Addition of Pembrolizumab Upon Progression on Enzalutamide in Men With mCRPC
Phase: PHASE2
Conditions: Castration-Resistant Prostate Carcinoma, Hormone-Resistant Prostate Cancer, PSA Progression, Recurrent Prostate Carcinoma, Stage IV Prostate Adenocarcinoma Cancer AJCC v8
Sponsor: OHSU Knight Cancer Institute

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SPONSOR: Oregon Health & Science University 
 
TITLE: Addition of Pembrolizumab Upon Progression on Enzalutamide in men with 
mCRPC 
 
 
Coordinating Center: 
 
 
Oregon Health & Science University 
 
Principal Investigator: 
Julie Graff, MD 
 
 
3485 S Bond Ave 
 
 
MC: OC14P 
 
 
Portland, OR 97239 
 
 
Co-Investigators: 
 
Christopher Ryan, MD 
 
 
3485 S Bond Ave 
 
 
MC: OC14P 
Portland, OR 97239 
 
Jeremy Cetnar, MD 
 
 
3485 S Bond Ave 
 
 
MC: OC14P 
Portland, OR 97239 
 
 
Collaborators on Correlative Work: 
 
Lisa Coussens, PhD 
Oregon Health & Science University 
 
William Redmond (William.redmond@providence.org) 
Yoshinobu Kogushi (yoshinobu.kogushi@providence.org) 
 
Statistician: 
 
Emile Latour 
 
 
latour@ohsu.edu 
Study Coordination: 
Rachel Slottke, BS, CCRP 
slottker@ohsu.edu 
503-494-6117 
 

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CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 7 
2.0 
TRIAL DESIGN.......................................................................................................... 7 
2.1 
Trial Design ............................................................................................................. 7 
2.2 
Trial Diagram .......................................................................................................... 8 
3.0 
OBJECTIVES & HYPOTHESES ............................................................................. 8 
3.1 
Primary Objectives & Hypotheses ........................................................................ 8 
3.2 
Secondary Objectives & Hypotheses ..................................................................... 8 
4.0 
BACKGROUND & RATIONALE ............................................................................ 9 
4.1 
Background ............................................................................................................. 9 
4.1.1 Pharmaceutical and Therapeutic Background ...................................................... 9 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 11 
4.2 
Rationale ................................................................................................................ 11 
4.2.1 Rationale for the Trial and Selected Subject Population .................................... 11 
4.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 11 
4.2.3 Rationale for Endpoints ...................................................................................... 12 
5.0 
METHODOLOGY ................................................................................................... 13 
5.1 
Entry Criteria ........................................................................................................ 13 
5.1.1 Diagnosis/Condition for Entry into the Trial: Metastatic, castration resistant 
prostate cancer progressing on enzalutamide after initial response to 
enzalutamide. ...................................................................................................... 13 
5.1.2 Subject Inclusion Criteria.................................................................................... 13 
5.1.3 Subject Exclusion Criteria .................................................................................. 14 
5.2 
Trial Treatments ................................................................................................... 16 

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5.2.1 Dose Selection/Modification .............................................................................. 17 
5.2.2 Timing of Dose Administration .......................................................................... 18 
5.2.3 Trial Blinding/Masking ....................................................................................... 19 
5.3 
Randomization or Treatment Allocation ............................................................ 19 
5.4 
Stratification .......................................................................................................... 19 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 19 
5.5.1 Acceptable Concomitant Medications ................................................................ 20 
5.5.2 Prohibited Concomitant Medications.................................................................. 20 
5.6 
Rescue Medications & Supportive Care ............................................................. 21 
5.6.1 Supportive Care Guidelines ................................................................................ 21 
5.7 
Diet/Activity/Other Considerations ..................................................................... 25 
5.7.1 Diet ...................................................................................................................... 25 
5.7.2 Contraception for participants and their female partners .................................... 25 
5.7.3 Pregnancy of Partner ........................................................................................... 26 
5.8 
Subject Withdrawal/Discontinuation Criteria ................................................... 26 
5.9 
Subject Replacement Strategy ............................................................................. 27 
5.10 
Clinical Criteria for Early Trial Termination ................................................... 27 
6.0 
TRIAL FLOW CHART ........................................................................................... 28 
6.1 
Study Flow Chart .................................................................................................. 28 
7.0 
TRIAL PROCEDURES ........................................................................................... 32 
7.1 
Trial Procedures ................................................................................................... 32 
7.1.1 Administrative Procedures .................................................................................. 32 
7.1.2 Clinical Procedures/Assessments ........................................................................ 35 

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7.1.3 Laboratory Procedures/Assessments .................................................................. 40 
7.1.4 Other Procedures ................................................................................................. 43 
7.1.5 Visit Requirements .............................................................................................. 43 
7.2 
Assessing and Recording Adverse Events .......................................................... 45 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ......................................................................................... 46 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 46 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 47 
7.2.4 Evaluating Adverse Events ................................................................................. 49 
7.2.5 Responsibility for Reporting Adverse Events ..................................................... 52 
8.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 52 
This is a single-arm phase II clinical trial to examine the efficacy of pembrolizumab 
in men with mCRPC who initially responded to single-agent enzalutamide but 
who are currently experiencing a PSA progression. ......................................... 52 
8.2 Statistical Analysis Plan ............................................................................................. 53 
8.3 Sample Size Computation .......................................................................................... 53 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 54 
9.1 
Investigational Product ........................................................................................ 54 
9.2 
Packaging and Labeling Information ................................................................. 54 
9.3 
Clinical Supplies Disclosure ................................................................................. 54 
9.4 
Storage and Handling Requirements .................................................................. 54 
9.5 
Returns and Reconciliation .................................................................................. 54 
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is 
the Investigator’s responsibility to arrange for disposal of all empty 
containers, provided that procedures for proper disposal have been established 

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according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. .......... 55 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 55 
10.1 
Confidentiality ....................................................................................................... 55 
10.2 
Compliance with Financial Disclosure Requirements ....................................... 55 
10.3 
Compliance with Law, Audit and Debarment ................................................... 55 
10.4 
Compliance with Trial Registration and Results Posting Requirements ........ 55 
10.5 
Quality Management System ............................................................................... 55 
10.6 
Data Management ................................................................................................. 56 
11.0 
LIST OF REFERENCES ......................................................................................... 59 
12.0 
APPENDICES ........................................................................................................... 62 
12.1 
ECOG Performance Status .................................................................................. 62 
12.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 62 
12.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors ................................................................ 62 
RECIST version 1.1* will be used in this study for assessment of tumor response. 
While either CT or MRI may be utilized, as per RECIST 1.1, CT is the 
preferred imaging technique in this study. ......................................................... 62 
* As published in the European Journal of Cancer: ..................................................... 62 
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. ................................................................................................... 62 
In addition, volumetric analysis will be explored by central review for response 
assessment. ............................................................................................................. 63 
12.4 
Correlative Work .................................................................................................. 64 
12.5 
Biopsy of Metastatic Lesion ................................................................................. 64 

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1. OVERVIEW ...................................................................................................................... 75 
3.1 
Pneumonitis ............................................................................................................ 78 
3.2 
Colitis ...................................................................................................................... 80 
3.3 
Endocrine ............................................................................................................... 83 
3.4 
Hematologic ........................................................................................................... 86 
3.5 
Hepatic .................................................................................................................... 87 
3.6 
Neurologic .............................................................................................................. 90 
3.7 
Ocular ..................................................................................................................... 91 
3.8 
Renal ....................................................................................................................... 92 
3.9 
Skin ......................................................................................................................... 93 
3.9.1. Immediate Evaluation for Potential Skin ECIs ................................................ 95 
3.10 
Other ....................................................................................................................... 97 
3.11 
Infusion Reactions ................................................................................................. 98 
3.12 
Follow-up to Resolution ....................................................................................... 100 
4. REFERENCES ................................................................................................................ 101 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table .......................... 102 
 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab plus enzalutamide in progression with enzalutamide 
alone 
Trial Phase 
II 
Clinical Indication 
Castration-resistant prostate cancer, progressing on enzalutamide 
Trial Type 
Interventional, single arm 
Type of control 
Historical 
Route of administration 
Intravenous Pembrolizumab 
Trial Blinding 
N/A 
Treatment Groups  
Single-arm Pembrolizumab + enzalutamide (standard of care) 
Number of trial subjects 
58 
Estimated duration of trial 
5 years (2.5 years of enrolment, 2.5 years of follow up) 
Duration of Participation 
2 years 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
Single-arm phase II study of adding pembrolizumab in men with metastatic, castration resistant 
prostate cancer progressing on enzalutamide. 

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2.2 
Trial Diagram 
 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objectives & Hypotheses 
Objectives: Measure the anti-cancer activity of pembrolizumab in men with metastatic, 
castration resistant prostate cancer. A response to treatment will be defined by a PSA decrease 
of at least 50%. Examine the safety of the combination of pembrolizumab with enzalutamide 
by looking at adverse events by the CTCAE v.4. 
Hypothesis:  Immunological therapy with pembrolizumab combined with a second generation 
receptor antagonist will be safe and lead to PSA responses in men with mCRPC beginning to 
progress on enzalutamide. 
3.2 
Secondary Objectives, Exploratory Objectives, & Hypotheses 
Secondary Objectives: 
(1) To investigate immunological and genetic parameters to evaluate for possible markers 
and functional changes that are predictive of a clinical response or linked to response or 
resistance to PD-1 inhibition.  Exploratory analyses will include:   

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o Immunohistochemistry for total CD45+ cells (leukocytes), lymphocytes (CD8+, CD4+, 
and B cells), and macrophages in prostate tissue at diagnosis (if original biopsy is 
available) and pre-treatment 
o Immunohistochemisty for PD-1, PD-L1 and PD-L2 in prostate tissue at diagnosis (if 
original biopsy is available) and pre-treatment 
o DNA sequencing 
(1) To collect circulating tumor cells (CTCs) and determine the degree to which tumor 
characteristics are shared by the CTCs. 
(2) Changes in T cell numbers, activation, and phenotype as measured in whole blood at 
diagnosis and throughout therapy  
o T effector/memory panel (CD45, CD3, CD8, CCR7, CD45RA,CD45RO, CD69, CD44, 
CD62L) 
o T regulatory panel (CD45, CD3, CD4, FoxP3, CD25, CD127, CD69, CD44)  
o T help panel (CD45, CD3, CD4, CD45RA, CD45RO, CD69, CD44, CD62L) 
o Cytokine propensity of the above T cell subsets (IFN-γ, IL-2, IL-4, IL-12, IL-13, IL-10, 
IL-18, TNF-α, TGF-β, IL-17)  
(3) Systemic inflammatory markers: Serum IL-8, IL-6, IL-1, TNF and TGF-beta 
(4) Objective disease response by radiographs 
(5) PSA progression free survival 
(6) Overall survival 
(7) Microbiome and correlation with response 
Exploratory Objectives:  
 
(1) Additional genetic (DNA, RNA) and protein analyses will be conducted to further evaluate 
immunotherapy and profile/characterize disease 
Hypotheses:  Clinical outcomes will correlate with T cell activation/phenotype, the presence 
of CD8+ lymphocytes in the prostate cancer biopsy (metastatic); circulating tumor cells will 
share tumor characteristics and can possibly be used as a surrogate to tissue biopsy in future 
studies; and, increases in systemic inflammatory markers will be inversely related to response. 
Immunological therapy with pembrolizumab combined with a powerful androgen receptor will 
lead to PSA progression free survival prolongation in men with mCRPC beginning to progress 
on enzalutamide. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades (1).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 

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malignancies (2-6).  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) (7, 8).  The structure of murine PD-1 has been 
resolved (9).  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 (7, 10-12).  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 (13, 14).  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 (15, 16).  Expression has also been shown during thymic development on CD4-CD8- 
(double negative) T-cells as well as subsets of macrophages and dendritic cells (17).  The ligands 
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types, including non-hematopoietic tissues as well as in various tumors (13, 18-20).  Both ligands 
are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs.  Binding of either 
PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues (13).  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) (21).  
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 (previously known as SCH 900475 and MK-3475) 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.   
Our 38th subject just completed four cycles of pembrolizumab. We have seen seven robust 
responses so far. The degree of response is surprising, and we do not currently understand the 

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mechanism. We are expanding enrolment to an additional 30 patients with enriched correlative 
work to help us understand which patients respond to this therapy. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure (IB) 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) is prostate cancer that no longer 
responds to castration alone, either surgically or chemically, and consequently is the terminal 
disease state in prostate cancer. There are several agents that can prolong survival after 
development of mCRPC, but none are curative. It is unclear how best to treat patients who are 
progressing on the androgen receptor antagonist enzalutamide. Patients who progress on 
enzalutamide do not respond as well to abiraterone as those who have not been exposed to 
enzalutamide(22) (23). The FDA approved immunotherapy, sipuleucel-T, has very little effect on 
tumor size and is only used in a select group of patients with very slow growing tumors.(24) 
Chemotherapy with docetaxel is another option for these patients, but its use is often delayed in 
order to avoid the associated toxicity.(25, 26) Additionally, there are data suggesting that the 
combination of enzalutamide with immunotherapy may be effective in this population.(27) 
4.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent pembrolizumab.  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 pembrolizumab 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 Maximum Tolerated Dose (MTD) has been identified to date.  Recent 
data from other clinical studies within the pembrolizumab program has shown that a lower dose 
of pembrolizumab and a less frequent schedule may be sufficient for target engagement and 
clinical activity. 
 
