Conditions: Hepatocellular Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 60
Healthy volunteers: no

Brief summary:
This is a single-arm, single-center, open-label trial of pembrolizumab (MK-3475) in subjects with advanced hepatocellular carcinoma as second-line treatment after failure of sorafenib.

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 12 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 RECIST 1.1.

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 3week 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, investigators' 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 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: Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W)

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
1 
 
 
 
 
 
TITLE:  
 
Phase II study of pembrolizumab in advanced hepatocellular carcinoma as second-line 
treatment after failure of sorafenib: integration of genomic analysis to identify predictive 
molecular subtypes  
 
 
 
 
 
 
 
 
 
Study Drug 
pembrolizumab 
Version Number 
1.2 
Version Date 
21 November 2016 
Study site 
Samsung Medical Center 
Principal Investigator (Sponsor-Investigator) 
 
Professor Jeeyun Lee M.D, Ph.D.  
 
 
 
 
 
 
 
Revision History 
 Version        
        
 Version        
        
 Version 1.2 
21 Nov 2016 
 
 
 


 
 
 
2 
 
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 advanced hepatocellular carcinoma as 
second-line treatment after failure of sorafenib: integration of genomic analysis to identify 
predictive molecular subtypes  
 
 
 
 
 
 
 
Investigator Signature  
 
Date 
 
 
 
 
 
 
 


 
 
 
3 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Phase II study of pembrolizumab in advanced hepatocellular carcinoma 
as second-line treatment after failure of sorafenib: integration of genomic 
analysis to identify predictive molecular subtypes 
Trial Phase 
II 
Clinical Indication 
Advanced hepatocellular carcinoma 
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 60 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 : Q4  2016 
Estimated date of last subject completed: Q4  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 3week 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, 
investigators’ 
 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 tha
n 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. 


 
 
 
4 
 
Estimated average length of 
treatment per patient 
About 9~12 weeks 
 
 
 


 
 
 
5 
 
 
 
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 ...................................................................................................................................... 8 
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 ................................................................................................................................. 16 
8.1 
Entry Criteria ..................................................................................................................................... 16 
8.2 
Trial Treatments ................................................................................................................................ 20 
8.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ...................................................... 22 
8.4 
Rescue Medications & Supportive Care ............................................................................................ 23 
8.5 
Diet/Activity/Other Considerations ................................................................................................... 27 
8.6 
Subject Withdrawal/Discontinuation Criteria ................................................................................... 29 
8.7 
Subject Replacement Strategy ........................................................................................................... 30 
8.8 
Clinical Criteria for Early Trial Termination .................................................................................... 31 


 
 
 
6 
 
9.0 
TRIAL FLOW CHART ......................................................................................................................... 32 
9.1 
Study Flow Chart .............................................................................................................................. 32 
10.0 
TRIAL PROCEDURES ......................................................................................................................... 35 
10.1 
Trial Procedures ................................................................................................................................ 35 
10.2 
Assessing and Recording Adverse Events......................................................................................... 41 
11.0 
STATISTICAL ANALYSIS PLAN ...................................................................................................... 50 
11.1 
Statistical Analysis Plan .................................................................................................................... 50 
11.2 
Sample size ........................................................................................................................................ 50 
12.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ....................... 51 
12.1 
Investigational Product ...................................................................................................................... 51 
12.2 
Packaging and Labeling Information ................................................................................................ 51 
12.3 
Clinical Supplies Disclosure ............................................................................................................. 51 
12.4 
Storage and Handling Requirements ................................................................................................. 52 
12.5 
Returns and Reconciliation ............................................................................................................... 52 
13.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................................................... 52 
13.1 
Confidentiality ................................................................................................................................... 52 
13.2 
Compliance with Financial Disclosure Requirements ....................................................................... 53 
13.3 
Compliance with Law, Audit and Debarment ................................................................................... 53 
13.4 
Compliance with Trial Registration and Results Posting Requirements ........................................... 53 
14.0 
Monitoring ............................................................................................................................................. 53 
15.0 
Data Handling ........................................................................................................................................ 53 
16.0 
Sample Identification and retension specimen ....................................................................................... 53 
17.0 
References .............................................................................................................................................. 54 
18.0 
APPENDICES ....................................................................................................................................... 54 
18.1 
ECOG Performance Status ................................................................................................................ 55 
18.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ................................................ 55 
 
