Conditions: Hepatocellular Carcinoma
Keywords: Hepatocellular Carcinoma Advanced Hepatocellular Carcinoma Unresectable Hepatocellular Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 29
Healthy volunteers: no

Brief summary:
This is a single-arm phase II trial of Pembrolizumab (Keytruda) in patients with advanced, unresectable hepatocellular carcinoma. The primary objective is to assess its therapeutic efficacy in patients with unresectable hepatocellular carcinoma (HCC).

Detailed description:

Arms:
arm 1: Patients will be treated in three-week cycles, with intravenous (IV) administration of 200 mg of pembrolizumab on day 1 of each 3-week cycle. Trial therapy will last until withdrawal of consent, disease progression and/or unacceptable toxicity, whichever occurs first.

Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Patients will be treated in three-week cycles, with intravenous (IV) administration of 200 mg of pembrolizumab on day 1 of each 3-week cycle.

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 100
EProst # 20151049
IND # 129017
NCT02658019
Phase II Study of Pembrolizumab (Keytruda®) in Advanced, Unresectable 
Hepatocellular Carcinoma (HCC)
VERSION #
5.0
VERSION DATE
01/DEC /2017
PRINCIPAL INVESTIGATOR (PI)
Lynn Feun, MD
Professor of Medicine
Division of Hematology/ Oncology
Confidentiality Statement: The information contained in this document, especially unpublished data, is 
confidential property.  The information in this document may not be disclosed to others unless federal or 
state law or regulations require such disclosure.  Subject to the foregoing, this information may be 
disclosed only to those persons involved in the study who have a need to know, with the obligation not to 
further disseminate this information.        
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CONTACT INFORMATION
PRINCIPAL 
INVESTIGATOR
Lynn Feun, MD
University of Miami/ Sylvester Comprehensive Cancer Center 
(SCCC)
Professor of Medicine
1475 NW 12th Avenue, Room 3300
Miami, FL 33136
Telephone: 305-243-6606
Email: lfeun@med.miami.edu 
SUB-
INVESTIGATOR(S)
Stephen Richman, MD
University of Miami/ Sylvester Comprehensive Cancer Center 
(SCCC)
Professor of Medicine
1475 NW 12th Avenue, Room 3300
Miami, FL 33136
Telephone: 305 243-6606
Email: srichman@med.miami.edu 
Riccardo Lencioni, MD
University of Miami
Department of Interventional Radiology
1150 NW 14th St
Miami FL 33136
Telephone: 305 243-1343
Email: rxl194@miami.edu
Niramol Savaraj, MD
Department of Medicine/University of Miami.
VA Medical Center
1201 NW 16th Street
Miami Fl 33125
Telephone: 305 324 4455 Ext 4496
Email: nsavaraj@med.miami.edu
Peter J. Hosein, MB BS
Assistant Professor of Clinical Medicine
University of Miami, Miller School of Medicine
1475 NW 12th Ave. Suite 3400
Miami, FL 33136
Telephone: 305-243-6402
Email:phosein@med.miami.edu
Cristina Herrera, ARNP
1475 NW 12th Avenue, Suite 3400
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Miami, FL 33136
Telephone: 305-799-9277
Email: cherrera@med.miami.edu
STATISTICIAN
Deukwoo Kwon, PhD
University of Miami/ Sylvester Comprehensive Cancer Center 
(SCCC)
Associate Scientist
Biostatistics and Bioinformatics Core
1120 NW 14th Street, 
Clinical Research Building, Room 1054
Miami, FL 33136
Telephone: 305-243-0181
Email: dkwon@med.miami.edu  
CLINICAL TRIAL 
MANAGEMENT
Clinical Research Services (CRS)
1550 NW 10th Avenue, Fox 308
Miami, FL 33136
Telephone: 305-243-1156
FUNDING SOURCE
Merck
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Regulatory Sponsor
Sylvester Comprehensive Cancer Center (SCCC)
PI: Lynn Feun, MD
Funding Source(s)
Merck
Investigational Agent(s)
Pembrolizumab (Keytruda®) – provided by Merck
Other Agent(s)
N/A
IND Status
IND or IDE #: 129017
IND Sponsor: 
Lynn Feun, MD
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INVESTIGATOR AGREEMENT
I confirm that I have read this protocol, I understand it, and I will work according to this protocol 
and to the ethical principles stated in the latest version of the Declaration of Helsinki, the applicable 
ICH guidelines for good clinical practices, and the applicable federal, state, and local laws, rules, 
and regulations relating to the conduct of the protocol.  
I have read and understand the information in the Investigators’ Brochure (and/or other such 
pertinent safety information) regarding the risks and potential benefits.  
I agree to inform all those who assist/collaborate with me in the conduct of this study of their 
responsibilities and obligations. 
Once the protocol has been reviewed and approved by the Institutional Review Board (IRB) I 
understand that any change(s) made during the course of the study must also (first) be approved 
by the IRB prior to implementation, except when such modification is made to remove any 
immediate hazard(s) to the subject(s).  
I certify that I and the study staff responsible, have received the requisite training to conduct this 
research protocol.  
I agree to maintain adequate and accurate records in accordance with the University of Miami 
policies, federal, state and local laws and regulations.  
I agree to maintain the confidentiality of all information received and/or developed in connection 
with this protocol.
eProst Number: 
Protocol Version Number:
Protocol Version Date:
Signature of Investigator:
Date:
Name of Investigator (printed):
Institution:
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PROTOCOL REVISION HISTORY
Version #
Summary of Changes
Version Date
1.1
(Pre-Approval Changes; Sponsor Designated) 
Contact Information

Added University of Miami Hospital (UMH) 
Hepatology Collaborator “Patricia Jones, MD”
Reference Safety Information as provided in Version 10 
(date: 31/AUG/2015) of Pembrolizumab Investigator's 
Brochure (IB) 
Section 9.1.4 (Management of Agent-Specific Adverse 
Events):

Updated safety information for patients with 
melanoma based on KEYNOTE-006 (i.e. AEs of 
Special Interest or AEOSI) 

“Clinical Trials Experience” 

“Immune-Related Adverse Reactions (irAEs)”

“Identification and Treatment of irAEs”

“Infusion Reactions”

“Other Immune-Mediated Adverse Reactions”:
o
added Guillain-Barré syndrome and 
vitiligo

“Immune-Mediated Pneumonitis”
o
Updated “pneumonitis” text
Reference Risk Language as provided in Version 1.0 (date: 
03/SEP/2015) of Risk Language Template for MK-3475 
Informed Consent Form (ICF) Version 1.1 (dated: 
06/NOV/2015): 

Updated pembrolizumab side effects  
06/NOV/2015
1.2
(Pre-Approval Changes; FDA Recommendations)

Section 10.2 Criteria modified for ALT, AST, and 
bilirubin toxicity to, “if these patients have Grade 3 
elevation of AST/ALT, hold therapy and resume 
treatment when AST/ALT returns to baseline or 
Grade ≤ 1.

Section 10.2 Criteria modified for bilirubin to 
“Toxicity does not resolve within 4 weeks of last 
dose or if clinically symptomatic.”
05/JAN/2016
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2.0
(Post-Approval Amendment; Sponsor Designated) 
Additional Sub-Investigators:

Beatrice Madrazo, MD 

Ricardo Lenicioni, MD;

Niramol Savaraj, MD;

Monica Garcia-Buitrago, MD; 

Patricia D. Jones, MD; 