PK data analysis of pembrolizumab 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 

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of pembrolizumab 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.  Pembrolizumab 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 pembrolizumab 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. 
 
Based on the studies described above, we will be using pembrolizumab 200 mg (fixed dose) IV 
every 3 weeks. 
 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
Patients with PSA progression on treatment are extremely unlikely to have a PSA response without 
a change in therapy. PSA changes, while not always correlated with survival, provide a readily 
measurable means of assessing prostate cancer response or progression. We will use this endpoint 
as our primary outcome. However, we will use radiographic progression when determining a 
subject’s suitability to continue on treatment. Furthermore, since the benefits of immunotherapy 
can take months to become apparent, we will not make treatment decisions within the first 12 
weeks. 
4.2.3.2 Biomarker Research 
First, T cell number can indicate response to immunotherapy – at least its pharmacokinetic 
effect.(28) We will look at T cell subtypes and correlate with clinical response. Second, we are 
collecting tissue from baseline diagnosis (archival tissue) and from metastatic tumor biopsy. There 
are data in melanoma and breast cancer correlating the immunophenotype to treatment response 
(29, 30). There are not yet many data in prostate cancer, and this trial seeks to increase our 
understanding of it. Third, we will look at inflammatory markers to see how they correspond with 
response. 
Banking of Specimens for Potential Future Research. Specimens collected and any leftover 
serum/plasma will be banked for future research under the “Master Protocol for Cancer Research 
Specimen Bank and Database” (OHSU IRB 2816), and will be used to search for biomarkers of 
response and resistance to therapy.  Future research may include genetic research. 
 

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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 progressing on enzalutamide after initial response to enzalutamide. 
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Histologically or cytologically confirmed adenocarcinoma of the prostate without 
pure small cell carcinoma. Patients without histologically confirmed adenocarcinoma 
may be eligible if both the treating physician and the study PI agree that the patient’s 
history is unambiguously indicative of advanced adenocarcinoma. 
2. Be willing and able to provide written informed consent/assent for the trial. 
3. Be ≥ 18 years of age on day of signing informed consent. 
4. Have metastatic disease. 
5. Have permission to access tissue from an archival tissue sample. (Absence of archival 
tissue will not preclude trial participation.) 
6. Has a metastatic deposit that can be biopsied. 
7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
8. Demonstrate adequate organ function as defined in Table 1, 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  
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 

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Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
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. 
 
9. Male subjects 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. 
10. Have a PSA or radiographic progression on enzalutamide.  PSA progression is defined as 
two consecutive increases in PSA with the second level obtained at least 3 weeks after the 
first, and the second level of at least 0.5 ng/mL. Soft tissue disease progression defined by 
RECIST 1.1 criteria or ≥ 2 new lesions on bone scan. 
11. Have had either surgical castration OR be on LHRH agonist or antagonist therapy with 
serum testosterone <50 ng/dl AND agree to stay on LHRH agonist or antagonist therapy 
during the study. 
5.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating in or has participated in a study of an investigational agent or using 
an investigational device within 4 weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
The use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor. 
 
3. Has had a prior monoclonal antibody 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. Denosumab is a prohibited medication on study and for 4 
weeks prior to day 1. 
4. Has had chemotherapy for castration-resistant disease. Chemotherapy for castration-
sensitive disease is permitted. 

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5. 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. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.   
6. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ bladder cancer that has undergone potentially curative therapy.   
7. Has known brain metastases and/or carcinomatous meningitis. 
8. Has a history of seizure 
9. Has allergy to enzalutamide 
10. Has an active automimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. A severe autoimmune disease is 
one that requires a significant medical intervention such as hospitalization.  Subjects with 
vitiligo or resolved childhood asthma/atopy would be an exception to this rule.  Subjects 
that require intermittent use of bronchodilators or local steroid injections would not be 
excluded from the study.  Subjects with hypothyroidism stable on hormone replacement or 
Sjorgen’s syndrome will not be excluded from the study. 
 
11. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. Has an 
active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion 
of the treating investigator.   
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or 

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any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathways). Previous treatment with sipuleucel-T is permitted. 
15. Has plans to receive cytotoxic chemotherapy, immune checkpoint inhibitors (eg CTLA-4 
blockade), sipuleucel-T, radiopharmaceuticals, abiraterone or other experiemental therapy 
during this study period. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
19. Has rapid progression of visceral disease and, thus is a candidate for docetaxel. This 
determination will be at the discretion of the treating physician. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 
Table 2  Trial Treatment 
Drug 
Dose/Pote
ncy 
Dose 
Frequenc
y 
Route of 
Administratio
n 
Regimen/Treatme
nt Period 
Use 
Pembrolizumab 
200 mg 
Every 3 
weeks 
IV infusion 
Four doses  
Experiment
al 
Enzalutamide 
80-160 
mg 
Daily 
By mouth 
Throughout 
study 
Standard of 
Care 
Then, if progressing after initial response or stability (see section 7.1.2.11), 
Pembrolizumab 
200 mg 
Every 3 
weeks 
IV infusion 
Four doses 
Experiment
al 
Enzalutamide 
80-160 
mg  
Daily 
By mouth 
Throughout 
study 
Standard of 
Care 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 
5.2.1.2. 
 

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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.  We will use pembrolizumab 200 mg (fixed dose) IV every 3 weeks. 
Details on the dose calculation, preparation and administration are provided in the Pharmacy 
Manual. 
5.2.1.2 Dose Modification  
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
hematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-threatening 
AEs as per Table 3 below. 
Table 3: Dose modification guidelines for non-immune related drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with 
Coordinating 
Center, 
OHSU) 
Hematological Toxicity 
 
1, 2 
No 
N/A 
N/A 
N/A 
3* 
*Excluding 
Grade 3 
neutropenia, 
anemia, and 
thrombocytopenia 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
4 
Yes 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May increase the 
dosing interval 
by 1 week  
Non-hematological toxicity 
 
Note:  Exception to be treated 
similar to grade 1 toxicity  
• Grade 2 alopecia 
• Grade 2 fatigue 
 
For 
additional 
information 
regarding Adverse Events with 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and 
schedule 
(reference 
Section 5.6.1.2 
for 
recommendations 
regarding 
pneumonitis) 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 

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Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with 
Coordinating 
Center, 
OHSU) 
a potential Immune-Etiology 
reference Section 5.6.1.1. 
Clinical AE does 
not resolve 
within 4 weeks:  
May increase the 
dosing interval 
by  1 week for 
each occurrence 
3, 4 
 
Yes 
 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
 
May increase the 
dosing interval 
by 1 week for 
each occurrence 
 
Toxicity does 
not resolve 
within 12 
weeks of last 
infusion 
Permanent 
discontinuation 
should be 
considered for 
any severe or 
life-threatening 
event 
 
 
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with Dr. Graff at OHSU.  With investigator and Dr. Graff 
agreement, subjects with a laboratory adverse event still at Grade 2 after 12 weeks may continue 
treatment in the trial only if asymptomatic and controlled.  For information on the management of 
adverse events, see Section 5.6.1.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial treatment. 
 
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. 

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Pembrolizumab will be administered as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 5.2.1.2).  Sites should make every effort to target 
infusion timing to be as close to 30 minutes as possible.  However, given the variability of infusion 
pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time 
is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
5.3 
Randomization or Treatment Allocation 
This is not a randomized trial. All patients will receive treatment. 
5.4 
Stratification 
There will not be up-front stratification. 
5.5 
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 
Dr. Graff.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.  However, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the Investigator and the subject.  
External beam radiation therapy is permitted on this study. Its use should be disclosed and 
described (dose, number of areas, number of treatments, treatment dates and response) as a 
Concomitant Therapy in clinical report forms. There are no data regarding the simultaneous use 
of radiation and pembrolizumab. Therefore, if radiation is needed, the pembrolizumab should be 
held one week prior to radiation and for 2 weeks after radiation therapy. 
Subjects eligible for this study are progressing on enzalutamide and must continue the 
enzalutamide while on this study. However, enzalutamide may be held for adverse events thought 
to be related to enzalutamide. If a subject is off of enzalutamide for longer than 30 consecutive 
days, either directly prior to starting the study or after enrollment, the principal investigator needs 
to be alerted. 

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5.5.1 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. 
As noted above, external beam radiation is permitted, and enzalutamide should be continued. 
Radium-223, strontium and samarium are prohibited. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment) of this trial: 
• Anti-cancer systemic chemotherapy, hormone therapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Radiopharmaceuticals such as Radium-223, strontium, and samarium 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and during active 
treatment.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
• Glucocorticoids for any purpose other than to modulate symptoms from an event of clinical 
interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.  
• Agents that can affect PSA, other than LHRH-agonists and enzalutamide. Examples of 
these agents include bicalutamide, flutamide, nilutamide, abiraterone, prednisone, and 
herbal agents such as PC-SPES and saw palmetto. 
• Denosumab (also known as Prolia and Xgeva) is prohibited because it can be 
immunosuppressive. 

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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 Monitoring Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Adverse events experienced on study may be related to the study agent (pembrolizumab), 
enzalutamide, cancer itself, or another etiology. If the side effect is felt related to the 
pembrolizumab, please follow the recommended supportive care guidelines below. If the side 
effect is attributable to something other than pembrolizumab, these guidelines may not apply, and 
a more appropriate treatment may be needed. Subjects should receive appropriate supportive care 
measures as deemed necessary by the treating investigator including but not limited to the items 
outlined below: 
• Diarrhea: 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).  In symptomatic subjects, infectious 
etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic 
evaluation should be considered. 
o In subjects with severe enterocolitis (Grade >2), pembrolizumab will be 
permanently discontinued and treatment with systemic corticosteroids should be 
initiated at a dose of 1 to 2 mg/kg/day of prednisone or equivalent.  When symptoms 
improve to Grade 1 or less, corticosteroid taper should be started and continued 
over at least 1 month. 
o In subjects with moderate enterocolitis (Grade 2), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started.  If symptoms are persistent 
for more than one week, systemic corticosteroids should be initiated (e.g., 0.5 
mg/kg/day of prednisone or equivalent).  When symptoms improve to Grade 1 or 
less, corticosteroid taper should be started and continued over at least 1 month.  
Regarding guidelines for continuing treatment with pembrolizumab, see Section 
5.2. 
o All subjects who experience diarrhea 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. 

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• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice.  Subjects should be strongly 
encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive oral or 
IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
• Immune-related adverse events: Please see Section 5.6.1.1 below and Section 12.6 
regarding diagnosis and management of adverse experiences of a potential immunologic 
etiology.   
• Management of Infusion Reactions:  Acute infusion reactions (which can include cytokine 
release syndrome, angioedema, or anaphylaxis) are different from allergic/hypersensitive 
reactions, although some of the manifestations are common to both AEs.  Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Signs/symptoms may include: 
Allergic reaction/hypersensitivity (including drug fever); Arthralgia (joint pain); 
Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, 
lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia (muscle pain); 
Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); 
Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); Urticaria 
(hives, welts, wheals); Vomiting. 
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
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 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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. 
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. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
5.6.1.1 Supportive Care Guidelines for Immune-related Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an 
adverse event of unknown etiology, associated with drug exposure and is consistent with an 
immune phenomenon.  irAEs may be predicted based on the nature of the pembrolizumab 
compound, its mechanism of action, and reported experience with immunotherapies that have a 
similar mechanism of action.  Special attention should be paid to AEs that may be suggestive of 
potential irAEs.  An irAE can occur shortly after the first dose or several months after the last dose 
of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin 
or other etiologic causes prior to labeling an adverse event as an irAE.  Information on how to 

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identify and evaluate irAEs has been developed and is included in the Event of Clinical Interest 
and Immune-Related Adverse Event Guidance Document. See Section 12.6.  Subjects who 
develop a Grade 2 or higher irAE should be discussed immediately with the Sponsor.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 
5. 
Table 5  General Approach to Handling irAEs 
irAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May withhold pembrolizumab 
Consider systemic corticosteroids in addition to 
appropriate symptomatic treatment 
Grade 3 and Grade 4 
Withhold pembrolizumab 
Discontinue if unable to reduce 
corticosteroid dose to < 10 mg 
per day prednisone equivalent 
within 12 weeks of toxicity 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 
Steroid taper should be considered once symptoms 
improve to Grade 1 or less and tapered over at least 4 
weeks. 
 
5.6.1.2 Supportive Care Guidelines for Pneumonitis 
Subjects with symptomatic pneumonitis should immediately stop receiving pembrolizumab and 
have an evaluation.  The evaluation may include bronchoscopy and pulmonary function tests to 
rule out other causes such as infection.  If the subject is determined to have study drug associated 
pneumonitis, the suggested treatment plan is detailed in Table 6. 
Table 6  Recommended Approach to Handling Pneumonitis 
Study drug associated 
pneumonitis 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 (asymptomatic) 
No action 
Intervention not indicated 
Grade 2 
Withhold pembrolizumab, 
may return to treatment if 
improves to Grade 1 or 
resolves within 12 weeks 
Systemic corticosteroids are indicated.  Taper if 
necessary. 
Grade 3 and Grade 4 
Discontinue pembrolizumab 
Systemic corticosteroids are indicated. The use of 
infliximab may be indicated as appropriate.  Refer to 
the Event of Clinical Interest and Immune-related 
Adverse Event Guidance Document for additional 
recommendations. 
 