 


 
 
 
7 
 
2.0 TITLE OF THE STUDY 
Phase II study of pembrolizumab in advanced hepatocellular carcinoma as second-line 
treatment after failure of sorafenib: integration of genomic analysis to identify predictive 
molecular subtypes  
 
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 
4.2 
Sub-Investigators 
Ho Yeong Lim M.D 
Seung Tae Kim, M.D. 
Su Jin Lee, M.D 
Yong Han Paik, M.D. 
Wonsuk Kang, M.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 hepatocellular carcinoma as second-line treatment after failure of sorafenib. 
 
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 


 
 
 
8 
 
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. 
 
5.2 
Trial Scheme 
 
 


 
 
 
9 
 
6.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
6.1 
Primary efficacy Objective(s) & Hypothesis(es) 
Objective: To evaluate RR per mRECIST in advanced hepatocellular carcinoma who 
have progressed on sorafenib, when treated with pembrolizumab 
Hypothesis: Pembrolizumab increases RR per mRECIST in advanced hepatocellular 
carcinoma who have progressed on sorafenib 
6.2 
Primary genomic Objective(s) & Hypotheses 
(1) Primary objective: Integrative genomic analysis to identify association of response (BOR, 
PFS and OS) and primary resistance to pembrolizumab with key genomic markers for 
immunotherapy (expression of PD-L1,  T-cell inflamed and cytolytic immune signatures 
as measured by RNA-seq and/or Nanostring, MSI-h status, mutation load, and pathogen 
covariates, in particular Hepatitis viruses) 
(2) Hypothesis:  
1. 
Pembrolizumab will be effective in hepatocellular carcinoma 
2. 
RNA-based cytolytic gene markers and immune signatures will 
associate with response to Pembrolizumab 
3. 
Increased mutation load will associate with Pembrolizumab response 
4. 
Pathogen infection will associate with Pembrolizumab response 
 
6.3 
Exploratory Objectives 
(1) 
Integrated Genomic Analyses will be performed in an exploratory fashion to determine 
potential immune correlates of response to pembrolizumab at baseline and post-treatment 
(estimated 20% of post-treatment tumor samples will be available). The key components 
of this integrated analysis will be WES in the tumor (with matched normal) at baseline, 
and RNA-seq and Nanostring in tumors and blood pre and post treatment.  
(2) 
NGS profiling will be performed at SMC and analyzed together by the BI team at MSD 
(Dr. Cristescu’s group) and SMC (Genome Center and Molecular Pathology).  
(3) 
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. 
(4) 
Preplanned analysis: ctDNA analysis (pre, prior to cycle 3, and at progression) is planned 
in every patient responder vs non-responder will be analyzed. 


 
 
 
10 
 
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 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 


 
 
