A Multicenter Phase II Study to Evaluate the Safety and Efficacy of Pembrolizumab (MK-3475) in Patients With Advanced Uveal Melanoma
Phase: PHASE2
Conditions: Stage IIIA Uveal Melanoma, Stage IIIB Uveal Melanoma, Stage IIIC Uveal Melanoma, Stage IV Uveal Melanoma
Sponsor: Vanderbilt-Ingram Cancer Center

Product:  MK-3475  
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Protocol date: August 30, 2016 
 
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TITLE: MEL1486 - A Multicenter Phase II Study to Evaluate the Safety and Efficacy of 
Pembrolizumab (MK-3475) in Patients with Advanced Uveal Melanoma 
 
IND NUMBER: 124395 
 
EudraCT NUMBER: 
 
 
 
Principal Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 TRIAL SUMMARY…………………………………………………………………7 
1.1 Summary of Rationale…………………………………………………………..7 
1.2 Summary of Trial Design……………………………………………………….8 
2.0 TRIAL DESIGN……………………………………………………………………..9 
2.1 Trial Diagram…………………………………………………………………....9 
2.2 Trial Design……………………………………………………………………..9 
2.2.1 Summary of Trial Design…………………………………………….9 
2.2.2 Dosage/Dosage Form, Route, and Dose Regimen…………………10 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) …………………………………………….11 
3.1 Primary Objective(s) & Hypothesis(es)…………………………………………11 
3.2 Secondary Objective(s) & Hypothesis(es)………………………………………11 
3.3 Exploratory Objectives………………………………………………………….11 
4.0 BACKGROUND AND RATIONALE………………………………………………11 
4.1 Background………………………………………………………………………11 
4.1.1 Pharmaceutical and Therapeutic Background………………………..11 
4.1.2 Preclinical and Clinical Trial Data……………………………………13 
4.1.2.1 Clinical Efficacy……………………………………………...14 
4.1.2.1.1 Clinical Efficacy in Melanoma……………………14 
4.1.2.1.2 Clinical Efficacy in NSCLC……………………..14 
4.1.2.2 Clinical Safety………………………………………………..15 
4.2 Rationale………………………………………………………………………..15 
4.2.1 Rationale for the Trial and Selected Subject Population…………….15 
4.2.2 Rationale for Dose Selection/Regimen/Modification………………..16 
4.2.3 Rationale for Endpoints……………………………………………..18 
4.2.3.1 Efficacy Endpoints………………………………………….18 
4.2.3.2 Biomarker Research…………………………………………18 
5.0 METHODOLOGY………………………………………………………………….19  
5.1 Entry Criteria……………………………………………………………………19 
5.1.1 Diagnosis/Condition for Entry into the Trial………………….……..19 
5.1.2 Enrollment Procedures………………………………………………19 
5.1.3 Subject Inclusion Criteria……………………………………………19 
5.1.4 Subject Exclusion Criteria……………………………………………20 
5.2 Trial Treatments…………………………………………………………………22 
5.2.1 Dose Selection/Modification…………………………………………22 
5.2.1.1 Dose Selection………………………………………………...22 
5.2.1.2 Dose Modification…………………………………………….23  
5.2.2 Timing of Dose Administration………………………………………24 
5.2.3 Duration of Therapy………………………………………………….24 
5.2.4 Trial Blinding/Masking………………………………………………25 

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5.3 Randomization or Treatment Allocation……………………………………….25 
5.4 Stratification……………………………………………………………………25 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited)………………25 
5.5.1 Acceptable Concomitant Medications………………………………26 
5.5.2 Prohibited Concomitant Medications……………………………….26 
5.6 Rescue Medications & Supportive Care……………………………………….27 
5.6.1 Supportive Care Guidelines…………………………………………27 
5.6.1.1 Supportive Care Guidelines for Events of Clinical Interest and 
Immune-related Adverse Events (irAEs)…………………..29 
5.6.1.2 Supportive Care Guidelines for Pneumonitis………………30 
5.7 Diet/Activity/Other Considerations……………………………………………30 
5.7.1 Diet…………………………………………………………………30 
5.7.2 Contraception………………………………………………………31 
5.7.3 Use in Pregnancy……………………………………………………31 
5.7.4 Use in Nursing Women…………………………………………….31 
5.8 Subject Withdrawal/Discontinuation Criteria…………………………………32 
5.9 Subject Replacement Strategy………………………………………………..33 
5.10 
Clinical Criteria for Early Trial Termination…………………………..33 
6.0 TRIAL FLOW CHART………………………………..………………………….34 
6.1 Study Flow Chart………………………………..……………………………34 
6.2 Second Course Treatment Flow Chart……………………………………….38 
7.0 TRIAL PROCEDURES………………………………..…………………………41 
7.1 Trial Procedures………………………………..…………………………….41 
7.1.1 Administrative Procedures………………………………………..41 
7.1.1.1 Informed Consent…………………………………………41 
7.1.1.2 Inclusion/Exclusion Criteria……………………………….42 
7.1.1.3 Medical History……………………………………………42 
7.1.1.4 Prior and Concomitant Medications Review……………...42 
7.1.1.4.1 Prior Medications………………………………42 
7.1.1.4.2 Concomitant Medications………………………43 
7.1.1.5 Disease Details and Treatments……………………………43 
7.1.1.5.1 Disease Details…………………………………43 
7.1.1.5.2 Prior Treatment Details………………………..43 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status………43 
7.1.1.6 Trial Compliance (Medication/Diet/Activity/Other)………43 
7.1.2 Clinical Procedures/Assessments…………………………………44 
7.1.2.1 Adverse Event (AE) Monitoring…………………………44 
7.1.2.2 Physical and Ophthalmologic Exam…………………………44 
7.1.2.3 Vital Signs……………………………………………….45 

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7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance 
Scale…………………………………………………………45 
7.1.2.5 Eligibility for Second Course of Treatment…………………45 
7.1.2.6 Tumor Tissue and Blood Collection………………………..45 
7.1.3 Tumor Imaging And Assessment of Disease……………………….46 
7.1.3.1 Assessment Guidelines……………………………………..47 
7.1.3.2 Measurable and Non-measurable Disease…………………48 
7.1.3.3 Response Criteria…………………………………………..49 
7.1.3.3.1 Immune Related RECIST criteria overview..…49 
7.1.3.3.2 Target Lesions…...…………………………….49 
7.1.3.3.3 Non-target ……………………………………..50 
7.1.3.3.4 New Lesions…………………………………...51 
7.1.3.3.5 Evaluation of Overall Response……………….51 
7.1.4 Laboratory Procedures/Assessments………………………………52 
7.1.4.1 Laboratory Safety Evaluations (Hematology, Chemistry)…52 
7.1.5 Other Procedures…………………………………………………..54 
7.1.5.1 Withdrawal/Discontinuation………………………………54 
7.1.5.2 Blinding/Unblinding………………………………………54 
7.1.6 Study Visits………………………………………………………...54 
7.1.6.1 Screening Period…………………………………………..55 
7.1.6.2 Treatment Period………………………………………….55 
7.1.6.2.1 Initial Treatment Period……………………….55 
7.1.6.2.2 Subsequent Treatment Period…………………55 
7.1.6.3 Post-Treatment Visits………………………………………56 
7.1.6.4 Follow-up Visits……………………………………………56 
7.1.6.4.1 Survival Follow-up…………………………….56 
7.2 Assessing and Recording Adverse Events……………………………………57 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor and to Merck………………………………………….57 
7.2.2 Reporting of Pregnancy / Lactation to the Sponsor and to Merck…58 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck…58 
7.2.3.1 Serious Adverse Events……………………………………58 
7.2.3.2 Events of Clinical Interest…………………………………59 
7.2.4 Evaluating Adverse Events…………………………………………60 
7.2.5 Sponsor Responsibility for Reporting Adverse Events…………….63 
7.2.6 Adverse Event Collection………………………………………….63 
8.0 Biomarkers and Correlative Studies……………………………………………….63 
8.1 Biomarker Study Overview…………………………………………………...63 
8.2 Correlative Studies……………………………………………………………64 

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8.2.1 Tumor Biopsies…………………………………………………….64 
8.2.2 PD-L1 Staining Assay……………………………………………...64 
8.2.3 Blood Collection…………………………………………………..65 
9.0 STATISTICAL ANALYSIS PLAN……………………………………………..65 
9.1 Statistical Analysis Plan Summary………………………………………….65 
9.2 Statistical Analysis Plan…………………………………………………….66 
9.2.1 Sample Size Assumptions………………………………………..66 
9.2.2 Efficacy Endpoints………………………………………………66 
9.2.2.1 Primary Endpoint………………………………………..66 
9.2.2.2 Secondary Endpoints……………………………………67 
9.2.2.2.1 Progression Free Survival……………………67 
9.2.2.2.2 Overall Survival……………………………...67 
9.2.2.2.3 Duration of Response………………………...67 
9.2.2.3 Subgroup Analyses………………………………………67 
9.2.3 Safety Endpoints………………………………………………...68 
9.2.4 Baseline Characteristics and Other Analyses……………………68 
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES….…………………………………………………………………….68 
10.1 
Investigational Product ………………………………………………68 
10.2 
Packaging and Labeling Information…………………………………68 
10.3 
Clinical Supplies Disclosure………………………………………….69 
10.4 
Storage and Handling Requirements…………………………………69 
10.5 
Returns and Reconciliation……………………………………………69 
11.0 
ADMINISTRATIVE AND REGULATORY DETAILS……………………69 
11.1 
Confidentiality……………………………………………………….69 
11.1.1 Confidentiality of Data……………………………………………69 
11.1.2 Confidentiality of Subject/Patient Records……………………….70 
11.1.3 Confidentiality of Investigator Information………………………70 
11.2 
Compliance with Financial Disclosure Requirements………………..70 
11.3 
Compliance with Law, Audit and Debarment………………………...71 
11.4 
Compliance with Trial Registration and Results Posting Requirements….71 
11.5 
Quality Management System………………………………………….71 
11.6 
Data Management……………………………………………………..72 
11.6.1 Compliance with Information Program On Clinical Trials For Serious Or 
Life Threatening Conditions………………………………………72 
11.6.2 Publications……………………………………………………….72   
11.7 
Trial Monitoring………………………………………………………73 
11.7.1 Trial Compliance………………………………………………….73 
11.7.2 Changes in Protocol and Informed Consent Document…………..73 

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11.7.3 Protocol Deviations……………………………………………….73 
11.7.4 Study Documentation……………………………………………74 
11.7.5 Monitoring and Quality Assurance………………………………74 
11.7.6 Data Verification…………………………………………………74 
11.7.7 Records Retention………………………………………………..74 
12.0 
LIST OF REFERENCES…………………………………………………….76 
13.0 
APPENDICES 
13.1 
ECOG Performance Status……………………………………………80 
13.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)…81 
13.3 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for   
           Evaluating Response in Solid Tumors………………………………..82 
13.4 
Pembrolizumab Event of Clinical Interest Guidance Document…...…83 
13.4.1 Overview………………………………………………..…………84 
13.4.2 ECI Reporting Guidelines………………………………………....86 
13.4.3 ECI Categories and Terms…………………………………...……86 
13.4.3.1 
Pneumonitis…………………………………………....87  
13.4.3.2 
Colitis………………………………………………….88 
  
13.4.3.3 
Endocrine……………………………………………...89 
 
13.4.3.4 
Hematologic…………………………………………...91 
 
13.4.3.5 
Hepatic………………………………………………...92 
 
13.4.3.6 
Neurologic…………………………………………….93 
 
13.4.3.7 
Ocular………………………………………………....94 
 
13.4.3.8 
Renal………………………………………………….94  
13.4.3.9 
Skin……………………………………………………95 
13.4.3.9.1 Immediate Evaluation for Potential Skin ECIs…96 
13.4.3.10 Other……………………………………………..……97 
13.4.3.11 Infusion Reactions……………………………….……98 
13.4.3.12 Follow-up to Resolution………………………………100 
13.4.4 Pembrolizumab Program References……………………………..101 
13.4.5 Supplementary Appendix 1 – Events of Clinical Interest (ECI) – 
Reference Table…………………………………………………..102 
13.4.6 Supplementary Appendix 2 – Past Medical History Related to 
Dermatologic Event……………………………………………....103 
13.4.7 Supplementary Appendix 3 – Presentation of the Dermatologic 
Event……………………………………………………………...104 
13.4.8 Supplementary Appendix 4 – Focused Skin Examination
 
………………………………………………………………..106 
13.5 
PD1 Eye Exam Source Document……………………………………107 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab (MK-3475) in uveal melanoma 
Trial Phase 
II 
Clinical Indication 
Advanced uveal melanoma 
Trial Type 
Two-stage, single arm trial 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups  
Pembrolizumab 200mg every 3 weeks 
Number of trial subjects 
10-29 
Maximum Duration of Therapy 24 months 
 