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For Grade 2 pneumonitis that improves to ≤ Grade 1 within 12 weeks, the following rules should 
apply: 
• First episode of pneumonitis 
o May increase dosing interval by one week in subsequent cycles 
• Second episode of pneumonitis – permanently discontinue pembrolizumab if upon 
rechallenge subject develops pneumonitis ≥ Grade 2 
 
5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.7.2 Contraception for participants and their female partners 
It is not known if pembrolizumab has transient adverse effects on the composition of sperm.  
Participants, who for this study are male, are likely to be sterile because radical prostatectomy and 
external beam radiation to the prostate are akin to vasectomy, and subjects are highly unlikely to 
impregnate their partners. For those subjects who have intercourse with a premenopausal woman 
who is potentially able to conceive, their partners will be asked to use 2 methods of birth control. 
The two birth control methods can be either two barrier methods or a barrier method plus a 
hormonal method to prevent pregnancy. Female partners of subjects should start using birth control 
from study Visit 1 throughout the study period up to 120 days after the last dose of study therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents). 
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 their partners must adhere to the contraception requirement (described above) for the 
duration of the study and during the follow-up period defined in section 7.2.2-Reporting of 
Pregnancy and Lactation to Dr. Graff at OHSU and to Merck.  If there is any question that a subject 
will not reliably comply with the requirements for contraception, that subject should not be entered 
into the study. 

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5.7.3 Pregnancy of Partner 
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as described 
above and in Section 7.2.2. 
5.8 
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 after 12 weeks of treatment (see Table 7) 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, but Dr. Graff must 
be contacted first. If the subject has continued radiographic progression after the next 
set of 4 treatments OR clinical deterioration (such as increased pain) during the 
treatment, he must be removed from the study. 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow Chart) 
and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be followed 
for 30 days for adverse event monitoring (serious adverse events will be collected for 90 days after 
the end of treatment as described in Section 7.2.3.1).  Subjects who discontinue for reasons other 
than progressive disease will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to 

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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. 
Patients will not be taken off study for PSA progression alone. 
5.9 
Subject Replacement Strategy 
Subjects who do not receive a single dose of pembrolizumab will be replaced. 
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 
6.1 
Study Flow Chart 
Trial Period: 
 
 
Treatment Cyclea 
 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
 
Monitoring 
Retreatment 
 
Discontinua-
tion (Discon) 
Safety 
Follow-up 
Survival 
Follow-Up 
Post-first 
course (3 
weeks 
after 
cycle 4) 
Assess 
Every 6 weeks 
after “post first 
course/retreatme
nt course” 
Assess 
Every 12 
weeks on study 
1 
2 
3 
4 
Post 
retreatment 
course ((3 
weeks after 
retreatment
cycle 4) 
 
Scheduling Window (Days): 
-28 to -1 
 
± 
3 
± 
3 
± 3 
± 3 
± 3 
±7 
± 
3 
± 
3 
± 
3 
± 
3 
± 3 
At time of 
Discon 
30 days 
post 
discon* 
Every 12 
weeks ± 2 
week 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival Tissue Collection 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biopsy of Metastatic Lesion 
X** 
 
 
 
 
X*** 
 
 
X^ 
 
 
 
X*** 
X***1 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior Medication Review 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
Testosterone, Lactate 
DeHydrogenase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treatment Administration 
(pembrolizumab) 
 
 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
 
 
 
Enzalutamide, daily 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Review Adverse Events, 
include Events of Clinical 
Interest 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
X 
X 
X 
 

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Trial Period: 
 
 
Treatment Cyclea 
 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
 
Monitoring 
Retreatment 
 
Discontinua-
tion (Discon) 
Safety 
Follow-up 
Survival 
Follow-Up 
Post-first 
course (3 
weeks 
after 
cycle 4) 
Assess 
Every 6 weeks 
after “post first 
course/retreatme
nt course” 
Assess 
Every 12 
weeks on study 
1 
2 
3 
4 
Post 
retreatment 
course ((3 
weeks after 
retreatment
cycle 4) 
 
Scheduling Window (Days): 
-28 to -1 
 
± 
3 
± 
3 
± 3 
± 3 
± 3 
±7 
± 
3 
± 
3 
± 
3 
± 
3 
± 3 
At time of 
Discon 
30 days 
post 
discon* 
Every 12 
weeks ± 2 
week 
Review Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
PT/INR and aPTT, pre-biopsy 
only 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
 
LDH 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X1 
 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive Serum 
Chemistry Panel 
X 
X 
X 
X 
X 
X 
X1 
 
X 
X 
X 
X 
X 
X 
X 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
X1 
 
X 
X 
X 
X 
X 
X 
X 
 
T3, FT4 and TSH 
X 
X 
X 
X 
X 
X 
X1 
 
X 
X 
X 
X 
X 
X 
X 
 
C Reactive Protein  
 
X 
X 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
 
 
 
Tumor Imaging 
X 
 
 
 
 
X£ 
 
X£ 
 
 
 
 
X£ 
 
 
 
 
1 Investigator(s) may reduce the frequency of these tests for subjects in the monitoring phase who are at least 3 months removed from their last dose of 
pembrolizumab. 

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Trial Period: 
 
 
Treatment Cyclea 
 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Main 
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
 
Monitoring 
Retreatment 
 
Discontinua-
tion (Discon) 
Safety 
Follow-up 
Survival 
Follow-Up 
Post-first 
course (3 
weeks 
after 
cycle 4) 
Assess 
Every 6 weeks 
after “post first 
course/retreatme
nt course” 
Assess 
Every 12 
weeks on study 
1 
2 
3 
4 
Post 
retreatment 
course ((3 
weeks after 
retreatment
cycle 4) 
 
Scheduling Window (Days): 
-28 to -1 
 
± 
3 
± 
3 
± 3 
± 3 
± 3 
±7 
± 
3 
± 
3 
± 
3 
± 
3 
± 3 
At time of 
Discon 
30 days 
post 
discon* 
Every 12 
weeks ± 2 
week 
Correlative Studies Blood 
Collection-PBMCs and Serum 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Xµ 
 
 
 
Correlative Studies Blood 
Collection-CTCs 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Correlative studies buccal 
swab, blood and/or tissue—
NORMAl control + 
X** 
 
 
 
 
X*** 
 
 
 
 
 
 
X*** 
X***1 
 
 
Correlatives studies: Rectal 
Swab, Questionnaireb, Mouth 
Swish 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
a Each Cycle is 3 weeks long, unless extended for toxicity in accordance with Section 5.2.1.2 
* If a subject initiates a new anti-cancer therapy within 30 days after discontinuing the study, the 30 day Safety Follow-up visit must 
occur before the first dose of the new therapy. 
**Does not necessarily have to be done within this 28 day period, but must be done prior to getting cycle 1. 
***Does not necessarily have to be done within 3 days of post-first/retreatment course/discontinuation. We prefer it be done close to 
the post-first course, but it may be done any time after this point. If there is no lesion amenable to biopsy, this will have to be skipped. 

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£ +/- 7 day window. For subjects entering retreatment phase, imaging must be repeated prior to retreatment (RT) cycle 1 (unless imaging occurred less than 28 days prior to RT 
cycle 1). For subjects in the monitoring phase, imagining frequency may be decreased with investigator approval.  
1 If progression after a period of response or stability. 
µ  PBMCs only at this time point (do not collect serum sample) 
b “General Gut Biome” questionnaire to be used at cycle 1 visit. The more truncated “Interval” questionnaire is to be used at other assessments. 
. 
^ Prior to restarting pembrolizumab if there is a lesion to be safely biopsied. 
 
 
 

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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.  
Individual trial procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require 
that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating 
in a clinical trial. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation in 
the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
 

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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 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.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the subject within 28 days 
before starting the trial.  Treatment for the disease for which the subject has enrolled in this study 
will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial.  All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days after 
the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the first dose 
of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move into 
survival follow-up.  

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7.1.1.6 Assignment of Subject ID Number 
This is a single-site study. Subjects will receive a study code that is 11025-number when they are 
enrolled (deemed eligible) on the study. For example, the first subject is 11025-01. 
7.1.1.7 This log will be submitted to the coordinating center on a regular basis. 
Assignment of Randomization Number 
Not applicable, as this is not a randomized study. 
7.1.1.8 Subject Registration  
A centralized registration procedure will be used. After eligibility screening, subjects who are 
selected to participate will be registered with the Lead Center (OHSU). A record of patients who 
fail to meet entry criteria (i.e., screen failures) will be maintained. Subject registration must be 
completed before beginning any treatment or study activities.  
7.1.1.8.1 Coordinating Center (OHSU) Registration 
All participants will be registered with OHSU. Registration will be completed via electronic 
Clinical Research Information System (eCRIS). A copy of the signed consent, a completed 
Eligibility Checklist and other relevant information must be included in the Electronic Registration 
System.   
7.1.1.8.2 Participating Sites  
Central registration for this study will take place at Oregon Health & Science University (OHSU). 
Knight Cancer Institute  
To complete registration and enroll a participant from another institution, the study staff at that 
site must contact the designated research staff at OHSU to notify him/her of the participant 
registration. The site staff then needs to fax or email registration/eligibility registration to: 
Multicenter Study Manager:  
Rachel Slottke Fax: 503.494.6197or Email: slottker@ohsu.edu  
The following documentation must be sent for each enrollment: 
• The completed Eligibility Checklist  
• The signed informed consent and HIPAA Authorization form 
• Supporting source documentation for eligibility questions (laboratory results, pathology 
report, radiology reports, MD notes, physical exams, medial history and prior treatment 
records.) 

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Upon receipt, the research staff at OSHU will conduct an interim review of all documents. If the 
participant meets all criteria, all source documentation is received, the participating site IRB has 
granted approval for the protocol and the site is in good standing with OHSU, the OHSU research 
staff will register the subject.  
Once eligibility has been established and the participant is registered, the participant will be 
assigned a protocol participant number. This number is unique to the participant and must be 
written on all data and correspondence for the participant. This protocol participant number will 
be relayed back to study staff at the registering site via e-mail and will serve as the enrollment 
confirmation.  
7.1.1.9 Institutional Registration  
Subject registration at each study site/institution will be conducted according to the institution’s 
established policies.  
7.1.1.10 Trial Compliance (Medication/Diet/Activity/Other) 
Subjects will fill out a medication diary describing their daily use of enzalutamide. The study team 
will review the medication diary at each visit. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up 
period according to NCI CTCAE Version 4.0 (see Section 12.2).  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology 
(irAE).  See Section 5.6.1.1 regarding the identification, evaluation and management of AEs of a 
potential immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording of AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  During screening, clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening.  Subsequent clinically 
significant findings may be recorded as AEs.  

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7.1.2.3 Directed Physical Exam 
N/A 
7.1.2.4 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 only be measured before the first trial treatment (screening or Cycle 1 Day 
1 pre-infusion).  
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.4) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Trial Flow Chart.  After Cycle 8 assessment of ECOG status will be performed in 
conjunction with the physical exam. 
7.1.2.6 Tumor Imaging and Assessment of Disease 
To ensure a uniform tumor assessment schedule, regular radiological imaging (eg, MRI/CT of 
chest, abdomen, pelvis, plus other nodal disease as applicable, and bone scans) will be performed 
for all subjects at Screening and Week 12. Subjects that have not met the Treatment Stopping 
Criteria specified in Section 5.8 will continue tumor assessments at Week 24, and every 12 
weeks thereafter. Frequency of tumor assessments may be decreased with investigator approval 
once a patient is no longer receiving pembrolizumab. 
 
All disease progression should be confirmed with a repeat tumor assessment at least 6 weeks 
after the initial progression assessment. See Table 7 for a detailed description of disease 
progression.  
 
Subjects that enter the Toxicity/Progression Follow-up Phase without confirmed PD will have 
tumor assessments performed as specified in Section 7.1.2.6.  
Pembrolizumab acts by increasing the magnitude of the immune response against tumor 
associated antigens. However, it is well described that such an immune response might take 
weeks, if not months, to fully mobilize the immune system before resulting in a clinically 
observable effect. Prior to this time, some subjects with CRPC may experience an increase in 
their level of PSA before the immune response is able to control the progression of their disease. 
PSA may then start to decline as the immune response effectively reduces the tumor burden. Due 
to the time it may take for a pembrolizumab-mediated immune response to take effect, PSA 
values obtained prior to Week 12 will not be considered in the determination of disease 
progression.  
 
It is also expected that a tumor flare might be observed at sites of disease on CT/MRI/bone scan, 

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even in the absence of tumor cell growth, since an intense immune response may take place at 
these sites due to the mechanism of action of pembrolizumab. Since this tumor flare may present 
upon radiologic assessment as an increase in tumor volume, it is strongly recommended that such 
assessments NOT be performed prior to Week 12, unless the subject is experiencing clinical 
deterioration that is indicative of possible disease progression.  
 