Peter J. Hosein, MB BS and 

Cristina Herrera, ARNP
Exclusion Criteria #11: Known history of, or any evidence of 
active, non-infectious pneumonitis or has a history of (non-
infectious) pneumonitis that required steroids or current 
pneumonitis
Correlative Studies, Section 1.5 modified for research blood 
draw collection up to 30 mL.
Cancelation Guidelines, Section 6.1: Modified sentence to 
indicate that patient may withdraw at any time.
Treatment Plan, Section 8.1: Added “iv line will be kept 
open with 250 mL normal saline for the drug infusion”
Hepatic Toxicity: Changed to resolution to 12 weeks for 
consistency throughout document.
Section 10.2.1 modified for HBV/HCV testing: “Patients 
who test negative for these hepatitis labs do not need to 
repeat these lab tests again, unless clinically indicated”
Section 12.2 modified HBV/HCV testing needed while on 
treatment “if tested positive at screening”
Section 13.1 and Sections 13.2-13.5: modified for research 
blood draw collection to up to 30 ml (2 green top tubes and 
1 red top tube)
Appendix F added that “PD-L1 testing will be performed by 
Monica Garcia Buitrago at Jackson Memorial Hospital”. 
Also, modified for research blood draw collection to 21 ml 
(2 green top tubes and 1 red top tube) 
12/SEP/2016
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3.0
Post Approval Amendment (Sponsor Designated)
Revisions after letter from sponsor indicated cases of 
Stevens-Johnson syndrome, Toxic Epidermal Necrolysis 
and Immune-mediated Myocarditis.
Descriptions were added to Section 9.1.4 Management of 
Agent-Specific adverse events and to Section 10.2 Dose 
modification guidelines of Pembrolizumab.
Correction of some protocol language contradictions 
and additional clarifications.  Pages 38, 57 and 59 
include updated language for procedures to assess 
disease progression and survival.
22/MAR/2017
4.0
Post Approval Amendment
Increase accrual to 35 patients to account for potential 
screen failures and non-evaluable patients.  The goal 
continues to be reach 28 evaluable patients.
Added additional risks brought forth by Sponsor (Merck) in 
their 28-Aug-2017 Risk Language document for MK-3475
25/OCT/2017
5.0
Post Approval Amendment (Sponsor Designated)
In response to Sponsor’s Dear Investigator Letter to update 
the Dose Modification Table.
01 DEC 2017
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Page 9 of 100
TABLE OF CONTENTS
CONTACT INFORMATION .............................................................................................................................2
INVESTIGATOR AGREEMENT ........................................................................................................................5
PROTOCOL REVISION HISTORY.....................................................................................................................6
TABLE OF CONTENTS ....................................................................................................................................9
ABBREVIATIONS & DEFINITIONS.................................................................................................................13
PROTOCOL SYNOPSIS..................................................................................................................................14
PROTOCOL SCHEMA ...................................................................................................................................20
1.0
BACKGROUND.................................................................................................................................21
1.1
Study Disease..............................................................................................................................21
1.2
Study Agent -Pembrolizumab (Keytruda®) .................................................................................22
1.3
Rationale.....................................................................................................................................26
1.4
Gender and Ethnicity ..................................................................................................................27
1.5
Correlative Studies......................................................................................................................27
2.0
OBJECTIVES.....................................................................................................................................28
2.1
Primary Objectives......................................................................................................................28
2.2
Secondary Objectives .................................................................................................................28
2.3
Exploratory Objectives................................................................................................................28
3.0
ENDPOINTS.....................................................................................................................................29
3.1
Primary endpoints ......................................................................................................................29
3.2
Secondary endpoints ..................................................................................................................29
3.3
Exploratory endpoints ................................................................................................................29
4.0
SUBJECT RECRUITMENT & SCREENING...........................................................................................30
5.0
PATIENT SELECTION........................................................................................................................30
5.1
Inclusion Criteria.........................................................................................................................30
5.2
Exclusion Criteria ........................................................................................................................32
6.0
Enrollment Procedures...................................................................................................................33
6.1
Cancellation Guidelines ..............................................................................................................33
7.0
STUDY DESIGN ................................................................................................................................34
8.0
TREATMENT PLAN ..........................................................................................................................34
8.1
Pembrolizumab (Keytruda®).......................................................................................................34
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8.2
Treatment Schema .....................................................................................................................35
8.3
Treatment Dispensation, Compliance and Accountability .........................................................35
8.4
Supportive Care Guidelines ........................................................................................................35
8.5
Duration of Treatment................................................................................................................37
8.6
Duration of Follow-Up ................................................................................................................37
9.0
AGENTS (DRUG FORMULATION AND PROCUREMENT)..................................................................38
9.1
Pembrolizumab...........................................................................................................................38
10.0
TREATMENT/ DOSE MODIFICATIONS .............................................................................................50
10.1
Unacceptable Toxicity.................................................................................................................50
10.2
Dose Modification Guidelines for Pembrolizumab.....................................................................51
11.0
TREATMENT DISCONTINUATION....................................................................................................56
12.0
SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS ................................................................57
12.1
Pre-Treatment Evaluations (Screening)......................................................................................57
12.2
Evaluations on Treatment...........................................................................................................59
12.3
Off-Treatment Evaluations .........................................................................................................60
12.4
30 Days After Off Treatment (OT) Safety Evaluations ................................................................61
12.5
Follow-up Evaluations.................................................................................................................62
12.6
Calendar of Clinical and Laboratory Evaluations ........................................................................63
13.0
SCHEDULE OF CORRELATIVE EVALUATIONS...................................................................................65
13.1
Pre-Treatment Specimen Collection (Screening)........................................................................65
13.2
On Treatment Specimen Collection............................................................................................65
13.3
Off-Treatment Specimen Collection (or at time of documented disease progression)..............65
13.4
30 Days after Off Treatment Safety visit.....................................................................................65
13.5
Calendar of Specimen Collection for Correlative Studies...........................................................65
14.0
MEASUREMENT OF EFFECT ............................................................................................................66
14.1
Antitumor Effect in Solid Tumors ...............................................................................................66
14.2
Definitions...................................................................................................................................66
14.3
Disease Parameters ....................................................................................................................67
14.4
Methods for Evaluation of Disease.............................................................................................68
14.5
Response Criteria........................................................................................................................70
14.6
Disease Control Rate (DCR).........................................................................................................72
14.7
Overall Response Rate (ORR)......................................................................................................72
14.8
Progression-Free Survival (PFS) ..................................................................................................73
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14.9
Overall Survival (OS) ...................................................................................................................73
15.0
ADVERSE EVENTS............................................................................................................................73
15.1
Purpose.......................................................................................................................................73
15.2
Adverse Event.............................................................................................................................73
15.3
Serious Adverse Events (see also Appendix A) ...........................................................................74
15.4
Adverse Event Collection Period.................................................................................................75
15.5
Adverse Event Reporting Requirements.....................................................................................75
15.6
Expedited Adverse Event Reporting Requirements....................................................................76
16.0
STATISTICAL CONSIDERATIONS ......................................................................................................76
16.1
Objectives and Endpoints ...........................................................................................................76
16.2
Study Design and Sample Size Justification ................................................................................77
16.3
Analysis Set.................................................................................................................................77
16.4
Patient Enrollment and Study Duration......................................................................................78
16.5
Statistical Analysis.......................................................................................................................78
17.0
DATA REPORTING ...........................................................................................................................79
17.1
Data and Safety Monitoring........................................................................................................79
17.2
Stopping Rules (for the study as a whole) ..................................................................................79
18.0
STUDY AUDITING AND MONITORING.............................................................................................81
19.0
INVESTIGATOR RESPONSIBILITIES...................................................................................................81
19.1
Investigator Responsibility/Performance ...................................................................................81
19.2
Confidentiality ............................................................................................................................81
19.3
Informed Consent and Permission to Use Protected Health Information..................................82
19.4
Source Documentation and Investigator Files............................................................................82
19.5
Recording and Processing of Data ..............................................................................................82
19.6
Non-Protocol Research...............................................................................................................83
19.7
Ethics...........................................................................................................................................83
19.8
Essential documents for the conduct of a clinical trial...............................................................83
REFERENCES ...............................................................................................................................................84
APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS ...........................................86
APPENDIX B: DATA SUBMISSION SCHEDULE..............................................................................................88
APPENDIX C: PERFORMANCE STATUS SCALES............................................................................................89
APPENDIX D: NYHA CLASSIFICATION OF HEART DISEASE...........................................................................90
APPENDIX E: INFORMATION ON POSSIBLE DRUG INTERACTIONS .............................................................91
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APPENDIX F: OPTIONAL BIOMARKER, CORRELATIVE AND SPECIAL STUDIES .............................................92
APPENDIX G: CHILD-PUGH CLASSIFICATION...............................................................................................94
APPENDIX H: PROTOCOL APPROVED METHODS OF CONTRACEPTION ......................................................95
APPENDIX I: EVENTS OF CLINICAL INTEREST & SUPPORTIVE CARE GUIDELINES FOR PEMBROLIZUMAB ..96
APPENDIX J: PREPARATION AND ADMINISTRATION/ RECONSTITUTION OF PEMBROLIZUMAB 
(KEYTRUDA®) FOR INJECTION (LYOPHILIZED POWDER)* .........................................................................100
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ABBREVIATIONS & DEFINITIONS
Term
Abbreviation
Definition
Disease Control Rate
DCR
The proportion of patients with a confirmed 
complete response, partial response or stable 
disease (CR, PR or SD), as per RECIST v1.1.
Duration of Response
DOR
The length of time from documentation of 
tumor response to documented disease 
progression.
Overall Response Rate
ORR
The proportion of patients with a confirmed 
complete or partial response (CR or PR), as per 
RECIST v1.1.
Overall Survival
OS
The length of time from the start of treatment 
for a disease, that patients diagnosed with the 
disease are still alive.  
Progression-Free Survival
PFS
The length of time during and after the 
treatment of a disease that a patient lives with 
the disease but it does not get worse.  
Reference: National Cancer Institute (NCI) Dictionary of Cancer Terms 
http://www.cancer.gov/dictionary 
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PROTOCOL SYNOPSIS
Protocol Title 
Phase II Study of Pembrolizumab (Keytruda®) in Advanced, 
Unresectable Hepatocellular Carcinoma (HCC)
Targeted Patient 
Population
Adult subjects (age ≥18 years) with confirmed advanced 
hepatocellular carcinoma (HCC).  
Study Design 
The study will be an open-label, single-institution, non-randomized, 
phase II study of pembrolizumab therapy in patients with advanced 
HCC.  Patients will be treated in three-week cycles, with intravenous 
(IV) administration of pembrolizumab on day 1 of each 3-week cycle. 
An interim analysis is planned after 14 evaluable patients are assessed 
for DCR to determine whether to continue with an additional 14 more.  
Treatment Schema
Pembrolizumab Treatment:
 Cycle(s)
1
2
3
4
5, 6, 7, etc. 
until 
progression
Week(s)
1
2
3
1
2
3
1
2
3
1
2
3
1
2
3
Day(s)
1
8
15
1
8
15
1
8
15
1
8
15
1
8
15
Pembrolizu
mab IV q21 
days
X
X
X
Imaging after every 
3rd cycle 
X
X
Duration of 
Treatment
Trial therapy will last until withdrawal of consent, disease progression 
and/or unacceptable toxicity, whichever occurs first. Trial therapy may 
last for a maximum of 2 years (24 months) if the patient shows no 
evidence of disease progression or intolerable toxicity.  
Follow-up Required 
Post-Treatment
All subjects will be followed at approximately 30-days (+5 days) after 
the last dose of trial treatment or before the initiation of a new anti-
cancer treatment, whichever occurs first.  
For subjects without documented evidence of objective disease 
progression a telephone call to the subject and/or the subject’s family 
may be made every 12 weeks to evaluate the patient’s status until 
documented disease progression, death, withdrawal of consent, or end 
of study, whichever occurs first.
Objectives
Primary Objectives: 

To determine the disease control rate (CR, PR, or SD) and 
response rate (CR and PR) of pembrolizumab in patients with 
advanced HCC.

