Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 80
Healthy volunteers: no

Brief summary:
This is a single-arm, single-center, open-label trial of pembrolizumab (MK-3475) in subjects with advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who have progressed after failure of any combination chemotherapy containing a platinum and a fluoropyrimidine agent.

Approximately 60 subjects will be enrollment to evaluate the efficacy and safety of pembrolizumab.

Enrollment will begin with all subjects without regard for PD-L1 expression status. An evaluable specimen for PD-L1 status must be available and confirmed prior to enrollment.

All study subjects will be evaluated every 6 weeks (+/- 7 days) following the date of IP drug adminstration for the first six months and every 12 weeks (+/- 7 days) thereafter until progression of disease is documented with radiologic imaging (computed tomography or magnetic resonance imaging).

In the expansion cohort (cohort B), it was expanded on the original cohort based on response analysis and will be opened separately.

Of the 5 MSI-high patients who were enrolled on to original cohort, all 5 MSI high GC patients (100% response rate) demonstrated dramatic response rate.

Based on this finding, in order to proven Pembrolizumab's efficacy to specific MSI-H GC population, we would like enroll 20 more patients in cohort B. Based on our screening protocol, the prevalence of MSI-high in GC is about 15 %. Only MSI-high GC patients will be included. All the eligibility will be the same.

Detailed description:
Each subject will participate in the trial from the time the subject signs the Informed Consent Form (ICF) through the final contact. After a screening phase of up to 28 days, eligible subjects will receive treatment beginning on Day 1 of each 3-week dosing cycle for pembrolizumab.

Treatment with pembrolizumab or paclitaxel will continue until documented disease progression, unacceptable adverse event(s), undercurrent illness that prevents further administration of treatment, Investigator's decision to withdraw the subject, subject withdraw consent, pregnancy of the subject, noncompliance with trial treatment o procedure requirements, subject receives 24 months of pembrolizumab, or administrative reasons requiring cessation of treatment. After the end of treatment, each subject will be followed for 30 days for adverse event monitoring (serious adverse events and events of clinical interest will be collected for 90 days after the end of treatment or 30 days after the end of treatment if the subject initiates new anticancer therapy, whichever is earlier).

Subjects within the pembrolizumab arm who discontinue after 24 months of therapy for reasons other than disease progression or intolerability or who discontinue after attaining a CR may be eligible for up to one year of retreatment after they have experienced radiographic disease progression.

Subjects who discontinue for reasons other than disease progression 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.

All subjects will be followed by telephone for overall survival until death, withdrawal of consent, or the end of the study.

Arms:
arm 1: Cohort A :gastric cancer patients Cohort B : MSI-H gastric cancer patients All Chort receive the following treatment.

* Pembrolizumab 200 mg every 3 weeks

Interventions: intervention 1: pembrolizumab
Intervention descriptions: intervention 1: 200 mg every 3 weeks

Protocol document:
Prot_SAP_000.pdf: 
Ver1.0_10SEP2015 
 
 
1 
 
Clinical Study Protocol 
 
 
 
 
TITLE:  
 
Phase II study of pembrolizumab in Subjects with Advanced Gastric or Gastroesophageal 
Junction Adenocarcinoma who Progressed after First-Line Therapy with Platinum and 
Fluoropyrimidine: integration of molecular subtypes through integrative genomic analysis. 
 
 
 
 
 
 
 
 
 
Study Drug 
pembrolizumab 
Version Number 
1.0 
Version Date 
10.SEP.2015 
Study site 
Samsug Medical Center 
Principal Investigator (Sponsor-Investigator) 
 
Professor Jee yun  Lee M.D, Ph.D.  
 
 
 
 
 
 
 
Revision History 
 Version        
        
 Version        
        
 Version        
        
 Version 1.0  
10 SEP 2015 
 


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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties 
include ensuring the safety of the study subjects enrolled under my supervision with 
complete and timely information, as outlined in the protocol.  It is understood that all 
information pertaining to the study will be held strictly confidential and that this 
confidentiality requirement applies to all study staff at this site. Furthermore, on behalf of the 
study staff and myself, I agree to maintain the procedures required to carry out the study in 
accordance with accepted GCP principles and to abide by the terms of this protocol. 
 
 
Protocol Title: Phase II study of pembrolizumab in  Subjects with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma who Progressed after First-Line Therapy with 
Platinum and Fluoropyrimidine: integration of molecular subtypes through integrative 
genomic analysis. 
 
 
 
 
 
Investigator Signature  
 
Date 
 
 
 
 
 
 
 


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1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase II study of pembrolizumab in Subjects with Advanced Gastric or 
Gastroesophageal Junction Adenocarcinoma who Progressed after 
First-Line Therapy with Platinum and Fluoropyrimidine: integration of 
molecular subtypes through integrative genomic analysis. 
Trial Phase 
II 
Clinical Indication 
Advanced      Gastric      or      Gastroesophageal      Junction      (GEJ) 
Adenocarcinoma 
Trial Type 
Interventional 
Type of control 
One arm 
Route of administration 
Intravenous 
Trial Blinding 
Open-label 
Treatment Groups  
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W) 
Number of trial subjects 
Approximately up to 40 subjects will be enrolled. 
Estimated enrollment period 
12 months 
Estimated duration of trial 
Investigator estimates that the trial will require approximately 
 
24 months from the time the first subject signs the informed consent until
last subject’s last visit. 
Estimated date of first subject enrolled : Q3  2015 
Estimated date of last subject completed: Q3  2017 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form (ICF) through the final contact. After a 
screening phase of up to 28 days, eligible subjects will receive treatment 
beginning on Day 1 of each 3-week dosing cycle for pembrolizumab.  
Treatment with pembrolizumab  will continue until 
documented    disease    progression,    unacceptable    adverse    event(s)
,intercurrent illness that prevents further administration of treatment, 
Investigator’s decision to withdraw the subject, subject withdraws 
consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, subject receives 24 months of pembrolizumab, 
or administrative reasons requiring cessation of treatment. After the end 
of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events and events of clinical interest will be 
collected for 90 days after the end of treatment or 30 days after the end 
of treatment if the subject initiates new anticancer therapy, whichever is 
earlier). 
Subjects  who discontinue after 24months of therapy for reasons other th
an disease progression or 
intolerability or who discontinue after attaining a CR may be eligible for 
up to one year of retreatment after they have experienced radiographic 
disease progression. 