This study proposes to perform radiologic tumor assessments, consisting of MRI/CT and bone 
scans, at 12-week intervals, starting at Week 12. The start of radiologic follow-up at Week 12 after 
pembrolizumab therapy accounts for the unique immunological mechanism and is consistent with 
The Prostate Cancer Clinical Trials Working Group 2 (PCWG2) recommendations of a “protocol-
specified minimum exposure of 12 weeks” to study therapy, in order to ensure that study drug is 
not discontinued before it has had a chance to work.(31) 
7.1.2.7 Definitions of Measurable and Non-measurable Lesions and Disease 
See Section 12.3. Measurable and Non-measurable disease is defined by RECIST 1.1. 
7.1.2.8 Definition of Target, Non-Target Lesions 
See Section 12.3.  
7.1.2.9 New Lesions 
See Table 7 for a description of the determination of progression based on the presence of new 
lesions.  
Note: The appearance of a new lesion does not by itself satisfy the criteria for confirmed 
progressive disease. Rather, the tumor burden imposed by the new lesion must be evaluated 
within the context of the total tumor burden (pre-existing plus new lesions). Confirmation of 
progression in Target lesions, Non-target (non-bone) lesions, and Bone lesions require 2 
assessment time points. The first of these (TP1) must occur at Week 12 or later with the second 
(TP2) occurring at least 6 weeks later. Progression declared at TP1 remains unconfirmed unless 
TP2 demonstrates continuing or worsening progression as described in Section 7.1.2.11.See 
section 12.3 for more information regarding soft tissue disease. 
 
7.1.2.10 Method of Tumor Response Assessment 
If, due to a radioisotope shortage, your imaging facility is unable to perform a Technetium-99 
(Tech-99) bone scan at a protocol-specified time point, then the following scanning options may 
be used:  
• Full body CT  
• Full body MRI  
• Fluoride PET 
 
7.1.2.11 Disease Progression Criteria 
At each disease assessment, progression (PD) will be determined using the criteria in Table 7. For 
treatment guidance, and for the purpose of efficacy assessments, confirmation PD is required. The 

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rationale for confirmation of PD is based on recommendations fromthe Prostate Cancer Working 
Group 2 (PCWG2): “Therapy may be prematurely discontinued if outcome measures do not reflect 
disease status accurately. As noted, bone scans in particular, are relatively insensitive in the early 
follow-up period. Consideration of drug pharmacodynamics is also important. For example, a 
successful vaccination might produce a lymphocytic infiltrate in a tumor mass that would 
transiently increase its size giving the false impression of worsening disease. To avoid 
misinterpreting these early results, PCWG2 asserts that any post-treatment change in disease 
status, be it favorable or unfavorable, be confirmed using a second assessment at a later time 
point.”(32)  
Therefore, confirmation of progression in PSA requires 3 assessment time points. Confirmation of 
progression in Target lesions, Non-target (non-bone) lesions, and Bone lesions requires 2 
assessment time points. The first of these (TP1) must occur at Week 12 or later with the second 
(TP2) occurring at least 6 weeks later. Progression declared at TP1 remains unconfirmed unless 
TP2 demonstrates continuing or worsening progression as described below: 
PSA: The first PSA at week 12 or after must demonstrate a ≥ 25% increase and ≥ 2 ng/ml 
increase above nadir (TP1). PSA progression at TP1 remains unconfirmed unless followed by a 
confirmed rising trend in 2 subsequent PSA values. PSA at TP2 must be > PSA at TP1.  
 
Note: Since PSA values obtained between week 1 and week 12 are not considered when 
determining progression, they cannot be used as nadir.  
 
• Target and Non-target (non-bone) lesions: Use RECIST 1.1 for progression, with 
additional requirements that progression at first assessment (TP1) be confirmed by a 
second scan 6 or more weeks later. See Section 12.3 for information about soft tissue 
disease.  
• Bone lesions: Assessment at TP1 must demonstrate the appearance of 2 or more new 
lesions. Progression at TP1 remains unconfirmed unless the TP2 assessment 
demonstrates the appearance of an additional 2 or more lesions when compared to TP1. 
After TP1 the appearance of 2 or more new lesions need to be confirmed with an 
additional scan 6 or more weeks later. The subsequent scan must show persistence of 
previous lesions or additional new lesions.  
 
Note: If unconfirmed progression noted at TP1 is not confirmed at TP2, the next assessment 
time point after TP1 that meets the criteria for progression is treated as TP1. 
Table 7: Definition of Disease Progression 
Disease Parameter 
Unconfirmed 
Progression Time 
Point 1 (TP1) 
Confirmed 
Progression 
Date of Progression 

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PSA (requires 2 
measurements)a 
≥ 25% increase and ≥ 
2 ng/ml increase 
above the nadir 
(Ignore PSA prior to 
week 12) 
PSA continues to 
climb 3 weeks after 
the first progression 
TP1 
Target Lesions 
(CT/MRI) Section 
12.3 for soft tissue 
disease assessment 
≥ 20% increase in the 
sum of diameters of 
target lesions. The 
sum must also 
demonstrate an 
absolute increase of 
at least 5mm. Or the 
appearance of one or 
more new lesions ≥ 
Week 12 
TP2 
Sum of diameters of 
TP2 ≥ Sum of 
diameters of TP1 
Confirmation of 
radiographic 
progression is not 
required for soft 
tissue after Week 12 
TP1 
Non-Target Lesions 
(non-bone) 
(CT/MRI) 
Unequivocal 
progression of 
existing non-target 
lesions (The 
appearance of one or 
more new lesions is 
also considered 
progression) 
See Section 12.3 for 
more information. 
 
TP 2 
Continued 
progression of non-
target lesions 
Confirmation of 
radiographic 
progression is not 
required for soft 
tissue after Week 12 
TP1 
Bone (Bone scan/X-
ray) 
Appearance of ≥ 2 
new lesions 
 
TP2 
Appearance of ≥ 2 
new lesions 
compared to TP1 
After Week 12 the 
appearance of two 
new lesions need to 
be confirmed 6 or 
more weeks later. 
The confirmatory 
scan must show 
TP1 

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persistence of 
previous lesions or 
additional new 
lesions 
Clinical 
Deterioration 
Clinical Deterioration at any time (defined as  
Persistent decrease in performance status (eg, 
lasting for more than 14 days) of at least 2 
points from baseline, attributable to disease 
progression) 
Any time 
Date of Clinical 
Deterioration 
a Since PSA values obtained between week 1 and week 12 are not considered when determining progression, they 
cannot be used as nadir.  
Definition of PSA and Radiographic Stability. Neither response nor progression. 
7.1.2.12 Disease Response Criteria 
PSA decrease of at least 50%. 
Radiographic Response will be determined using RECIST 1.1.(33) 
See Section 12.3. 
7.1.2.13 Tumor Tissue Collection and Correlative Studies Blood Sampling 
For all subjects, we will request the tumor block or 10 unstained slides from the initial diagnosis, 
such as biopsy or from radical prostatectomy. In addition, for subjects with a biopsy accessible 
metastatic deposit, we will collect 6 tissue cores. Blood (100 mL) will be collected just prior to 
pembrolizumab at each dose. See Appendices 12.4 and 12.5 for additional details. 
7.1.2.14 Normal Tissue Collection 
Normal tissue can be collected from any non-tumor source, including whole blood (20 mLs), 
normal tissue collected during study biopsy or during non-study procedure (surgical discard), skin, 
or saliva.  Our plan is to collect whole blood on patients (20 mLs) during screening, treatment, or 
non-treatment follow-up.  However, if non-cancer tissue has already been collected (study biopsy 
or other procedure) and is available, we will use that tissue in lieu of an additional blood draw.  
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  Please contact the sponsor for details concerning the total amount of blood/tissue 
to be drawn/collected over the course of the trial (from pre-trial to post-trial visits), including 
approximate blood/tissue volumes drawn/collected by visit and by sample type per subject.  

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7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 8.  
Please contact the sponsor for details concerning the total amount of blood/tissue to be 
drawn/collected over the course of the trial (from pre-trial to post-trial visits), including 
approximate blood/tissue volumes drawn/collected by visit and by sample type per subject can 
be found in Sections 12.4 and 12.5. 
 

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Table 8  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 per 
institutional standard) 
Aspartate aminotransferase (AST) 
Specific gravity  
Free tyroxine (T4) 
Red Blood Cell Count 
Carbon Dioxide ‡ 
 
Thyroid stimulating hormone (TSH) 
Absolute Neutrophil Count 
  (CO2 or bicarbonate) 
 
C Reactive Protein  
 
 
 
 
 
Calcium 
 
Blood for correlative studies 
 
Chloride 
 
 Lactate Dehydrogenase (LDH) 
 
Glucose 
 
  
 
Creatinine 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
 
 
  
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
 
Blood Urea Nitrogen 
 
 
 
 
 
 

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Laboratory tests for screening or prior to retreatment should be performed within 28 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.  
7.1.3.2 Pharmacokinetic/Pharmacodynamic Evaluations 
7.1.3.2.1 Blood and Tissue Collection for Correlative Work and Serum Pembrolizumab 
See Appendices 12.4 and 12.5 for details. 
PK data will not be done for this study. PK analysis has been done on previous studies with 
pembrolizumab. The PK is not changed by chemotherapy or other concomitant medications. This 
is not surprising considering it is an antibody. 
7.1.3.2.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples are provided in Section 
12.4. 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities scheduled 
for the final trial visit should be performed at the time of discontinuation.  Any adverse events 
which are present at the time of discontinuation/withdrawal should be followed in accordance with 
the safety requirements outlined in Section 7.2 - Assessing and Recording Adverse Events. After 
discontinuing treatment following assessment of CR, these subjects should return to the site for a 
Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-Up Period 
of the study (described in Section 7.1.5.4). 
7.1.4.2 Blinding/Unblinding. This is an open label study. 
7.1.5 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. 
7.1.5.1 Screening 
7.1.5.1.1 Screening Period 
The screening period begins at the time of consent and lasts 28 days. During this time, subjects 
will undergo imaging studies (CT and NM bone scan) and blood work to ensure they are suitable 
candidates. They will also undergo a biopsy if they have a lesion amenable to biopsy. Assessments 

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completed prior to consenting for clinical purposes (such as CT or Bone scans, or blood work) will 
not be required to be repeated if they are within the 28 day screening period. 
7.1.5.2 Treatment Period 
All subjects will receive four doses of pembrolizumab, unless they withdraw from the study. No 
official assessments of response will occur during these treatments, even though the PSA will be 
drawn. Those subjects who have stable disease or a disease response by PSA or imaging at 12 
weeks can go on to receive additional treatments until disease progression. Those subjects who 
have clearly progressive disease after the initial four treatments will not be retreated with 
pembrolizumab. 
7.1.5.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the end 
of treatment visitor 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.   
7.1.5.4 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 (84 ± 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 7.1.5.2.  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 7.1.5.2 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment.   Of note, it is possible to be retreated indefinitely. 
7.1.5.4.1 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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7.2 
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. 
For laboratory abnormalities, the criteria for determining whether an abnormal test finding should 
be reported as an adverse event are as follows: 
•         Test result is associated with accompanying symptoms, and/or 
•         Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
•         Test result leads to a change in study dosing outside of protocol-stipulated dose 
adjustments or discontinuation from the study, significant additional concomitant drug 
treatment, or therapy, and/or 
•         Test result is considered to be an adverse event by the Investigator 
 
 
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 within 
the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose 
(whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and 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. 

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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.  If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first 
required to provide consent to the main study and AEs will be captured according to guidelines for 
standard AE reporting. 
 
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 will be defined as any dose exceeding the prescribed dose 
for pembrolizumab by 20% over the prescribed dose. No specific information is available on the 
treatment of overdose of pembrolizumab. In the event of overdose, pembrolizumab should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose 
without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 
7.2.2 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 of a male subject's female partner that 
occurs during the trial or within 120 days of completing the trial completing the trial, or 30 days 
following cessation of treatment if the subject initiates new anticancer therapy, whichever is 
earlier.  All female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, missed 
abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage 
and stillbirth must be reported as serious events (Important Medical Events).  If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
From the time these events become known to the study team, they must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220) 

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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 a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is any other important medical event  
Refer to Table 9 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
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 that occurs to any subject from the time the 
consent is signed through 90 days following cessation of treatment, or the initiation of new anti-
cancer therapy, whichever is earlier, whether or not related to Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. The clock 
begins at the time the study team learns of the event. 
Non-serious Events of Clinical Interest will be forwarded to the Sponsor (OHSU) and to Merck 
Global Safety and will be handled in the same manner as SAEs.  
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 outside 
of the time period specified in the previous paragraph also must be reported immediately to the 
Sponsor and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to the 
Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 

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All subjects with serious adverse events must be followed up for outcome. 
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 recorded as such on the Adverse Event case report forms/worksheets and reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) 
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.  The trial site guidance for assessment and follow up of 
these criteria can be found in the Investigator Trial File Binder (or equivalent). 
3.  In the event a subject develops any of the following AEs, a detailed narrative of the event should 
be reported as an ECI to the Sponsor within 24 hours and to Merck Global Safety within 2 working 
days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥ 2 colitis 
c.  Grade ≥ 2 pneumonitis 
d.  Grade ≥ 3 hypo- or  hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and Immune-
Related Adverse Event Guidance Document.”  This document provides guidance regarding 
identification, evaluation and management of ECIs and irAEs.  Additional ECIs are identified in 
this guidance document and also need to be reported to the Sponsor within 24 hours and to Merck 
Global Safety within 2 working days of the event.   
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be evaluated 
and subjects should be asked for signs and symptoms suggestive of an immune-related event.  
Subjects who develop an ECI thought to be immune-related should have additional testing to rule 
out other etiologic causes.  If lab results or symptoms indicate a possible immune-related ECI, then 
additional testing should be performed to rule out other etiologic causes.  If no other cause is found, 
then it is assumed to be immune-related.  

