female cannot be used together)

Cervical cap with spermicide (only if your partner has not given birth)

Contraceptive sponge (only if your partner has not given birth)

Hormonal contraceptives (estrogen/progestin pill or progestin-only pill), 
contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection.
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OR
One (1) of the following:

Intrauterine Device (IUD)

Vasectomy or surgical sterilization of your partner

Contraceptive rod implanted into your partner’s skin
If your partner becomes pregnant during the study you must notify the study doctor right away. 
You must also agree to not donate sperm from the day study treatment begins and for a period of 
120 days after your last dose of study drug.
Risk of inadequate specimens for diagnostic purposes: Providing parts of your surgically-
removed tissue for research could, in rare cases, result in too little tissue being available for your 
doctors to make a clinical diagnosis (or complete other clinically important tests). To minimize 
this risk, a Pathologist (or a pathology designee) carefully evaluates every tissue specimen at the 
time of surgery to decide if it can safely be provided for research. With this process in place, we 
believe the risk of negatively impacting your clinical care through providing tissue for research is 
extremely small (below 1%).
Unknown Risks: The experimental treatments may have side effects that no one knows about. 
You will be told about any important new findings that may affect your decision to remain in the 
research study.  
For more information about risks and side effects, ask your research study doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
There is no guarantee that you will receive any benefits from this study, and taking part in this 
study may or may not cause your health to improve. Receiving pembrolizumab alone may not be 
effective in treating your cancer.  Information from this study may help doctors learn more about 
pembrolizumab and the treatment of prostate cancer.  This information may benefit other patients 
with prostate cancer or a similar condition in the future.
HOW WILL MY SPECIMENS AND INFORMATION BE USED?
Researchers will use your specimens and information to conduct this study. Once the study is 
done using your specimens and information, we may share them with other researchers so they 
can use them for other studies in the future. We will not share your name or any other personal 
information that would let the researchers outside of UCSF know who you are. We will not ask 
you for additional permission to share the de-identified information and specimens.
Your specimens will be stored in a repository, also called a ‘tissue bank’, at UCSF. The manager 
of tissue bank and select tissue bank staff members will have access to your specimens and 
information about you, but they will not release any identifying information about you to 
researchers using your specimens. We may give your specimens and certain medical information 
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about you (for example, diagnosis, blood pressure, age if less than 85) to other scientists or 
companies not at UCSF, including to an unrestricted or controlled-access government health  
research database, but we will not give them your name, address, phone number, or any other 
identifiable information. Your specimens and information will be kept indefinitely until they are 
used up or destroyed. Research results from these future studies will not be returned to you and 
will not be put in your medical record. Future research performed on your de-identified samples 
will not change the care you receive.
Researchers may use your specimens (for example, blood, tissue, saliva, etc.) to look at 
all of your DNA (this is called “whole genome sequencing. DNA contains information 
that determines things like eye color, height, or disease risk that are passed on from 
parent to child. Genetic information (also known as genotype data) and the medical 
record data (also known as phenotype data) may be shared broadly in a coded form for 
future genetic research or analysis.
Donating data and specimens may involve a loss of privacy, but information about you 
will be handled as confidentially as possible. Study data will be physically and 
electronically secured. As with any use of electronic means to store data, there is a risk of 
breach of data security. Genetic information that results from this study does not have 
medical or treatment importance at this time. However, there is a risk that information 
about taking part in a genetic study may influence insurance companies and/or employers 
regarding your health. Taking part in a genetic study may also have a negative impact or 
unintended consequences on family or other relationships. It is possible that future 
research could one day help people of the same race, ethnicity, or sex as you. However, it 
is also possible through these kinds of studies that genetic traits might come to be 
associated with your group. In some cases, this could reinforce harmful stereotypes.
There will be no direct benefit to you from allowing your data and specimens to be kept 
and used for future research. However, we hope we will learn something that will 
contribute to the advancement of science and understanding of health and disease. If the 
data or specimens, or any new products, tests or discoveries that result from this research 
have potential commercial value, you will not share in any financial benefits. If you 
decide later that you do not want your information to be used for future research, you can 
notify the investigator in writing at:
Lawrence Fong, MD
San Francisco, CA 94143
and any remaining data will be destroyed. However, we cannot retract any data has been 
shared with other researchers.
WHAT OTHER CHOICES DO I HAVE IF I DO NOT TAKE PART IN THIS STUDY?
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Your other choices may include:

Getting treatment or care for your cancer without being in a study. You may be able to 
receive treatment with drugs approved to treat your type of cancer (such as abiraterone, 
enzalutamide, docetaxel, cabazitaxel or carboplatin).

Taking part in another study.

Receiving no treatment at this time.

Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems, and other problems caused by the cancer.  It does not treat the 
cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as 
active and comfortable as possible.
Talk to your doctor about your choices and their risks and benefits before you decide if you will 
take part in this study.
HOW WILL INFORMATION ABOUT ME BE KEPT CONFIDENTIAL?
Participation in research involves some loss of privacy. We will do our best to make sure that the 
personal information about you is kept confidential, but we cannot guarantee total privacy. Some 
information from your medical records will be collected and used for this study. Your signed 
consent form and some of your research tests will be added to your medical record as a result of 
your participation. Study tests that are performed by research labs, and information gathered 
directly from you by the researchers will be part of your research records and may be added to 
your medical record. Your personal information may be given out if required by law.  If 
information from this study is published or presented at scientific meetings, your name and other 
personal information will not be used.
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Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

The University of California

The National Cancer Institute (NCI) and other government agencies, e.g., the FDA, 
involved in keeping research safe for people. 