 
11 
 
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 
Primary tumors of the liver now represent the fifth most frequently diagnosed type of cancer 
worldwide, but the second most frequent cause of cancer death [1]. More than 75% of cases 
occur in the Asia-Pacific region, largely in association with chronic hepatitis B virus (HBV) 
infection [2]. Surgical resection leads to a 60–70% 5-year survival for patients with 
hepatocellular carcinoma (HCC) who present with solitary tumor and have excellent liver 
function. However, surgical resection is only an option for less than 20% of patients [3]. 
Disease that is diagnosed at an advanced stage or with progression after locoregional therapy 
has a dismal prognosis, owing to the underlying liver disease and lack of effective treatment 
options [4]. The only systemic treatment resulting in significant improvement in survival in 
patients with advanced HCC is sorafenib, a multi-kinase inhibitor targeting RAF kinase and 
receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptor (PDGFR), 
vascular endothelial growth factor receptor (VEGFR), and c-KIT (a receptor specific for stem 
cell factor)[5,6]. Sorafenib simultaneously inhibits two key pathways that are reported to play 
an important role in the pathogenesis of HCC including regulation of tumor growth (via Raf-
MEK-ERK) and angiogenesis (via VEGFR and PDGFR) [7]. Despite the encouraging 
achievement, sorafenib treatment was only 2-3months longer than placebo with a low partial 
response rate (3%) [5,6]. 
 
Starting 2014, SMC has launched a clinical sequencing program for the first time in Korea for 
oncology patients using targeted sequencing.  The SMC team has extensive experience 
regarding clinical sequencing, including fresh biopsies, cfDNA, sequence reporting system etc.  
The NEXT-1 trial is a master protocol to route participants to different candidate drugs in trials 
based on clinical sequencing report. In this trial, we used a customized targeted enrichment 
panel consisting of cancer-related genes to interrogate single nucleotide variants (SNVs), 
insertions and deletions (Indels), copy number variations (CNVs) and a subset of gene fusions. 
Somatic mutations profiled by this targeted deep sequencing approach were classified into 
three tiers based on their clinical or biological significance, and guided oncologists in selection 


 
 
 
12 
 
of individualized treatments. In this master protocol, the response rate was assessed as the 
primary end point in patients who had molecularly-matched or standard therapy.  From August 
2014 through April 2015, 541 patients consented to participate at a single center in precision 
oncology clinic, and 419 cancer patients had sequencing data available to clinician for 
guidance to matched trials. The patient cohorts were gastric cancer (N = 127), colorectal cancer 
(N =123), pancreatic/biliary tract cancer (N=62) and rare cancers (N = 67). Out of 419 cancer 
patients, 260 (62.1%) patients either had no genomic alterations or no available matched trial, 
and 59 (22.7%) patients were successfully routed to genome-based matched clinical trial. In 
gastric cancer, the response rate of molecularly-matched group was significantly higher than 
that of the conventional treatment group (28.1% versus 5.9%, P<0.001). In particular, 16 rare 
cancer patients with matched therapy showed better response than cancer patients with the 
conventional salvage treatment (56.2% versus 12.5%, respectively; P=0.003). This was the 
first such master protocol reported in Asia. Through this trial, SMC has established a platform 
and a team where we can reliably perform upfront biopsy and sequencing.  
 
In addition, SMC has previously worked with Pfizer to profile 286 HCC patients and has 
defined a predictive gene signature for tumor recurrence [8]. We identified 29 recurrently 
amplified and 22 recurrently deleted regions with a high level of copy number changes. These 
regions harbor established oncogenes and tumor suppressors, including CCND1 (cyclin D1), 
MET (hepatocyte growth factor receptor), CDKN2A (cyclin-dependent kinase inhibitor 2A) 
and CDKN2B (cyclin-dependent kinase inhibitor 2B), as well as many other genes not 
previously reported to be involved in liver carcinogenesis [9].  
 