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Subjects who discontinue for reasons other than disease progression 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. All subjects will be followed by 
telephone for overall survival until death, withdrawal of consent, or the 
end of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0 
TRIAL SUMMARY ................................................................................................................................. 3 
2.0 
Title of the study ....................................................................................................................................... 7 
3.0 
Participating Center .................................................................................................................................. 7 
4.0 
name of Principal Investigator, sub-investigators .................................................................................... 7 
4.1 
Principal Investigator ........................................................................................................................... 7 
4.2 
Sub-Investigators ................................................................................................................................. 7 
5.0 
TRIAL DESIGN ....................................................................................................................................... 7 
5.1 
Trial Design ......................................................................................................................................... 7 
5.2 
Trial Diagram ....................................................................................................................................... 9 
6.0 
OBJECTIVE(S) & HYPOTHESIS(ES) ................................................................................................... 9 
6.1 
Primary efficacy Objective(s) & Hypothesis(es) ................................................................................. 9 
6.2 
Primary genomic Objective(s) & Hypothesis(es) ................................................................................ 9 
6.3 
Exploratory Objective .......................................................................................................................... 9 
7.0 
BACKGROUND & RATIONALE ........................................................................................................ 10 
7.1 
Background ........................................................................................................................................ 10 
7.2 
Rationale ............................................................................................................................................ 11 
8.0 
METHODOLOGY ................................................................................................................................. 14 
8.1 
Entry Criteria ..................................................................................................................................... 14 
8.2 
Trial Treatments ................................................................................................................................. 18 
8.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ...................................................... 21 
8.4 
Rescue Medications & Supportive Care ............................................................................................ 22 
8.5 
Diet/Activity/Other Considerations ................................................................................................... 25 
8.6 
Subject Withdrawal/Discontinuation Criteria .................................................................................... 27 
8.7 
Subject Replacement Strategy ........................................................................................................... 28 
8.8 
Clinical Criteria for Early Trial Termination ..................................................................................... 28 


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9.0 
TRIAL FLOW CHART .......................................................................................................................... 29 
9.1 
Study Flow Chart ............................................................................................................................... 29 
10.0 
TRIAL PROCEDURES .......................................................................................................................... 32 
10.1 
Trial Procedures ................................................................................................................................. 32 
10.2 
Assessing and Recording Adverse Events ......................................................................................... 38 
11.0 
STATISTICAL ANALYSIS PLAN ....................................................................................................... 45 
11.1 
Statistical Analysis Plan ..................................................................................................................... 45 
11.2 
Sample size ........................................................................................................................................ 45 
12.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ....................... 46 
12.1 
Investigational Product ...................................................................................................................... 46 
12.2 
Packaging and Labeling Information ................................................................................................. 46 
12.3 
Clinical Supplies Disclosure .............................................................................................................. 47 
12.4 
Storage and Handling Requirements ................................................................................................. 47 
12.5 
Returns and Reconciliation ................................................................................................................ 47 
13.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................................................... 47 
13.1 
Confidentiality ................................................................................................................................... 47 
13.2 
Compliance with Financial Disclosure Requirements ....................................................................... 48 
13.3 
Compliance with Law, Audit and Debarment ................................................................................... 48 
13.4 
Compliance with Trial Registration and Results Posting Requirements ........................................... 48 
14.0 
Monitoring .............................................................................................................................................. 48 
15.0 
Data Handling ......................................................................................................................................... 48 
16.0 
Sample Identification and retension specimen ....................................................................................... 48 
17.0 
References ............................................................................................................................................... 49 
18.0 
APPENDICES ........................................................................................................................................ 51 
18.1 
ECOG Performance Status ................................................................................................................ 51 
18.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ................................................ 51 
 
 


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2.0 TITLE OF THE STUDY 
Phase II study of pembrolizumab in Subjects with Advanced Gastric or Gastroesophageal 
Junction Adenocarcinoma who Progressed after First-Line Therapy with Platinum and 
Fluoropyrimidine: integration of molecular subtypes through integrative genomic analysis. 
3.0 PARTICIPATING CENTER 
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, 
Sungkyunkwan University School of Medicine, Seoul, Korea 
 
4.0 NAME OF PRINCIPAL INVESTIGATOR, SUB-INVESTIGATORS 
4.1 
Principal Investigator 
Professor Jeeyun Lee M.D, Ph.D.  
4.2 
Sub-Investigators 
Won Ki Kang, M.D, Ph.D. 
Ho Yeong Lim, M.D , Ph.D. 
Young Suk Park, M.D , Ph.D. 
Joon Oh Park, M.D, Ph.D.                                            
 Se Hoon Park, M.D , Ph.D.                                                 
Seung Tae Kim, M.D , Ph.D. 
Sujin Lee, M.D , Ph.D. 
 
5.0 TRIAL DESIGN 
5.1 
Trial Design 
This is a single-arm, single-center, open-label trial of pembrolizumab (MK-3475) in subjects 
with advanced gastric or gastroesophageal junction (GEJ) 
adenocarcinoma 
who 
have 
progressed after failure of any combination chemotherapy containing a platinum and a 
fluoropyrimidine agent. 
 
Approximately 40 subjects will be enrollment to evaluate the efficacy and safety of 
pembrolizumab.  
 
Enrollment will begin with all subjects without regard for PD-L1 expression status.  


Ver1.0_10SEP2015 
 
 
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An evaluable specimen for PD-L1 status must be available and confirmed prior to enrollment.  
 
All study subjects will be evaluated every 6 weeks (+/- 7 days) following the date of IP drug 
adminstration for the first six months and every 12 weeks (+/- 7 days) thereafter until 
progression of disease is documented with radiologic imaging (computed tomography or 
magnetic resonance imaging). 
 