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ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related 
to the Merck’s product, must be reported within 24 hours to the Sponsor and to Merck Global 
Safety within 2 working days. 
7.2.3.3 Responsibility of Participating Sites 
Participating sites are responsible for reporting all SAEs to their local IRB per local guideline.  
Participating sites are responsible for reporting all SAEs and Events of Clinical Interest to OHSU 
via fax or email within 24 hours of becoming aware of the event. Please see section 7.2.3.1 and 
7.2.3.2. 
Responsibility of OHSU 
The OHSU research staff is responsible for submitting all SAEs/UPs to the OHSU IRB.  
The OHSU research staff is responsible for submitting all SAEs and Events of Clinical Interest to 
Merck Global Safety. 
The OHSU PI is responsible for informing all participating sites about all SAEs.  
 
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 9  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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); 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) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the 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 the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the 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 the 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 the 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 Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the 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) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the 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 a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not reasonable 
OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 

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7.2.5 Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
8.0 STATISTICAL ANALYSIS PLAN 
This is a single-arm phase II clinical trial to examine the efficacy of pembrolizumab in men with 
mCRPC who initially responded to single-agent enzalutamide but who are currently experiencing 
a PSA progression. 
8.1 Primary and Secondary Endpoints 
Primary endpoint: PSA response, defined by a PSA decrease of at least 50% confirmed by a second 
measurement at least 3 weeks later. 
Secondary endpoints: 
• % change in PSA 
• Immunological parameters, including leukocytes, lymphocytes (CD8+, CD4+, and B 
cells), and macrophages in prostate tissue at diagnosis (if original biopsy is available) and 
pre-treatment.  
• Immunohistochemisty for PD-1, PD-L1 and PD-L2 in prostate tissue at diagnosis (if 
original biopsy is available) and pre-treatment 
• Circulating tumor cells (CTCs) (binary variable)  
• Changes in T cell numbers, activation, and phenotype as measured in PBMC at diagnosis 
and throughout therapy, including T effector/memory panel (CD45, CD3, CD8, CCR7, 
CD45RA,CD45RO, CD69, CD44, CD62L), T regulatory panel (CD45, CD3, CD4, FoxP3, 
CD25, CD127, CD69, CD44), T help panel (CD45, CD3, CD4, CD45RA, CD45RO, 
CD69, CD44, CD62L), and cytokine propensity of the above T cell subsets (IFN-γ, IL-2, 
IL-4, IL-12, IL-13, IL-10, IL-18, TNF-α, TGF-β, IL-17)  
• Systemic inflammatory markers: Serum IL-8, IL-6, IL-1, TNF and TGF-beta 
• Objective disease response by radiographs 
• Overall survival 
• PSA progression free survival where the definition of progression will be PSA progression 
per Prostate Cancer Working Group 2 criteria. If there is a decline from baseline, 
progression is an increase in PSA that is 25% and 2 ng/ml above the nadir, which is 
confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend) 

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• DNA mutations. 
8.2 Statistical Analysis Plan 
Descriptive statistical analysis will be conducted for all primary and secondary endpoints, for all 
patients, and for subgroups (abiraterone versus no prior abiraterone and sipuleucel-T versus no 
prior sipuleucel-T). The proportion estimate will be reported with 95% confidence interval, and 
the continuous variables will be summarized using nmissing, mean, std, median, min, and max. 
Safety and adverse events will be presented in a tabular form. 
One-sample binomial test will be used to assess whether the proportion of PSA response (PSA 
decrease of at least 50%) is significantly greater than 0.05. Univariable logistic regression analysis 
will be conducted to assess the association between immunological parameters and PSA response 
responses. Scale  
in logit will be assessed for all continuous parameters that are identified to 
be significantly associated with PSA response. Our hypothesis is that Microsatellite instability and 
PD-L1 expression together with other immunological parameters are potential predictors for PSA 
response. As the incidence of MSI and the presence of PD-L1 expression are relatively small 
(under 10% for MSI), we propose to enroll  30 additional subjects to this study to help find 1) 
whether MSI and PD-L1 expression are likely predictors for PSA response and 2) whether any 
other immunological parameters independently or jointly predicts the PSA response. Multivariable 
logistic regression model will be fitted to identify the potential predictors. Stepwise variable 
selection will be used to find the final model.  Random forest will also be used as a parallel method 
for building the predictive model. The area under the Receiver Operating Characteristic (ROC) 
curve will be computed for the discrimination ability of the predictive model. 10-fold cross 
validation will be performed to assess the validation of the proposed model. Due to the limited 
sample size, we will not have a separate testing set to validate the predictive model. Therefore, all 
findings are exploratory and need to be validated.  Kaplan-Meier curve will be plotted to illustrate 
the PSA progression free survival for all, and for subgroups (abiraterone versus no prior 
abiraterone and sipuleucel-T versus no prior sipuleucel-T). 
8.3 Sample Size Computation 
Patients with PSA progression on treatment are extremely unlikely to have a PSA response without 
a change in therapy. If 25% of subjects treated with pembrolizumab upon progression with 
enzalutamide have a PSA response, this therapy would be worthy of further study. Using a null 
hypothesis of 5% and alternate hypothesis of 25%, 25 evaluable patients are needed with 90% 
power and a one-sided alpha of 0.05. To account for potential drop-out, we will enroll 28 subjects.  
We propose to add 30 additional subjects to this study (for a total of 58) to better evaluate the 
association between PSA responses and candidate risk factors (MSI and PD-L1 expression with 
other immunological parameters), and to build a prognostic model. The proposed sample size will 
achieve 80% power to detect AUC of 0.85 against AUC of 0.6 using two-sided z test at 5% 
significance level.  We understand that it is not guaranteed that a predictive model with good 
predictive ability can be constructed, because both MSI and PD-L1 expressions are relatively rare. 
However, the collected data and analysis will be clinically valuable to help us determine whether 
a future larger study is worthy. . In the initial study, we did biopsies on any subject that had a 

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metastatic lesion that could be biopsied, but subjects were not required to have a lesion that could 
be biopsied. We are doing biopsies on all 30 additional patients along with the tests we did on 
earlier participants. 
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 10. 
Table 10  Product Descriptions 
Product Name & Potency 
Dosage Form 
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 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee 
are not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from 
Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining 
at the conclusion of the trial.  

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Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines and 
procedures, and provided that appropriate records of disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Patient confidentiality will be protected by keeping all hard copies in a locked file cabinet or in a 
locked room, on a protected floor that only allows access to those with the appropriate badge. Any 
information stored on a computer will be behind the OHSU firewall. HIPAA procedures will also 
be followed. 
10.2 Compliance with Financial Disclosure Requirements 
Funds given to investigators will be reported via the Sunshine Act by Merck. 
10.3 Compliance with Law, Audit and Debarment 
This trial will be conducted in compliance with all applicable institutional, local, and federal 
regulations.  This includes auditing by appropriate regulatory authorities if necessary. 
 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible 
for determining whether the trial and its results are subject to the requirements for submission to 
the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.     
10.5 Quality Management System 
OHSU Knight Cancer Institute, through the auditing function of the Knight Clinical Trials 
Office, is responsible for ensuring that all member investigators and affiliate investigators 
conduct clinical research studies in compliance with local IRB standards, FDA regulations and 
NIH policies and in accordance with the Data and Safety Monitoring Plan policies and 
procedures http://ozone.ohsu.edu/cancer/sharedres/kctoresdocs.cfm  
Locally initiated studies will be audited by OHSU Knight CI Auditor.  Newly approved studies 
may be audited anytime after enrollment has been initiated.  Each OHSU Knight approved 
treatment protocol will be audited on an annual basis in accordance with the Knight Data and 
Safety Monitoring Plan.  

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It is the responsibility of each participating site’s principal investigator to ensure that the study is 
conducted in compliance with local IRB standards, FDA regulations, and NIH policies. It is also 
the responsibility of each site’s principal investigator to ensure that quality assurance audits at 
their site are conducted according to their institution’s policies and procedures.  The quality 
assurance audit process provides assurance that reported data accurately reflects the data in the 
primary subject record. 
 
10.6 Data Management 
The Sponsor will be responsible for developing data collection tools such as Case Report Forms 
(CRF), Study Management Tools, and a database if appropriate.  Data required to meet the 
objectives of this protocol will be collected via CRF and transmitted in a secure fashion.  A Study-
Specific Data Monitoring Plan (SsDMP) will be developed as a separate document for both the 
Lead Site and any participating Sub-sites.  Risk based monitoring will be utilized, with remote 
monitoring of source documentation and protocol compliance. At the discretion of the Sponsor, 
monitoring or auditing in addition to that outlined in the SsDMP may be conducted. 
10.7 
Inclusion of Women, Children and Minorities 
No OHSU Knight Cancer Institute study will focus on any particular racial or ethnic subset. No 
subject will be excluded from the study on the basis of racial or ethnic origin. Male and minority 
volunteers will be recruited for this study from the general population and 100% men will be 
studied.  
The racial and ethnic composition of the study should represent that of the state of Oregon (see 
Table 11). If the prevalence of the disease being studied is consistent across race, ethnicity and 
gender, then these figures can be used to calculate projected enrollments in Table 12. If the 
disease being studied does not affect both genders or all races and ethnicities equally (e.g., 
cervical cancer only affects women and Black males are more likely than White males to have 
prostate cancer), then this information should be taken into account when calculating the 
projected enrollment. The OHSU General Clinical Research Center has links to various sources 
of statistics on their webpage at www.ohsu.edu/gcrc. If a different source is used in calculating 
projected enrollments, that source should be cited below Table 2. 
Table 11: Population Demographics - Oregon (%)              
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 
 
11.7 
Not Hispanic or Latino 
 
 
88.3 

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Source:   U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
 
Table 12: Projected Accrual for the Present Study  
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
0 
2 
0 
 
Not Hispanic or Latino 
0 
26 
0 
 
Unknown 
0 
0 
0 
 
Ethnic Category: Total of all subjects* 
0 
28 
0 
28* 
Racial Category 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Ethnic Category: Total of all subjects* 
 
 
100* 
Racial Category 
 
American Indian or Alaskan Native 
 
 
1.4 
Asian 
 
 
3.7 
Black or African American 
 
 
1.8 
Native Hawaiian or other Pacific Islander 
 
 
0.3 
White 
 
 
83.6 
More than one race 
 
 
3.8 
Unknown/Other 
 
 
5.3 
Racial Category: Total of all subjects* 
 
 
100* 
TOTALS 
50.4 
49.6 
100* 

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Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
American Indian or Alaskan Native 
0 
0-1 
0 
 
Asian 
0 
0-1 
0 
 
Black or African American 
0 
0-1 
0 
 
Native Hawaiian or other Pacific Islander 
0 
0-1 
0 
 
White 
0 
26 
0 
 
More than one race 
0 
0-1 
0 
 
Unknown 
0 
0-2 
0 
 
Racial Category: Total of all subjects* 
0 
28 
0 
28* 
Source:   Adapted from U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
This protocol does not include children for the following reason: Prostate cancer does not affect 
children under the age of 18.  
 
 

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11.0 LIST OF REFERENCES 
1. 
Disis ML. Immune regulation of cancer. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2010;28(29):4531-8. Epub 2010/06/03. 
2. 
Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nature medicine. 
2002;8(8):793-800. Epub 2002/07/02. 
3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature reviews Immunology. 
2002;2(2):116-26. Epub 2002/03/26. 
4. 
Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. 
J Immunol. 2003;170(3):1257-66. Epub 2003/01/23. 
5. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunological reviews. 2010;236:219-42. Epub 2010/07/20. 
6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 is 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with 
renal cell carcinoma. Clinical cancer research : an official journal of the American Association for 
Cancer Research. 2007;13(6):1757-61. Epub 2007/03/17. 
7. 
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer metastasis reviews. 2007;26(3-4):373-400. Epub 2007/08/25. 
8. 
Usubutun A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in renal 
cell carcinoma. Journal of experimental & clinical cancer research : CR. 1998;17(1):77-81. Epub 
1998/07/01. 
9. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund LT. Prognostic 
effect of epithelial and stromal lymphocyte infiltration in non-small cell lung cancer. Clinical 
cancer research : an official journal of the American Association for Cancer Research. 
2008;14(16):5220-7. Epub 2008/08/14. 
10. 
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon F, et al. Tumor 
infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC 
immunology. 2010;11:19. Epub 2010/04/14. 
11. 
Diez M, Pollan M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer research. 
1998;18(1B):689-94. Epub 1998/05/16. 
12. 
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict clinical 
outcome. Science. 2006;313(5795):1960-4. Epub 2006/09/30. 
13. 
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. International journal of clinical oncology. 2010;15(6):544-51. Epub 2010/10/07. 
14. 
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival 
of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell 
infiltration after interleukin-2 immunotherapy. Report of a case. Tumori. 2008;94(3):426-30. Epub 
2008/08/19. 
15. 
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. Journal 
of cutaneous pathology. 2010;37 Suppl 1:48-53. Epub 2010/05/28. 