Merck and its authorized agents
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY?
Merck will provide pembrolizumab at no cost to you while you are participating in this study. 
You will not be billed for DNA damage repair testing using the Promega MSI test and a 
mutation sequencing test.
Two types of procedures will be done during this study.  Some are part of your standard medical 
care and others are only for research.  You or your insurer will be billed for the standard medical 
care.  You will be responsible for your co-pays, deductibles, and any other charges that your 
insurer will not pay. Any procedures done only for research will not be charged to you or your 
insurer. There is a possibility that your insurer may not cover all standard medical care costs 
because you are in a research study or because you are receiving medical services out of 
network.
 WILL I BE PAID FOR TAKING PART IN THIS STUDY?
You will not be paid for taking part in this study.
 WHAT HAPPENS IF I AM INJURED BECAUSE I TOOK PART IN THIS STUDY?
It is important that you tell your research study doctor, Lawrence Fong, M.D., if you feel that 
you have been injured because of taking part in this research study. You can tell the doctor in 
person or call him 
.
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. The costs of the treatment 
may be billed to you or your insurer just like any other medical costs, or covered by the 
University of California or Merck, depending on a number of factors. The University and Merck 
do not normally provide any other form of compensation for injury. For further information 
about this, you may call the office of the UCSF Institutional Review Board at 415- 476-1814. 
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WHAT ARE MY RIGHTS IF I TAKE PART IN THIS STUDY?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
We will tell you about new information or changes in the study that may affect your health or 
your willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
WHO CAN ANSWER MY QUESTIONS ABOUT THE STUDY?
You can talk to your research study doctor about any questions, concerns, or complaints you 
have about this research study.  Contact your research study doctor Lawrence Fong, M.D. at 415-
353-7171
If you wish to ask questions about the research study or your rights as a research participant to 
someone other than the researchers or if you wish to voice any problems or concerns you may 
have about the research study, please call the UCSF Institutional Review Board at 415-476-1814.   
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
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************************************************************
OPTIONAL RESEARCH
Please note: This section of the informed consent form is about optional research studies 
that are being done with people who are taking part in the main study. You may take part 
in these optional studies if you want to. You can still be a part of the main study even if you 
say "no" to taking part in any of these optional studies.
You can say "yes" or "no" to each of the following studies. Please mark your choice for 
each study.
Optional Tumor Biopsies/Future Research
About Optional Tumor Biopsies and Future Research
Depending how your disease responds to pembrolizumab, the study doctor would like to perform 
up to 2 additional tumor biopsies:
1. If your disease worsens while receiving pembrolizumab, you may have an additional 
biopsy before beginning chemotherapy described under “Optional Chemotherapy 
Cycles.”
2. If you have a clinical response to this chemotherapy and begin taking pembrolizumab 
again, you may have an additional biopsy within 28 days of restarting pembrolizumab.
These biopsies are optional. If you choose not to have one or both of these optional tumor 
biopsy, you can still participate in the main part of the study. 
The optional biopsies will be similar to the biopsy described in the section “Before you begin the 
main part of the study.”
If you agree to the optional tumor biopsies, we will share the specimens with other researchers so 
they can use them for other studies in the future. The specimens will be shared and certain 
medical information about you will be shared, as described in the section entitled “How will my 
specimens and information be used?” Please review this section to learn about what information 
about you will be shared, who it will be shared with, and the risks of sharing your medical 
information and tumor tissue for future research.
Things to Think About
The choice to undergo the optional tumor biopsies and give your specimens to researcher’s for 
future research is up to you. No matter what you decide to do, it will not affect your care.
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If you decide now that you want to have the optional research biopsies, you can change your 
mind at any time before the procedures. Just contact us and let us know that you do not want to 
have the optional research biopsy.
Benefits
There is no direct benefit to you.
The benefits of research using tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them.
Risks
The risks of tumor biopsies are described in the section “Other Risks Related to This Study 
Include”
The risks of donating tumor tissue for future research are described in the section “How will my 
specimens and information be used?”
Making Your Choice
Please read the sentence below and think about your choice. After reading the sentence, put your 
initials in the "Yes" or "No" box.  If you have any questions, please talk to your doctor or nurse, 
or call the Institutional Review Board at 415-476-1814.
No matter what you decide to do, it will not affect your care.
1. I agree to undergo an optional tumor tissue biopsy if my disease worsens while receiving 
pembrolizumab. This tumor tissue will be kept for use in future research to learn about, prevent, 
or treat cancer (including DNA and genetic tests).
YES 
NO
2. I agree to undergo an optional tumor tissue biopsy if I begin taking pembrolizumab again after 
chemotherapy. This tumor tissue will be kept for use in future research to learn about, prevent, or 
treat cancer (including DNA and genetic tests).
YES 
NO
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3. Someone may contact me in the future to ask me to take part in more research.
YES 
NO
*************** End of Optional Research Section ****************
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CONSENT
You have been given a signed and dated copy of this consent form and a copy of the 
Experimental Subject's Bill of Rights to keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of 
health information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to 
participate or to withdraw at any point in this study without penalty or loss of benefits to which 
you are otherwise entitled.
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Date
Signature of Person Obtaining Consent
Date
Signature of Witness – Only required if the participant is a 
                                    non-English speaker
IRB NUMBER: 17-22165
IRB APPROVAL DATE: 11/28/2022
IRB EXPIRATION DATE: 11/06/2023