The primary efficacy endpoint is ORR (objective response rate) per mRECIST. 
If a subject has progression of disease by mRECIST, it is recommended that the subject be 
discontinued from the study treatment unless, in the Investigator’s opinion, the subject is 
 deriving benefit from  treatment. 
Clinically stable subjects may continue to receive trial therapy at the discretion of the  
Investigator. If a repeat scan confirms progression of disease and the subject remains  
clinically stable, the subject may continue treatment . 
 
Adverse events will be monitored throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0. 
 
Except as noted above, treatment with pembrolizumab  will continue until documented 
disease progression, unacceptable adverse event(s), intercurrent illness that prevents 
further administration of treatment, Investigator’s decision to withdraw the subject, 
subject withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, completion of 24 months of pembrolizumab, or administrative 
reasons requiring the cessation of treatment. 
 
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events and events of clinical interest will be collected for 90 
days after the end of treatment or 30 days after the end of treatment if the subject initiates 
new anticancer therapy, whichever is earlier).Subjects who discontinue treatment for 
reasons other than disease progression will 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. All subjects will be followed by telephone contact for overall 
survival until death, withdrawal of consent or the end of the study, whichever comes first. 
 
This study will be conducted in conformance with Good Clinical Practices. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart. Details of each 
procedure are provided in Trial Procedures. 
 
 
 


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5.2 
Trial Diagram 
 
 
6.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
6.1 
Primary efficacy Objective(s) & Hypothesis(es) 
Objective: To evaluate RR per mRECIST in advanced gastric or GEJ adenocarcinoma 
who have progressed on one previous line of therapy, when treated with pembrolizumab 
Hypothesis: Pembrolizumab increases RR per mRECIST with advanced gastric or 
GEJ adenocarcinoma who have progressed on 1 previous line of therapy 
6.2 
Primary genomic Objective(s) & Hypothesis(es) 
(1) Objective: Integrative genomic analysis to identify predictive markers (i.e. immune 
signatures) and analyze the response rate according to molecular signatures identified 
through the ACRG effort.;  Categorization: 1) mesenchymal, 2) MSI, 3) MSS-TP 53 
intact, 4) MSS- TP53 mutation 
Hypothesis: Association of response with tumor histology  
Association of response with molecular signatures at baseline  
Activation of immune pathways post treatment and association with 
response 
Be good response to Pembrolizumab in MSS-MSI molecular and high-
mutational burden type 
6.3 
Exploratory Objective 
(1) 
Objective: Genomic analysis: Whole Exome Sequencing at baseline, RNA-seq pre and 
post (WES will be performed at SMC and analyzed together with the BI team at 
MERCK MSD (GpGx CSB and PGx Groups, Drs. Cristescu, Nebozhyn, Ayers, Hirsch 
and Loboda) and SMC (Genome Center and Molecular Pathology). 
(2) 
As an exploratory analysis, we will isolate T cells using FACS sorting and sequence 
these cells. In addition, in order to identify the relationship between neoantigen drivers 


Ver1.0_10SEP2015 
 
 
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like infection and response to pembrolizumab, we will prospectively collect serum 
antigens from blood at baseline. 
7.0 BACKGROUND & RATIONALE 
7.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on MK-3475. 
7.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  
The structure of murine PD-1 has been resolved.  PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are 
involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on 
activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and 
Natural Killer cells.  Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.  The 
ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a 
variety of cell types, including non-hematopoietic tissues as well as in various tumors.  Both 
ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the 
extracellular region and contain short cytoplasmic regions with no known signaling motifs.  
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell 
receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 


Ver1.0_10SEP2015 
 
 
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antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments.  
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma (MEL). In gastric cancer PD-L1 and PD-L2 
overexpression have recently been associated with EBV-positive tumors. This suggests that 
the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the 
United Stated for the treatment of patients with unresectable or metastatic melanoma and 
disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF 
inhibitor. 
7.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
7.2 
Rationale 
7.2.1 Rationale for the Trial and Selected Subject Population 
Gastric cancer (GC) is the second most common cause of cancer related mortality and the 
fourth most common cancer worldwide. The molecular classification of GC and the 
relevance of pre-clinical models are not well established, creating challenges in discovering 
novel molecularly targeted therapies. In order to address these issues, we conducted an 
integrated molecular data analysis of three hundred Asian Gastric tumors through the Asian 
Cancer Research Group (ACRG). We performed an integrated genomic analyses based on 
target sequencing, gene expression profiling, copy number variations, Lauren’s histological 
classification, Epstein Barr Virus (EBV) status, TP53 status in three hundred GC specimens. 
We first divided GC into four subgroups based on gene expression profiling and TP53 status: 
1) epithelial MSS-TP53 inactive; 2) epithelial MSS-TP53 active; 3) MSI; and 4) 
mesenchymal. With an integrative analysis with target sequencing and copy number 
variations, epithelial MSS-TP53 inactive GCs are characterized by predominantly 
hypermutated intestinal tumors (including majority of mutations in KRAS) with MLH1 loss 
through promoter methylation and MSS-TP53 active GCs are characterized by intact TP53 
pathway with high frequency of EBV infection or frequently mutated oncogenes (e.g. 
PIK3CA). MSI subtype with TP53 pathway inactive characterized by TP53 loss through 
deleterious mutations in TP53 or MDM2 amplification and further characterized by both 
focal amplifications in oncogenes such as HER2, EGFR, cMET, CCNE1 as well as large 
scale chromosomal gains and losses. The above subtypes exhibited differential prognosis 
with the mesenchymal subtype displaying the worst survival (2.2 years) and the MSI subtype 
the most favorable survival (5.6 years). The GC subtypes and their association with 