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16. 
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. The lancet oncology. 
2009;10(9):840-1. Epub 2009/09/01. 
17. 
Hillen F, Baeten CI, van de Winkel A, Creytens D, van der Schaft DW, Winnepenninckx 
V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in 
primary cutaneous melanoma. Cancer immunology, immunotherapy : CII. 2008;57(1):97-106. 
Epub 2007/07/03. 
18. 
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. British journal of cancer. 
2008;99(10):1704-11. Epub 2008/10/23. 
19. 
Leffers N, Gooden MJ, de Jong RA, Hoogeboom BN, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of 
advanced stage ovarian cancer. Cancer immunology, immunotherapy : CII. 2009;58(3):449-59. 
Epub 2008/09/16. 
20. 
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice. The Journal of experimental medicine. 
2000;191(5):891-8. Epub 2000/03/08. 
21. 
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory 
T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis 
in renal cell carcinoma. BJU international. 2011;107(9):1500-6. Epub 2010/08/26. 
22. 
Stevenson R, Ford D, Zarkar AM, Glaholm J, Porfiri E, Tew A, et al. The sequential use 
of abiraterone and enzalutamide (MDV3100) in castrate resistant prostate cancer patients: 
Experience from Birmingham, United Kingdom. Journal of clinical oncology : official journal of 
the American Society of Clinical Oncology. 2013;31(suppl). 
23. 
Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, Tannahill C, et al. Distinct 
transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its 
splice variants in castration-resistant prostate cancer. Cancer research. 2012;72(14):3457-62. Epub 
2012/06/20. 
24. 
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T 
immunotherapy for castration-resistant prostate cancer. The New England journal of medicine. 
2010;363(5):411-22. Epub 2010/09/08. 
25. 
Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus 
prednisone or mitoxantrone plus prednisone for advanced prostate cancer. The New England 
journal of medicine. 2004;351(15):1502-12. Epub 2004/10/08. 
26. 
Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jr., Jones JA, Taplin ME, et al. Docetaxel 
and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate 
cancer. The New England journal of medicine. 2004;351(15):1513-20. Epub 2004/10/08. 
27. 
Graff JN, Drake CG, Beer TM. Complete biochemical (prostate-specific antigen) response 
to sipuleucel-T with enzalutamide in castration-resistant prostate cancer: a case report with 
implications for future research. Urology. 2013;81(2):381-3. Epub 2013/02/05. 
28. 
Jochems C, Tucker JA, Tsang KY, Madan RA, Dahut WL, Liewehr DJ, et al. A 
combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer 
patients: immune correlates. Cancer immunology, immunotherapy : CII. 2014;63(4):407-18. Epub 
2014/02/12. 

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29. 
DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte 
complexity predicts breast cancer survival and functionally regulates response to chemotherapy. 
Cancer discovery. 2011;1(1):54-67. Epub 2011/11/01. 
30. 
Erdag G, Schaefer JT, Smolkin ME, Deacon DH, Shea SM, Dengel LT, et al. Immunotype 
and immunohistologic characteristics of tumor-infiltrating immune cells are associated with 
clinical outcome in metastatic melanoma. Cancer research. 2012;72(5):1070-80. Epub 2012/01/24. 
31. 
Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and 
end points of clinical trials for patients with progressive prostate cancer and castrate levels of 
testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of 
clinical oncology : official journal of the American Society of Clinical Oncology. 
2008;26(7):1148-59. Epub 2008/03/04. 
32. 
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma VM. Prognostic value of 
tumour-infiltrating lymphocytes (TILs) in colorectal cancer. The Journal of pathology. 
1997;182(3):318-24. Epub 1997/07/01. 
33. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. Epub 2008/12/23. 

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12.0 APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
12.2 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) 
12.3 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for Evaluating 
Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either CT 
or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
 
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, 

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J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
 
 
 

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12.4 Correlative Work –Contact study sponsor  for information regarding collection, 
processing, and shipping of blood and tissue. 
12.5 Biopsy of Metastatic Lesion 
Due to the nature of metastatic prostate cancer, most biopsies will be from bone. This biopsy is 
being done for the correlative endpoints (see section 4.2.3.2). Bone biopsies present unique 
challenges with respect to the collection and processing. However, regardless of collection 
technique, rapid freezing of the biopsy material is critical to subsequent success. As part of the 
trial, we will provide kits to each site enrolling patients so as to facilitate a standardized 
collection of tissue.  
 
Patients are positioned by radiology and conscious sedation may be administered to improve 
patient comfort. This is based on the judgment of the interventional radiologist and may be 
restricted in some centers due to the availability of supportive services.  
 
During the image-guided biopsy procedure we recommend the following general rules when 
choosing a metastatic site and a specific location within the metastatic tumor for biopsy:  
 
1)  
If the patient has bone only disease, the pelvis is the preferred site for biopsy.  
2)  
Any biopsy kit capable of obtaining core biopsies from bone is acceptable. The 
Bonopty Coaxial biopsy system with eccentric drill 
(http://www.vasocare.co.kr/product04-
5.html).http://www.vasocare.co.kr/product04-5.html) is a recommended system. 
Internal diameter is 1.3mm. This is the smallest for collection of usable material.  
3)  
In the bone, extremely blastic lesions seldom yield usable material. Yields are 
greater if biopsies are performed in marrow of abnormal signal intensity directly 
adjacent to blastic lesions. Often, we pass the needle tangential to the blastic 
lesion in the marrow space for our most successful collections.  
4)  
In soft tissue, do not biopsy from regions of metastatic lesions that appear necrotic 
on CT or MRI due to extremely poor yield.  
5)  
It is important that excessive compressive force is not required or used to expel 
the biopsy from the biopsy needle. This obscures cellular morphology. If it is 
difficult to expel the biopsy from the core needle, alternative biopsy kits should be 
used.  
 
 
Please follow the directions below when processing the biopsy material:  
 
Required Materials  
 
Included in Kit:  
• Disposable cryo-molds 15x15x5mm  
• Sakura Tissue-Tek OCT compound  
• Metal plate or tray  

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• Sarstedt black permanent marker  
• Tissue-Tek Mega-Cassettes  
• Styrofoam cooler  
• Container of neutral buffered formalin (2 provided, keep extra, an additional vial will be 
included with the new box)  

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*Keep all remaining materials after procedure is completed for use on future biopsies unless 
otherwise noted  
 
Not Included (should be available on site)  
• Dry Ice (pellet form, smaller pellet size works best)  
• Syringe needle (core manipulation; ≤19g)  
• Forceps (fine toothed)  
 
Protocol for Biopsies  
1. Prepare a cold working surface by filling the supplied styrofoam cooler container roughly half 
full of dry ice. Shake the container to form a fairly even layer.  
2. Place the metal sheet or tray into the cooler and allow it to cool below -10°C. Temperatures 
below this point will freeze OCT compound quickly, facilitating the block formation. Having a 
flat metallic surface is also important.  
 
3. Prior to heading to the collection, place several cryomolds on the cold metal surface allowing 
them to cool down prior to the biopsy.  
 
4. Label 5 tissue cassettes, then place on dry ice to pre-chill before use during the procedure.  
 
5. Take the cooler setup to the location of the biopsy and be sure to have easy access to it during 
the procedure. Be sure to take the formalin vial in the zip-lock bag as well.  
 
6. Once the radiologist says a core is about ready, fill one of the cryomold trays roughly half-full 
of OCT so that the compound is partially frozen by the time the core is added. The OCT 
compound will appear opaque as it solidifies.  
 
7. Transfer a core to the partially solidified OCT layer in the cryomold. The best method of 
tissue transfer from the biopsy needle to the pallet will depend on the type of needle used. The 
core biopsy can be directly placed into the cryomold of OCT, but care must be taken to ensure 
the core is lying as close to flat as possible as it freezes. Bonopty and other hollow core needles 
will yield a cylindrical core that is ejected via a plunger needle. The pressure created by the 
plunger directly onto the core can unpredictably eject the core from the needle. If the core cannot 
be placed directly on the OCT, it can be ejected onto a gauze pad and transferred immediately 
onto the OCT so as to minimize time for RNA degradation and protein de-phosphorylation. This 
helps to maintain needle sterility and allows for more careful manipulation of the core away from 
the sterile procedure cart. Manipulation of the core from gauze pad to cryomold is done with a 
syringe needle.  
 
8. Positioning of the core is very important. Be sure to place the core flat down on the center of 
the OCT layer. The tissue can freeze on contact if the OCT layer has solidified, thus preventing 
manipulation once the tissue is on the OCT surface. Adding the core to OCT prior to 
solidification is ideal since the tissue and OCT will then freeze at the same time, resulting in 
better sectioning later. Layers frozen in different stages tend to cause separation during 
sectioning. 

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9. Immediately cover the core with OCT, working in a slow circular motion around the core such 
that OCT fills in the sides, then surrounds the top. Contact of the liquid OCT with the tissue core 
is important to preserve the tissue and facilitate in cryo sectioning later.  
 
10. Once the OCT becomes opaque in each cryomold, the tissue block is ready to be transferred 
to the labeled cold cassette.  
 
11. In addition to collecting fresh-frozen biopsy cores, 2 core must be collected for paraffin 
embedding. This core should be placed in the container of neutral buffered formalin. Close the 
jar tightly, and return to the zip-lock bag.  
 
12. Package the biopsies into the provided insulated box. The cold cryo cassettes should be 
placed in dry ice in the insulated section of the box, and the formalin vial contained within the 
zip-lock bag should be placed outside of the insulated region of the box. The appropriate spot for 
the formalin vial will be labeled.  
 
13. Include with the shipment, the sample shipment log that should include comments regarding 
core quality (long cylindrical core, bone shards, mostly blood clot, etc), the quantity of cores and 
any irregularities in the freezing process. The technician performing the collection should be sure 
to note their unique patient ID, the biopsy date, and the time of the procedure as well.  
 
14. Prior to any shipments, the study coordinator and designated laboratory staff at OHSU must 
be notified. Notification should come in the form of email at least 2 – 3 days or, if possible, a 
week prior to an anticipated shipment. The email should consist of the date of scheduled biopsy, 
unique patient ID, participating site name and site contact; this should be sent to Specimen 
Manager. 
 
15. Mail by Express Overnight delivery to the address specified on the provided shipping labels. 
Unless special arrangements are made, do not ship on Fridays, Saturdays, or Sundays. 

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12.6 Event of Clinical Interest and Immune-Related Adverse Event Guidance Document 
 
 
 
 
 
 
 
 
 
PEMBROLIZUMAB PROGRAM 
(MK-3475) 
 
 
 
EVENT OF CLINICAL INTEREST 
GUIDANCE DOCUMENT 
 
Version 5.0 

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REVISION HISTORY LOG 
 
Version 
Effective 
Date* 
Revision 
Author 
Action 
1 
08-Aug-2012 
Kevin Gergich 
Initial Release of guidance document for MK-3475 
2 
07-June-2013 
Marty Huber, 
Kevin Gergich, 
Holly Brown 
Revised title, formerly was “MK-3475 Immune-Related 
Adverse Event Identification, Evaluation and Management 
Guidance Document for Investigators” 
Revised the format of irAE Guidance document, including 
layout, font, sectioning, etc. for consistency with Sponsor 
Events of Clinical Interest guidance documents. 
Modified Categories for irAEs: 
– 
Replaced GI with Colitis category. 
– 
Removed Neurologic category. 
– 
Added Renal category. 
Removed detail in the irAE Guidance document that can 
be located in the Investigator’s Brochure for MK-3475. 
Removed details regarding non-MK-3475 compounds. 
Added ECI reporting guidelines. 
Included a Table Events of Clinical Interest: Immune- 
Related Adverse Events that includes the key terms. 
– 
Also placed a pull-out quick-review sheet in the 
Appendix. 
Updated background, diagnosis and course of treatment 
details for irAEs. 

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3 
10-Sep-2014 
Marty Huber, 
Kevin Gergich, 
Holly Brown 
Renamed the document: “Pembrolizumab Program (MK- 
3475) - Events of Clinical Interest Guidance Document”. 
Introduced generic name: pembrolizumab (MK-3475) and 
inserted throughout the document. 
Updated Overview – Section 1 
- Clarified the scope of the document and the reporting 
window for ECIs 
- Updated Table 1 with medDRA Preferred Terms for 
adverse events to correspond with reporting of terms to 
clinical database, rearranged the order, and updated the 
reporting criteria. 
- Updated the dose modification/discontinuation section to 
clarify discontinuation and hold terminology. 
Updated Section 2 – ECI Reporting Guidelines 

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– Clarified that ECIs must be reported to Merck within 24 
hours regardless of attribution to study treatment or 
etiology. 
Updated Section 3 
– For All Sections, removed the Course of Action for 
Grade 1 events. 
- Section 3.1 Pneumonitis 
– 
Moved Pneumonitis to beginning of ECI Section 
– 
Updated management guidelines for Grade 2 and 
Grade 3-4 events 
- 
Section 3.2 Colitis: 
- 
Updated AE terms and ECI criteria, updated 
course of action language for clarity 
- Section 3.3 Endocrine: 
- 
Updated ECI criteria and updated course of action 
language for clarity. 
- 
Added subsections for hypophysitis, 
hyperthyroidism and hypothyroidism to clarify 
management guidelines. 
- Section 3.4 Hematologic: 
- 
New section added. 
- Section 3.5: Hepatic: 
- 
Updated terms and added additional guidance for 
reporting of DILI ECI; updated course of action 
for clarity 
- Section 3.6 Neurologic: 
- 
New section added. 
- Section 3.7 Ocular: 
- 
Changed the name of this section from Eye to 
Ocular 
- 
Added the term “iritis”, updated ECI guidance, 
and updated course of action language for clarity 
- Section 3.8 Renal: 
- 
Updated section for clarity. 
- Section 3.9 Skin: 
- 
Updated list of terms and added terms for 
reporting of other skin ECIs; added section 3.9.1: 
Immediate Evaluation for Potential Skin ECIs 
- Section 3.10 Other: 
- 
Updated list of terms for clarity; revised course of 
action for clarity. 