To determine the safety of pembrolizumab in HCC patients.
Secondary Objective:
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
To determine the progression-free survival (PFS), overall survival 
(OS), objective response rate (ORR), and duration of response 
(DOR).
Exploratory Objective(s):

To assess HCC tumor specimens (if available) for PD-L-1 
expression, and correlate with response to therapy.

To assess immunologic markers (if serum, available) for response.

To assess changes in hepatitis B and/or hepatitis C viral titer loads 
with pembrolizumab treatment for HCC.
Expected Number of 
Patients
35
Expected Number of 
Centers
Single center: Sylvester Comprehensive Cancer Center (SCCC).  Note: 
SCCC is inclusive of the constituent satellite sites. 
Expected Duration of 
the Protocol
Estimated duration of the main protocol (e.g. from start of screening to 
last subject processed and finishing the study): 3 years. This includes 
long term follow-up of patients, some of whom may have durable 
responses to therapy. 
Patient accrual is expected to be completed in 1.5 years (18 months). 
Planned accrual goals include 10-12 subjects within 1 year.
Inclusion Criteria
1. Patients must have diagnosis of advanced hepatocellular cancer 
(HCC) by one of the following:
a.
Histopathology
b. Elevated serum alpha-fetoprotein (AFP) >400 ng/ml and 
findings on magnetic resonance imaging (MRI) or CT 
scans characteristic of HCC
c.
Findings on triple phase MRI or CT scans characteristic of 
HCC in patients with cirrhosis and tumors at least 1 cm or 
greater, without a curative treatment option (transplant, 
resection, or ablation).
2. Measurable disease as defined by RECIST v1.1 (provided in 
Section 14.0). 
3. Radiographic progression on previously treated areas (as defined 
by RECIST v1.1).
4. Subject refusal for sorafenib treatment or intolerance to sorafenib  
are also allowed (intolerance is defined as ≥28 days of sorafenib 
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(not necessarily consecutive) or ≥grade 3 toxicity due to sorafenib 
which does not resolve with appropriate supportive care).
5. Patients should have failed at least one prior systemic therapy 
regimen which could include sorafenib. Patients may have 
progressed on sorafenib, been intolerant of, or refused sorafenib.   
Patients who are documented to refuse systemic chemotherapy or 
sorafenib are also eligible. No limit to prior systemic therapy. Prior 
locoregional therapy such as surgery, radiofrequency ablation or 
transarterial chemoembolization are also allowed, provided that 
progression has been documented after these therapies, and ≥4 
weeks have elapsed since the last therapy; (these will not be 
counted as systemic therapy).
6. Child-Pugh Classification with score ≤ 7 points.  See Appendix G 
for criteria.
7. Age ≥ 18 years 
8. Estimated life expectancy, in the judgement of the Investigator, of 
at least ≥ 12 weeks.
9. ECOG performance status of 0 or 1.  See Appendix C.
10. Adequate bone marrow function as defined below:
a.
absolute neutrophil count (ANC) ≥ 1.2 x 109/L,
b. platelets (PLT) ≥ 50 x 109/L
11. Adequate liver function as defined below:
a.
serum bilirubin < 2 mg/dl
b. AST(SGOT) ≤ 5 x ULN,
c.
ALT(SGPT) ≤ 5 x ULN
12. Adequate coagulation as defined by: 
a.
serum prothrombin time (PT) ≤ 16 seconds
13. Adequate renal function as defined by one of the following:
a.
serum creatinine ≤ 1.5 x ULN
OR
b. (measured or calculated) creatinine clearance ≥ 60 mL/min 
for patients with serum creatinine levels > 1.5 x ULN.
14. Suitable venous access to allow for all study-related blood 
sampling.
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15. Female subject of childbearing potential (CBP) must have a 
negative urine or serum pregnancy within 3 days prior to receiving 
the first dose of study medication.  
16. Females of child bearing potential that are sexually active must 
agree to either practice 2 medically accepted highly effective 
methods of contraception at the same time or abstain from 
heterosexual intercourse from the time of signing the informed 
consent through 120 days after the last dose of study drug. See 
Appendix H for protocol-approved highly effective methods of 
contraceptive combinations. Subjects of childbearing potential are 
those who have not been surgically sterilized or have not been free 
from menses for > 1 year.
17. Negative test for pregnancy is required of females of child-bearing 
potential; A female of child bearing potential is any woman, 
regardless of sexual orientation or whether they have undergone 
tubal ligation, who meets the following criteria: 
a.
has not undergone a hysterectomy or bilateral 
oophorectomy; or 
b. has not been naturally postmenopausal for at least 24 
consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months or 730 days).
18. Conception while on treatment must be avoided
19. Male subjects should agree to use an adequate method of 
contraception starting with the first dose of study therapy through 
120 days after the last dose of study therapy.
20. Ability to understand and willingness to sign a written informed 
consent document.
Exclusion Criteria
1. Active autoimmune disease that has required systemic treatment in 
the past 2 years (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment. 
2. Diagnosis of immunodeficiency or is receiving systemic steroid 
therapy or any other form of immunosuppressive therapy within 2 
years  prior to the first dose of trial treatment.
3. Major surgical procedure within 28 days prior to enrollment.  
Note:  If subject received major surgery, they must have recovered 
adequately from the toxicity and/or complications from the 
intervention prior to starting therapy.
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4. Any unresolved toxicity > CTCAE grade 2 despite optimal 
care/support, from previous anti-cancer therapy, within 28 days 
prior to first dose of study drug.  [Exceptions: Alopecia and ≤grade 
2 neuropathy.] 
5. Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
6. Receipt of anti-cancer monoclonal antibody within 4 weeks prior 
to first dose of study drug.
7. Prior treatment with any other chemotherapy, radiotherapy, 
immunotherapy, or anticancer drug, agent or biologic within 4 
weeks prior to first dose of study drug. 
8. 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.
9. Receipt of any other investigational agents for their cancer ≤4 
weeks of the first dose of study treatment.
10. Known history of active TB (Bacillus Tuberculosis).
11. Known history of, or any evidence of active, non-infectious 
pneumonitis or has a history of (non-infectious) pneumonitis that 
required steroids or current pneumonitis.
12. Known history of Human Immunodeficiency Virus (HIV), HIV1/2 
antibodies.
13. Known hypersensitivity to pembrolizumab or any of its excipients.
14. Known active central nervous system (CNS) metastases and/or 
carcinomatous meningitis.  [Exception: Subjects with previously 
treated brain metastases may participate provided they are stable 
(without evidence of progression by imaging, for at least 4 weeks 
prior to the first dose of study drug 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 apply to carcinomatous 
meningitis which is excluded regardless of clinical stability.]
15. Is pregnant or breastfeeding, or expecting to conceive or father 
children within the projected duration of the trial through 120 days 
after the last dose of trial treatment.
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16. Any uncontrolled, intercurrent illness including but not limited to 
ongoing or active infection, symptomatic congestive heart failure, 
unstable angina pectoris, symptomatic cardiac arrhythmia. 
17. Has a known additional malignancy that is progressing or requires 
active treatment. [Exception also 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.] 
18. Any other serious medical or psychiatric illness/condition likely in 
the judgment of the Investigator(s) to interfere or limit compliance 
with study requirements/treatment
19. Treatment for active HCV within 60 days of study entry.  [Note: 
Untreated HCV positive subjects are eligible, and if stable on 
pembrolizumab for 6 months after study entry, consideration may 
be given to starting anti-HCV therapy, at the discretion of the 
treating Investigator.] 
20. HCC patients with evidence of prior HBV must fulfill the 
following criteria in order to be eligible for the study: HBV VL 
<100 IU/mL before study enrollment, and subjects with active 
HBV need to be on anti-HBV suppression ≥3 months, throughout 
treatment and for at least 6 months after completion of therapy.
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PROTOCOL SCHEMA 
ICF and Screening
Eligible: Enrollment
Treat 14 evaluable 
subjects
Assess Disease Control Rate 
(DCR) by CR, PR or SD in the 
first 14 evaluable subjects
Interim 
Analysis
2 or less subjects 
with CR, PR, or SD 
3 or more subjects 
with CR, PR or SD
Terminate Study
Treat 14 more 
subjects 
Assess Disease Control Rate 
(CR, PR or SD) in 28 
evaluable subjects
8 or less subjects 
with CR, PR, or SD 
9 or more subjects 
with CR, PR, or SD 
Reject Treatment
Accept Treatment
Estimate Disease Control (DCR), 
Progression-Free Survival (PFS), 
and Overall Survival (OS)
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1.0 BACKGROUND
1.1 Study Disease
Hepatocellular carcinoma (HCC) is a major health problem worldwide. It is the fifth most 
common neoplasm in the world, and the third most common cause of cancer-related death 
[1]. More than 500 000 new cases are currently diagnosed yearly, with an age-adjusted 
worldwide incidence of 5.5 - 14.9 per 100 000 population. In some areas of Asia, HCC 
is the most common cause of death due to cancer. In Europe [2] and the USA [3], HCC 
has gained a major interest because of the rising mortality rates in the past decade (4). 
HCC is now the leading cause of death among patients with cirrhosis in Europe [5]. 
Therefore, the treatment of HCC is of great concern.  
HCC’s which are diagnosed at an early stage may be curable by resection, liver 
transplantation, or percutaneous treatment. In the West and Japan, these treatments can 
be applied to 30% of patients, and result in 5-year survival rates higher than 50% [6]. 
Resection is indicated among patients who have one tumor and well- preserved liver 
function. Liver transplantation benefits patients who have decompensated cirrhosis and 
one tumor smaller than 5 cm or three nodules smaller than 3 cm, but donor shortages 
limit its applicability. 
Unfortunately, most HCC patients are diagnosed at an advanced stage and are not 
candidates for curative therapy. Until recently, there was no standard palliative therapy 
for patients with advanced or unresectable HCC.  In 2007, the results of the SHARP trial 
[7] were reported. This led to the approval of sorafenib (Nexavar, Bayer-Onyx) as the 
first and only therapeutic agent definitively proven to prolong survival in patients with 
advanced HCC. Despite having a very low response rate of 2%, sorafenib improved 
overall survival and time to radiological progression by about 3 months compared to 
placebo in a Western population.  The approval of sorafenib for HCC has sparked 
renewed enthusiasm in studying new agents in this disease for which very few options 
exist.
Immunotherapy is also attractive for HCC patients for several reasons: HCC is typically 
an inflammation-associated cancer and can be immunogenic. Cases of spontaneous 
regression of HCC have been reported. 
Spontaneous immune responses have also been described in HCC (8,9). Activation of 
immune response and T-cell infiltration has been reported after percutaneous alcohol 
injection and radiofrequency ablation (RFA) (10).
Tumor-associated antigen (TAA)-specific CD8+ T-cell immune responses have also 
been reported including AFP, glypican-3, NY-ESO-1, MAGE-A and hTERT (9,11)
One report showed that HCC-infiltrating TAA-specific CD 8+ T cells were found in more 
than 50% of HCC patients.  These cell numbers correlated with survival (12).
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Other studies have shown that T regs are increased in blood and HCC tumor. These 
intratumoral Treg numbers also correlate with disease progression and worse prognosis 
(13).  
Myeloid-derived suppressor cells (MDSCs) with immunosuppressive activity have also 
been reported to occur in the blood and tumor of HCC patients. These cells inhibit 
effector T cells and decrease NK cell cytotoxicity and cytokine production.  MDSCs 
correlate with survival. It has been suggested that these cells may interact with Kupffer 
cells and induce PD-1 expression which will inhibit T cells (14). MDSCs can also expand 
the Treg population.
Recently, immunotherapy has been shown to produce antitumor effects in HCC, a tumor 
which has shown resistance to chemotherapy. CTLA-4 inhibition with tremelimumab 
was evaluated in HCV-associated HCC patients (18). Seventeen patients were evaluable 
for response. The disease control rate was 76.4% with 3 partial responses for 3.6, 9.2 and 
15.8 months. Almost half of the stable disease patients had that status for >6 months. 
At the 2015 ASCO, the preliminary results of a Phase I-II trial of PD1 (nivolumab) in 