1.1 
SUMMARY OF RATIONALE 
The programmed cell death 1 (PD-1) pathway represents a major immune control switch 
which may be engaged by tumor cells to overcome active T-cell immune surveillance (1). 
The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in 
various tumors (2-5). High expression of PD-L1 on tumor cells (and to a lesser extent of PD-
L2) has been found to correlate with poor prognosis and survival in various cancer types, 
including renal cell carcinoma (RCC) (6), pancreatic carcinoma (7), and ovarian carcinoma 
(8). Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion and 
function in patients with malignant melanoma (9, 10). Preclinical in vitro and in vivo 
experiments have shown that PD-1 and/or PD-L1 blockade using monoclonal antibodies 
(mAb) enhances tumor-cell specific T-cell activation, cytokine production, anti-tumor 
effector mechanisms, and clearance of tumor cells by the immune system (7, 9, 11-15).  
Recent data with nivolumab (BMS-936558), an IgG4 antibody against PD-1, have validated 
PD-1 as an attractive target for clinical therapeutic intervention (16). In a recent report of the 
clinical trial data with nivolumab a total of 296 patients with advanced melanoma, non-small 
cell lung cancer (NSCLC), castration-resistant prostate cancer, renal-cell carcinoma or 
colorectal cancer were treated at a dose of 0.1, 0.3, 1, 3, or 10 mg/kg every 2 weeks. Among 
236 evaluable patients, cumulative response rates (all doses and defined by the Response 
Evaluation Criteria in Solid Tumors [RECIST] were 18% among patients with NSCLC, 28% 
among patients with melanoma, and 27% among patients with renal-cell cancer. Responses 
were reported to be durable: 20 of 31 responses lasted 1 year or more in patients with 1 year 
or more of follow-up. Grade 3 or 4 adverse events were observed in 49% of patients, while 
14% of patients had treatment related Grade 3 or 4 adverse events. Drug-related adverse 
events of special interest (e.g., those with potential immune-related causes) occurred in 41% 
of patients and included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis 
(16). 

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Pembrolizumab (MK-3475, previously known as SCH 900475) is a potent and highly-
selective humanized mAb of the IgG4/kappa isotype designed to directly block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab strongly 
enhances T lymphocyte immune responses in cultured blood cells from healthy human 
donors, cancer patients, and primates. In T-cell activation assays using human donor blood 
cells, the EC50 was in the range of 0.1 to 0.3 nM. Pembrolizumab also modulates the level of 
interleukin-2 (IL-2), tumor necrosis factor alpha (TNFα), interferon gamma (IFNγ), and other 
cytokines. The antibody potentiates existing immune responses only in the presence of 
antigen and does not nonspecifically activate T-cells (for details see the Pembrolizumab 
Investigator’s Brochure). 
Despite the recent advances in the treatment of melanoma patients, overall outlook for 
patients with metastatic disease remains dismal and the development of new effective therapy 
is still needed. Particularly, the outlook for uveal melanoma remains especially grim. Anti-
PD1 mAb nivolumab has reported a response rate of 28% in cutaneous melanoma patients 
(16). Pembrolizumab has shown a very promising early response rate of 42% in patients who 
have not received prior ipilimumab treatment, which is much higher than the 11 or 15% 
response rate observed in ipilimumab registration trials (17).  
Uveal melanoma is an uncommon cancer occurring in 3000 patients per year in the United 
States. At the onset of advanced/metastatic disease, however, this condition has an especially 
poor prognosis without clearly effective treatment options. Preclinical rationale for use of 
pembrolizumab in this population is strong. Uveal melanoma cell lines express PD-L1, which 
predicts for response to therapy in cutaneous melanoma and in NSCLC (18). Uveal 
melanomas are heavily infiltrated with leukocytes, including CD8+ T cells, potentially 
indicating functional exhaustion of the immune response (19-21). Finally, although responses 
occur less frequently than in cutaneous melanoma, objective responses have been reported 
with ipilimumab in uveal melanoma (22, 23). Taken together, the existing data support the 
evaluation of the safety and efficacy of pembrolizumab in patients with uveal MEL for whom 
additional treatment options are needed. 
1.2 
SUMMARY OF TRIAL DESIGN 
Patients will receive pembrolizumab at 200mg IV Q3W at a fixed dose. All patients with 
advanced uveal melanoma enrolled in the study will receive up to 24 months of 
pembrolizumab treatment until disease progression, unacceptable toxicity, the withdrawal of 
consent, confirmed complete response or they require another form of antineoplastic therapy 
as determined by the Investigator. In the event of a confirmed complete response (CR), it is 
at the discretion of the investigator to keep a patient on study treatment or to suspend study 
treatment based on the criteria outlined in section 5.2.3. Patients will continue to be 
monitored with scheduled disease assessments as described in the protocol (as if the patient 
were continuing on study treatment), and in the event of a disease recurrence, 
pembrolizumab may be resumed (Second Course treatment) upon disease recurrence in these 
patients. Second Course treatment with pembrolizumab may be given for up to 12 additional 
months. See Section 7.1.6.2 for details regarding second course treatment.  
 

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After receiving 24 months of treatment with pembrolizumab, patients with CR, PR or SD 
will no longer receive treatment with pembrolizumab and will complete the 30-Day Safety 
Follow Up visit and then proceed to the Post Treatment Follow up visits for up to an 
additional 48 months per the Flow Chart Section 6.1. At any point in the Post treatment 
follow up period, if a patient experiences disease progression they are eligible to receive the 
12 month Second Course Treatment with pembrolizumab. 
 
Patients who discontinue study treatment for reasons other than documented progression 
should continue to have CT imaging assessments per schedule as indicated in the Post-
Treatment Discontinuation Follow-up per Section 6.0 of the Flow Chart. Patients will enter 
the survival follow-up phase after confirmed disease progression is documented. 
 
2.0 TRIAL DESIGN 
2.1 
Trial Diagram 
 
 
 
Figure 1: Study schema 
2.2 
Trial Design 
2.2.1 Summary of Trial Design 
This is an open-label, two stage, single arm pivotal study of intravenous (IV) pembrolizumab 
in patients with advanced or metastatic uveal melanoma. The primary endpoint of the study 
will be objective response rate (ORR). Other endpoints include progression-free survival 
(PFS), overall survival (OS), response duration, safety, and correlation of response rate with 
biomarkers (GNAQ/GNA11 mutational status, PD-L1 expression). 
The study will enroll 10 patients in stage I of this two stage design; if one or more responses 
occur, an additional 19 patients will be enrolled. The sample size was designed to test 
whether pembrolizumab has a ≥20% response rate in uveal melanoma with a clinically 
uninteresting response rate of 5%. In addition, if ≥2 patients experience stable disease (SD) 
for >24 weeks, then the study may proceed to stage 2 if the sponsor and PIs are in agreement. 
The primary objective of the study is to evaluate the activity of pembrolizumab in terms of 
ORR. The overall type I error rate for this study is strictly controlled at 5% (two-sided) and 
the study has a power of 80%. The study is considered to be positive if at least 4 patients 
treated with pembrolizumab have an objective response (of 29 subjects enrolled). All patients 
receiving pembrolizumab will receive pembrolizumab as IV infusion at a dose of 200mg 
every 3 weeks. until disease progression, intolerable toxicity, confirmed complete response, 
Advanced uveal 
melanoma 
Study screening 
Pembrolizumab 200mg 
IV q3W until disease 
progression, intolerable 
side effects, or 2 years of 
therapy 

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withdrawal of consent, or they require another form of antineoplastic therapy as determined 
by the Investigator. 
We anticipate an accrual rate of 1 to 2 patients per month from 3 participating centers.   
After the baseline tumor evaluation, tumor assessment during the study will be performed by 
radiological scans every 6 weeks starting from Week 12 until Week 24. At the discretion of 
investigators, patients who remain on study after 24 weeks and are clinically stable may 
decrease imaging frequency to every 12 weeks in the following schedule:  
• First scheduled disease assessment: week 12 
• Disease assessments every 6 weeks from week 18-24 
• Disease assessments every 12 weeks from week 36-96 
Patients will be evaluated for tumor response and patient management by sites based on the 
Immune Related RECIST [irRECIST] criteria (Section 7.1.3.3) by the investigator with site 
radiology reading. Guidelines for irRECIST as described in section 7.1.3.3. On-study 
assessments by irRECIST take into account the observation that some patients with 
melanoma can have a transient tumor flare in the first few months after start of 
immunotherapy with subsequent disease response. Clinical decisions will be based on the 
interpretation of the investigator at the site treating the patient in real time using the 
irRECIST criteria.  
All patients must have at least one baseline measurable lesion by RECIST 1.1 definition on 
CT or MRI (as assessed by investigators) (24). The timing for tumor assessments should be 
based on the calendar and not adjusted for delays or variation in cycle starts.  
Patients will be monitored regularly for safety and efficacy throughout the study, as per 
Section 6.0, Study Flow Chart. Fresh tumor tissue or archived tumor tissue is required for 
biomarker analysis prior to randomization, then optional at specific timepoints during the 
study (see Sections 6.1). 
2.2.2 DOSAGE/DOSAGE FORM, ROUTE, AND DOSE REGIMEN 
All patients will receive pembrolizumab as an IV infusion at 200mg every 3 weeks for a total 
of 24 months or, until disease progression, intolerable toxicity, confirmed complete response, 
or withdrawal of the consent. Treatment must be administered within a window of (+/- 2 
days) of the scheduled infusion.  Patients who have a confirmed complete response by two 
scans ≥4 weeks apart and who have been on pembrolizumab treatment for at least 6 months 
may discontinue pembrolizumab treatment at the discretion of the investigator after receiving 
at least two doses beyond the initial determination of CR. Patients who stop study treatment 
in CR should continue to undergo disease evaluations with imaging studies as otherwise 
scheduled in the protocol, and in the event of disease recurrence, pembrolizumab may be 
resumed in these patients. 

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The second-course treatment is fully described in Sections 6.2 and 7.1.6.2.2, but in brief, 
patients should follow the same schedule of pembrolizumab treatment to which they were 
initially allocated and should be followed with study visits and disease assessments as if they 
were starting study therapy anew (first scheduled disease assessment at week 12 and then 
every 6 weeks until week 24). Patients who discontinue study therapy in the second course 
treatment phase for any reason (progression of disease, AEs, or any other reason) should 
have a post-study visit within 30 days and then undergo survival follow-up. 
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: To evaluate objective response rate (ORR) in patients with advanced 
uveal melanoma receiving pembrolizumab. 
Hypothesis:  Pembrolizumab has a response rate of 20% (and >5%) 
3.2 
Secondary Objective(s) & Hypothesis(es) 
(1) To evaluate progression-free survival (PFS) in patients with advanced uveal 
melanoma receiving pembrolizumab. 
(2) To evaluate safety, tolerability and adverse experience profile of pembrolizumab in 
uveal melanoma. 
(3) To evaluate overall survival (OS) in patients with advanced uveal melanoma 
receiving pembrolizumab. 
3.3 
Exploratory Objectives 
(1) To evaluate objective response rate (ORR; complete response + partial response)) in 
patients with advanced uveal melanoma receiving pembrolizumab as stratified by PD-
L1 expression and GNAQ/GNA11 mutation status. 
(2) To evaluate ORR in patients previously treated with ipilimumab or with MEK 
inhibitors.  
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 malignancies (25-29).  In particular, the presence of CD8+ T-cells and the ratio of 

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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, 
30).  The structure of murine PD-1 has been resolved (31).  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 (31-35).  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 (5, 36).  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 (37, 38).  Expression has also been shown during thymic development on 
CD4-CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells 
(39).  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 (1-5).  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 (5).  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) (9).  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 (MK-3475; previously known as SCH 900475) 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. Both 
pembrolizumab and MDX-1106 contain the S228P stabilizing mutation and have no 
antibody-dependent 
cell-mediated 
cytotoxicity 
(ADCC) 
or 
complement-dependent 
cytotoxicity (CDC) activity. Pembrolizumab strongly enhances T lymphocyte immune 

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responses in cultured blood cells from healthy human donors, cancer patients, and primates. 
In T- cell activation assays using human donor blood cells, the EC50 was in the range of 0.1 
to 0.3 nM. Pembrolizumab also modulates the level of interleukin-2 (IL-2), tumor necrosis 
factor alpha (TNFα), interferon gamma (IFNγ), and other cytokines. The antibody potentiates 
existing immune responses only in the presence of antigen and does not nonspecifically 
activate T- cells. A one-month repeat dose GLP-toxicity study with four months observation 
post dosing revealed no major safety findings. The no observed adverse event level 
(NOAEL) was ≥200 mg/kg. (For details on the pre-clinical data of pembrolizumab, see the 
IB). 
4.1.2 Preclinical and Clinical Trial D 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a mono-therapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo (7, 11, 12, 14, 15). In addition, the combination of 
gemcitabine and anti-PD-L1 mAb demonstrated synergy in the rejection of pancreatic mouse 
tumors (7). In-house experiments have confirmed the in vivo efficacy of PD-1 blockade as a 
mono-therapy as well as in combination with chemotherapy in syngeneic mouse tumor 
models (see the investigator’s brochure). 
Melanoma is the sixth most common malignancy in men and the seventh most common 
malignancy in women (40). The incidence of melanoma is increasing worldwide, with a 
growing fraction of patients with advanced disease for which prognosis remains poor. The 
median survival for patients with metastatic melanoma has traditionally been under 1 year; 
the 5-year survival rate of patients with visceral involvement has been under 10% (41). 
Treatment options for metastatic melanoma have been limited to chemotherapeutic agents 
such as dacarbazine and high-dose interleukin-2 immunotherapy in a small percentage of 
patients. In the past few years there has been steady progress in the development of targeted 
therapy and immunotherapy for metastatic melanoma. Vemurafenib, a BRAF inhibitor, was 
approved in 2011 for the treatment of patients with unresectable or metastatic melanoma with 
BRAFV600E mutation (42). Ipilimumab, an anti-CTLA4 monoclonal antibody, was also 
approved in 2011 for the treatment of patients with unresectable or metastatic melanoma 
(43). In spite of these newly approved therapies, overall outlook for patients with metastatic 
melanoma remains dismal and the development of new effective therapy is still needed. Of 
note, the recently developed therapeutics for cutaneous melanoma have largely not translated 
to benefits for patients with uveal melanoma; effective therapies for this cohort are urgently 
needed. 