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prognosis were independently validated in three GC cohorts. We additionally showed 
significant association of global gene expression immune patterns, like adaptive immune 
system and inflammation, as well as expression of PD-L1, with the genomic defined 
subtypes.  
In the phase Ib KEYNOTE-012 study which evaluated pembrolizumab monotherapy at 10 
mg/kg ever 2 weeks in patients with gastric cancer were recently reported. Most patients had 
two or more prior lines of therapy. In the study, 41% of evaluable patients showed tumor 
shrinkage. The overall response rate in 39 patients were 31%.  
The preliminary data showed a Not significant correlation between PD-L-1 expression and 
ORR (P=0.071).  
Given the mutual association of tumor genetic markers, gene expression and potential 
markers of response to immune therapy identified through the collaborative work between 
SMC and MERCK MSD and Lilly, we plan to perform a phase II study with integrative 
genomic analysis (whole exome and RNA sequencing) in pre and post biopsy specimens to 
better define those GCs who may benefit from pembro. 
7.2.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and 
clinical activity of single agent 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. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This 
early PK and pharmacodynamic data provides scientific rationale for testing a Q2W and 
Q3W dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 patients. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  MK-3475 has been found to have a wide therapeutic 
range based on the melanoma indication.  The differences in exposure for a 200 mg fixed 


Ver1.0_10SEP2015 
 
 
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dose regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in the 
melanoma indication. The exposure margins are based on the notion of similar efficacy and 
safety in melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 
5-fold higher dose and exposure). The population PK evaluation revealed that there was no 
significant impact of tumor burden on exposure. In addition, exposure was similar between 
the NSCLC and melanoma indications. Therefore, there are no anticipated changes in 
exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at 
either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response 
relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg 
Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on distribution 
behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption 
that the dynamics of pembrolizumab target engagement will not vary meaningfully with 
tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based 
on simulations performed using the population PK model of pembrolizumab showing that the 
fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent 
with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. 
7.2.3 Rationale for Endpoints 
7.2.3.1 Efficacy Endpoints 
mRECIST will be adapted to account for the unique tumor response profile seen with 
immunotherapies such as pembrolizumab. Immunotherapeutic agents such as pembrolizumab 
may produce antitumor effects by potentiating endogenous cancer-specific immune 
responses which may be functionally anergic. The response patterns seen with such an 
approach may extend beyond the typical time course of responses seen with cytotoxic agents, 
and can manifest a clinical response after an initial increase in tumor burden or even the 
appearance of new lesions. 
 
When feasible, subjects within the pembrolizumab arm should not be discontinued until 
progression is confirmed. This allowance to continue treatment despite initial radiologic 
progression takes into account the observation that some subjects can have a transient tumor 


Ver1.0_10SEP2015 
 
 
14 
 
flare in the first few months after the start of immunotherapy, but with subsequent disease 
response. 
7.2.3.2 Biomarker Research 
We will conduct Biomarker Research on specimens collected during this clinical trial. This 
research may include genetic analyses (DNA), gene expression profiling (RNA), proteomics, 
metabolomics (serum, plasma) and/or the measurement of other analytes. 
 
Genomic analysis: Whole Exome Sequencing at baseline, RNA-seq pre and post (Whole 
Exome Sequencing will be performed at SMC and analyzed together with the BI team at 
MERCK MSD (GpGx CSB and PGx Groups, Drs. Cristescu, Nebozhyn, Ayers, Hirsch and 
Loboda) and SMC (Genome Center and Molecular Pathology). 
Asian Cancer Research Group (ACRG) cohort with operable gastric cancer subjects found a 
strong association between high expression of PD-L1 and either MSI/hypermutation or EBV 
infection. In addition, the above subtypes exhibited differential prognosis on overall survival, 
with the EBV infection subtype and the MSI subtype displaying the best prognosis among all 
the subtypes. 
The objective of collecting specimens for Biomarker Research is to explore and identify 
biomarkers that inform the scientific understanding of diseases and/or their therapeutic 
treatments. Integrative genomic analysis (i.e. gene signature, MSH, etc.) measured may be a 
predictive biomarker for patients who receive pembrolizumab treatment.  
 
As an exploratory analysis, we will isolate T cells using FACS sorting and sequence these 
cells. In addition, in order to identify the relationship between neoantigen drivers like 
infection and response to pembrolizumab, we will prospectively collect serum antigens from 
blood at baseline. 
8.0 METHODOLOGY 
8.1 
Entry Criteria 
8.1.1 Diagnosis/Condition for Entry into the Trial 
8.1.2 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. The 
subject may also provide consent for Biomedical Research. However, the subject may 
participate in the main trial without participating in Biomedical Research. 
2. Be ³ 19years of age on day of signing informed consent (or acceptable age according 
to local regulations, whichever is older). 
3. Have histologically or cytologically-confirmed diagnosis of gastric or GEJ  


Ver1.0_10SEP2015 
 
 
15 
 
adenocarcinoma. 
 
4. Have metastatic disease or locally advanced, unresectable disease. 
5. Has experienced documented objective radiographic or clinical disease progression 
during or after first-line therapy containing any platinum/fluoropyrimidine doublet. 
a. To be considered as second-line, the subject needs to have the documentation 
of disease progression on first-line treatment. The disease progression can be 
confirmed by CT scan or by clinical evidence (such as cytology report from 
newly developed ascites and plural effusion). 
b. Any new or worsening malignant effusion (documented by ultrasound) may 
be confirmed by pathologic criteria (histology and/or cytology) if appropriate. 
c. A subject experiencing clinical disease progression during or within 6 months 
following the last dose of adjuvant therapy will be eligible for enrollment 
provided they received a platinum/fluoropyrimidine doublet as required. 
d. To be eligible, the subject is required to have received at least one dose of 
platinum and fluoropyrimidine therapy. 
 