Recently [ASCO 2015], a phase I/II study of nivolumab has been reported. Patients enrolled 
in the study were required to have histologically confirmed advanced HCC with a Child-Pugh 
score of 7 or less and not be candidates for curative treatment options. Patients were allowed 
to have one or more prior lines of systemic therapy that failed, including sorafenib, the current 
standard of care in advanced HCC. In this dose-escalation study, patients received 0.1 to 10.0 
mg/kg of nivolumab intravenously for up to 2 years. Dose escalation occurred in parallel 
cohorts based on whether they had hepatitis B (11 patients), hepatitis C (12 patients), or were 
noninfected (24 patients). Safety was the primary endpoint of the study. Response was 
measured using modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Of 42 
patients evaluable for response, CR was reported in two patients (5%) and partial response (PR) 
in six patients (14%) for an overall objective response rate of 19%. Responses were seen across 
all three cohorts (HBV, HCV, non-B non-C) of patients, and responses were durable. 
Preliminary 1-year overall survival (OS) was 62%. These responses were much higher than 
those seen with sorafenib (http://am.asco.org/nivolumab-hcc-and-pembrolizumab-tumors-
mismatch-repair-deficiency). However, the molecular profile of the responders is currently 
unknown.   Since not all HCC patients respond to anti-PD1 treatment, it is desirable to 
understand the molecular factors that affect response in order to design potential patient-
tailored strategies of treatment with immune-modulating therapies such as anti-PD1. 
 


 
 
 
13 
 
 A comprehensive molecular analysis of HBV-infected HCC was previously performed in the 
context of the ACRG collaboration (Asian cancer research group; a consortium of academic 
and pharma partners that included Merck and SMC) [10,11]. As part of that analysis, a subtype 
of HCC (S1) has been identified with particularly poor prognosis.  A landmark of that subtype 
is the presence of immune markers consistent with T-cell infiltration of the tumor and cytolytic 
activity.  Such a signature has been previously associated with response to pembrolizumab in 
multiple cancer types, including gastric cancer [12].  Given the dismal prognosis of the subjects 
in HCC group S1, we hypothesize that elements of the signature will also be enriched in 
sorafenib-refractory tumors and will indicate a potential for increased response to 
Pembrolizumab. 
 
Hence, in this study, we propose to identify for the first time DNA- and RNA-based molecular 
as well as etiology subtypes of sorafenib-refractory HCC who may respond to pembrolizumab, 
by building upon the previous successful ACRG collaborative work in Gastric cancer [13] 
between MERCK MSD and SMC team.  
 
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 dose regimen relative 


 
 
 
14 
 
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 
flare in the first few months after the start of immunotherapy, but with subsequent disease 
response. 


 
 
 
15 
 
7.2.3.2 Biomarker Research 
The key goal of this effort is to determine genomic correlates of response to pembrolizumab 
in HCC.  Nivolumab activity has been reported in HCC and genomic characterization of 
HCC has been a part of large scale cancer characterization such as TCGA and ACRG.  
Moreover, important independent and universal key genomic markers of response have been 
identified in multiple tumor types, in particular RNA based (T-cell inflamed signature) and 
DNA based (mutational load). However, to the best of our knowledge these interactions and 
associations have not been explored to date in the case of HCC.  Although our effort will be 
focused on patients refractory to SOC, it is expected that identification of such biomarkers 
will importantly impact clinical strategies also for earlier stages of disease. 
 
To characterize the tumors in this protocol we will perform tumor NGS sequencing (RNA 
sequencing for estimating the T-cell inflamed signature and other immunogical covariates, 
WES and/or TES cancer panel for estimating the mutation load and other somatic 
covariates), as well as IHC for key markers like PDL1, FOXP3, CD4, CD8 and MLH1.   
 
We expect that 20% of the patients will also have post-treatment tumors available for which 
similar NGS characterization will be performed (WES and RNA-seq), with the goal of 
identifying potential tumor-specific mechanisms of acquired resistance to pembrolizumab in 
patients with progressive disease after initial response. 
 
 
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. 
 