advanced HCC was reported (19).  Patients received nivolumab 0.1- 10 mg/kg 
intravenously for up to two years. The study enrolled 41 patients. Eighteen patients 
remained on the study and 23 discontinued treatment due to progressive disease (n=17), 
complete response (n=2), drug-related adverse events (AEs, n=2) and non-drug-related 
AEs (n=2). Drug-related AEs of any grade occurred in 29 patients (71%, 17% grade 3 or 
4) with >10% of patients experiencing aspartate aminotransferase (AST) increase and 
rash (each 17%), alanine aminotransferase (ALT) and lipase increase (each 15%) and 
amylase increase (12%). Grade 3 and 4 AEs >5% were AST increase (12%), ALT 
increase (10%) and lipase increase (5%). A dose-limiting toxicity occurred in one patient 
at 10 mg/kg;no maximum tolerated dose was defined in any cohort. Response was 
evaluable in 39 patients: 2 CR (5%) and 7 partial response (PR 18%). Response duration 
was 14-17+ months for CR, <1-8 months for PR and 1.5-17+ months for stable disease. 
Overall survival rate at 6 months is 72%. The conclusions were that nivolumab had 
manageable AE profile and produced durable responses across all dose levels and HCC 
cohorts (no active hepatitis virus infection or virus-infected HCC), with a favorable 6-
month overall survival rate. 
The promising results with the tremelimumab and nivolumab trials suggest that further 
evaluation of immunotherapy in HCC is indicated. These also provide a rational basis 
to conduct further investigation into this approach.
1.2 Study Agent -Pembrolizumab (Keytruda®)
1.2.1 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 
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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 been suggested to regulate 
tumor-specific T-cell expansion in subjects with melanoma (MEL).  This suggests 
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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. The 
approved dose was 2 mg/kg iv every 3 weeks which is the dose to be used in this 
trial.
1.2.2 Preclinical and Clinical Trial Data from the Investigator’s Brochure for 
Pembrolizumab (Keytruda®)
Overall Summary of Toxicology Data in Animals
The safety of pembrolizumab was characterized in the 1-month repeat-dose 
toxicity study in Cynomolgus monkeys when administered as IV doses of 6, 40, 
or 200 mg/kg once a week (a total of 5 doses) and in the 6-month repeat-dose 
toxicity study in Cynomolgus monkeys when administered as IV doses of 6, 40, 
or 200 mg/kg every other week (a total of 12 doses). Pembrolizumab was well-
tolerated in Cynomolgus monkeys with a systemic exposure (AUC) of up to 
approximately 170,000 μg.day/mL over the course of the 1-month study and with 
a systemic exposure (AUC) of up to approximately 67,500 μg.day/mL over the 
course of the 6-month study. No findings of toxicological significance were 
observed in either 1-month or 6-month toxicity study with pembrolizumab, and 
the NOAEL was ≥200 mg/kg. In addition, no findings of toxicological relevance 
were observed in the in vitro tissue cross-reactivity study using human and 
Cynomolgus monkey tissues. There were no nonclinical findings that would 
preclude testing of pembrolizumab in clinical trials.
Efficacy Summary in Human Subjects
The P001 overall response rate (ORR) demonstrated the antitumor activity of 
pembrolizumab in subjects with melanoma (ipilimumab-naïve and previously 
treated with ipilimumab). P002 demonstrated superior PFS for both 
pembrolizumab treatment arms compared to the chemotherapy control arm. 
Treatment with pembrolizumab led to an ORR that was >4 fold higher than the 
response rate of the chemotherapy control arm. This difference was highly 
statistically significant, with a one sided p-value of <0.0001. The overall response 
rates for pembrolizumab treatment in P001 and P002 compared favorably to 
historical response rates for available treatments for melanoma, particularly in 
subjects who had progressed after multiple prior therapies. For example, the 
largest randomized clinical trial in previously treated advanced melanoma 
subjects, in which carboplatin and paclitaxel were used in the control arm, and 
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sorafenib plus carboplatin and paclitaxel in the experimental arm, produced a 
response rate of 11% and 12%, respectively.
Overall Adverse Events
The pembrolizumab monotherapy trials in [the] Investigator’s Brochure are as 
follows: P001/P002, P012, P013, and P028, plus the P011 monotherapy arm. The 
pembrolizumab combination therapy trials in [the] section of the Investigator’s 
Brochure are as follows: P021 and P023.
In general, the safety profile observed in P011 (monotherapy arm), P012, P013, 
and P028 was similar to that observed in P001/P002. In the pembrolizumab 
monotherapy trials, the overall incidence of AEs ranged from 83.0% (73 of 88 
subjects in P013) to 100% (10 of 10 subjects in P011). In the combination therapy 
trials, the overall incidence of AEs was 95.4% (62 of 65 subjects) in P021 and 
80% (8 of 10 subjects) in P023.
In the pembrolizumab monotherapy trials, in general, the most commonly reported 
AEs included fatigue, diarrhea, decreased appetite, nausea, dyspnea, and anemia. 
In P021, the most commonly reported AEs in this population across the dose 
regimens were fatigue (49.2%), constipation and nausea (26.2% each), decreased 
appetite (23.1%), diarrhea (18.5%), and anemia and alopecia (15.4% each). In 
P023, the most commonly reported AEs experienced in this population across the 
dose regimens were neutropenia and thrombocytopenia (50.0% each), followed by 
anemia, respiratory tract infection, and back pain (30.0% each).
In the pembrolizumab monotherapy trials, the incidence of drug-related AEs 
(DRAEs) ranged from 39.8% (35 of 88 subjects in P013) to 80.0% (8 of 10 
subjects in P011). In the combination therapy trials, the incidence of DRAEs was 
86.2% (56 of 65 subjects in this population) in P021 and 60.0% (6 of 10 subjects 
in this population) in P023. In the pembrolizumab monotherapy trials, the most 
commonly reported DRAEs across all studies were nausea, fatigue, and diarrhea. 
In P021, the most commonly reported DRAEs experienced in this population 
across the dose regimens were fatigue (35.4%); nausea, decreased appetite, and 
alopecia (13.8% each); diarrhea (12.3%); and constipation and aspartate 
aminotransferase increased (10.8% each). In combination therapy trial P023, the 
most commonly reported DRAEs experienced in this population across the dose 
regimens were neutropenia and thrombocytopenia (50.0% each), anemia (30.0%), 
dysphonia, hiccups, and pruritus (20.0% each).
In the pembrolizumab monotherapy trials, the incidence of Grade 3-5 DRAEs 
across studies ranged from 6.8% (6 of 88 in P013) to 12.0% (187 of 1562 subjects) 
in P001/P002. In the combination therapy trials, Grade 3-5 DRAEs were reported 
in 23.1% (15 of 65 subjects in this population) in P021 and 50.0% (5 of 10 subjects 
in this population) in P023.
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In the pembrolizumab monotherapy trials, the most commonly reported Grade 3-
5 DRAEs were anemia, alanine aminotransferase increased, aspartate 
aminotransferase increased, and colitis. In P021, the most common Grade 3-5 
DRAEs in this population across dose regimens were aspartate aminotransferase 
increased (6.2%) and anemia and alanine aminotransferase increased (4.6% each). 
In P023, the only Grade 3-5 DRAEs that occurred in more than 1 subject in this 
population across dose regimens were neutropenia (40.0%) and anemia (20.0%).
In the pembrolizumab monotherapy trials, most subjects who experienced an AE 
continued in the study, with the incidence of AEs leading to discontinuation 
ranging from 4.2% (18 of 430 subjects in P028) to 12.3% (192 of 1562 subjects in 
P001/P002). The majority of AEs leading to discontinuation were not considered 
drug related. Discontinuations due to a DRAE were infrequent and ranged from 
0% (no subjects in P011) to 4.5% (4 of 88 subjects in P013). The most commonly 
reported DRAE leading to discontinuation was pneumonitis.
In P021, most subjects continued treatment despite AEs, and only 4.6% 
discontinued due to an AE. Only 3.1% of subjects discontinued study treatment 
due to an AE that was considered related to study treatment by Investigators. 
Interstitial lung disease, dermatitis allergic and drug eruption were the only 
DRAEs resulting in discontinuation and were reported in 1 subject each (1.5%). 
In P023, no subjects discontinued due to an AE.
1.3 Rationale
1.3.1 Rationale for the Trial and Selected Subject Population
In our study, we will study a different PD 1 drug (Pembrolizumab, Merck) for 
advanced HCC. This drug has been approved for treatment of malignant 
melanoma and has shown antitumor activity in several other malignancies. We 
have experience with this drug in treating cancer patients here at Sylvester. Since 
check point inhibitors (CPI) such as tremelimumab and nivolumab have shown 
activity in HCC, it is reasonable to assess Pembrolizumab in advanced HCC 
patients.
1.3.2 Rationale for Dose Selection/ Regimen/ Modification
An open-label Phase I trial (Protocol 001) was 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, 
was the highest dose tested in PN001.  Recent data from other clinical studies 
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within the MK-3475 program has shown that a lower dose of MK-3475 and a less 
frequent schedule may be sufficient for target engagement and clinical activity.
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target 
engagement is durable (>21 days).  This early PK and pharmacodynamic data 
provides scientific rationale for testing a Q2W and Q3W dosing schedule.  
A population pharmacokinetic analysis has been performed using serum 
concentration time data from 476 patients. Within the resulting population PK 
model, clearance and volume parameters of MK-3475 were found to be dependent 
on body weight. The relationship between clearance and body weight, with an 
allometric exponent of 0.59, is within the range observed for other antibodies and 
would support both body weight normalized dosing or a fixed dose across all body 
weights.  MK-3475 has been found to have a wide therapeutic range based on the 
melanoma indication.  The differences in exposure for a 200 mg fixed dose 
regimen relative to a 2 mg/kg Q3W body weight based regimen are anticipated to 
remain well within the established exposure margins of 0.5 – 5.0 for MK-3475 in 
the melanoma indication. The exposure margins are based on the notion of similar 
efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 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 choice of the 200 mg Q 3W as an appropriate dose 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 exposure 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 and reduce wastage.                      
1.4 Gender and Ethnicity
There are no limitations in terms of gender or ethnicity for eligibility.
1.5 Correlative Studies
If available, tumor tissue either at time of diagnosis or archived tumor may be stained for 
PD-L-1 expression. In tumors such as melanoma, PD-L-1 expression is associated with 
higher response rate to PD-1 or PD-L-1 agents but even patients with no PD-L-1 
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expression may respond to these agents. To our knowledge, no data exists for HCC and 
PD-1 agents or PD-L-1 agents. Obtaining tumor tissue for correlative studies is optional 
for the patient. We will assess PD-L-1 tumor expression with clinical outcome. This is 
exploratory and there is no formal statistical analysis planned. 
Patients who agree may have blood drawn (up to 30 mL if feasible) to perform 
immunologic markers (such as phenotype for T and NK cell markers by flow cytometry).  
Patients with hepatitis B or C will have blood (7 ml) drawn to assess viral titer load. 
These blood samples will be performed at baseline, every 3 weeks while on drug 
treatment and at the time of tumor response or progression. The purpose is to determine 
if immunologic markers and/or viral titers change with treatment. This is exploratory and 
no formal statistical analysis is planned. A descriptive analysis will be done for 
hypothesis-generating purposes but a statistical analysis will not be done as there may 
not be enough tumor tissue and blood samples collected (to conduct a formal statistical 
analysis).
We will also analyze several representative cytokines associated with T cell activation 
and suppression in serum, tumor biopsy and PBMCs from patients with pretreatment of 
anti-PD-1 and every 9 weeks (2-3 times) after anti-PD-1 treatment. T cell proliferation 
and activation in response to T cell receptor (TCR) and CD28 signals require IL-2, IL-
12, IFN-r stimulation, but can be suppressed by immunosuppressive cytokines such as 
IL-10 and TGF-β. This is exploratory and no formal statistical analysis is planned. A 
descriptive analysis will be done for hypothesis-generating purposes but a statistical 
analysis will not be done as there may not be enough tumor tissue and blood samples 
collected (to conduct a formal statistical analysis).
2.0 OBJECTIVES
2.1 Primary Objectives