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4.1.2.1 Clinical Efficacy 
4.1.2.1.1 Clinical Efficacy in Melanoma 
For more details, please see investigator’s brochure for pembrolizumab. In trial PN001, 
patients with non-uveal melanoma were treated with pembrolizumab. Preliminary analysis 
was stratified by whether patients had previously received ipilimumab. The overall response 
rate using IRO by RECIST v1.1 is very similar to the overall response rate using Investigator 
Assessment by irRC in the IPI-exposed melanoma patients, 24.9% and 27.1 % respectively 
(17). In the ipilimumab-naïve melanoma patients the overall response rate using an IRO 
assessment by RECIST was 38.7% (95% CI 31.3%, 46.5%). The response rates were similar 
in the 2 mg/kg Q3W (35.4%: 95% CI 23.9%, 48.2%) and 10 mg/kg Q3W (36.4%; 95% CI 
24.9%, 49.1%) dose schedules in sample sizes of 65 and 66 patients, respectively. A higher 
overall response rate was noted in the 10 mg/kg Q2W dose schedule (48.6%; 95% CI 31.9%, 
65.6%) in a smaller sample of 37 patients.  
 
The median PFS and the PFS rate at 24-Weeks based on IRO Assessment per RECIST across 
all doses were 17.9 weeks (95% CI 13.3 weeks, 24.0 weeks) and 41.7 %, respectively. The 
median PFS and the PFS rates at 24-Weeks are similar in the 2 mg/kg Q3W (median PFS 
22.1 weeks (95% CI 12.1 weeks, 31.0 weeks) and 43.7%) and 10 mg/kg Q3W (median PFS 
14.4 weeks (95% CI 12.1 weeks, 23.9 weeks) and 36.4%) dose schedules in samples of 89 
and 116 patients, respectively. A higher median PFS and PFS rate at 24-Weeks were noted in 
the 10 mg/kg Q2W dose schedule (median PFS not reached (95% CI 11.6 weeks, -) and 
66.7%) in a smaller sample of 16 patients. The median PFS and the PFS rate at 24-Weeks 
based on Investigator Assessment per irRC across all doses were 29.7 weeks (95% CI 23.6 
weeks, 54.0 weeks) and 54.7%, which are slightly higher than the rates using IRO per 
RECIST. 
4.1.2.1.2 Clinical Efficacy in NSCLC 
MK-3475 PN001 Part C enrolled 38 patients with NSCLC who experienced progression of 
cancer after initiation of their second line of systemic therapy to receive pembrolizumab 
monotherapy. The preliminary objective response rate (ORR) by investigator assessed irRC 
was 24% (95% CI 11%, 40%); by RECIST v1.1; the objective response rate was 21% (95% 
CI 9%, 39%). Preliminary median overall survival was 51 weeks (95% CI 14 weeks, -). 
Preliminary median progression free survival amongst responders has not yet been reached 
with a minimum of 62 weeks, with most patients remaining on treatment.  
Patients were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with MK-3475 to evaluate the tumors for expression of PD-L1, the presumptive predictive 
biomarker of MK-3475, using an immunohistochemistry assay. A modified H-score scoring 
system of PD-L1 expression was established for NSCLC by analyzing tumor specimens from 
resected NSCLC specimens. This scoring system was then applied to the samples from 
PN001 Part C. A receiver-operating characteristics curve was constructed from the data and 
the Youden Index identified from that analysis to help determine a preliminary cut point. 
Preliminary data suggest higher levels of PD-L1 expression are associated with increased 

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activity (ORR in patients with tumor PD-L1 expression above a preliminary cutoff was 67% 
(95% CI 30%, 93%)); additional data are required to define the optimal PD-L1 cut point. 
4.1.2.2 Clinical Safety 
Among all melanoma patients treated in study PN001, adverse events were reported in 400 
(97.3%) out of 411 patients. The most commonly reported treatment emergent AEs 
experieced in this population across the dose regimens are fatigue (43.6%), nausea (27.5%), 
cough (26.0%), pruritus (25.1%), diarrhea (24.1%) and rash (22.4%). There was not a 
significant difference in the most common terms reported across dose schedules. 
Among 135 melanoma patients with published efficacy and safety data from PN001, 
pneumonitis was observed in 4% of patients; none were grade 3-4 (17).  In contrast to 
ipilimumab, only one case of grade 3 diarrhea was observed which resolved with 
corticosteroids. Other grade 3-4 events included aminotransferase elevations (1%), renal 
failure (2%), and rash (2%). Eight percent developed hypothyroidism which was managed 
with thyroid replacement; one patient developed grade 2 adrenal insufficiency. Vitiligo 
occurred in 9% of patients. Other low-grade toxicities included fatigue, asthenia, myalgias, 
rash, headaches, and fevers. 
See section 5.6 for management of adverse events.  
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Uveal melanoma is the most common primary intraocular malignancy in adults, and arises 
from melanocytes within the choroid plexus of the eye (44). Melanomas of the ocular and 
adnexal structures comprise approximately 5% of all melanomas and are biologically and 
prognostically distinct from cutaneous melanoma (45).  In the United States, an estimated 
3000 patients are diagnosed with this disease each year. Although uveal melanoma is an 
uncommon disease, the lack of effective treatment options and poor prognosis makes this 
condition ideal for developing novel therapeutic strategies. Selumetinib, a selective MEK1/2 
inhibitor, demonstrated improved PFS compared to cytotoxic chemotherapy although median 
survival remained less than one year. Additionally, ipilimumab and chemotherapy may be 
used although outcomes remain poor. More effective therapies are urgently needed. 
In addition to the high response rate of pembrolizumab in non-uveal melanoma, other 
preclinical and clinical rationale suggests that anti-PD-1 therapy is a promising strategy in 
uveal melanoma. First, uveal melanoma is associated with an inflammatory phenotype. The 
majority of uveal melanoma have high levels of tumor infiltrating lymphocytes (TILs) 
present that co-occur with unfavorable prognostic markers (46). A wide array of leukocytes 
are present in the tumor microenvironment, including CD8+, CD4+, and regulatory T cells, 
natural killer cells, and macrophages, potentially indicating functional exhaustion of the 
antitumor immune response (19-21). This inflammatory infiltrate in the tumor 
microenvironment may be exploited with immune stimulation as an effective therapeutic 

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strategy in uveal melanoma. Second, uveal melanoma cell lines demonstrate PD-L1 
expression. In a group of metastasis cultures of uveal melanoma cell lines, nearly all lines 
demonstrated PD-L1 expression which was further augmented with interferon-γ stimulation 
(11). Although very few patients with uveal melanoma have been treated with anti-PD-1 
therapies or have been assessed for PD-L1 expression, this suggests that the PD-1/PD-L1 
axis may be a functionally relevant mechanism of immune evasion in uveal melanoma. 
Third, to evaluate the functional consequences of PD-1 blockade, uveal melanoma cell lines 
were grown in culture with CD3+ T cells (12).  In IFN-γ stimulated cell lines, the addition of 
anti-PD-1 caused a T cell activation and significant increase in IL-2 production by the CD3+ 
T cells. Additionally, T-cell activation was found to be promoted by RNA interference of 
PD-L1 in a co-cultured uveal melanoma cell line with CD3+ T cells (13). Fourth, early phase 
studies have suggested that PD-L1 expression correlates with response to anti-PD-1/PD-L1, 
even in cancers other than melanoma, lung cancer, and renal cell carcinoma. (16, 47, 48). 
Based on cell line experiments, at least a subset of uveal melanomas would be predicted to 
express PD-L1, potentially predicting benefit from pembrolizumab. Finally, ipilimumab has 
demonstrated benefit in patients with uveal melanoma. In a retrospective review 39 patients 
with metastatic uveal melanoma were treated with ipilimumab. ORR by IrRC was 5.4% with 
one complete response and one partial response. An additional 28% of patients demonstrated 
stable disease at 23 weeks demonstrating that immune checkpoint inhibition may be an 
effective therapeutic strategy in uveal melanoma (16). 
4.2.2 Rationale for Dose Selection/Regimen/Modification 
In the first-in-human study (PN001, refer to IB), 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). PK data analysis of pembrolizumab administered in Q2W 
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 Q2W and Q3W dosing schedules. As such, Phase I expansion cohorts of PN001 
enrolled patients at Q2W and Q3W dosing schedules. A recent interim analysis from PN001 
was conducted to inform the dose decision for this protocol. PN001 enrolled expansion 
cohorts with advanced melanoma that are naïve to ipilimumab or previously treated with 
ipilimumab and treated patients on three different dosing regimens of pembrolizumab: 2 
mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks. One of the key 
clinical findings from this analysis suggests that there are not major differences in the AE 
profile or overall objective response rate from pembrolizumab when given on an every 3 
week schedule at doses of 2 mg/kg or 10 mg/kg. In cohorts of patients who had follow-up of 
at least 6 months duration (n=46 ipi-naïve patients), the objective response rate was 36% on 
the Q3W schedules, based on independent central review of imaging studies (confirmed and 
unconfirmed responses) in the patients who had at least one measurable lesion at baseline. 
The treatment was well tolerated on the Q3W doses with few SAEs or AEs leading to 
discontinuation that were attributed to study treatment. 

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Another key clinical finding of this analysis was a suggestion that a more frequent schedule 
of pembrolizumab administration may lead to higher efficacy, but at the expense of more 
AEs. Patients who received pembrolizumab at a Q2W schedule, regardless of prior treatment 
with IPI (n=57) had an overall objective response rate of 56% based on independent central 
review of imaging studies (confirmed and unconfirmed responses) in patients who had at 
least one measurable lesion at baseline. In addition, 9 patients (17%) were reported to have 
achieved an (unconfirmed) complete remission. Furthermore, progression free survival for 
patients treated with 10 mg/kg given every 2 or every 3 weeks was evaluated, and showed an 
overall median PFS of 61 weeks for patients who received pembrolizumab on an every 2 
week schedule and 29 weeks for patients who received pembrolizumab on an every 3 week 
schedule (pooled ipi-naïve and ipi-treated cohorts). However, it is important to note that 
these were not randomized cohorts of patients which precludes drawing firm conclusions 
about the differences in response rate between the two doses. In addition, AEs were 
somewhat more frequent and more severe on the more frequent dosing schedule. For 
example, grade 3 or higher AEs were reported in 44% of patients receiving 10 mg/kg Q2W 
and 30% of patients receiving 10 mg/kg Q3W, SAEs were reported in 49% and 39% (Q2W 
and Q3W respectively), and AEs leading to treatment discontinuation attributed to study 
treatment were reported in 14% and 7% (Q2W and Q3W, respectively). Thus, while both 
pembrolizumab schedules are generally tolerable, there may be a higher frequency of 
clinically important AEs as well as a higher objective response rate when pembrolizumab is 
given every 2 weeks compared to every 3 weeks. 
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent MK-3475.  The dose escalation portion of this trial evaluated 
three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in 
subjects with advanced solid tumors.  All three dose levels were well tolerated and no dose-
limiting toxicities were observed.  This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 
3 mg/kg and 10 mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity.  Recent data from other clinical studies 
within the MK-3475 program has shown that a lower dose of MK-3475 and a less frequent 
schedule may be sufficient for target engagement and clinical activity [43].   
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 