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- Section 3.11 Infusion Reactions: 
- 
New section added. 
- Section 3.12: Follow-up to Resolution: 
- 
New section added. 
- Section 4: 
- 
References updated. 
- Section 5: 
- 
ECI table updated for consistency with Table 1. 
- Section 6: Appendix 2 – Past Medical History Related to 
Dermatologic Event:  New section added. 
- Section 7: Appendix 3 – Presentation of the 
Dermatologic Event:  New section added. 
- Section 8: Appendix 4 – Focused Skin Examination: 
New section added. 
4 
04-Dec-2014 
Scot Ebbinghaus, 
Oswaldo Bracco, 
Holly Brown, 
Kevin Gergich 
- Table 1 
- 
Updated Endocrine (reported as ECI if ≥ Grade 3 
or ≥ Grade 2 and resulting in dose modification or 
use of systemic steroids to treat the AE) Section 
to include: 
- 
Hyperglycemia, if ≥Grade 3 and associated 
with ketosis or metabolic acidosis (DKA) 
- 
Created new section in Table 1 – Endocrine 
(reported as ECI) and added: 
- 
Type 1 diabetes mellitus (if new onset) 
- 
Hepatic: Clarified Transaminase elevations as: 
- 
Transaminase elevations (ALT and/or AST) 
- Section 3.2 Colitis 
- Updated the duration of diarrhea requirments 
under the Course of Action for Grade 2 and Grade 
3 
- Section 3.3 Endocrine 
- 
Clarified Course of Action for hyperthyroidism 
and hypothyroidism 
- 
Added Course of Action section for Type 1 
diabetes mellitus (if new onset) and ≥ Grade 3 
hyperglycemia 
- Section 5 
- 
Updated Reference Table in Appendix 1 
5 
18-Dec-2014 
Holly Brown 
Kevin Gergich 
- Section 3.3 Endocrine 
- 
Updated the Course of Action for Hypophysitis 
- 
Merged Grades 2-4 into one course of action 
*Ensure that you are using the most current version of this document. 

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TABLE OF CONTENTS 
1. OVERVIEW 
 
2. ECI REPORTING GUIDELINES 
 
3. ECI CATEGORIES AND TERMS 
 
3.1 Pneumonitis 
 
3.2 Colitis 
 
3.3 Endocrine 
 
3.4 Hematologic 
 
3.5 Hepatic 
 
3.6 Neurologic 
 
3.7 Ocular 
 
3.8 Renal 
 
3.9 Skin 
 
3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
3.10 Other 
 
3.11 Infusion Reactions 
 
3.12 Follow-up to Resolution 
 
4. REFERENCES 
 
5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
 
6. APPENDIX 2 – Past Medical History Related to Dermatologic Event 
 
7. APPENDIX 3 – Presentation of the Dermatologic Event 
 
8. APPENDIX 4 – Focused Skin Examination 
 

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1. OVERVIEW 
 
The purpose of this document is to provide study sites with guidance on the identification and 
management of Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) program. 
 
Based on the literature review [1-11], and consideration of mechanism of action of pembrolizumab, 
potential immune-related adverse events (irAEs) are the primary Event of Clinical Interest (ECI). 
Immune-related AEs are adverse events associated with the treatment of patients with immunotherapy 
treatments that appear to be associated with the immune therapy’s mechanism of action. Based on these 
potential irAEs, the sponsor has defined a list of specific adverse event terms (ECIs) that are 
selected adverse experiences that must be reported to Merck within 24 hours from the time the 
Investigator/physician is aware of such an occurrence, regardless of whether or not the 
investigator/physician considers the event to be related to study drug(s). In addition, these ECIs require 
additional detailed information to be collected and recorded. ECIs may be identified through 
spontaneous patient report and / or upon review of subject data. Table 1 provides the list of terms 
and reporting requirements for AEs that must be reported as ECIs for MK-3475 protocols. Of note, 
the requirement for reporting of ECIs applies to all arms, including comparators, of MK- 3475 clinical 
trials 
 
Given that our current list of events of clinical interest is not comprehensive for all potential immune-
related events, it is possible that AEs other than those listed in this document may be observed in 
patients receiving pembrolizumab. Therefore any Grade 3 or higher event that the investigator/physician 
considers to be immune-related should be reported as an ECI regardless of whether the specific event 
term is in Table 1 and reported to Merck within 24 hours from the time the Investigator/physician is 
aware of such an occurrence. Adverse events that are both an SAE and an ECI should be reported one 
time as an SAE only, however the event must be appropriately identified as an ECI and recorded. 

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Table 1: Events of Clinical Interest 
 Pneumonitis (reported as ECI if ≥ Grade 2)  
 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
 Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)  
 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat the 
AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
 Endocrine (reported as ECI)  
 
Type 1 diabetes mellitus (if new onset) 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation 
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
 Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE)  
 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or AST) 
 Infusion Reactions (reported as ECI for any grade)  
 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 Neurologic (reported as ECI for any grade)  
 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)  
 
Uveitis 
Iritis 
 Renal (reported as ECI if ≥ Grade 2)  
 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
 Skin (reported as ECI for any grade)  
 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 Skin (reported as ECI if ≥ Grade 3)  
 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Any rash considered clinically significant in the physician’s judgment 
 Other (reported as ECI for any grade)  
 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 

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Each of the events above is described within this guidance document, along with site requirements 
for reporting these events to the Sponsor. The information collected should be entered into the narrative 
field(s) of the Adverse Event module in the database (please note, if narrative entry into the database is 
not available, please use the narrative text box on the 1727/AER Form). If additional Medical History 
or Concomitant Medications are reported, the Medical History and Concomitant Medication modules 
in the database must be updated. 
 
In addition, the guidelines include recommendations on the management of these ECIs. These 
guidelines are intended to be applied when the physician determines the events to be related to 
pembrolizumab. Note: if after the evaluation the event is determined not to be related, the physician is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment guidance 
(below). Therefore, these recommendations should be seen as guidelines and the treating physician 
should exercise individual clinical judgment based on the patient. For any question of dose 
modification or other treatment options, the specific language in the protocol should be followed. Any 
questions pertaining to the collection of this information or management of ECIs should be directed to 
your local Sponsor contact. 
 
Dose Modification/Discontinuation 
 
The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab for 
each immune related adverse event. Of note, when the guidance states to “discontinue” pembrolizumab 
this is the permanent discontinuation of treatment with pembrolizumab. “Hold” means to stop 
treating with pembrolizumab but resumption of treatment may be considered assuming the patient 
meets the criteria for resumption of treatment. 
 
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck within 24 
hours regardless of attribution to study treatment. The AEs listed in this document and any event that 
meets the ECI criteria (as noted) in Table 1 or in the respective protocol (event term and Grade) must 
be reported regardless of physician-determined causality with study medication and whether or not 
considered immune-related by the 
physician (unless otherwise specified).  Physicians/study 
coordinators/designated site personnel are required to record these experiences as ECIs on the Adverse 
Experience electronic Case Report Forms (eCRFs) (or on paper) and to provide supplemental 
information (such as medical history, concomitant medications, investigations, etc.) about the event. 
 
– 
Please refer to the Data Entry Guidelines (DEGs) for your protocol. 
– 
Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug 
Induced Liver Injury (DILI). 
 
3. ECI CATEGORIES AND TERMS 
This section describes the ECI categories and outlines subject management guidelines when an 
ECI is reported. 

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3.1 Pneumonitis 
 
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
 
– 
Pneumonitis 
– 
Interstitial lung disease 
– 
Acute interstitial pneumonitis 
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a 
cardiology consultation should be considered. 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral 
infection.  It is important that patients with a suspected diagnosis of pneumonitis be managed as 
per the guidance below until treatment-related pneumonitis is excluded. Treatment of both a 
potential infectious etiology and pneumonitis in parallel may be warranted. Management of the 
treatment of suspected pneumonitis with steroid treatment should not be delayed for a 
therapeutic trial of antibiotics. If an alternative diagnosis is established, the patient does not 
require management as below; however the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
– 
Consider ID consult 
– 
Conduct an in person evaluation approximately twice per week 
– 
Consider frequent Chest X-ray as part of monitoring 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient 
develops a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab. 
– 
Hospitalize patient 
– 
Bronchoscopy with biopsy and/or BAL is recommended. 
– 
Immediately treat with intravenous steroids (methylprednisolone 125 mg IV). When symptoms 
improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once per 
day or dexamethasone 4 mg every 4 hours) taper should be started and continued over no less 
than 4 weeks. 
– 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 

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48 to 72 hours, treat with additional anti-inflammatory measures. Discontinue additional 
anti-inflammatory measures upon symptom relief and initiate a prolonged steroid taper over 
45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of steroids 
starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and 
administer additional anti-inflammatory measures, as needed 
– 
Add prophylactic antibiotics for opportunistic infections. 

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3.2 Colitis 
 
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic 
steroids to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of the 
event: 
 
– 
Colitis 
– 
Colitis microscopic 
– 
Enterocolitis 
– 
Enterocolitis hemorrhagic 
– 
Gastrointestinal perforation 
– 
Intestinal obstruction 
– 
Necrotizing colitis 
– 
Diarrhea 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic 
infection, viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by 
examination for stool leukocytes, stool cultures, a Clostridium difficile titer and endoscopy. However 
the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, 
abdominal pain, mucus or blood in stool): 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Symptomatic Treatment 
– 
For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or 
mucus, 
o Consider GI consultation and endoscopy to confirm or rule out colitis 
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
– 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Rule out bowel perforation. Imaging with plain films or CT can be useful. 
– 
Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. 
– 
Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral 
steroids (prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours) 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. Taper over 6 to 8 weeks in patients with diffuse and severe 
ulceration and/or bleeding. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 

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prednisone or equivalent per day within 12 weeks. 
– 
If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 
48 to 72 hours, consider treatment with additional anti-inflammatory measures as described in 
the literature [5]. Discontinue additional anti-inflammatory measures upon symptom relief 
and initiate a prolonged steroid taper over 45 to 60 days. If symptoms worsen during steroid 
reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 mg followed 
by a more prolonged taper and administer additional anti-inflammatory measures as needed. 

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Grade 4 events: 
– 
Report as ECI 
– 
Permanently discontinue pembrolizumab. 
– 
Manage as per Grade 3. 

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3.3 Endocrine 
 
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require holding/discontinuation/ 
modification of pembrolizumab dosing, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Adrenal insufficiency 
– 
Hyperthyroidism 
– 
Hypophysitis 
– 
Hypopituitarism 
– 
Hypothyroidism 
– 
Thyroid disorder 
– 
Thyroiditis 
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or 
infection. However the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
 
Grade 2-4 events: 
– 
Report as ECI if appropriate 
– 
Hold pembrolizumab 
– 
Rule out infection and sepsis with appropriate cultures and imaging. 
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– 
Pituitary  gland imaging should be considered (MRIs  with gadolinium and selective  cuts  
of the pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– 
Treat with prednisone 40 mg p.o. or equivalent per day. 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. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
Hypophysitis  with  clinically  significant  adrenal  insufficiency  and  hypotension,  
dehydration,  and electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes 
adrenal crisis. 
– 
Consultation with an endocrinologist may be considered. 

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Hyperthyroidism and Hypothyroidism 
 
Thyroid disorders can occur at any time during treatment and within three months of the last 
dose of pembrolizumab. 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. 
 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
– 
Report as ECI if appropriate (see Table 1) 
– 
Monitor thyroid function or other hormonal level tests and serum chemistries more 
frequently until returned to baseline values. 
– 
Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
– 
Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is 
instituted. 
– 
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. 
– 
Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
– 
Report as ECI 
– 
Hold pembrolizumab. 
– 
Rule out infection and sepsis with appropriate cultures and imaging. 
– 
Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day. 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. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab. 
– 
Manage as per Grade 3 

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Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 hours 
of the event: 
 
– 
Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA) 
– 
Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA). 
 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening of pre- 
existing diabetes associated with laboratorial evidence of beta cell failure. All attempts should be made 
to rule out other causes such as type 2 diabetes mellitus (T2DM), T2DM decompensation, steroid-
induced diabetes, physiologic stress-induced diabetes, or poorly controlled pre-existing diabetes (either 
T1DM or T2DM), but events meeting the above criteria should be reported as ECIs regardless of 
etiology. The patients may present with hyperglycemia (abrupt onset or abrupt decompensation) with 
clinical evidence of diabetic ketoacidosis or laboratory evidence of insulin deficiency, such as 
ketonuria, laboratory evidence of metabolic acidosis, or low or undetected c-peptide. 
 