The dose reduction and discontinuation of one of these drugs, switching 
to/adding new drugs on the first-line treatment is allowed; however, the 
documentation of disease progression on/after the first-line treatment is 
required. Therefore, subjects with discontinuation due to adverse events on 
first-line treatment prior to disease progression are not eligible until disease 
progression is confirmed by documentation. 
6. Have measurable disease based on mRECIST as determined by investigator. Tumor 
lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions. 
a. Note: The exact same image acquisition and processing parameters should be 
used throughout the study. 
7. Be willing to provide fresh tissue for biomarker analysis, and, based on the adequacy 
of the tissue sample quality for assessment of biomarker status. Repeat samples may 
be required if adequate tissue is not provided. Newly obtained endoscopic biopsy 
specimens are preferred to archived samples and formalin-fixed, paraffin-embedded 
(FFPE) block specimens are preferred to slides. 
a. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) 
prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may 
submit an archived specimen. 
b. Collection of an archived tissue sample will also be requested (where 
available) to support evaluation of the clinical utility of biomarker assessment 


Ver1.0_10SEP2015 
 
 
16 
 
in newly obtained vs. archived tissue samples; however, a subject will not be 
precluded from participating in the study if an archived tissue sample is not 
available for collection or is otherwise insufficient for analysis. 
8. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
9. 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 without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
10. 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.   
11. 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.  


Ver1.0_10SEP2015 
 
 
17 
 
12. 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. 
8.1.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
2. Has squamous cell or undifferentiated gastric cancer. 
3. 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. 
 
4. Has a known history of active TB   (Bacillus Tuberculosis) 
 
5. Hypersensitivity to pembrolizumab or any of its excipients. 
 
6. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
7. 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.   
8. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases, and are 


Ver1.0_10SEP2015 
 
 
18 
 
not using steroids for at least 7 days prior to trial treatment.  This exception does not 
include carcinomatous meningitis which is excluded regardless of clinical stability.   
10. Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. 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.   
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. 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. 
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days of planned start of study therapy. 
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
20. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) who is investigational site or staff directly involved with this trial, unless 
prospective IRB approval (by chair or designee) is given allowing exception to this 
criterion for a specific subject. 
8.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 


Ver1.0_10SEP2015 
 
 
19 
 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg X 
mg/kg 
Q3W 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
 
8.2.1 Dose Selection/Modification 
8.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Background and 
Rationale.   
8.2.1.2 Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Pembrolizumab must be withheld for 
drug-related toxicities and severe or life-threatening AEs as per Table 3 below. Events of 
Clinical Interest Guidance Document for supportive care guidelines, including use of 
corticosteroids. 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 
diabetes 
mellitus 
or 
Grade 
3-4 
hyperglycemia associated with evidence of 
beta cell failure.  
 
Resume pembrolizumab when patients are clinically and 
metabolically stable. 
Hypophysitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 


Ver1.0_10SEP2015 
 
 
20 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Discontinue Subject 
Hypothyroidism 
2-4 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted 
Therapy with pembrolizumab can be continued while treatment for 
the thyroid disorder is instituted. 
Infusion Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.   
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption. The reason for interruption should be documented in the 
patient's study record. 
8.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Section 
6.0).  Trial treatment may be administered up to 3 days before or after the scheduled Day 1 of 
each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  
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). 
8.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 


Ver1.0_10SEP2015 
 
 
21 
 
8.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
8.3.1 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. 
8.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may 
be allowed at the investigator’s discretion.   
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Merk. 


Ver1.0_10SEP2015 
 
 
22 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  
Subjects may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
8.4 
Rescue Medications & Supportive Care 
8.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below and in greater detail in the 
ECI guidance document. Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if 
symptoms do not improve with administration of corticosteroids.   Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care. The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance (as outlined in the ECI guidance document). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. Suggested conditional procedures, as 
appropriate, can be found in the ECI guidance document. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  


Ver1.0_10SEP2015 
 
 
23 
 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out 
colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
§ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
§ Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 


Ver1.0_10SEP2015 
 
 
24 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
§ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
§ In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
§ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
§ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
None 


Ver1.0_10SEP2015 
 
 
25 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
not indicated; intervention not 
indicated 
stable in the opinion of the investigator. 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
8.5 
Diet/Activity/Other Considerations 
8.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
8.5.2 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 


Ver1.0_10SEP2015 
 
 
26 
 
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 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. 
8.5.3 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 Merck without delay and 
within 24 hours to the Merck  and within 2 working days to Merck 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 Merck.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Merck and followed as described above and in 
Section 7.2.2. 
8.5.4 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. 


Ver1.0_10SEP2015 
 
 
27 
 
8.6 
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 if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons.  Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
• 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 uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided 
they meet the requirements detailed in Section 7.1.5.5 
• 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 


Ver1.0_10SEP2015 
 
 
28 
 
who discontinue for reasons other than progressive disease will have post-treatment follow-
up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent or becoming lost to follow-up.  After documented disease progression 
each subject will be followed by telephone for overall survival until death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
8.6.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  Subjects 
who then experience radiographic disease progression may be eligible for up to one year of 
additional treatment with pembrolizumab via the Second Course Phase at the discretion of 
the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial is open.  Subjects will resume therapy at the same dose and schedule at 
the time of initial discontinuation.  Additional details are provided in Section 7.1.5.5. 
8.7 
Subject Replacement Strategy 
A subject who discontinues from the trial will not be replaced. 
 
8.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 


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Protocol/Amendment No.:   
 
 
 
 
 
 
9.0 TRIAL FLOW CHART 
9.1 
Study Flow Chart 
Trial Period: 
Screening 
Phase 
Treatment Cycles a 
End of Treatment 
Post-Treatment 
 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated 
beyond 6 cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits b 
Survival 
Follow Up c 
5 
6 
 
 
 
 
 
 
 
At time of discon 
30 days 
post discon 
Every 6 
weeks 
post discon 
Every 12 
weeks 
Scheduling Window (Days) d: 
-28 to -1  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 7 
± 7 
Administrative Procedures 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent e 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Clinical Procedures/Assessments 
 
 
 
 
 
 
 
 
 
 
 
Review Adverse Events g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG  
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Height, Weight, and Vital Signs (T, P, RR, BP) h 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Post-study Anticancer Therapy Status 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
X 
Trial Treatment Administration 
 
 
 
 
 
 
 
 
 
 
 
Pembrolizumab i 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
Laboratory Procedures/Assessments: 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test – Urine or Serum b-HCG  j 
X 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTT k 
X 
 
 
 