To determine the disease control rate (CR, PR or SD) and response rate (CR and 
PR) of pembrolizumab in patients with advanced HCC.

To determine the safety of pembrolizumab in HCC patients.
2.2 Secondary Objectives

To determine the progression-free survival (PFS), overall survival (OS), and 
objective response rate (ORR) and duration of response (DOR)
2.3 Exploratory Objectives

To assess HCC tumor specimens (if available) for PD-L-1 expression, and correlate 
with response to therapy.

To assess immunologic markers (if serum, available) for response.
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
To assess changes in hepatitis B and/or hepatitis C viral titer load with 
pembrolizumab treatment for HCC. 
3.0 ENDPOINTS
3.1 Primary endpoints

Disease control rate (DCR) will be calculated per RECIST 1.1, as the proportion of 
patients with best overall response of complete response (CR), partial response (PR) 
or stable disease (SD) that is maintained for at least 8 weeks.  

Treatment-related adverse events (AEs) including serious adverse events (SAEs). 
AEs will be assessed by and assigned severity using the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03.
3.1.1 Evaluable: 

Evaluable for DCR: Eligible subjects who receive at least one dose of 
pembrolizumab, have measurable disease at baseline, and have at least one 
post-baseline disease response assessment.

Evaluable for Safety: Eligible subjects who receive at least one dose of 
pembrolizumab.
3.2 Secondary endpoints

Progression-free survival (PFS) will be defined as the elapsed time from the first date 
of study treatment until documented disease progression (as per RECIST 1.1) or 
death from any cause, whichever is earlier. For patients who remain alive without 
progression, follow-up time will be censored at the date of last disease assessment 
(as per RECIST 1.1).

Overall survival (OS) will be defined as the elapsed time from the first date of study 
treatment to death from any cause. For surviving patients, follow-up will be censored 
at the date of last contact (or last date known to be alive). Follow-up for OS will occur 
every 12 weeks (±1 month) until death or withdrawal of consent from the study.

Objective response rate (ORR) will be defined as the proportion of the patients with 
a confirmed complete or partial response (CR or PR), as per RECIST 1.1.

Duration of Response (DoR) will be defined as the elapsed time from documented 
tumor response to documented disease progression.
3.2.1 Evaluable for PFS, OS, ORR and DOR: Eligible subjects who receive at least 
one dose of pembrolizumab, have measurable disease at baseline, and have at 
least one post-baseline disease response assessment.
3.3 Exploratory endpoints

The expression levels of PD-L-1 in tumor tissue, and immunologic markers as well 
as serum titers of hepatitis B or C in patients with hepatitis B or C, respectively, for 
whom specimens are available.
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3.3.1 Evaluable:

Evaluable for Tissue Correlative Study: Eligible subjects who agree to tissue 
sampling, receive at least one dose of pembrolizumab, have measurable 
disease at baseline, and have at least one post-baseline disease response 
assessment.  