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fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 
dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary endpoint for this study is ORR, with the hypothesis that the ORR will be 
approximately 20% (and >5%) in patients with uveal melanoma. This ORR was chosen in 
that currently no effective therapies are approved for uveal melanoma and therefore an ORR 
in the 20% range would be highly desirable clinically. In addition, for the immune therapies, 
including anti-PD-1, patients who experience objective responses often have durable benefit 
and superior PFS and OS. Particularly for a phase II trial, therefore, ORR is an appropriate 
primary endpoint.  
PFS and OS will also be assessed as secondary endpoints. These metrics are clearly clinically 
relevant although the study is not powered to assess these endpoints.  
4.2.3.2 Biomarker Research 
To assess whether common genetic and protein expression characteristics in uveal melanoma 
correlate with ORR, we will assess GNAQ/GNA11 mutation status on each patient per 
institutional protocol. We will furthermore evaluate PD-L1 expression status on archival or 
fresh tissue from all patients and correlate with ORR.  
This study will also investigate other molecular characteristics of uveal melanoma when 
treated with pembrolizumab. Analysis will focus on tumor and blood markers prior to 
therapy and early-on-treatment (at the time of the second dose).  
Strongly encouraged tumor biopsies may also be performed to allow for assessment of the 
pharmacodynamics effects of pembrolizumab treatment. Such biopsies may be performed 
within 21 days of the start of treatment, and on Cycle 2 Day 1 (+/- 3 days). Assessment of 
these samples will include, but are not limited to, changes in lymphocyte profile in the tumor 
and blood. 
Blood samples (2X 10 ml) will be collected as indicted in the Time and Events Table (see 
Section 7.1). Blood will be processed to isolate both PBMCs and serum for future biomarker 
analyses at the conclusion of the study, as to be determined by the investigators based on the 

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state of knowledge at that time, and available molecular analysis platforms. Possible analyses 
include, but are not limited to, immune cell populations, circulating free DNA (cfDNA), 
circulating miRNA, and proteins/cytokines. 
5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Histologic confirmation of advanced (metastatic or unresectable) uveal melanoma. If uveal 
melanoma has been diagnosed clinically and/or by gene expression profiling, patients may be 
included following discussion with the principal investigator.  
5.1.2 Enrollment Procedures 
All patients MUST be registered with the 
rior to the start of protocol treatment. Each participating 
site must also be registered with their own institution according to their institutional 
guidelines prior to start of protocol treatment.  Prior to the first patient registration, a copy of 
IRB approval at the respective sites will be requested and on file at the VICC Coordinating 
Center.  
 
 
  
• 
Copy of the patient’s signed and dated Informed Consent  
• 
Eligibility Checklist 
5.1.3 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be ≥ 18 years of age on day of signing informed consent. 
3. Have measurable disease based on RECIST 1.1.   
4.  Histologic confirmation of advanced (metastatic or unresectable) uveal melanoma. If 
uveal melanoma has been diagnosed clinically and/or by gene expression profiling, 
patients may be included following discussion with the principal investigator.  
5. Have provided tissue from an archival tissue sample or newly obtained core or 
excisional biopsy of a tumor lesion. 

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6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 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 
 
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. 
 
8. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
9. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of childbearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 1 year.  
10. 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. 
 

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5.1.4 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. 
 
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.  
4. 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.   
5. 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 cervical cancer that has undergone potentially curative therapy.   
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to trial treatment.   
7. 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.  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. 
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 

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9. Has an active infection requiring systemic therapy. 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or anti-
CD137. Patients who received anti-CTLA4 (ipilimumab, tremelimumab) will NOT 
be excluded and are eligible for inclusion.  
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475 200mg 
Q3 weeks 
IV infusion 
2 years 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity as described in Section 5.2.1.2. 
 
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.   
The dose amount will be 200mg given intravenously every 3 weeks.  

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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 drug-related adverse events. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject (after 
consultation 
with Sponsor) 
Hematological Toxicity 
 
1, 2, 3 
No 
N/A 
N/A 
N/A 
4 
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 
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 a potential Immune-
Etiology 
reference 
Section 
5.6.1.1. 
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) 
Clinical AE does 
not resolve 
within 4 weeks:  
May increase the 
dosing interval 
by  1 week for 
each occurrence 
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 Sponsor) 
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 the Sponsor.  With investigator and 
Sponsor 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. 
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). 
5.2.3 Duration of Therapy 
Pembrolizumab will be administered every 3 weeks until one of the following occurs: 
• Confirmed radiographic disease progression 

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• Indications for subject discontinuation from the trial as outlined in section 5.8 
• Treatment for 24 months 
• Confirmed complete response (CR) 
In the event of a confirmed complete response (CR), it is at the discretion of the 
investigator to keep a patient on study treatment or to suspend study treatment based on 
the criteria.  
• Radiographic CR as defined by RECIST criteria 
• Confirmation with repeat imaging at least 4 weeks after the initial imaging 
Patients will continue to be monitored with scheduled disease assessments as described in 
the protocol (as if the patient were continuing on study treatment), and in the event of a 
disease recurrence, pembrolizumab may be resumed (Second Course treatment) upon 
disease recurrence in these patients. Second Course treatment with pembrolizumab may 
be given for up to 12 additional months. 
5.2.4 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
5.3 
Randomization or Treatment Allocation 
All patients will receive pembrolizumab 200mg IV q3W. There is no randomization in this 
study. 
5.4 
Stratification 
No treatment stratification will be performed. Pre-planned analyses will evaluate response 
rate and PFS by expression of PD-L1 by immunohistochemistry (positive vs. negative) and 
by GNAQ/GNA11 mutation status.  
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 the coordinating center.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  However, the decision to 
continue the subject on trial therapy or vaccination schedule requires the mutual agreement 
of the Investigator, the coordinating center, and the subject.  

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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. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Anti-cancer systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed after consultation with Sponsor.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, 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.  
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. 

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There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
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 3), 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 5.2.1.2. 
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. 
• 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 the separate 
guidance document in the administrative binder regarding diagnosis and management 
of adverse experiences of a potential immunologic etiology.   

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• 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 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab. 
 
Table 5 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); prophylactic 
medications indicated for < =24 
hrs 
 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 mL/hr).  
Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
 
No subsequent dosing 

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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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 
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. 
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 Events of Clinical Interest and 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.   
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in 
Table 6. 
Table 6  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 < 
Systemic corticosteroids are indicated in addition to 
appropriate symptomatic treatment.  May utilize 1 to 
2 mg/kg prednisone or equivalent per day. 

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10 mg per day prednisone 
equivalent within 12 weeks of 
toxicity 
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 7. 
Table 7  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. 
 
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. 

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5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, 
non-breast-feeding women may be enrolled if they are willing to use 2 methods of birth 
control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has 
not had menses for greater than 1 year will be considered postmenopausal), or 3) not 
heterosexually active for the duration of the study.  The two birth control methods can be 
either two barrier methods or a barrier method plus a hormonal method to prevent pregnancy. 
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 they 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 the Sponsor 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. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.   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. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 

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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 
Note: For unconfirmed radiographic disease progression in the absence of clinical 
deterioration, patients may continue on 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 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of treatment with pembrolizumab 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.2.6. 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 

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each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
5.9 
Subject Replacement Strategy 
If a patient withdraws consent or dies prior to receiving the first dose of pembrolizumab, an 
additional patient will be enrolled.  
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 
5. Lack of efficacy as defined by no responses in the first 10 patients AND <2 patients with 
stable disease at 24 weeks.  
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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Protocol/Amendment No. 02 
 
 
Protocol date: November 17, 2014 
 
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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
Visit 
1 
2  
3 
4 
5 
Repeat every 12 weeks 
Discontinuation 
Safety 
Follow-up16 
Follow Up 
Visits17 
Survival 
Follow-Up18 
6 
7 
8 
 
 
9 
Week (approximate) 
 
0 
3 
6 
9 
 
 12 
 
15 
 
18 
 
21 
 
24 
 
 
 
 
 
Scheduling Window 
(Days)2: 
-28 to -1 
days 
 
± 3 
± 3 
± 3 
 
± 3 
± 3 
± 3 
± 3 
 
± 3 
At time of 
Discon 
30 days post 
discon 
Every 12 weeks 
post discon 
Every 12 weeks  
Administrative Procedures 
Informed Consent2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History and Prior 
Medications3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
Post-study anticancer 
therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events4 
 
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 
 

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Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
Visit 
1 
2  
3 
4 
5 
Repeat every 12 weeks 
Discontinuation 
Safety 
Follow-up16 
Follow Up 
Visits17 
Survival 
Follow-Up18 
6 
7 
8 
 
 
9 
Optional Eye Exam19 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
Vital Signs and Weight5 
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 
 
12-Lead EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab 
Administration (30 Minute 
Infusion) 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or 
Serum β-HCG8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Screening7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT9 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
CBC with Differential10 
X10 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Comprehensive Serum 
Chemistry Panel 
X10 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
T3, FT4 and TSH 
X11 
 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
Efficacy Measurements 
Tumor Imaging12 
X 
 
 
 
 
X 
 
X15 
 
X 
 
 
X 
 

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Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
Visit 
1 
2  
3 
4 
5 
Repeat every 12 weeks 
Discontinuation 
Safety 
Follow-up16 
Follow Up 
Visits17 
Survival 
Follow-Up18 
6 
7 
8 
 
 
9 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival or Newly Obtained 
Tissue Collection13 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
Correlative Studies Blood 
Collection14 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
1 Routine laboratory tests (serum chemistry; hematology) for screening should be performed within 10 days of enrollment. 
2 Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame (e.g. within 28 days prior to Cycle 1, Day 1). Assign Baseline 
number when the study informed consent is signed. 
3 Includes history of treatment for the primary diagnosis, including prior systemic, radiation treatment and surgical treatment, and best response to prior 
systemic treatments. Date of last prior cancer treatment must be documented. Radiographic studies performed prior to study entry may be collected for 
review by the investigator. Report complete medication history for 30 days prior to the screening visit (Visit 1). 
4 Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse experiences, whether gradable by 
CTCAE or not, will also be evaluated for seriousness. 
5 Vital signs to include temperature, pulse, respiratory rate and blood pressure. If a patient's baseline weight does not fluctuate by more than 10%, this 
weight can be used to calculate dose. 
6 Electrocardiogram (12-lead ECG) should be performed at Screening. 
7 Testing will be performed by the local laboratory at Screening: Hepatitis B and C serologies should be obtained for patients without a known history of 
hepatitis B or C. Those with a known history are ineligible. Include HCV RNA (qualitative), HBsAg. See Appendix 6.3 for list of laboratory tests. 
8 For women of reproductive potential, a urine pregnancy test will be performed within 72 hours of the first dose. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required.  
9 PT/INR and aPTT should be collected at Screening and at the mandatory Safety Follow-up Visit after discontinuation of study therapy. Coagulation 
parameters should be determined throughout the study if clinically indicated. PT/INR and aPTT will be analyzed by the local study site laboratory. 
10 Routine laboratory tests (e.g., CBC with differential; comprehensive serum chemistry panel) will be performed by the local study site laboratory or their 
contract laboratory.  
11 Following Cycle 4, TSH, T3, and T4 testing will be performed every other cycle. 
12 Tumor imaging will be performed within 30 days prior to enrollment. CT scans are the required modality for measureable disease unless a patient has a 
clinical condition e.g. severe contrast allergy, or the lesions are significantly better visualized through the use of an MRI. The same imaging technique has 
to be used in a patient throughout the study. Patients with an objective response should have repeat imaging at least 4 weeks later to confirm the objective 

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Trial Period: 
Screening 
Phase 
Treatment Cycles 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
Visit 
1 
2  
3 
4 
5 
Repeat every 12 weeks 
Discontinuation 
Safety 
Follow-up16 
Follow Up 
Visits17 
Survival 
Follow-Up18 
6 
7 
8 
 
 
9 
response. In addition, patients with progressive disease should undergo a second scan at least 4 weeks later to confirm progression and exclude the 
possibility of a tumor flare reaction, according to irRECIST guidelines (see Section 7.1.3.3). Response status will be assessed by the investigator. Tumor 
imaging will be performed every 6 weeks starting at Week 12 through Week 24. Following Week 24, tumor imaging may be performed approximately 
every 12 weeks (or whenever clinically indicated) while the patient remains on study therapy at the discretion of the investigator (Weeks 36, 48, 60, 72, 84, 
96).  Timing of imaging scans should follow the calendar and not be adjusted for treatment delays. 
13 A newly obtained biopsy sample of at least one tumor lesion or acceptable archival tissue prior to therapy start is required in all patients for PD-L1 
evaluation. PD-L1 status must be assessed, and if the tumor biopsy submitted is inadequate for determination of PD-L1 status by immunohistochemistry at 
a central pathology laboratory, a repeat biopsy is encouraged. If a biopsy at baseline is not judged to be safe by the investigator, this requirement will be 
waived. Additional biopsy samples approximately at Week 3 and at disease progression are highly desirable when it is feasible.  The tissue sample should 
have proper size to enable multiple planned biomarker analyses, and fine needle aspiration will not be acceptable. The biopsy techniques allowed in the 
study include core needle biopsies or surgical biopsies. Study sites should use the same biopsy techniques in this study as they routinely use for a given 
tumor lesion/location. Detailed instructions for tissue collection, processing and shipment are provided in section 8.2.1. 
14 Informed consent for future biomedical research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained 
predose, on Day 1 (or with the next scheduled blood draw), as the last sample drawn, on randomized subjects only, or at a later date as soon as the 
informed consent is obtained. 20mL in two 10mL sodium heparin tubes will be collected at each time point.  
15 Tumor imaging should be performed at week 18 and week 24 but should be repeated only every 12 weeks thereafter or as clinically indicated. 
16 PLEASE NOTE- This visit is to be completed within 3 weeks of a patient experiencing disease progression, intolerable toxicity or withdrawal of 
consent. For Imaging Only- If a scan has been performed within 6 weeks of this visit, the site does not need to repeat the scan. 
17 If subjects discontinue therapy for reasons other than disease progression, they should be followed in the clinic every 3 months with surveillance studies 
as indicated until completion of the study. At the time of subsequent progression, if Second Cycle Treatment is not pursued, then subjects should be 
followed by phone contact every 3 months 
18 If subjects discontinue therapy for disease progression, they should be followed by for overall survival by phone contact every 3 months until 
completion of the study 
19 On-treatment eye exam may be performed up to 3 weeks after cycle 5.  
 