 
 
 
 
 
 
 
CBC with Differential l 
X 
 
X 
X 
X 
X 
Xl 
X 
Xl 
 
 


Product:  Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
Trial Period: 
Screening 
Phase 
Treatment Cycles a 
End of Treatment 
Post-Treatment 
 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
1 
2 
3 
4 
To be repeated 
beyond 6 cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits b 
Survival 
Follow Up c 
5 
6 
 
 
 
 
 
 
 
At time of discon 
30 days 
post discon 
Every 6 
weeks 
post discon 
Every 12 
weeks 
Scheduling Window (Days) d: 
-28 to -1  
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 7 
± 7 
± 7 
Chemistry Panel l 
X 
 
X 
X 
X 
X 
Xl 
X 
Xl 
 
 
Urinalysis l 
X 
 
 
 
 
 
 
 
 
 
 
T3, FT4 and TSH l 
X 
 
X 
 
X  
X 
 
X 
 
 
Serum carcinoembryonic antigen (CEA) l 
X 
 
X 
 
X  
Xl 
 
 
 
 
Serum CA 19-9 l  
X 
 
X 
 
X  
Xl 
 
 
 
 
Blood for Genetics m 
 
X 
 
 
 
 
 
 
 
 
 
Correlative Blood Samples (DNA) n 
 
X 
X 
X 
 
 
 
X 
 
 
 
Correlative Blood Samples (RNA) n 
 
X 
X 
X 
 
 
 
X 
 
 
 
Correlative Blood Samples (plasma) n 
 
X 
 
 
 
 
 
 
 
 
 
Correlative Blood Samples (serum) n 
 
X 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
 
 
 
 
 
 
 
 
 
 
 
Tumor Imaging o 
X 
 
X 
 
X 
 
X 
Xp 
 
X 
 
Tumor Tissue Collection 
 
 
 
 
 
 
 
 
 
 
 
Archival and/or Newly-Obtained Tissue 
Collection 
X 
q 
---------------------------X ------------------------------------ 
q 
X 
 
 
 
 
 
 
 


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Protocol/Amendment No.:   
 
 
 
 
 
 
a.     Unless otherwise specified, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle. 
b. 
In subjects who discontinued study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 6 weeks (± 7 days) if prior to 1 year  or every  9 weeks (± 7 days) if after 1 year, until (1) the start of new anti-cancer treatment, (2) disease progression as 
assessed by  imaging , (3) death, or (4) the end of the study, whichever occurs first. 
c. 
After the start of new anti-cancer treatment or documented disease progression by the  imaging , the subject should be contacted by telephone every 12 weeks to 
assess for survival status. Note: All efforts should be made to ensure telephone contact occurs at least 90 days post discontinue to capture SAEs 
d. 
Unless otherwise specified, the window for each visit is ± 3 days. Cycle 1 treatment must be given within 3 days of enrollment. 
e. 
Written consent must be obtained prior to performing any protocol specified procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of trial treatment). 
f. 
Prior medications – Record all medications taken within 28 days of screening visit. Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit. Record all medications taken for SAEs  
g. 
Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first. Afterwards, report only SAEs and ECIs that are related to trial treatment. 
h. 
Height will be measured at Visit 1 only. Vitals Signs include temperature, pulse, respiratory rate, and blood pressure. 
i. 
Pembrolizumab should be administered on Day 1 of each three week cycle after all procedures/assessments have been completed. 
j. 
For women of reproductive potential, a serum pregnancy test should be performed within 72 hours prior to first dose of trial treatment. A urine test can be considered if serum is 
not appropriate. Pregnancy tests (serum and/or urine tests) should be repeated if required by local guidelines. 
k. 
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. 
l       Laboratory tests for screening are to be performed within 10 days prior to the first dose of trial treatment.  
After Cycle1, lab samples can be collected up to 72 hours prior to the  scheduled time point. To be repeated every 2 cycles after Cycle 6. Unresolved abnormal labs that are dr
ug relatedAEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range. Serum CEA and CA 19-
9 should be collected at screening (baseline) and every 6 weeks (conducted at corresponding study visits) through Week 24 (6 months). After Week 24, serum CEA and CA19-
9 should be collected every 12 weeks until study treatment discontinuation.. 
 
m. This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless the 
IRB/IEC does not approve of the collection of the sample for these purposes.  
n. 
Whole blood sample for correlative studies should be collected at Cycle 1, Day 1- Pre-dose, Cycle 2 Day 1- Pre-dose, Cycle 3 Day 1 Pre-dose and again at treatment 
discontinuation. Blood for serum and blood for plasma to be collected only prior to Cycle 1 Day 1.  
o. 
Baseline tumor imaging will be performed within 14 days prior to enrollment. Scans performed as part of routine clinical management are acceptable for use as the baseline 
scan if they are of diagnostic quality . The exact same image acquisition and processing parameters should 
be used throughout the study. The first on-study imaging time point will be performed 6 weeks (± 7 days) or earlier if clinically indicated and will continue to be performed 
every 6 weeks (± 7 days) regardless of any treatment delays. Following week 24 (6 months), imaging time point will occur every 12 weeks (± 7 days) while the subject remain 
on trial. Imaging timing should follow calendar days. On-study scans should be submitted immediately to the imaging . 
p. 
In subjects who discontinue study therapy without  verified disease progression, a radiologic evaluation should be performed at the time of treatment discontinuation 
(i.e., date of discontinuation ± 4 week window). If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is 
not required. 
q. 
An optional newly-obtained core or excisional biopsy (FNA not adequate) is requested at any post-treatment time point during the study, (preference would be as close to 
dosing at Week 12 as possible). A biopsy is also requested at the time of discontinuation for PD, but will not be required. Endoscopic biopsies are permitted.  
 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
10.0 TRIAL PROCEDURES 
10.1 Trial Procedures 
The Trial Flow Chart 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. 
10.1.1 Administrative Procedures 
10.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
10.1.1.2  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB approval/favorable 
opinion in advance of use.  The subject or his/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. 
The informed consent will adhere to IRB requirements, applicable laws and regulations  
10.1.1.3 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.  
10.1.1.4 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 