Immune checkpoint molecules are dysregulated in HCC, most notably PD-1, PD-L1, CTLA-
4, TIM-3, KIR, and LAG3. Although all these molecules can potentially be leveraged for 
therapeutic benefit, the PD-1 and PD-L1 axis is the most topical. PD-L1 is heavily expressed 
in HCC and surrounding PACs (LSECs, KCs, and tumor-associated monocytes). Retrospective 
studies have indicated that PD-L1 expression, as assessed by flow cytometry, Western blot 
analysis, and immunohistochemical staining, ranges from 45% to 100% in HCC samples. In a 
cohort of 240 patients with surgically resected HCC, tumoral PD-L1 expression was associated 
with aggressive clinicopathologic features and statistically significantly shorter disease-free 
survival [14]. Certain HCC etiologic factors enrich for PD-L1 expression and it will be 
interesting to formally assess how expression changes across HCC subtypes [15]. 
Arrays of cytokine profiles (increased IL-4, 5, 8, and IL-10 secretion and relative suppression 
of IL-1, tumor necrosis factor, and IFN-r) in the HCC microenvironment results in blunting of 
the normally protective T-helper 1 immune response needed to effectively combat malignancy 
[16]. This cytokine signature is associated with a poor prognosis and aggressive disease 
characteristics. High levels of circulating TGF-b also portend inferior survival in patients with 
HCC. Although the tumor-promoting effects of TGF-b include enhanced neovascularization, 


 
 
 
16 
 
the promotion of metastasis, and induction of fibrosis, there is clear evidence that this molecule 
is immunosuppressive. TGF-b induces Treg polarization and differentiation, and is a key 
negative regulator of CD81T cells, promoting T-cell exhaustion. 
 
For HCC, pembrolizumab has not been extensively tested in terms of efficacy, especially in 
correlation with genomic profiling. Thus, herein we aim to identify for the first time DNA- and 
RNA-based molecular as well as etiology subtypes of Asian-specific HCC who may respond 
to pembrolizumab.  
 
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  20 years 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 HCC (fibrolamellar and 
mixed hepatocellular/cholangiocarcinoma subtypes are not eligible) based on 
pathology report. 
4. Have Barcelona Clinic Liver Cancer (BCLC) Stage C disease, or BCLC Stage B 
disease not amenable to locoregional therapy or refractory to locoregional therapy, and 
not amenable to a curative treatment approach. 
5. Have a Child-Pugh class A liver score 
6. Has experienced documented objective radiographic or clinical disease progression 
during first-line sorafenib therapy.  
7. 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. 


 
 
 
17 
 
8. 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 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. 
9. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
10. Subjects are eligible to enroll if they have non-viral-HCC, or if they have HBV-HCC, 
or HCV-HCC defined as follows: 
i) HBV-HCC: Resolved HBV infection (as evidenced by detectable HBV surface 
antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable 
HBV surface antigen) or Chronic HBV infection (as evidenced by detectable HBV 
surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV 
DNA < 100 IU/mL and must be on antiviral therapy. 
ii) HCV-HCC: Active or resolved HCV infection as evidenced by detectable HCV RNA 
or antibody. 
11. 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) 
≥1,200 /mcL 
Platelets 
≥60,000 / mcL 
Hemoglobin 
≥8 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 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 


 
 
 
18 
 
(GFR can also be used in place of 
creatinine or CrCl) 
Hepatic 
 
Serum total bilirubin 
≤ 2 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
2 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 5 X ULN   
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. 
 
12. 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.   
13. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception,  for the 
course of the study through 120 days after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
14. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate 
method of contraception as outlined in Section 5.7.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
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 received sorafenib within 14 days of first dose of study medication.  
3. Has had esophageal or gastric variceal bleeding withint the last 6 months. All subjects will 
be screened for esophageal varices, unless such screening has been performed in the past 
12 months before first dose of treatment. If varices are present, they should be treated 
according to institutional standards before starting study treatment. 


 
 
 
19 
 
4. Had a solid organ transplant. 
5. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e., 
with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
6. 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. 
 