 
Course of Action 
 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
- 
Report as ECI if appropriate (see Table 1) 
- 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia 
associated with evidence of beta cell failure,  and resume pembrolizumab when  patients 
are  clinically and metabolically stable. 
- 
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. 
- 
Consultation with an Endocrinologist is recommended. 
- 
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin 
may be obtained. 

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3.4 Hematologic 
 
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic 
steroids to treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of 
the event: 
 
– 
Autoimmune hemolytic anemia 
– 
Aplastic anemia 
– 
Disseminated Intravascular Coagulation (DIC) 
– 
Haemolytic Uraemic Syndrome (HUS) 
– 
Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
– 
Thrombotic Thrombocytopenic Purpura (TTP) 
– 
Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection. 
Relevant diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone 
marrow biopsy or Coomb’s test, etc., should be considered to confirm the diagnosis. However the 
AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab 
– 
Prednisone 1-2 mg/kg daily may be indicated 
– 
Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone 
or equivalent per day within 12 weeks. 
 
Grade 3 events: 
– 
Report as ECI 
– 
Hematology consultation. 
– 
Hold pembrolizumab  Discontinuation should be considered as per specific protocol guidance. 
– 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Report as ECI 
– 
Hematology consultation 
– 
Discontinue pembrolizumab for all solid tumor indications; refer to protocol for 
hematologic malignancies. 
– 
Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as 
appropriate 

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3.5 Hepatic 
 
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification or 
use of systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Autoimmune hepatitis 
– 
Hepatitis 
– 
Transaminase elevations 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other 
hepatic diseases. However the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient 
meets the laboratory criteria for potential DILI defined as: 
• 
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is 
greater than or equal to three times (3X) the upper limit of normal (ULN) and 
• 
An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and 
• 
At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
• 
As a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI event. 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 
3.0 times ULN. 
– 
Monitor liver function tests more frequently until returned to baseline values (consider weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT 
returns to grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic 
antibiotics for opportunistic infections, and resume pembrolizumab per protocol 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
– 
Permanently discontinue pembrolizumab for patients with liver metastasis who begin 
treatment with Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative 
to baseline and lasts ≥1 week. 
 
Grade 3 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 
times ULN. 
– 
Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if 
necessary 
– 
Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms 

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improve to Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or 
prednisone at 1 to 2 mg/kg should be started and continued over no less than 4 weeks. 
– 
If serum transaminase levels do not decrease 48 hours after initiation of systemic 
steroids, oral mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not 
recommended due to its potential for hepatotoxicity. 

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– 
Several courses of steroid tapering may be necessary as symptoms may worsen when the 
steroid dose is decreased. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 4 events: 
– 
Report as ECI 
– 
Permanently discontinue pembrolizumab 
– 
Manage patient as per Grade 3 above 

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3.6 Neurologic 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
 
– 
Autoimmune neuropathy 
– 
Demyelinating polyneuropathy 
– 
Guillain-Barre syndrome 
– 
Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other medications or 
infectious causes. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Report as ECI 
– 
Moderate (Grade 2) – consider withholding pembrolizumab. 
– 
Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
– 
Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
– 
Report as ECI 
– 
Discontinue pembrolizumab 
– 
Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day. If condition worsens consider IVIG or other immunosuppressive therapies as per local 
guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. 

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3.7 Ocular 
 
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic 
steroids to treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of 
the event: 
 
– 
Uveitis 
– 
Iritis 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other 
ocular disease (e.g. glaucoma or cataracts). However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events: 
– 
Evaluation by an ophthalmologist is strongly recommended. 
– 
Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– 
Discontinue  pembrolizumab  as  per  protocol  if  symptoms  persist  despite  treatment  with  
topical immunosuppressive therapy. 
 
Grade 3 events: 
– 
Evaluation by an ophthalmologist is strongly recommended 
– 
Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. 
– 
Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day. 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
 
Grade 4 events: 
– 
Evaluation by an ophthalmologist is strongly recommended 
– 
Permanently discontinue pembrolizumab. 
– 
Treat with corticosteroids as per Grade 3 above 

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3.8 Renal 
 
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
 
– 
Nephritis 
– 
Nephritis autoimmune 
– 
Renal failure 
– 
Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to 
treat the AE. 
 
 
All attempts should be made to rule out other causes such as obstructive uropathy, progression of 
disease, or injury due to other chemotherapy agents. A renal consultation is recommended. However 
the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
 
Grade 2 events: 
– 
Hold pembrolizumab 
– 
Treatment with prednisone 1-2 mg/kg p.o. daily. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
– 
Discontinue pembrolizumab 
– 
Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent 
once per day. 
 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. 

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3.9 Skin 
 
Rash and Pruritus 
 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Pruritus 
– 
Rash 
– 
Rash generalized 
– 
Rash maculo-papular 
– 
In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the 
physician's judgment, should be treated as an ECI. Clinical significance is left to the physician 
to determine, and could possibly include rashes such as the following: 
o rash with a duration >2 weeks; OR 
o rash that is >10% body surface area; OR 
o rash that causes significant discomfort not relieved by topical medication or temporary 
cessation of study drug. 
 
Other Skin ECIs 
The following AEs should always be reported as ECIs, regardless of grade, and should be reported 
to the Sponsor within 24 hours of the event: 
– 
Dermatitis exfoliative 
– 
Erythema multiforme 
– 
Steven’s Johnson syndrome 
– 
Toxic epidermal necrolysis 
Please note, the AE should be reported regardless of etiology. 
Course of Action 
Grade 2 events: 
– 
Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., 
betamethasone 0.1% cream or hydrocortisone 1%) or urea-containing creams in combination 
with oral anti-pruritics (e.g., diphenhydramine HCl or hydroxyzine HCl). 
– 
Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
– 
Hold pembrolizumab. 
– 
Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– 
Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent 
once per day or dexamethasone 4 mg four times orally daily. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
 

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Grade 4 events: 
– 
Permanently discontinue pembrolizumab. 
– 
Dermatology consultation and consideration of biopsy and clinical dermatology photograph. 
– 
Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 

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3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
A. Photographs: 
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as 
possible. Obtain appropriate consent for subject photographs if a consent form addendum is 
required by your IRB/ERC. 
– 
Take digital photographs of: 
o the head (to assess mucosal or eye involvement), 
o the trunk and extremities, and 
o a close-up of the skin lesion/rash. 
 
– 
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed 
marker of distance. 
– 
The time/date stamp should be set in the 'ON' position for documentation purposes. 
– 
Photographs should be stored with the subject’s study records. 
– 
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will 
provide guidance to the site, if needed. 
 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past Medical 
History Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported 
(e.g., drug allergy) should be entered into the Medical History eCRF. 
 
C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the questions in 
Appendix 3 (Presentation of the Dermatologic Event) as a guide. This information should be summarized 
and entered in narrative format in the AE eCRF. Please use the available free-text fields, such as Signs 
and Symptoms. Note pertinent negatives where applicable to reflect that the information was collected. 
Any treatments administered should be entered on the Concomitant Medication eCRF. 
 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital 
Signs eCRF. Perform standard laboratory tests (CBC with manual differential and serum chemistry 
panel, including LFTs). 
 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin Examination) 
as a guide. Information should be summarized and entered on the Adverse Experience eCRF as 
part of the narrative. 
 
F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
– 
For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
– 
For clinically significant rash, the subject should be seen within 3-5 days. 
 
The dermatologist should submit a biopsy sample to a certified dermatopathology laboratory or to a 
pathologist experienced in reviewing skin specimens. 

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The site should provide the dermatologist with all relevant case history, including copies of clinical 
photographs and laboratory test results. 

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3.10 Other 
 
The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
– 
Myocarditis 
– 
Pericarditis 
– 
Pancreatitis 
– 
Any additional Grade 3 or higher event which the physician considers to be immune related 
 
All  attempts  should  be made  to  rule  out  other  causes. 
Therapeutic specialists should be 
consulted as appropriate. However the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
– 
Withhold pembrolizumab. 
– 
Systemic corticosteroids may be indicated. 
– 
Consider biopsy for confirmation of diagnosis. 
– 
If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
– 
Hold pembrolizumab 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day. 
– 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
– 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may 
be restarted and the dose modified as specified in the protocol 
 
Grade 4 events: 
– 
Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per 
day. 
– 
Discontinue pembrolizumab 

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3.11 Infusion Reactions 
 
The following AE terms, regardless of grade, are considered ECIs and should be reported to the 
Sponsor within 24 hours of the event: 
– 
Allergic reaction 
– 
Anaphylaxis 
– 
Cytokine release syndrome 
– 
Serum sickness 
– 
Infusion reactions 
– 
Infusion-like reactions 
 
Please note, the AE should be reported regardless of etiology. 
 
 
Course of Action 
 
Refer to infusion reaction table in the protocol and below.

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Infusion Reactions 
 
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. 
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 
with: 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
p.o. (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. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 

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3.12 Follow-up to Resolution 
 
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with 
information regarding duration and clinical course of the event. Information obtained from the 
consulting specialist, including diagnosis, should be recorded in the appropriate AE fields. Free-text 
fields should be used to record narrative information: 
 
– 
Clinical course of the event 
– 
Course of treatment 
– 
Evidence supporting recovery 
– 
Follow-up to the clinical course 
 
Any treatments administered for the event should also be entered in the Concomitant Medication eCRF. 

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4. REFERENCES 
 
1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews 
Cancer 2012; 12:252-264. 
 
2. Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint 
Protein Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 1092-9118/10/1-
10. 
 
3. Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events and 
Kinetics 
of 
Response 
With 
Ipilimumab. 
J 
Clin 
Oncol 
30. 
2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
 
4. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with 
Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
 
5. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, Activity, 
and Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454. 
 
6. Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 
Antibody in Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465. 
 
7. Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase II 
study 
comparing the tolerability and efficacy of ipilimumab administered with or without 
prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 
15:5591-5598, 2009. 
 
8. Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the 
Management of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
 
9. Phan GQ, Weber JS, and Sondak VK. CTLA-4 Blockade with Monoclonal Antibodies in Patients 
with Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–3021. 
 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse 
reactions— 
YERVOY 
Risk 
Evaluation 
and 
Mitigation 
Strategy 
(REMS). 
http://www.yervoy.com/hcp/rems.aspx 
 
11. Bristol-Myers Squibb: YERVOY (ipilimumab) prescribing information revised March 2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf 

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5. APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
 
 Pneumonitis (reported as ECI if ≥ Grade 2)  
 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
 Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)  
 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
Endocrine (reported as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
 Endocrine (reported as ECI)  
 
Type 1 diabetes mellitus (if new onset) 
Hematologic (reported as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura 
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation 
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
 Hepatic (reported as ECI if ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE)  
 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or AST) 
 Infusion Reactions (reported as ECI for any grade)  
 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
 Neurologic (reported as ECI for any grade)  
 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 Ocular (report as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE)  
 
Uveitis 
Iritis 
 Renal (reported as ECI if ≥ Grade 2)  
 
Nephritis 
Nephritis autoimmune 
Renal Failure 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
 Skin (reported as ECI for any grade)  
 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 Skin (reported as ECI if ≥ Grade 3)  
 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
Any rash considered clinically significant in the physician’s judgment 
 Other (reported as ECI for any grade)  
 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 

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6. APPENDIX 2 – Past Medical History Related to Dermatologic 
Event 
 
Past Medical History: 
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the 
Medical History eCRF. 
 
1. Does the subject have any allergies? □ Yes □ No If 
yes, please obtain the following information: 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No 
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
 
 
 
 
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.?  
□ Yes □ No 
 
Describe the agent and type of allergic response:   
 
 
 
 
c. Any allergy to food? □ Yes □ No 
 
Describe the food and type of allergic response:   
 
 
 
 
d. Any allergy to animals, insects? □ Yes □ No 
 
Describe the allergen and type of allergic response:   
 
 
 
 
e. Any other allergy? □ Yes □ No 
 
Describe the allergen and type of allergic response:   
 
 
 
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No 
If so what kind?   
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No 
 
If so what kind?   
 
 
4. Is the current finding similar to a past experience? □ Yes □ No 

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7. APPENDIX 3 – Presentation of the Dermatologic Event 
 
Presentation of the event: 
Collect information on clinical presentation and potential contributing factors. Key information should 
be summarized and entered on the Adverse Experience eCRF. Any treatments administered should be 
entered on the Concomitant Medication eCRF. 
 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
 
 
 
2. Has the subject contacted any known allergens? □ Yes □ No 
 
If so what kind?   
 
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, 
personal care product, poison ivy, etc.)? □ Yes □ No 
 
If so what kind?   
 
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)? 
□ Yes □ No 
 
If so what kind?   
 
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
 
If so what kind?   
 
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
 
If so what kind?   
 
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes 
□ No If so who and what?   
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. 
Molluscum Contagiosum)? □ Yes □ No 

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9. Has the subject had recent sun exposure? □ Yes □ No 
 
 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
 
If so what kind?   
 
 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No 
iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? □ Yes □ No 
 
If so what kind?   
 
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
 
List medication(s) and dose(s):   
 
 
 
 
13. Is the rash pruritic (itchy)? □ Yes □ No 

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8. APPENDIX 4 – Focused Skin Examination 
 
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience eCRF. 
 
Primary Skin Lesions Description 
Color:   
 
 
General description: 
 
 
 
 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
 
 
 
 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
 
 
 
 
 
Any associated signs on physical examination?