 

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6.2 
Second Course Treatment Flow Chart 
 
Second Course Treatment Pembrolizumab 
 
 
Trial Period: 
Treatment Cycles 
Treatment Cycle/Title: 
1 
2  
3 
4 
5 
To be repeated every 12 weeks 
6 
 
 
7 
 
 
8 
 
 
9 
Week (approximate) 
0 
3 
6 
9 
12 
15 
 
18 
 
21 
 
24 
 
Scheduling Window (Days)2: 
 
± 3 
± 3 
± 3 
± 3 
± 3 
 
 
± 3 
 
 
± 3 
 
 
± 3 
Eligibility Criteria1 
X 
 
 
 
 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Survival Status 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Review Adverse Events3 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Physical Examination 
X 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 

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Second Course Treatment Pembrolizumab 
 
 
Trial Period: 
Treatment Cycles 
Treatment Cycle/Title: 
1 
2  
3 
4 
5 
To be repeated every 12 weeks 
6 
 
 
7 
 
 
8 
 
 
9 
Vital Signs and Weight2 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Pembrolizumab Administration (30 Minute Infusion) 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Pregnancy Test – Urine or Serum β-HCG8 
X 
 
 
 
 
 
 
 
 
PT/INR and aPTT5 
X 
 
 
 
 
 
 
 
 
CBC with Differential10 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
Comprehensive Serum Chemistry Panel4 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
T3, FT4 and TSH7 
X 
X 
X 
X 
 
 
 
X 
X 
Tumor Imaging8 
X 
 
 
 
X 
 
 
 
X9 
X 
Correlative Studies Blood Collection 
X 
X 
 
 
 
 
 
 
 
1 Patients who attain a CR, PR or SD at 24 months and discontinue treatment may restart trial treatment if they meet 

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Protocol date: November 17, 2014 
 
Confidential  
 
Second Course Treatment Pembrolizumab 
 
 
Trial Period: 
Treatment Cycles 
Treatment Cycle/Title: 
1 
2  
3 
4 
5 
To be repeated every 12 weeks 
6 
 
 
7 
 
 
8 
 
 
9 
the criteria specified in Section 7.1.2.5 
2 Vital signs to include temperature, pulse, respiratory rate and blood pressure. 
3 Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse 
experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness. 
4 Laboratory tests for screening or entry into the Second Course Phase should be performed within 10 days prior to 
the first dose of treatment. Routine laboratory tests (e.g., CBC with differential; comprehensive serum chemistry 
panel; urinalysis) will be performed by the local study site laboratory or their contract laboratory. 
5 PT/INR and aPTT should be collected at Cycle 1 and at the mandatory Safety Follow-up Visit after discontinuation 
of study therapy. Coagulation parameters should be determined throughout the study when clinically indicated. 
PT/INR and aPTT will be analyzed by the local study site laboratory. 
6 For women of reproductive potential, a urine pregnancy test will be performed within 72 hours of the first dose. If 
urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. . 
7 Following Cycle 4, testing will be performed every third cycle. 
8 Tumor imaging will be performed within 28 days prior to restarting with pembrolizumab after relapse from CR, PR 
or SD. The same imaging technique has to be used in a patient throughout the study. If a retreated patient has a 
response or progression, repeat imaging is required approximately 4 weeks later for confirmation, as per immune 
related response criteria (irRECIST) guidelines (see Section 7.1.3.3). Response status will be assessed by the study 
site. Following Week 24, tumor imaging will be performed approximately every 12 weeks (or whenever clinically 
indicated) while the patient remains on study therapy 
9 Tumor imaging should be performed at week 18 and week 24 but should be repeated only every 12 weeks thereafter 
or as clinically indicated. 

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Protocol/Amendment No. 03 
 
 
Protocol date: August 30, 2016 
 
Confidential  
 
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. 
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. 
If the patient is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion. Afterward, the patient should sign and date the informed 
consent, if capable. The impartial witness should also sign and date the informed consent 
along with the individual who read and discussed the informed consent (i.e. study staff 
personnel). 
If the patient is legally incompetent (i.e., a minor or mentally incapacitated), the written 
consent of a parent, legal guardian or legal representative must be obtained. Depending on 

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local law or review committee requirements such consent may also need to be signed by an 
impartial witness. 
A copy of the signed and dated consent form should be given to the patient before 
participation in the study. Patients may undergo study screening tests prior to giving written 
informed consent provided that these tests are considered part of standard care. 
The initial informed consent form and any subsequent revised written informed consent 
form, and written information must receive the IRB/IEC’s approval/favorable opinion in 
advance of use. The patient or his/her legally acceptable representative should be informed in 
a timely manner if new information becomes available that may be relevant to the patient’s 
willingness to continue participation in the trial. The communication of this information 
should be documented. 
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. 
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. See section 5.1.2 and 5.1.3 for full list of 
inclusion and exclusion criteria.  
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.  

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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. These may be recorded at screening for some aspects (e.g. sites of disease). This will 
include the following: 
• Prior treatments including response 
• Date of diagnosis of primary tumor and advanced disease 
• Sites of organ involvement 
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.  
7.1.1.6 Trial Compliance (Medication/Diet/Activity/Other) 
A representative from the coordinating institution will review records to ensure compliance. 
Data will be collected via CRFs and entered into the database per Sponsor guidelines. The 
Sponsor will check data accuracy by performing source data verification. Source data 
verification is a direct comparison of the entries made on the CRFs against the appropriate 
source documentation. Discrepancies in the data will be brought to the attention of the 
Investigator and/or the Investigator’s staff.  Any necessary corrections will be made directly 
to the CRFs or via queries by the Investigator and/or the Investigator’s staff. 

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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 and the separate guidance document in the 
administrative binder 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 Physical and Ophthalmologic Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  
Subjects may have an optional standard ophthalmic examination performed by an 
ophthalmologist at the times described (Section 6) to assess changes in any residual primary 
tumor (including treated tumors). At certain time points in the trial and if visual changes 
develop, an eye exam is indicated. The exam will include best corrected visual acuity, color 
vision (Ishihara color plates), measurement of tear production with Shirmer's strips, 
tonometry, slit lamp biomicroscopic examination, and dilated indirect fundoscopy with 
special attention to retinal abnormalities.  Fundus photography of both maculas and optic 
discs, and of the tumor, should be obtained at all visits.  Optical coherencetomography is 
strongly recommended at scheduled visits, and if retinal abnormalities are suspected. Other 
types of ancillary testing including fluorescein angiography are also recommended if 
clinically indicated. B scan ultrasonographic measurements of residual tumor height should 
be obtained at baseline and at follow-up visits.  All adverse events should be graded and 
documented separately for the tumor and for the non-tumor eye. See Appendix 13.5 for 
Ophthalmology Documentation Form.  

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7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 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 every other cycle in conjunction with the directed or full physical 
exam. 
7.1.2.5 Eligibility for Second Course of Treatment 
Patients who discontinue pembrolizumab with a CR prior to 24 months or with best response 
of PR or SD may be eligible for a second course of pembrolizumab therapy. Prior to 
enrollment in a second course, screening tests are required as outlined in section 6.2.  
Subjects will receive pembrolizumab 200mg IV q3 weeks for up to 12 months. All other on-
treatment procedures are the same as in the initial phase and are outlined in section 6.2.  
Subjects are eligible for retreatment if they meet the following criteria: 
• Best response of CR, PR, or SD 
• Treatment for 12 months or more if confirmed CR, PR, or SD 
• Subsequent progression of disease as defined by irRECIST criteria 
• If immune related adverse events occurred on the initial course, they must have not 
caused treatment discontinuation and must be resolved at the time of consideration 
• ECOG performance status of 0-1 
• No intervening systemic therapies following initial course of pembrolizumab 
• Other inclusion criteria as outlined in section 5.1.2 and 5.1.3. 
If extenuating circumstances occur, discussion with the PI can occur and consideration will 
be given to retreatment.  
7.1.2.6 Tumor Tissue and Blood Collection 
Collection of tumor tissue is required prior to enrollment in this study to evaluate an 
important potential biomarker, PD-L1 that may be predictive of treatment benefit from 
pembrolizumab. A newly obtained tumor biopsy is highly desirable and preferred, but an 

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archival tumor specimen is acceptable if a new biopsy cannot be obtained. Patients should 
submit the specimen for central pathology assessment of PD-L1 status. The results of PD-L1 
status are not required to initiate pembrolizumab.  
Patients who submit an inadequate archival sample may undergo new biopsy and patients 
who submit an inadequate recent biopsy may undergo a rebiopsy at the discretion of the 
investigator. Fine needle aspirations are not acceptable specimens. If a patient is unable to 
provide a newly obtained tumor biopsy, then collection of archival tumor tissue is required. If 
a patient has multiple archival tumor tissue samples, the most recently obtained tissue sample 
is preferred. Finally, if an acceptable archival sample or new biopsy specimen is unable to be 
obtained due to safety reasons, the requirement may be waived and a patient may be enrolled.  
If a patient is unable to provide an archival tissue sample, then collection of a newly obtained 
tumor biopsy is highly encouraged. Tru-cut (or equivalent) core needle biopsies and surgical 
biopsies are acceptable. Fine needle aspirations are not acceptable. In addition, tumor 
biopsies while on study therapy at approximately Week 6, Week 12, and Week 24 and at 
disease progression are also desirable, especially in patients who initially responded but then 
progressed on pembrolizumab as changes in biomarkers compared to baseline may provide 
meaningful insights into characteristics associated with sensitivity or resistance to 
pembrolizumab. 
In addition, at the discretion of the investigator, new lesions or fluid collections may require 
histological or cytological confirmation if progression is suspected, if indicated by the 
clinical circumstances. If a new lesion or fluid collection is biopsied during the course of the 
study to document progressive disease or evaluate suspicious new findings, the date of the 
procedure, type of procedure, and the histological or cytological results of the biopsy should 
be recorded in the case report forms. 
Assessment of peripheral blood lymphocyte profiles may also yield critical insights into 
response and resistance to pembrolizumab. Blood collection is required on day 1 of 
pembrolizumab treatment, two weeks into treatment (cycle 2), and at the time of progression. 
Twenty (20) ml of peripheral blood should be obtained at each timepoint. 
7.1.3 Tumor Imaging and Assessment of Disease 
The Immune Related RECIST (irRECIST) will be used for assessment of tumor response for 
the purposes of managing patients on protocol treatment and decision making for 
discontinuation of study therapy due to disease progression. These disease assessments will 
be performed by the investigator with site radiology reading. At least one measurable lesion 
according to RECIST 1.1 criteria must be present on a bi-dimensional imaging study (CT or 
MRI) at baseline. A measurable lesion is defined as measuring at least 10 mm in longest 
diameter or twice the slice thickness whichever is greater; the exception being that lymph 
nodes must measure 15 mm in short axis for lymph nodes.  