7. Has received locoregional therapy to liver (transcatheter chemoembolization [TACE], 
transcatheter embolization [TAE], radiation, radioembolization, or ablation) or major 
surgery to liver or other site within 6 weeks prior to the first dose of study drug. Minor 
surgery (e.g., simple excision, tooth extraction) must have occurred at least 7 days prior 
to the first dose of study treatment (Cycle 1, Day 1). Subjects must have recovered 
adequately (i.e., Grade ≤1 or baseline) from the toxicity and/or complications from any 
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 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 a known history of, or any evidence of, interstitial lung disease or active 
noninfectious 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.   


 
 
 
20 
 
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 untreated active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
Note: To qualify for enrollment, antiviral therapy for HBV must be given for at least 3 
months, and HBV viral load must be less than 100 IU/mL prior to first dose of study drug. 
Those on active HBV therapy with viral loads under 100 IU/ml should stay on the same 
therapy throughout study treatment. Those subjects who are anti-HBc (+) and negative 
for HBsAg and negative for anti-HBs, and have an HBV viral load under 100 IU/mL do 
not require HBV anti-viral prophylaxis, but need close monitoring. 
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. 
 
8.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg  
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.   


 
 
 
21 
 
8.2.1.2 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 3 below. See Section 8.4 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 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
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 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite adequate 
premedication  
 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated  for the next scheduled dose; Refer to  


 
 
 
22 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
 
Table  – Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
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. 
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. 


 
 
 
23 
 
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. 
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. 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 


 
 
 
24 
 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 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.  
 


 
 
 
25 
 
 Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
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.  
 


 
 
 
26 
 
 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 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 


 
 
 
27 
 
NCI CTCAE Grade 
Treatment 
Premedication at 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.  
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   


 
 
 
28 
 
 
Acceptable methods of contraception are‡: 
  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
  
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
 
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 


 
 
 
29 
 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
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. 
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 


 
 
 
30 
 
 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 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. 
 


 
 
 
31 
 
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. 
 


 
 
 
 
 
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 -HCG 
X 
PT/INR and aPTT k 
X 
CBC with Differential l 
X 
X 
X 
X 
X 
Xl 
X 
Xl 


 
 
 
 
 
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 
Hepatitis Lab, Serum AFP, PIVKA-II l  
X 
X 
X 
Xl 
Blood for Genetics m 
X* 
Correlative Blood Samples (DNA) n 
X* 
 
 
 
Correlative Blood Samples (RNA) n 
X* 
X 
X 
X 
Correlative Blood Samples (plasma for ctDNA
X* 
Correlative Blood Samples (serum) n 
      
X* 
 X 
          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 
*Denotes baseline (-7 day before treatment) 
 
 
 
 


 
 
 
 
 
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 
drug relatedAEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs are within normal range.  
At screening, Hepatitis labs include HepB surface antigen, HepB surface antibody, Hep B Core antibody, HepB DNA Viralload (PCR),  
Hep C viral load (PCR) and Hep C Antibody, Hep D antibody. During treatment, hepatitis labs will be conducted as follows ; Fo r 
HCV infected--HCV RNA every 6 weeks on treatment (every other cycle) through cycle 8, then every 6 cycles thereafter.  
For HBV infected--HBV DNA every 6 weeks on treatment  
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.  


 
 
 
 
 
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 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. 
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.  
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.   
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.   


 
 
 
 
 
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 
 
HBV 
 
Potassium   
 
HCV 
 
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.   
 
 
 
 


 
 
 
 
 
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 
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-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 


 
 
 
 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials or as 
prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting. 
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 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) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, 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 an other important medical event  
 Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 


 
 
 
 
 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details) that occurs to any subject must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the subject 
to be excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details), whether or not related to the Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
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 reported within 24 hours to IRB and within 2 working days to Merck Global 
Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 


 
 
 
 
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 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.   
10.2.3.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g.transportation issues etc.) will not be considered a 
SAE. 
 


 
 
 
 
 
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. 


 
 
 
 
 
Table 6  Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include 
an adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has 
not worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is 
documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck 
within 2 working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection 
purposes. An overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours 
to the Sponsor and to Merck within 2 working days.. 