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Protocol/Amendment No.:   
 
 
 
 
 
 
for which the subject has enrolled in this study will be recorded separately and not listed as 
medical history.   
10.1.1.5 Prior and Concomitant Medications Review 
10.1.1.5.1 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.  
10.1.1.5.2 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 should be recorded. 
10.1.1.6 Disease Details and Treatments 
10.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
10.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
10.1.1.6.3 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.  
10.1.1.7 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to enrollment. Each subject will be assigned 
only one screening number. Screening numbers must not be re-used for different subjects. 
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
10.1.1.8 Assignment of Enrollment Number 
All eligible subjects will be enrollment and will receive a enrollment number. 
10.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
pembrolizumab doses require consultation between the investigator and written 
documentation of the collaborative decision on subject management.  
Administration of trial medication will be witnessed by the investigator and/or trial staff. 
10.1.2 Clinical Procedures/Assessments 
10.1.2.1 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 .Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to 
trial treatment.  
For subjects receiving treatment with pembrolizumab 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 (termed immune-
related adverse events, or irAEs 
10.1.2.2 Physical Exam 
The investigator or qualified designee will perform a physical exam during the study period.  
Clinically significant abnormal findings should be recorded as medical history.  
10.1.2.3 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. 
10.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 18.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.   


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
10.1.2.5 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Participation in this trial will be dependent upon supplying a tumor tissue specimen. Newly 
obtained endoscopic biopsy specimens are preferred to fresh samplses, archived samples and 
formalin -fixed, paraffin-embedded (FFPE) block specimens are preferred to slides.  
Note: A fine needle aspirate (FNA) or cytologic specimen will not be acceptable. Newly 
obtained endoscopic biopsy specimen or archived tissue should be submitted. If there is an 
existing specimen obtained with surgical resection or core needle biopsy, these can be 
submitted. Newly-obtained specimens are defined as FFPE-preserved blocks of tissue 
collected up to 12 weeks prior to Day 1. 
10.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided belowLaboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Uric Acid 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
Calcium 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Chloride 
 
 
 
Glucose 
 
Blood for correlative studies 
 
Phosphorus 
 
 
 
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.   
 
 
 
 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures 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.  
10.1.4 Other Procedures 
10.1.4.1 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined - 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. After discontinuing treatment following assessment of CR, these 
subjects should return to the site for a Safety Follow-up Visit and then proceed to the Follow-
Up Period of the study  
10.1.5 Visit Requirements 
Visit requirements are outlined in Section 9.0 - Trial Flow Chart. Specific procedure-related 
details are provided above in Section 10.0 - Trial Procedures. 
10.1.5.1 Screening 
10.1.5.1.1 Screening Period 
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine 
 that they fulfill the entry requirements as set forth in Section 8.1. 
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose trial 
treatment except for the following: 
• Laboratory tests and ECOG PS are to be performed within 10 days prior to the first 
dose of trial treatment. 
• For women of reproductive potential, a serum pregnancy test will be performed 
within 72 hours prior to the first dose of trial treatment. A urine test may be 
considered if serum test is not appropriate. 
• Baseline tumor imaging will be performed within 14 days prior to enrollment for 
all subjects. Scans performed as part of routine clinical management are acceptable 
for use as the baseline scan 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
10.1.5.2 Treatment Period 
Visit requirements are outlined in Section 9.0 
10.1.5.3 Discontinuation Visit 
The Discontinuation Visit should occur at the time study treatment is discontin ued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow up Visit, procedures do not need to be repeated. 
Visit requirements are outlined in Section 9.0 
10.1.5.4 Post-Treatment Visits 
10.1.5.4.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-
1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer 
treatment should also be followed and recorded.  
10.1.5.4.2 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 6 weeks (42 ± 7 days) by 
radiologic imaging to monitor disease status.  After 1 year, the imaging time point will occur 
every 9 weeks (± 7 days). 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 .Information regarding post-study anti-neoplastic treatment will be collected if new 
treatment is initiated. 
10.1.5.4.3 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.  
10.2 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-


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
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. 
Progression of the cancer under study is not considered an adverse event unless it is 
considered to be drug related by the investigator. 
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. 
10.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 


Product:   Pembrolizumab 
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Protocol/Amendment No.:   
 
 
 
 
 
 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to the IRB and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
10.2.2 Reporting of Pregnancy and Lactation 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 completing the trial, or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier.  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. 
Such events must be reported within 24 hours to the IRB and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
10.2.3 Immediate Reporting of Adverse Events to Merck 
10.2.3.1 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 an other important medical event  
Refer to Table 6 for additional details regarding each of the above criteria. 
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 


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Protocol/Amendment No.:   
 
 
 
 
 
 
product, must be reported within 24 hours to IRB and within 2 working days to Merck 
Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to IRB and to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
All subjects with serious adverse events must be followed up for outcome. 
10.2.3.2 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 IRB and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220)Events of clinical interest for this trial 
include: 
1.  an overdose of Merck product, as defined in Section 10.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to Merk, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.   
1. Additional adverse events: 
 
ECIs (both non-serious and serious adverse events) identified in this guidance document 
from the date of first dose through 90 days following cessation of treatment, or 30 days 
after the initiation of a new anticancer therapy, whichever is earlier, need to be reported 
within 24 hours to IRB and within 2 working days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220), regardless of attribution to study 
treatment, consistent with standard SAE reporting guidelines. 


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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. 
 
10.2.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 


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Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [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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10.2.5 investigators Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB in accordance with all 
applicable global laws and regulations.  
11.0 STATISTICAL ANALYSIS PLAN 
11.1 Statistical Analysis Plan 
11.1.1 Efficacy  
11.1.1.1 ORR 
The intention to treat (ITT) population included all patients who received at least one dose of 
permbrolizumab.  ORR was calculated with two-sided 95% confidence intervals for the 
overall population. ORR was defined as (CR + PR)/(number of ITT population). 
11.1.1.2 Biomarker 
To explore and identify biomarkers (inform the scientific understanding of diseases and/or 
their therapeutic treatment), the contingency tables will be presented by response for each of 
tumor histology, molecular signatures, immune pathways and etc..  
11.1.2 Safety 
Safety will be assessed by clinical review of all relevant parameters including, adverse events 
(AEs), laboratory tests, vital signs, etc. 
No statistical hypothesis tests will be performed on safety variables. These will be 
summarized by descriptive statistics or categorical tables. 
 