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The irRECIST criteria are described in Section 7.1.3.3. For the purposes of the efficacy 
endpoints of the study, response assessment based on irRECIST will be applied as the 
primary measure. 
If imaging shows a complete response (CR) or partial response (PR), tumor imaging should 
be repeated at least 4 weeks later to confirm response, per irRECIST recommendations. 
Patients will then return to regular scheduled imaging, starting with the next scheduled 
imaging time point. Patients who obtain a confirmation scan do not need to undergo 
scheduled imaging assessment 2 weeks later (e.g. If a patient obtains a scan at Week 16 to 
confirm a Week 12 response, they will not also be required to complete the scheduled Week 
18 scan). 
If imaging shows PD, it is at the discretion of the investigator to keep a patient on study 
treatment or to stop study treatment until imaging is repeated approximately 4 weeks later in 
order to confirm PD, as described in the irRECIST recommendations. Patients that are 
deemed clinically unstable or who have biopsy proven new metastatic lesions are not 
required to have repeat imaging for confirmation. This decision will be based on clinical 
judgment of a patient’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. At a minimum, patients must meet the following criteria for 
continued treatment on study after disease progression is identified at a tumor assessment: 
• Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
If repeat imaging shows an objective response or stable disease relative to baseline, treatment 
with pembrolizumab will continue/resume and the next imaging studies will be conducted 
every 6 weeks as previously scheduled. If repeat imaging confirms PD, patients will be 
discontinued from study therapy. 
In patients who discontinue study therapy early without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
following the guidelines described in Section 7.1.6.4. 
7.1.3.1 Assessment Guidelines 
Please note the following: 
• The same diagnostic method, including use of contrast when applicable, must be used 
throughout the study to evaluate a lesion. 
• All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers. 

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• Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required. 
• FDG-PET is generally not suitable for ongoing assessments of disease. However 
FDG-PET can be useful in confirming new sites of disease where a positive FDGPET 
scan correlates with the new site of disease present on CT/MRI or when a baseline 
FDG-PET was previously negative for the site of the new lesion. FDG-PET may also 
be used in lieu of a standard bone scan providing coverage allows interrogation of all 
likely sites of bone disease and FDG-PET is performed at all assessments. 
• If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the required 
anatomical coverage and prescribed use of contrast. The method of assessment should 
be noted as CT on the electronic CRF. 
• CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended. 
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimized for the 
evaluation of the type and site of disease and lesions must be measured in the same anatomic 
plane by use of the same imaging examinations. Whenever possible, the same scanner should 
be used. 
X-ray: Should not be used for target lesion measurements owing to poor lesion definition. 
Lesions on chest X-ray may be considered measurable if they are clearly defined and 
surrounded by aerated lung; however chest CT is preferred over chest X-ray. 
Brain Scan: If brain scans are required, then contrast enhanced MRI is preferable to contrast 
enhanced CT. 
7.1.3.2 Measurable and Non-measurable Definitions 
A measurable lesion is a non-nodal lesion that can be accurately measured in at least one 
dimension (longest dimension) of: 
• ≥10 mm with MRI or CT when the scan slice thickness is no greater than 5mm. If the 
slice thickness is greater than 5mm, the minimum size of a measurable lesion must be 
at least double the slice thickness (e.g., if the slice thickness is 10 mm, a measurable 
lesion must be ≥20 mm). 
• ≥10 mm caliper/ruler measurement by clinical exam or medical photography. 
• ≥20 mm by chest x-ray. 
Additionally, lymph nodes can be considered pathologically enlarged and measurable if: 

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• ≥15 mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5 mm). At baseline and follow-up, only the short axis will be 
measured. 
A non-measurable lesion is: 
• All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥10 mm and <15 mm short axis) 
as well as truly non-measurable lesions, which include: ascites, pleural or pericardial 
effusions, inflammatory breast disease, lymphangitic involvement of the skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques (Eisenhauer 2009). 
Measurable disease: The presence of at least one measurable lesion. Palpable lesions that are 
not measurable by radiologic or photographic evaluations may not be utilized as the only 
measurable lesion. 
Non-Measurable only disease: The presence of only non-measurable lesions. Note: 
nonmeasurable only disease is not allowed per protocol. 
7.1.3.3 Response Criteria (irRC) 
7.1.3.3.1 Immune-related RECIST Criteria (irRECIST) Overview 
• All measurements are undimensional 
• If a patient is classified as having progressive disease, confirmation by a second scan 
at least 4 weeks later in the absence of rapid clinical deterioration is required to assess 
for a late response. 
• The presence of new lesions does not constitute disease progression by itself. 
• Target lesions and new lesions are incorporated into overall tumor burden which is 
used to evaluate progression or responses as in the following:  
Tumor Burden = Sum of the Diameter (target) + Sum of the Diameter (new) 
7.1.3.3.2 Target Lesions 
• Up to 5 lesions may be selected as target lesions (up to 2 per organ).  
• Immune-related Complete Response (irCR): Disappearance of all target lesions. Any 
pathological lymph nodes must be <10 mm in the short axis. 
• Immune-related Partial Response (irPR): At least a 30% decrease in the total tumor 
burden, including target lesions and new lesions, taking as a reference, the baseline 
sum of the diameters (e.g. percent change from baseline). 

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• Immune-related Stable Disease (irSD): Neither sufficient shrinkage to qualify for PR 
nor sufficient increase to qualify for progressive disease. 
• Immune-related Progressive Disease (irPD): At least a 20% increase in the tumor 
burden (defined as the sum of diameters of target lesions and new lesions), taking as a 
reference, the smallest sum of diameters recorded since the treatment started (e.g. 
percent change from nadir, where nadir is defined as the smallest sum of diameters 
recorded since treatment start). In addition, the sum must have an absolute increase 
from nadir of 5mm. 
• Not Applicable (NA): No target lesions at baseline. 
• Not Evaluable (NE): Cannot be classified by one of the five preceding definitions. 
NOTE: 
• If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g. sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions). When lymph nodes decrease to 
non-pathological size (short axis <10mm) they should still have a measurement 
reported in order not to overstate progression. 
• If at a given assessment time point all target lesions identified at baseline are not 
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, PR, 
or SD, or for use as the nadir for future assessments. However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented. If an assessment of 
PD cannot be made, the response assessment should be NE. 
• All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g., 2 mm). If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported. 
• If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured. The response at the time when the lesion reappears will depend upon 
the status of the other lesions. For example, if the disease had reached a irCR status 
then irPD would be documented at the time of reappearance. However, if the 
response status was irPR or irSD, the diameter of the reappearing lesion should be 
added to the remaining diameters and response determined based on percent change 
from baseline and percent change from nadir. 
7.1.3.3.3 Non-Target Lesions 
Non-target lesions are not incorporated into tumor burden calculations. However, for the 
diagnosis of CR to be achieved, all non-target lesions must also resolve.   

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NOTE: 
• In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. 
• Sites of non-target lesions, which are not assessed at a particular time point based on 
the assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable"). 
7.1.3.3.4 New Lesions 
New lesions do not automatically qualify as irPD. The diameter of new lesions should be 
added to the sum of target lesions to assess disease burden.  
Any equivocal new lesions should continue to be followed. Treatment can continue at the 
discretion of the investigator until the next scheduled assessment. If at the next assessment 
the new lesion is considered to be unequivocal, it should be added to the disease burden. 
Table 8 presents the overall response at an individual time point for all possible combinations 
of tumor responses in target and non-target lesions with or without the appearance of new 
lesions for subjects with measurable disease at baseline. 
7.1.3.3.5 Evaluation of Overall Response 
Table 8 Evaluation of Overall Response for Subjects with Measurable Disease at Baseline 
Overall Response  irRECIST  
(total tumor burden = target 
lesions + new lesions) 
Non-target 
lesions 
New lesions 
irCR 
Disappearance of all lesions 
Absence 
Absence 
irPR 
> 30% decrease in tumor burden 
compared with baseline 
Any 
Any 
irSD 
<30% decrease to < 20% increase in 
total tumor burden compared with 
baseline 
Any 
Any 
irPD 
> 20% increase in tumor burden 
compared with nadir or baseline with 
confirmation of progression by a 
second scan at least 4 weeks later 
Any  
Any 
ir=immune related, CR=complete response, PR = partial response, SD=stable disease, 
PD=progressive disease, NA= Not applicable, and NE=Not Evaluable 

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NOTE: 
• Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 
• In some circumstances, it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of CR depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the 
CR. 
• If patients experience irPD and remain clinically stable or improved, an exception 
may be granted to continue on study after discussion with the PI. If confirmed irPD is 
documented and an exception is granted, repeat imaging should be performed in 4-6 
weeks and if further progression is documented then study treatment should be 
discontinued. If an isolated lesions progresses and is treated with local therapy 
(surgical resection or radiation therapy), imaging should be performed to document 
local stability and overall irRECIST re-evaluation.  
7.1.4 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
7.1.4.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 9.   

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Table 9 Laboratory Tests 
Hematology 
Chemistry 
Other 
Hematocrit 
Albumin 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
Free tyroxine (T4) 
 
  (CO2 or biocarbonate) 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
Calcium 
 
 
Chloride 
Blood for correlative studies 
 
Glucose 
  
 
Potassium   
  
 
Sodium 
  
 
Magnesium 
  
 
Total Bilirubin 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
Total protein 
 
 
Blood Urea Nitrogen 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 14 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.5 Other Procedures 
7.1.5.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of 
treatment with pembrolizumab may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.6.2.2.  After discontinuing 
treatment following assessment of CR, these subjects should return to the site for a Safety 
Follow-up Visit (described in Section 7.1.6.3) and then proceed to the Follow-Up Period of 
the study (described in Section 7.1.6.4). 
7.1.5.2 Blinding/Unblinding 
No blinding will be performed in this trial. 
7.1.6 Study Visits 
Study procedures should be performed as close to the scheduled time as possible. The exact 
time at which a procedure is performed must be recorded in the patients study records or 
appropriate worksheet (if applicable). Any nonscheduled procedures required for urgent 
evaluation of safety concerns take precedence over all routine scheduled procedures. 
A detailed outline of all scheduled study procedures is provided in the Study Flow Chart 
(Section 6.0). Procedures should be performed at the study center where the patient is being 
treated. 
Blood collections for safety evaluation assume priority over other procedures. Whenever 
possible, blood samples should be obtained by fresh peripheral venipuncture. If a patient 
does not have peripheral access, the sample may be collected from a central catheter 
immediately after an initial withdrawal of at least 10 mL of blood; or preferably, after a 
series of other blood sample collections from the central catheter. 
The patient will be assessed for adverse experiences per the Study Flow Chart (Section 6.0) 
and at all unscheduled visits. 
Specific procedure-related details are provided above in Section 7.1 - Trial Procedures. 

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7.1.6.1 Screening Period 
All screening procedures will be performed during the screening period. Screening 
requirements are outlined in Section 6.0 - Trial Flow Chart.    
7.1.6.2 Treatment Period 
7.1.6.2.1 Initial Treatment Period 
Treatment visits will occur every 3 weeks with symptom evaluation, physical exam, and 
laboratory studies as documented in Section 6.0. If grade 3-4 adverse events that meet the 
criteria listed in Table 3, then the treatment interval may be lengthened to every 4 weeks.  
7.1.6.2.2  Subsequent Treatment Period 
Patients who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping pembrolizumab. The 
following criteria must be met to be eligible for second-course treatment: 
• Patient had a confirmed CR and stopped pembrolizumab treatment after at least 6 
months plus an additional 2 doses of study therapy OR  
Patient had SD, PR or CR and stopped pembrolizumab treatment after at least 12 
months of study therapy 
• Patient has documented disease progression after stopping pembrolizumab study 
treatment 
• Patient did not discontinue pembrolizumab due to AEs from study treatment 
• Patient did not initiate new anti-cancer treatment since stopping pembrolizumab (note 
– local surgery or radiation therapy with palliative intent may be allowed).  
• Have a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrate adequate organ function as detailed in Section 5.1.2 
• Female patient of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment with study medication. 
• Female patients of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or a barrier method plus a hormonal method of 
contraception to prevent pregnancy, or abstain from heterosexual activity for the 
course of the study through 120 days after the last dose of study medication 
(Reference Section 2.2). Patients of child bearing potential are those who have not 
been surgically sterilized or have been free from menses for > 18 months (see Section 
2.2). 

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• Male patients should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy. 
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the patient’s participation for the full duration of 
the trial or is not in the best interest of the patient to participate, in the opinion of the 
treating investigator.  
Patients who restart treatment will be retreated at the dose and dose frequency they received 
upon initial treatment with pembrolizumab. Treatment will be administered for up to 12 
additional months. 
See Section 5.1.2.5 for eligibility requirements for reinduction and Section 6.2 for flowchart 
for induction.  
7.1.6.3 Post-Treatment Visits 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.   
7.1.6.4 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 7.1.6.2.2.  Information regarding post-study anti-neoplastic treatment 
will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab will move from the 
follow-up phase to the Second Course Phase when they experience disease progression.  
Details are provided in Section 6.0 – Trial Flow Chart.    
7.1.6.4.1 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. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
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. 
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, 

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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.” 
 