Evaluable for Serum Correlative Study: Eligible subjects who agree to serum 
sampling and receive at least one dose of pembrolizumab.
4.0 SUBJECT RECRUITMENT & SCREENING
Subjects will be recruited at Sylvester Comprehensive Cancer Center via clinical practice 
offices.  Both men and women of all races and ethnic groups are eligible for this trial.  
5.0 PATIENT SELECTION
5.1 Inclusion Criteria
1
Patients must have diagnosis of advanced hepatocellular cancer (HCC) by one of 
the following:
a) Histopathology
b) Elevated serum alpha-fetoprotein (AFP) >400 ng/ml and findings on 
magnetic resonance imaging (MRI) or computed tomography (CT) scans 
characteristic of HCC
c) Findings on triple phase MRI or CT scans characteristic of HCC in patients 
with cirrhosis and tumors at least 1 cm or greater, without a curative 
treatment option (transplant, resection, or ablation).
2
Measurable disease as defined by RECIST v1.1 (provided in Section 14.0). 
3
Radiographic progression on previously treated areas (as defined by RECIST 
v1.1).
4
Subject refusal for sorafenib treatment or intolerance to sorafenib  are also 
allowed (intolerance is defined as ≥28 days of sorafenib (not necessarily 
consecutive) or ≥grade 3 toxicity due to sorafenib which does not resolve with 
appropriate supportive care).
5
Patients should have failed at least one prior systemic therapy regimen which 
could include sorafenib. Patients may have progressed on sorafenib, been 
intolerant of, or refused sorafenib.   Patients who are documented to refuse 
systemic chemotherapy or sorafenib are also eligible. No limit to prior systemic 
therapy. Prior locoregional therapy such as surgery, radiofrequency ablation or 
transarterial chemoembolization are also allowed, provided that progression has 
been documented after these therapies, and ≥4 weeks have elapsed since the last 
therapy; (these will not be counted as systemic therapy).
6
Child-Pugh Classification with score ≤ 7 points.  See Appendix G for criteria.
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7
Age ≥ 18 years 
8
Estimated life expectancy, in the judgement of the Investigator, of at least ≥ 12 
weeks.
9
ECOG performance status of 0 or 1.  See Appendix C.
10
Adequate bone marrow function as defined below:
a) absolute neutrophil count (ANC) ≥ 1.2 x 109/L,
b) platelets (PLT) ≥ 50 x 109/L
11
Adequate liver function as defined below:
a) serum bilirubin < 2 mg/dl
b) AST(SGOT) ≤ 5 x ULN,
c) ALT(SGPT) ≤ 5 x ULN
12
Adequate coagulation as defined by: 
a) serum prothrombin time (PT) ≤ 16 seconds
13
Adequate renal function as defined by one of the following:
a) serum Creatinine ≤ 1.5 x ULN     
OR
b) (measured or calculated) Creatinine clearance ≥ 60 mL/min for patients 
with serum creatinine levels > 1.5 x ULN.
14
Suitable venous access to allow for all study-related blood sampling.
15
Female subject of childbearing potential (CBP) must have a negative urine or 
serum pregnancy within 3 days prior to receiving the first dose of study 
medication.  
16
Females of child bearing potential that are sexually active must agree to either 
practice 2 medically accepted highly effective methods of contraception at the 
same time or abstain from heterosexual intercourse from the time of signing the 
informed consent through 120 days after the last dose of study drug. See 
Appendix H for protocol-approved highly effective methods of contraceptive 
combinations. Subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year.
17
Negative test for pregnancy is required of females of child-bearing potential; A 
female of child bearing potential is any woman, regardless of sexual orientation 
or whether they have undergone tubal ligation, who meets the following criteria: 
a) has not undergone a hysterectomy or bilateral oophorectomy; or
b) has not been naturally postmenopausal for at least 24 consecutive months 
(i.e., has had menses at any time in the preceding 24 consecutive months 
or 730 days).
18
Conception while on treatment must be avoided
19
Male subjects should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy.
20
Ability to understand and willingness to sign a written informed consent 
document.
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5.2 Exclusion Criteria
1
Active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
2
Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 2 years prior to the first dose 
of trial treatment.
3
Major surgical procedure within 28 days prior to enrollment.  Note:  If subject 
received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy.
4
Any unresolved toxicity > CTCAE grade 2 despite optimal care/support, from 
previous anti-cancer therapy, within 28 days prior to first dose of study drug.  
[Exceptions: Alopecia and ≤grade 2 neuropathy.] 
5
Prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
6
Receipt of anti-cancer monoclonal antibody within 4 weeks prior to first dose of 
study drug.
7
Prior treatment with any other chemotherapy, radiotherapy, immunotherapy, or 
anticancer drug, agent or biologic within 4 weeks prior to first dose of study 
drug. 
8
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.
9
Receipt of any other investigational agents for their cancer ≤4 weeks of the first 
dose of study treatment.
10
Known history of active TB (Bacillus Tuberculosis).
11
Known history of, or any evidence of active, non-infectious pneumonitis or has a 
history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
12
Known history of Human Immunodeficiency Virus (HIV), HIV1/2 antibodies.
13
Known hypersensitivity to pembrolizumab or any of its excipients.
14
Known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  [Exception: Subjects with previously treated brain metastases may 
participate provided they are stable (without evidence of progression by 
imaging, for at least 4 weeks prior to the first dose of study drug 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 apply to carcinomatous meningitis 
which is excluded regardless of clinical stability.]
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15
Is pregnant or breastfeeding, or expecting to conceive or father children within 
the projected duration of the trial through 120 days after the last dose of trial 
treatment.
16
Any uncontrolled, intercurrent illness including but not limited to ongoing or 
active infection, symptomatic congestive heart failure, unstable angina pectoris, 
cardiac arrhythmia. 
17
Has a known additional malignancy that is progressing or requires active 
treatment. [Exception: Basal cell carcinoma of the skin or squamous cell 
carcinoma of the skin that has undergone potentially curative therapy, or in situ 
cervical cancer.] 
18
Any other serious medical or psychiatric illness/condition likely in the judgment 
of the Investigator(s) to interfere or limit compliance with study 
requirements/treatment. 
19
Treatment for active HCV within 60 days of study entry.  [Note: Untreated HCV 
positive subjects are eligible, and if stable on pembrolizumab for 6 months after 
study entry, consideration may be given to starting anti-HCV therapy, at the 
discretion of the treating Investigator.] 
20
HCC patients with evidence of prior HBV must fulfill the following criteria in 
order to be eligible for the study: HBV VL <100 IU/mL before study enrollment, 
and subjects with active HBV need to be on anti-HBV suppression ≥3 months, 
throughout treatment and for 6 months after.
6.0 Enrollment Procedures
To enter a patient, the Investigator or Study Team will contact the Clinical Research 
Services’ (CRS) Representative.  All eligibility requirements must be reviewed prior to the 
patient entering the study.  The following information must be provided to the CRS 
Representative:
1) Completed and signed protocol-specific eligibility checklist;
2) All pages of the original signed informed consent form (ICF) including HIPAA Form 
B;
3) Relevant source documents including but not limited to: subject medical history and 
physical exam, concomitant medications, admission or discharge notes, diagnostic 
reports, pathologic confirmation of diagnosis, and relevant subject-specific written 
communication.
6.1 Cancellation Guidelines
Patient may withdraw from the study at any time.  Contact the CRS Representative, or 
e-mail the information including the reasons for withdrawal within 10-business days. 
  