 
 
 
 
 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event 
when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause Merck product to be discontinued? 
Relationship to Merck 
Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on 
the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time 
frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and 
the adverse event based upon the available information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time 
Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely 
Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 
Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 


 
 
 
 
 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED 
BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE 
SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR 
the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


 
  
 
 
 
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. 
①     prospective storage of plasma for ctDNA evaluation (Streck tubes) in all enrolled-patients. 
 
②     In the actual Seq, comparison btw responder vs non-responder will be conducted in 
selected-population 
using 
prospectively 
collected 
samples. 
 
③     Timepoints of collection : 1) pre-treatment (baseline), 2)prior to 3rd dose (C3), and 3)at 
progression. 
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  
About using one-stage design response rate (ORR) hypothesis opposed to expect 5% of the 
null hypothesis that the response rate of 18.5% or more (two-tailed), the first species of 5%. 
Assuming about 10% of attrition due to ineligibility and dropout, we will recruit 60 patients 


 
  
 
 
 
 
 
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. 
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 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.  
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. 
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. 
CA Cancer J Clin 2011;61:69-90. 
2. 
Kirk GD, Lesi OA, Mendy M, Akano AO, Sam O, Goedert JJ, et al. The Gambia Liver 
Cancer Study: Infection with hepatitis B and C and the risk of hepatocellular carcinoma in 
West Africa. Hepatology 2004;39:211-9. 
3. 
Hung H. Treatment modalities for hepatocellular carcinoma. Curr Cancer Drug Targets 
2005;5:131-8. 
4. 
Bruix J, Sherman M. Management of hepatocellular carcinoma. Hepatology 
2005;42:1208-36. 
5. 
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, et al. Sorafenib in 
advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90. 
6. 
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of 
sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a 
phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 2009;10:25-34. 
7.   Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, et al. BAY 43-9006 
exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and 
receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 
2004;64:7099-109. 
8.     Lim HY et al, Ann Surg Oncol 20(12):3747-53 
9.    Wang K, Lim HY, Shi S, Lee J, Deng S, Xie T, Zhu Z, Wang Y, Pocalyko D, Yang WJ, 
Rejto PA, Mao M, Park CK, Xu J. Genomic landscape of copy number aberrations enables the 
identification of oncogenic drivers in hepatocellular carcinoma. Hepatology. 2013 
Aug;58(2):706-17 
10.     Kan et al, Whole-genome sequencing identifies recurrent mutations in hepatocellular 
carcinoma, Genome Res 2013 
11 .   Sung et al, Genome-wide survey of recurrent HBV integration in hepatocellular 
carcinoma, Nature Gen, 2012 
12.   Shankaran et al, Correlation of gene expression signatures and clinical outcomes in 
patients with advanced gastric cancer treated with pembrolizumab (MK-3475). 
13.   R. Cristescu, JY Lee et al Molecular analysis of gastric cancer identifies subtypes 
associated with distinct clinical outcomes, Nature Medicine 21, 449–456 (2015) 


 
  
 
 
 
14.   Gao Q, Wang XY, Qiu SJ, et al. Overexpression of PD-L1 significantly associates with 
tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin 
Cancer Res. 2009;15: 971-979. 
15. Wang BJ, Bao JJ, Wang JZ, et al. Immunostaining of PD-1/PD-Ls in liver tissues of 
patients with hepatitis and hepatocellular carcinoma. World J Gastroenterol. 2011;17:3322-
3329. 
16. Budhu A, Forgues M, Ye QH, et al. Prediction of venous metastases, recurrence, and 
prognosis in hepatocellular carcinoma based on a unique immune response signature of the 
liver microenvironment. Cancer Cell. 2006;10:99-111. 
 
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: 
Pleural effusion and ascites: Cytopathologic confirmation of the neoplastic nature of any 
effusion that appears or worsens during treatment is required to declare PD.