 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial or within 120 days of completing the trial.  All subjects and 
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. 
 
 
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 another important medical event  

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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 
  
Non-serious Events of Clinical Interest will be forwarded 
 
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. 
 
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 
 the time of submission.  
 
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 
 
 
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 

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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 
 
within 2 working days of the event: 
a.  Grade ≥ 3 diarrhea 
b.  Grade ≥  3 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 
 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.  
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 
 within 2 working days. 
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 10 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 Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
7.2.6 Adverse Event Collection 
Adverse events forms developed by the sponsor institution will be distributed and collected to 
document adverse events of interest. The sponsor institution will collect, maintain, and monitor 
CRFs. 
8.0 BIOMARKERS AND CORRELATIVE STUDIES 
8.1 
Biomarker Study Overview 
Tumor GNAQ and GNA11 status will be determined for all patients treated on this study using 
archived or newly acquired tumor material. PD-L1 expression by IHC will also be performed on 
all baseline tumor samples (either archival or new biopsies). All patients with safely accessible 
tumor will undergo pre- and post-treatment (day 14 +/- 3 days) tumor biopsies for biomarker and 
correlative analysis.  The decision to not pursue these biopsies must be made in collaboration 
with the Principal Investigator.  An additional tumor biopsy will be requested from patients at the 
time of disease progression; however, this biopsy is optional.   
In addition to GNAQ and GNA11 mutational status and PD-L1 staining, peripheral blood and 
tumor will be collected to assess other immune correlates including but not limited to peripheral 
circulating lymphocytes and tumor infiltrating lymphocytes prior to therapy and at the time of 
progression by multiplexed mass cytometry. Specific populations of T cells assessed will include 
(but not limited to) CD8+ cytotoxic T cells, regulatory T cells, and PD-1+ T cells.  
8.2 
Correlative Studies 
8.2.1 Tumor Biopsies 
Investigators are highly encouraged to collect tumor biopsies at baseline (in the absence of 
sufficient archival tissue) and 14 days (+/- 3 days) following initiation of therapy, with an 
optional tumor biopsy conducted at the time of disease progression.  The pre-treatment biopsy 
will be obtained within 28 days of starting therapy. As noted, archival tissue within one year of 
starting therapy of sufficient quantity will preclude the need for an initial biopsy.  Issues that 
would cause treatment delays should be discussed with the PI who may grant permission on a 
case-by-case basis to analyze tissue from a protocol pre-treatment biopsy that has occurred 
greater than 28 days prior to study treatment.  The post-treatment biopsy will be performed at 
day 14 ± 3 days following the morning dose of the study medications.  An optional third tumor 
biopsy will be requested of these patients at the time of tumor progression, with particular efforts 
made at obtaining such biopsies in patients who have developed progression after achieving a 
radiographic response to treatment or after prolonged disease control (i.e., greater than 4 
months).  Up to eight core samples will be obtained with each biopsy, providing sufficient tissue 
for the correlative studies.   

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Tissue will be divided such that a portion (one core in the case of core needle biopsy procedures) 
is formalin fixed and designated for immunohistochemistry (IHC) and the remainder flash frozen 
in liquid nitrogen. 
 
Fresh tumor biopsy samples should be snap-frozen using liquid nitrogen or a dry ice slurry as 
outlined below.  The tissue must be frozen as soon as possible after biopsy to minimize any form 
of degradation and to avoid risking the viability of the tissue.   
 
Snap-Freezing in Liquid Nitrogen: 
• 
Label cryogenic vial(s) with the subject’s study identification number (ie. Accession 
number for MSKCC patients), the date of collection, time point (baseline, day 14, or 
progression) and the study center performing the biopsy.  Ensure that the label adheres 
to the vial and does not come off when placed in liquid nitrogen.  Labels cannot be 
adequately affixed to the vials after freezing. 
• 
Immediately place the freshly obtained tissue into the labelled cryogenic vial.  Place the 
vial with tissue in liquid nitrogen for 2 minutes or longer to snap-freeze the tissue.  
Tumor cores should be frozen individually in separate cryovials as collected in order to 
minimize the time between removal and freezing. 
• 
Remove the crygenic vial from the liquid nitrogen. 
• 
Store the sample in a -80°C freezer (-65°C to -80°C is acceptable) until ready for 
shipping. 
 
Freezing Procedure with Dry Ice Slurry 
• 
Materials required include: 5 lbs dry ice, alcohol (ethanol or comparable), basin, long 
forceps 
• 
Place at least 5 lbs of dry ice into a basin and pour one liter of alcohol over the ice. 
• 
Label cryogenic vial(s) with the subject’s study identification number, the date of 
collection, and the study center performing the biopsy.  Ensure that the label adheres to 
the vial and does not come off when placed in liquid nitrogen.  Labels cannot be 
adequately affixed to the vials after freezing. 
• 
Immediately place the freshly obtained tissue into the labelled cryogenic vial.  Place the 
vial with tissue in liquid nitrogen for 2 minutes or longer to snap-freeze the tissue.  
Tumor cores should be frozen individually in separate cryovials as collected in order to 
minimize the time between removal and freezing. 
• 
Pace the lower half of the sealed cryotube containing tissue into the solution for at least 
2 minutes until frozen solid. 
• 
Store the sample in a -80°C freezer (-65°C to -80°C is acceptable) until ready for 
shipping. 
 
8.2.2 PD-L1 Staining Assay 
Archival or fresh tissue biopsies obtained prior to start of treatment will be subjected to PD-L1 
by immunohistochemistry per a proprietary assay. Percentage of tumor cells expressing PD-L1 
will be correlated to duration of progression-free survival. Cutoffs of strong PD-L1 staining 

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Protocol date: August 30, 2016 
(≥50% of cells) and weak PD-L1 staining (1-49% of cells) will be used and correlated with 
response rate by irRECIST criteria.  
Biopsies should be processed in the following manner: 
• Formalin fixed paraffin embedded tissue samples are acceptable; a fine needle aspirate, 
frozen sample, plastic embedded sample, cell block, clot, bone, bone marrow or 
cytologic specimen will not be acceptable for IHC analysis. 
• It is recommended that FFPE blocks be sectioned fresh (within 7 days of sectioning and 
sending for PD-L1 analysis) onto positively charged slides; slides should be stored and 
shipped (and stored upon receipt at Qualtek) at 2-8C in the dark. 
• Recommended fixation time for samples is 24 hours to 48 hours in 10% neutral buffered 
formalin. 
 
8.2.3 Blood Collection 
Two 10 ml sodium heparin tubes will be collected from patients prior to treatment, at the 
beginning of cycle 2 (week 3), and at the time of progression.  Samples will be subsequently 
stored for future correlative studies. The samples drawn prior to treatment can be drawn on 
C1W1 prior to initiation of study drug.   
Process samples in the following manner. 
• 
Utilizing the 3 sodium heparin tubes, use your institutions choice of best practices to 
isolate mononuclear cells (i.e., accuspin system, leucosep system, CPT tubes, general 
ficoll layering). 
• 
Transfer the cells to a BD Falcon ® tube and wash the cells three times with PBS (ex: 
aliquot cellular layer to falcon tube and fill with 15 ml of PBS, invert several times to 
mix. Cap and centrifuge at 300 x g for 10 min, pour off PBS and repeat). 
• 
After the third wash, carefully pour off the PBS one last time and freeze the cell pellet 
at -80°C until shipment to the respective biorepository 
• 
 Label tubes with the subject’s study identification number, initials, the date of 
collection, time point and protocol number.  
 
9.0 STATISTICAL ANALYSIS PLAN 
9.1 
Statistical Analysis Plan Summary 
The primary objective is to determine whether pembrolizumab is an effective therapy in uveal 
melanoma. The null hypothesis is that the objective response rate (ORR; percentage of patients 
achieving a confirmed CR or PR) is not attractive (defined as ≤5%). The alternative hypothesis is 
that the response rate is of interest for further development (defined as ≥20%).  

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Protocol/Amendment No. 03 
 
 
Protocol date: August 30, 2016 
The final analysis of the overall response rate will be performed with a power of 80% with one 
sided α=0.05. It is calculated that at least 4 responses are needed out of a total of 29 patients to 
reject the null hypothesis.  
To allow early termination of the trial due to lack of efficacy, the trial will be conducted in two 
stages per Simon’s Optimal Design. If no responses are demonstrated in the first 10 patients, 
then the trial will be terminated early for futility. If ≥1 responses are observed, enrollment will 
continue to 29 patients. Notably, in the absence of ≥1 response, if ≥2 patients experience stable 
disease (SD) for >24 weeks, then the study may proceed to stage 2 if the sponsor and PIs are in 
agreement. This provision was added since the probability of early termination was as high as 
10% even with a response rate of 20%. 
9.2 
Statistical Analysis Plan 
9.2.1 Sample Size Assumptions 
To determine the overall sample size and the interim sample size, a two stage Simon’s Optimal 
design was evaluated. To test the hypotheses (ORR=5% vs. 20%), 1 response from the first 10 
subjects would be required to progress to stage 2 and a total of 29 subjects will be needed to 
achieve the desired type I (<5%) and type II error rate (Power>80%). The risk of prematurely 
stopping the trial after stage I if the drug is effective is approximately 10%. To reduce this risk, 
we will include the condition that if 2 or more patients experience stable disease for at least 24 
weeks then the trial will proceed to stage 2.  
Table 11: Sample Size Calculations 
If the True Response Rate to 
pembrolizumab is: (%) 
Probability of Early Termination 
after Stage I 
Probability of Rejecting the Null 
Hypothesis 
5% 
0.599 
0.047 (type 1 error) 
10% 
0.349 
0.289 
15% 
0.197 
0.589 
20% 
0.107 
0.801 
25% 
0.056 
0.913 
30% 
0.028 
0.963 
 
9.2.2 Efficacy Endpoints 
9.2.2.1 Primary Endpoint 
Objective response rate (ORR) as defined by immune-related response criteria (irRC) will be the 
primary endpoint of the study. As mentioned, the primary hypothesis is that ORR of 
pembrolizumab in uveal melanoma will be 20%. We will enroll 10 patients in stage I to allow for 
early termination for futulity. If no responses are observed the trial will be terminated. However, 
if ≥1 objective response occurs, OR if ≥2 patients experience stability of disease for ≥24 weeks, 
the trial will proceed to stage II.  

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Protocol date: August 30, 2016 
In stage II, an additional 19 patients will be enrolled. If ≥4 responses occur in all patients treated 
on stage I and stage II, the trial will be considered positive.  
Of note, response rates by RECIST 1.1 criteria will also be assessed although irRC will be used 
for the primary endpoint.  
ORR will be stratified by PD-L1 expression and GNAQ/GNA11 mutation status (see section 
8.2.2.3).  
9.2.2.2 Secondary Endpoints 
9.2.2.2.1 Progression Free Survival 
Progression-free survival (PFS) as defined as the time from the first dose of pembrolizumab to 
progression as defined by RECIST 1.1 criteria. PFS will be summarized in the method of Kaplan 
and Meier. Median PFS and PFS at one year will be reported with 95% confidence intervals. PFS 
analysis based on investigator’s assessment using irRC will also be carried out. 
Since disease progression is assessed periodically, progressive disease (PD) can occur any time 
in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. For the primary analysis, for the patients who have PD, the 
true date of disease progression will be approximated by the date of first assessment at which PD 
is objectively documented using RECIST 1.1 criteria, regardless of discontinuation of study 
drug. Death is always considered as a confirmed PD event. Patients without documented 
PD/death will be censored at the last disease assessment date. 
9.2.2.2.2 Overall Survival 
Overall survival is defined as the interval between the first dose of pembrolizumab and death for 
any reason. The Kaplan-Meier method will be used to estimate the overall survival. The 
treatment difference in survival will be assessed by the stratified log-rank test. Median survival 
and its 95% confidence interval will be estimated and reported.  
9.2.2.2.3 Duration of Response 
If sample size permits, response duration will be summarized descriptively using Kaplan-Meier 
medians and quartiles. Only the subset of patients who show a complete response or partial 
response will be included in this analysis. 
9.2.2.3 Subgroup Analyses 
To investigate predictors of response to pembrolizumab in uveal melanoma, we will stratify 
outcomes (ORR, PFS, OS) by clinical and laboratory factors. Clinical factors will include 
baseline LDH, visceral involvement, ECOG performance status, prior ipilimumab, and prior 
MEK inhibitor therapy.  To investigate for possible genetic biomarkers for response, we will 
perform GNAQ209/GNA11Q209 mutation analysis and evaluate outcomes by mutation status. In 
addition, we will perform stratification by PD-L1 expression status.   