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7.0 STUDY DESIGN
The study will be an open-label, single-institution, non-randomized, single-arm, Phase II 
study of pembrolizumab therapy in patients with advanced HCC.  Patients will be treated in 
three-week cycles, with intravenous (IV) administration of pembrolizumab on day 1 of each 
3-week cycle.  Trial therapy will last until withdrawal of consent, disease progression and/or 
unacceptable toxicity, whichever occurs first.
Correlative studies investigating PD-L-1 expression in tumor tissue will be assessed with 
clinical outcome.  Peripheral blood will also be drawn to perform immunologic markers and 
hepatitis B or C viral titers.  This is to determine if viral titers change with treatment.  These 
studies are included for all patients who consent to the correlative studies (See Appendix F). 
There is an additional consent for the correlative studies.     
Up to 28 evaluable patients will be enrolled at Sylvester Comprehensive Cancer Center 
(SCCC).  We expect to enroll 10-12 patients per year based on our institution’s enrollment 
capacity. Expected time to complete total accrual is approximately 1.5 years. Expected time 
to study completion is 3 years from date open to enrollment to allow for survival data. An 
interim analysis is planned after 14 evaluable patients are assessed for DCR to determine 
whether to continue with an additional 14 more.
8.0 TREATMENT PLAN
8.1 Pembrolizumab (Keytruda®)
Pembrolizumab 200 mg shall be administered in the outpatient setting as a 30 minute 
intravenous (IV) infusion, once every 21 days.  The intravenous line should contain a 
sterile, non-pyrogenic, low-protein binding 0.2 micron to 5 micron in-line or add-on 
filter. Do not co-administer other drugs through the same infusion line. Every effort to 
target infusion timing to be as close to 30 minutes as possible, should be made. The iv 
line will be kept open with 250 ml normal saline for the drug infusion.  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/+10min). 
For additional information on pembrolizumab including mechanism of action, drug 
metabolism, pharmacokinetics & toxicology, known side effects, composition, and 
storage recommendations, see Section 9.0.
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8.2 Treatment Schema
Regimen Description
Agent
Premedications; 
Precautions
Dose
Route
Schedule
Cycle 
Length
Pembrolizumab
Grade 2 infusion reactions 
will be premedicated with 
diphenhydramine 50 mg IV 
and acetaminophen 500-1000 
mg PO prior to subsequent 
infusions.
Diet: Subjects should maintain 
a normal diet unless 
modifications are required to 
manage an AE such as 
diarrhea, nausea or vomiting.
200 mg
IV 
infusion 
over 30 
minutes 
(-5min/ 
+10min)
Day 1 
(±3), 
every 3 
weeks
21 
days 
(3 
weeks)
8.3 Treatment Dispensation, Compliance and Accountability
Eligible subjects shall be treated with the investigational supply of pembrolizumab.  
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.  Drug identity (name, strength) is included in the label text.  Clinical 
supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.  
Receipt and dispensing of investigational product must be recorded by authorized 
person(s) at the trial site.  The Investigator is responsible for maintaining accurate records 
of the clinical supplies received from Merck, the amount dispensed to 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 the 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.
8.4 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 (AEs) with potential immunologic etiology are outlined below.  Where 
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appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids.  
Note that several courses of steroid tapering may be necessary as symptoms may worsen 
when the steroid dose is decreased.  For each disorder, attempts should be made to rule 
out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care.  
It may also become necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of the event.  Suggested conditional 
procedures for Events of Clinical Interest (ECI) associated with pembrolizumab, can be 
found in Appendix I. 
The treatment guidelines are intended to be applied when the Investigator(s) determine 
the events to be related (possible, probable or definite) to trial treatment.  Note: if after 
an evaluation the event is determined not to be related to the trial treatment, the 
Investigator is instructed to follow the reporting guidance in Appendix A (and Section 
15.0).  Refer to Section 10.0 for dose modification(s).    
8.4.1 Concomitant Medications/ Vaccinations
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 these 
Investigator(s) and/or the subject’s primary physician.   
[Exception: Eligible HCC patients with HBV must be on anti-HBV suppression 
throughout treatment and for 6 months after the end of treatment.]
8.4.1.1. Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may 
be administered at the discretion of the investigator in keeping with the community 
standards of medical care.  All concomitant medication will be recorded on the 
case report form (CRF) including all prescription, over-the-counter (OTC), herbal 
supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial 
treatment should be recorded for SAEs and ECIs as defined in Appendix I.
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8.4.1.2. 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 
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 Sponsor.
• Treatment for hepatitis C within 60 days  of study entry. Note: If stable on 
pembrolizumab for 6 months after study entry, consideration may be given to 
start anti-HCV therapy, at the discretion of the treating Investigator.
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 (Section 5.2) describes other medications which are 
prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase.
8.5 Duration of Treatment
Trial therapy will last until withdrawal of consent, disease progression, after CR (as 
specified below), and/or unacceptable toxicity, whichever occurs first. Trial therapy may 
last for a maximum of 2 years (24 months) if the patient shows no evidence of disease 
progression or intolerable toxicity.  
8.6 Duration of Follow-Up  
All subjects will be followed at approximately 30-days (+5 days) after the last dose of 
trial treatment or before the initiation of a new anti-cancer treatment, whichever occurs 
first.  
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Every effort should be made to collect information regarding disease status until disease 
progression, withdrawal of consent, death, end of the study (EoS) or if new anti-
neoplastic treatment is initiated. 
For patients without documented evidence of objective disease progression the following 
assessments should be performed every 12 weeks until documented disease progression, 
death, withdrawal of consent, or end of study, whichever occurs first. A telephone call to 
the patient and/or the patient’s family may be made to evaluate the patient’s status on the 
following:
•
Post-study anticancer therapy status
•
Survival status”
Following confirmed disease progression or initiation of new anti-cancer therapy, 
survival will be assessed (at a minimum) by telephone contact every 12 weeks (±2 
weeks).
Following confirmed disease progression or initiation of new anti-cancer therapy, 
survival will be assessed (at a minimum) by telephone contact every 12 weeks (±2 
weeks).  
See Section 12.4 and 12.5 for further details on Follow-Up assessments. 
9.0 AGENTS (DRUG FORMULATION AND PROCUREMENT)
9.1 Pembrolizumab 
[Refer to the FDA-approved package insert and most current version of the 
Investigator’s Brochure for more information.]  
9.1.1 Other name(s)
MK-3475, Keytruda ®
9.1.2 Mechanism of Action
MK-3475 is a potent and highly selective humanized mAb designed to block the 
interaction between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 potently 
blocks binding to both ligands with half maximal inhibitory concentration (IC50) 
values below 1 nM. MK-3475 enhances T cell responses in human donor blood 
cell cultures with an EC50 of ~0.1 to 0.3 nM. MK-3475 binds to cynomolgus PD-1 
with similar affinity, blocking activity, and demonstrates equivalent enhancement 
of cynomolgus T cell responses. It does not cross-react with rodent PD-1.  MK-
3475 strongly enhances T lymphocyte immune responses in cultured blood cells 
from healthy human donors, cancer patients, and primates. The antibody 
potentiates existing immune responses only in the presence of antigen-receptor 
stimulation and does not nonspecifically activate all T cells.  Using an anti-mouse 
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PD-1 analog antibody, PD-1 blockade is demonstrated to significantly inhibit 
tumor growth in a variety of syngeneic murine tumor models. In experiments in 
mice, anti-PD-1 therapy is synergistic with chemotherapeutic agents such as 
gemcitabine and 5-FU and combination therapy results in increased efficacy and 
increased complete regression rates in vivo.
9.1.3 Drug Metabolism, Pharmacokinetics and Toxicology
The pharmacokinetics of pembrolizumab was studied in 479 patients who received 
doses of 1 to 10 mg/kg every 2 weeks or 2 to 10 mg/kg every 3 weeks. Based on a 
population pharmacokinetic analysis, the mean [% coefficient of variation (CV%)] 
clearance (CL) is 0.22 L/day (28%) and the mean (CV%) elimination half-life (t1/2) 
is 26 days (24%). Steady-state concentrations of pembrolizumab were reached by 
18 weeks of repeated dosing with an every 3-week regimen and the systemic 
accumulation was 2.1-fold. The peak concentration (Cmax), trough concentration 
(Cmin), and area under the plasma concentration versus time curve at steady state 
(AUCss) of pembrolizumab increased dose proportionally in the dose range of 2 to 
10 mg/kg every 3 weeks.  In animal models, inhibition of PD-1 signaling resulted 
in an increased incidence of infections and enhanced inflammatory responses. M. 
tuberculosis-infected PD-1 knockout mice exhibit markedly decreased survival 
compared with wild-type controls, which correlated with increased bacterial 
proliferation and inflammatory responses in these animals. PD-1 knockout mice 
have also shown decreased survival following infection with lymphocytic 
choriomeningitis 
virus 
(LCMV). 
Administration 
of 
pembrolizumab 
in 
chimpanzees with naturally occurring chronic hepatitis B infection resulted in two 
out of four animals with significantly increased levels of serum ALT, AST, and 
GGT, which persisted for at least 1 month after discontinuation of pembrolizumab.
9.1.4 Management of Agent-Specific Adverse Events
There are no specific safety concerns based on the results of nonclinical studies. 
Pembrolizumab has the same mechanism of action as other anti–PD-1 monoclonal 
antibodies. 
Preclinical 
studies 
have 
suggested 
similar 
potency, 
and 
pharmacokinetic (PK) modeling has suggested similar human PK in the class. 
Accordingly, the AEs observed with other anti–PD-1 antibodies may serve as an 
indicator for the AEs to expect in cancer subjects. Furthermore, AEs from other 
immunotherapies for cancer were considered in the Pembrolizumab Program (MK-