11.2 Sample size  
A Sample size of 23, using a binomial test with a two-sided test at type I error of 0.05 and 
type II error of 0.2, and assuming a proportion of 0.25 for the alternative hypothesis (0.05 for 
the null proportion) were calculated. To explore and identify biomarkers, the 17 additional 
patients were added. Thus, the 40 patients were planned to be enrolled. 
 


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12.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
12.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
12.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 


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12.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, designee are not 
blinded to treatment. Drug identity (name, strength) is included in the label text  
12.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
12.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided that 
procedures for proper disposal have been established according to applicable federal, state, 
local and institutional guidelines and procedures, and provided that appropriate records of 
disposal are kept. 
13.0 ADMINISTRATIVE AND REGULATORY DETAILS 
13.1 Confidentiality 
13.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms to the investigator that information 
furnished will be maintained in confidence, and such information will be divulged to the 
institutional review board, ethics review committee (IRB) or similar or expert committee; 
affiliated institution and employees, only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees. Data 
generated by this trial will be considered confidential by the investigator, except to the extent 
that it is included in a publication as provided in the Publications section of this protocol. 
13.1.2 Confidentiality of Subject Records 
By signing this protocol, the investigator agrees that IRB, or regulatory authority 
representatives may consult trial documents in order to verify worksheet/case report form 
data. By signing the consent form, the subject agrees to this process. If trial documents will 


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be photocopied during the process of verifying worksheet/case report form information, the 
subject will be identified by unique code only 
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations. 
13.2 Compliance with Financial Disclosure Requirements 
Not applicable to this study. 
13.3 Compliance with Law, Audit and Debarment 
13.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the investigator of the trial is 
solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.     
14.0 MONITORING 
A clinical monitoring will make regularly scheduled trips to the investigational site to review 
the progress of the trial. The actual frequency of monitoring trips will depend on the 
enrollment rate and performance at each site. The investigator will allow monitor, and/or its 
representatives of designees, access to all pertinent medical records in order to allow for the 
verification of data gathered in the CRFs and for the review of the data collection process. At 
each visit, the monitor will review various aspects of the trial including, but not limited to: 
screening and enrollment logs; compliance with the protocol and study manual and with the 
principles of Good Clinical Practice; completion of case report forms; source data 
verification; study drug accountability and storage; facilities and staff. 
15.0 DATA HANDLING  
To enable evaluations and/or audits from regulatory authorities, the Investigator agrees to 
keep records, including the identity of all participating subjects (sufficient information to link 
records, eg, CRFs and hospital records), all original signed informed consent forms, copies of 
all CRFs, source documents, and detailed records of treatment disposition. The records 
should be retained by the Investigator according to ICH, local regulations, or as specified in 
the Clinical Study Agreement, whichever is longer.  
 
16.0 SAMPLE IDENTIFICATION AND RETENSION SPECIMEN 
All subjects information will be anonymized. A ‘Sample ID’ number will be recorded.  


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Upon expiration of the retention period determined by subject, the human-derived material 
shall be destroyed in accordance with the standards and methods per the [Wastes Control 
Act] Article 13. 
17.0 REFERENCES 
1. DISIS ML. IMMUNE REGULATION OF CANCER. J CLIN ONCOL 2010; 
28(29):4531-8.  
2. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-
associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. 
Nat Med 2002;8(8):793-800.  
3. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26.  
4. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66.  
5. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42.  
6. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
patients with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61.  
7. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400.  
8.  Usubütün A, Ayhan A, Uygur MC, Ozen H, Toklu C, Ruacan S. Prognostic factors in 
renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.  
9. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. 
Clin Cancer Res 2008;14(16):5220-7.  
10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19.  
11.  Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 
1998;18:689-94.  
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict 
clinical outcome. Science 2006;313:1960-4.  
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51.  
14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged 


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survival of a patient affected by pancreatic adenocarcinoma with massive lymphocyte 
and dendritic cell infiltration after interleukin-2 immunotherapy. Report of a case. 
Tumori 2008;94:426-30.  
15.  Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol 2010;37(Suppl 1):48-53.  
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10:840-841.  
17. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters 
of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 
2008;57:97-106.  
18. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11.  
19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic 
lesions of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-59.  
20. Nishimura H, Honjo T, Minato N. Facilitation of ? selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7.  
21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of 
regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates 
with poor prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6.  
22. Bass, AJ et.al, Comprehensive molecular characterization of gastric adenocarcinoma. 
Nature 513:202-209, 2014 Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, 
Kosma V-M. Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal 
cancer. J Pathol 1997;182:318-24.  


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18.0 APPENDICES 
18.1 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. 
 
18.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
18.3 Response Evaluation Criteria in Solid Tumors mRECIST Criteria for Evaluating 
Response in Solid Tumors 
Complete response (CR) is the disappearance of any all target lesions; 
Partial response (PR) is at least a 30% decrease in the sum of diameters of viable target 
lesions, taking as reference the baseline sum of the diameters of target lesions; 
Progressive disease (PD) is an increase of at least 20% in the sum of the diameters of viable 
target lesions, taking as reference the smallest sum of the diameters of viable target lesions 
recorded since the treatment started; 
Stable disease (SD) is any cases that do not qualify for either partial response or progressive 
disease. 
Non-target lesions: 
CR is disappearance of all non-target lesions 
SD is persistence of one or more non-target lesions PD is appearance of one or more new 
lesions and/or unequivocal progression of existing non-target lesions 
mRECIST recommendations: 


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Pleural effusion and ascites: Cytopathologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is required to declare PD.