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Protocol date: August 30, 2016 
Differences in PFS and OS between subgroups will be assessed by the stratified logrank test. 
Differences in ORR between subgroups will be assessed by the Pearson chi-square test. No 
adjustments will be made for multiple comparisons. 
9.2.3 Safety Endpoints 
Adverse events attributed to pembrolizumab will be listed by CTCAE grade and reported in 
terms of the number of patients who experienced adverse events as a percentage of all treated 
patients. This endpoint will be reported descriptively without formal statistical analysis.  
9.2.4 Baseline Characteristics and Other Analyses 
Each relevant clinical characteristic will be recorded by the use of tables and/or graphs. No 
statistical hypothesis tests will be performed on these characteristics. The number and percentage 
of patients treated, and the primary reason for discontinuation will be displayed. Demographic 
variables (such as age) and baseline characteristics will be summarized by descriptive statistics. 
Drug accountability data for pembrolizumab will be collected during the study. Compliance with 
pembrolizumab administration will be measured by patients: 1) receiving unscheduled study 
agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages of patients 
and infusion/injection visits with any deviation in these measures will be reported. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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IWAI Y, ISHIDA M, TANAKA Y, OKAZAKI T, HONJO T, MINATO N. 
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TSUSHIMA F, TANAKA K, OTSUKI N, YOUNGNAK P, IWAI H, OMURA K, ET 
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TOPALIAN SL, HODI FS, BRAHMER JR, GETTINGER SN, SMITH DC, 
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HAMID O, ROBERT C, DAUD A, HODI FS, HWU WJ, KEFFORD R, ET AL. 
SAFETY AND TUMOR RESPONSES WITH LAMBROLIZUMAB (ANTI-PD-1) IN 
MELANOMA. N ENGL J MED. 2013. 
18. 
JIA R, JIAO Z, XU X, WANG J, ZHOU Y, SONG X, ET AL. FUNCTIONAL 
SIGNIFICANCE OF B7-H1 EXPRESSED BY HUMAN UVEAL MELANOMA CELLS. MOL 
MED REP. 2011;4:163-7. 
19. 
BRONKHORST IH, VU TH, JORDANOVA ES, LUYTEN GP, BURG SH, JAGER MJ. 
DIFFERENT SUBSETS OF TUMOR-INFILTRATING LYMPHOCYTES CORRELATE 
WITH MACROPHAGE INFLUX AND MONOSOMY 3 IN UVEAL MELANOMA. INVEST 
OPHTHALMOL VIS SCI. 2012;53:5370-8. 
20. 
BRONKHORST IH, JAGER MJ. INFLAMMATION IN UVEAL MELANOMA. EYE 
(LOND). 2013;27:217-23. 
21. 
BRONKHORST IH, LY LV, JORDANOVA ES, VROLIJK J, VERSLUIS M, LUYTEN 
GP, ET AL. DETECTION OF M2-MACROPHAGES IN UVEAL MELANOMA AND 
RELATION WITH SURVIVAL. INVEST OPHTHALMOL VIS SCI. 2011;52:643-50. 
22. 
LUKE JJ, CALLAHAN MK, POSTOW MA, ROMANO E, RAMAIYA N, BLUTH M, 
ET AL. CLINICAL ACTIVITY OF IPILIMUMAB FOR METASTATIC UVEAL 
MELANOMA: A RETROSPECTIVE REVIEW OF THE DANA-FARBER CANCER 
INSTITUTE, 
MASSACHUSETTS 
GENERAL 
HOSPITAL, 
MEMORIAL 
SLOAN-
KETTERING CANCER CENTER, AND UNIVERSITY HOSPITAL OF LAUSANNE 
EXPERIENCE. CANCER. 2013. 
23. 
MAIO M, DANIELLI R, CHIARION-SILENI V, PIGOZZO J, PARMIANI G, 
RIDOLFI R, ET AL. EFFICACY AND SAFETY OF IPILIMUMAB IN PATIENTS WITH 
PRE-TREATED, UVEAL MELANOMA. ANN ONCOL. 2013;24:2911-5. 
24. 
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;45:228-47. 
25. 
SHIRABE K, MOTOMURA T, MUTO J, TOSHIMA T, MATONO R, MANO Y, ET 
AL. TUMOR-INFILTRATING LYMPHOCYTES AND HEPATOCELLULAR CARCINOMA: 
PATHOLOGY AND CLINICAL MANAGEMENT. INT J CLIN ONCOL. 2010;15:552-8. 
26. 
DIEDERICHSEN AC, HJELMBORG J, CHRISTENSEN PB, ZEUTHEN J, FENGER 
C. PROGNOSTIC VALUE OF THE CD4+/CD8+ RATIO OF TUMOUR INFILTRATING 
LYMPHOCYTES IN COLORECTAL CANCER AND HLA-DR EXPRESSION ON TUMOUR 
CELLS. CANCER IMMUNOL IMMUNOTHER. 2003;52:423-8. 
27. 
HILLEN F, BAETEN CI, VAN DE WINKEL A, CREYTENS D, VAN DER SCHAFT 
DW, WINNEPENNINCKX V, ET AL. LEUKOCYTE INFILTRATION AND TUMOR CELL 

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PLASTICITY ARE PARAMETERS OF AGGRESSIVENESS IN PRIMARY CUTANEOUS 
MELANOMA. CANCER IMMUNOL IMMUNOTHER. 2008;57:97-106. 
28. 
GAO Q, QIU SJ, FAN J, ZHOU J, WANG XY, XIAO YS, ET AL. INTRATUMORAL 
BALANCE OF REGULATORY AND CYTOTOXIC T CELLS IS ASSOCIATED WITH 
PROGNOSIS OF HEPATOCELLULAR CARCINOMA AFTER RESECTION. J CLIN 
ONCOL. 2007;25:2586-93. 
29. 
OSHIKIRI T, MIYAMOTO M, SHICHINOHE T, SUZUOKI M, HIRAOKA K, 
NAKAKUBO Y, ET AL. PROGNOSTIC VALUE OF INTRATUMORAL CD8+ T 
LYMPHOCYTE IN EXTRAHEPATIC BILE DUCT CARCINOMA AS ESSENTIAL 
IMMUNE RESPONSE. J SURG ONCOL. 2003;84:224-8. 
30. 
GREENWALD RJ, FREEMAN GJ, SHARPE AH. THE B7 FAMILY REVISITED. 
ANNU REV IMMUNOL. 2005;23:515-48. 
31. 
ZHANG X, SCHWARTZ JC, GUO X, BHATIA S, CAO E, LORENZ M, ET AL. 
STRUCTURAL AND FUNCTIONAL ANALYSIS OF THE COSTIMULATORY RECEPTOR 
PROGRAMMED DEATH-1. IMMUNITY. 2004;20:337-47. 
32. 
OKAZAKI T, MAEDA A, NISHIMURA H, KUROSAKI T, HONJO T. PD-1 
IMMUNORECEPTOR INHIBITS B CELL RECEPTOR-MEDIATED SIGNALING BY 
RECRUITING SRC HOMOLOGY 2-DOMAIN-CONTAINING TYROSINE PHOSPHATASE 
2 TO PHOSPHOTYROSINE. PROC NATL ACAD SCI U S A. 2001;98:13866-71. 
33. 
CHEMNITZ JM, PARRY RV, NICHOLS KE, JUNE CH, RILEY JL. SHP-1 AND SHP-
2 ASSOCIATE WITH IMMUNORECEPTOR TYROSINE-BASED SWITCH MOTIF OF 
PROGRAMMED DEATH 1 UPON PRIMARY HUMAN T CELL STIMULATION, BUT 
ONLY RECEPTOR LIGATION PREVENTS T CELL ACTIVATION. J IMMUNOL. 
2004;173:945-54. 
34. 
SHEPPARD KA, FITZ LJ, LEE JM, BENANDER C, GEORGE JA, WOOTERS J, ET 
AL. PD-1 INHIBITS T-CELL RECEPTOR INDUCED PHOSPHORYLATION OF THE 
ZAP70/CD3ZETA SIGNALOSOME AND DOWNSTREAM SIGNALING TO PKCTHETA. 
FEBS LETT. 2004;574:37-41. 
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RILEY JL. PD-1 SIGNALING IN PRIMARY T CELLS. IMMUNOL REV. 
2009;229:114-25. 
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PARRY RV, CHEMNITZ JM, FRAUWIRTH KA, LANFRANCO AR, BRAUNSTEIN 
I, KOBAYASHI SV, ET AL. CTLA-4 AND PD-1 RECEPTORS INHIBIT T-CELL 
ACTIVATION BY DISTINCT MECHANISMS. MOL CELL BIOL. 2005;25:9543-53. 
37. 
AGATA Y, KAWASAKI A, NISHIMURA H, ISHIDA Y, TSUBATA T, YAGITA H, 
ET AL. EXPRESSION OF THE PD-1 ANTIGEN ON THE SURFACE OF STIMULATED 
MOUSE T AND B LYMPHOCYTES. INT IMMUNOL. 1996;8:765-72. 
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VIBHAKAR R, JUAN G, TRAGANOS F, DARZYNKIEWICZ Z, FINGER LR. 
ACTIVATION-INDUCED EXPRESSION OF HUMAN PROGRAMMED DEATH-1 GENE IN 
T-LYMPHOCYTES. EXP CELL RES. 1997;232:25-8. 
39. 
NISHIMURA H, HONJO T, MINATO N. FACILITATION OF BETA SELECTION 
AND MODIFICATION OF POSITIVE SELECTION IN THE THYMUS OF PD-1-
DEFICIENT MICE. J EXP MED. 2000;191:891-8. 
40. 
SIEGEL R, MA J, ZOU Z, JEMAL A. CANCER STATISTICS, 2014. CA CANCER J 
CLIN. 2014;64:9-29. 

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41. 
KORN EL, LIU PY, LEE SJ, CHAPMAN JA, NIEDZWIECKI D, SUMAN VJ, ET AL. 
META-ANALYSIS OF PHASE II COOPERATIVE GROUP TRIALS IN METASTATIC 
STAGE IV MELANOMA TO DETERMINE PROGRESSION-FREE AND OVERALL 
SURVIVAL BENCHMARKS FOR FUTURE PHASE II TRIALS. J CLIN ONCOL. 
2008;26:527-34. 
42. 
CHAPMAN PB, HAUSCHILD A, ROBERT C, HAANEN JB, ASCIERTO P, LARKIN 
J, ET AL. IMPROVED SURVIVAL WITH VEMURAFENIB IN MELANOMA WITH BRAF 
V600E MUTATION. N ENGL J MED. 2011;364:2507-16. 
43. 
HODI FS, O'DAY SJ, MCDERMOTT DF, WEBER RW, SOSMAN JA, HAANEN JB, 
ET AL. IMPROVED SURVIVAL WITH IPILIMUMAB IN PATIENTS WITH METASTATIC 
MELANOMA. N ENGL J MED. 2010;363:711-23. 
44. 
STRICKLAND D, LEE JA. MELANOMAS OF EYE: STABILITY OF RATES. AM J 
EPIDEMIOL. 1981;113:700-2. 
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CHANG AE, KARNELL LH, MENCK HR. THE NATIONAL CANCER DATA BASE 
REPORT ON CUTANEOUS AND NONCUTANEOUS MELANOMA: A SUMMARY OF 
84,836 CASES FROM THE PAST DECADE. THE AMERICAN COLLEGE OF SURGEONS 
COMMISSION ON CANCER AND THE AMERICAN CANCER SOCIETY. CANCER. 
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MAAT W, LY LV, JORDANOVA ES, DE WOLFF-ROUENDAAL D, SCHALIJ-
DELFOS 
NE, 
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MJ. 
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OF 
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3 
AND 
AN 
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OPHTHALMOL VIS SCI. 2008;49:505-10. 
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WEBER JS, KUDCHADKAR RR, GIBNEY GT, DE CONTI RC, YU B, ET AL. 
PHASE I/II TRIAL OF PD-1 ANTIBODY NIVOLUMAB WITH PEPTIDE VACCINE IN 
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TABERNERO J, POWERDERLY JD, HAMID, O, ET AL. . CLINICAL ACTIVITY, 
SAFETY, AND BIOMARKERS OF MPDL3280A, AN ENGINEERED PD-L1 ANTIBODY IN 
PATIENTS WITH LOCALLY ADVANCED OR METASTATIC CRC, GASTRIC CANCER 
(GC), SCCHN, OR OTHER TUMORS. . J CLIN ONCOL. 2013;31:3622. 

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Protocol date: August 30, 2016 
13.0  APPENDICES 
13.1 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. 
 
 
 
 
 
 
 
 
 
 

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Supplementary Table 3: Events of Clinical Interest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

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higher dose of 80 or 100 mg followed by a more prolonged taper and administer additional anti-
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
–
 
 
 

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–
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
Grade 3 events: 
– 
Report as ECI 

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Infusion Reactions  

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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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Appendix 13.5 – PD1 Eye Exam Source Document 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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MD Signature: _______________________________________            Date: _______________________