3475) Event of Clinical Interest (ECI) Guidance Document.
Pembrolizumab is generally well tolerated and demonstrates a favorable safety 
profile in comparison to chemotherapy. Pembrolizumab is an immunomodulatory 
agent, and based on this mechanism of action, immune mediated adverse events are 
of primary concern.
Important identified risks for pembrolizumab are of an immune mediate nature, 
including: 
pneumonitis, 
colitis, 
thyroid 
disorders 
(hypothryoidism/ 
hyperthyroidism), hepatitis, hypophysitis, Type I diabetes mellitis, uveitis, and 
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nephritis. After a recent review of data, events newly characterized as identified 
risks also include pancreatitis, myositis, and severe skin reaction; these are included 
in the reference safety information below. The majority of immune-mediated 
adverse events were mild to moderate in severity, were manageable with 
appropriate care, and rarely required discontinuation of therapy. Further details 
around frequency, reporting, and management of immune-related adverse events 
(irAEs) are described below. In addition to the previously noted identified risks, 
infusion-related reactions are a risk but are not considered immune mediated; these 
are further described below.
Clinical Trials Experience
The safety of KEYTRUDA was investigated in two controlled, randomized studies 
(KEYNOTE-002 and KEYNOTE-006) for the treatment of unresectable or 
metastatic melanoma and in an uncontrolled, open-label study (KEYNOTE-001) 
for the treatment of unresectable or metastatic melanoma and metastatic non-small 
cell lung carcinoma (NSCLC). Overall, 1567 subjects with melanoma (699 
previously treated with ipilimumab and 868 naïve to ipilimumab) and 550 subjects 
with NSCLC were treated. Safety is described for the pooled population of 2117 
subjects (studied across three doses; 2 mg/kg every 3 weeks and 10 mg/kg every 2 
or 3 weeks). The median treatment duration was 4.6 months (range 1 day to 28.3 
months) including 906 subjects treated for greater than or equal to 6 months and 
203 subjects treated for greater than or equal to one year.
KEYTRUDA was discontinued for treatment-related adverse reactions in 4% of 
subjects. Treatment-related serious adverse events (SAEs) reported up to 90 days 
after the last dose occurred in 9% of subjects receiving KEYTRUDA. Of these 
treatment-related SAEs, those occurring in more than five subjects (out of 2117) 
were pneumonitis (n=24), colitis (n=19), diarrhea (n=16), pyrexia (n=8), adrenal 
insufficiency (n=6) and autoimmune hepatitis (n=6).
Immune-Related Adverse Events (irAEs)
An irAE is defined as a clinically significant AE of any organ that is associated 
with study drug exposure, is of unknown etiology, and is consistent with an 
immune-related mechanism. AEs of Special Interest (AEOSI) data for melanoma 
and lung subjects demonstrates that irAEs were reported in 16.1% of subjects (251 
of 1562) overall; AEOSI were considered by the Investigators to be drug related in 
14.3% of subjects (223 of 1562). The majority of AEOSI were Grade 1 or 2 in 
severity. Overall, serious AEOSI occurred in 4.2% of subjects at 2 mg/kg Q3W, 
3.7% of subjects at 10 mg/kg Q3W, and 3.9% of subjects at 10 mg/kg Q2W. There 
was one AEOSI (pneumonitis) related to death in 10 mg/kg Q3W arm, in a subject 
with NSCLC.
The rate of discontinuation due to AEOSI was low (2.6%). The most commonly 
reported immune-related adverse events across the dose schedules are 
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hypothyroidism (7.2%), pneumonitis (2.9%), hyperthyroidism (2.2%), colitis 
(1.3%) and skin AEOSI (1.3% including all terms). Based on the mechanism of 
action of MK-3475 and similar immunomodulatory agents, the Sponsor is 
interested in potential irAEs, and encourages appropriate investigation of signs and 
symptoms suggestive of these.
Consultation with the appropriate medical specialist should be considered when 
investigating a possible irAE. These events can occur after the first dose to several 
months after the last dose of treatment. Mild irAEs are usually treated 
symptomatically and do not require dosing delays or discontinuation. Higher grade 
and persistent lower grade irAEs typically necessitate withholding or discontinuing 
treatment and administration of systemic steroids or other immunosuppressive 
agents (such as tumor necrosis factor blockers), when systemic steroids are not 
effective. Early recognition of irAEs and initiation of treatment are critical to reduce 
the risk of complications, since the majority of irAEs are reversible with the use of 
steroids and other immune suppressants.
Identification and Treatment of irAEs
If an irAE is suspected, a thorough evaluation should be conducted in an effort to 
possibly rule out neoplastic, infectious, metabolic, toxin or other etiologic causes 
prior to diagnosing an irAE. Serological, immunological, and histological (biopsy) 
data should be considered to support the diagnosis of an immune-related toxicity.
A separate document entitled Pembrolizumab Program (MK-3475) Event of 
Clinical Interest Guidance Document is maintained and distributed to 
investigational sites along with this IB and study protocols. Please refer to this 
guidance document in conjunction with this IB when assessing irAEs. Updates and 
modifications to the irAE guidance document will be made and distributed to 
Investigators to provide the most current information, and therefore will be 
independent of the IB update cycle.
It is possible that irAEs other than those listed in the guidance document may be 
observed in subjects receiving pembrolizumab; therefore, all AEs of unknown 
etiology associated with drug exposure should be evaluated to determine if it is 
possibly immune related. This is meant to be a general guidance; therefore, 
recommendations in the current document might not be all inclusive. As such 
Investigators are encouraged to contact a Merck Clinical Monitor as needed to 
discuss cases that warrant separate discussion outside of the scope of current 
guidelines. Permanent discontinuation of pembrolizumab due to irAE may be 
subject of discussion between the SPONSOR and treating Investigator. The general 
approach to handling irAEs can be found in Appendix I.
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All AEs are to be graded according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 
(http://ctep.cancer.gov).
If an irAE does not resolve or improve to ≤ Grade 1 (or to Grade 2 for ALT or 
AST) within 12 weeks from the start of grade 2 toxicity (or start of grade 3 
toxicity for AST, ALT)  study therapy discontinuation should be considered at the 
PI discretion or  after discussion with a Merck Clinical Director.
Infusion Reactions
Infusion reactions have been reported with pembrolizumab at a rate of 2.5%; these 
were generally Grade 1 and 2 and the majority were considered related by the 
Investigator. One event of Grade 4 anaphylaxis has been reported. Infusion 
reactions may present as allergic reaction, serum sickness, infusion reaction, 
cytokine release syndrome, or anaphylaxis. Mild infusion reactions can generally 
be treated with interruption of the infusion and medical intervention including IV 
fluids, antihistamines, nonsteroidal anti-inflammatory drugs, acetaminophen, and 
narcotics as needed. More severe or life thereatening reactions may require 
pressors, corticosteroids, and epinephrine. Pembrolizumab therapy should not be
redosed in these more severe cases.
Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)
One fatal case of SJS in a clinical trial and one fatal case of TEN in the post-
marketing setting have been reported in patients treated with Pembrolizumab.  In 
total 8 cases of SJS and 2 cases of TEN all of which were serious.  The risk of SJS 
and TEN is reported at approximately 0.4 – 7 cases per million patient years in the 
general adult population.  Independent risk factors include certain medications 
such as anticolvulsants, sulfonamines, aminopenicillins, allopurinol and NSAIDs.   
Non-medication triggers include infection, contrast media, and vaccinations.  
Malignancy is associated with an increased mortality rate in patients with SJS and 
TEN.
Monitor patients for signs and symptoms of SJS and/or TEN, withhold 
Pembrolizumab and refer patient for specialized care and treatment.  Administer 
corticosteroids for SJS grade 3 or 4 or TEN grade 4 (initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper). Permanently discontinue 
Pembrolizumab for any grade of SJS or TEN.
Immune-Mediated Myocarditis 
A total of 6 cases of myocarditis have been reported in patients treated with 
Pembrolizumab in clinical trials or in expanded access program.  One fatal case 
was reported from a clinical trial.   Immune-mediated myocarditis should be 
suspected if other causes of myocarditis, such as infection or prior radiation 
therapy, have been excluded.  Risk factors include certain medications and 
treatment modalities such as radiation, anthracycline, alkylating agents and most 
recently checkpoint inhibitors.
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Monitor patients for signs and symptoms of Immune-Mediated Myocarditis and 
ensure adequate evaluation to exclude the other ethiologies.  Administer 
corticosteroids for grade 2 immune-mediated myocarditis (initial dose of 1-2 
mg/kg/day prednisone or equivalent followed by a taper). Permanently discontinue 
Pembrolizumab for grade 3-4 myocarditis or if toxicity does not resolve within 12 
weeks of start of grade 2 toxicity or inability to reduce corticosteroid to 10 mg or 
less of prednisone or equivalent per day within 12 weeks. 
Immune-Mediated Pneumonitis
Pneumonitis occurred in 12 (2.9%) of 411 melanoma patients, including Grade 2 
or 3 cases in 8 (1.9%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA 
in Trial 1. The median time to development of pneumonitis was 5 months (range 
0.3 weeks-9.9 months). The median duration was 4.9 months (range 1 week-14.4 
months). Five of eight patients with Grade 2 and the one patient with Grade 3 
pneumonitis required initial treatment with high-dose systemic corticosteroids 
(greater than or equal to 40 mg prednisone or equivalent per day) followed by a 
corticosteroid taper. The median initial dose of high-dose corticosteroid treatment 
was 63.4 mg/day of prednisone or equivalent with a median duration of treatment 
of 3 days (range 1-34) followed by a corticosteroid taper. Pneumonitis led to 
discontinuation of KEYTRUDA in 3 (0.7%) patients. Pneumonitis completely 
resolved in seven of the nine patients with Grade 2-3 pneumonitis. 
Pneumonitis (including fatal cases) has been reported in subjects receiving 
KEYTRUDA. Monitor patients for signs and symptoms of pneumonitis. Evaluate 
patients with suspected pneumonitis with radiographic imaging and administer 
corticosteroids for Grade 2 or greater pneumonitis (initial dose of 1-2 mg/kg/day 
prednisone or equivalent followed by a taper). Withhold KEYTRUDA for 
moderate (Grade 2) pneumonitis, and permanently discontinue KEYTRUDA for 
severe (Grade 3), life-threatening (Grade 4) or recurrent moderate (Grade 2) 
pneumonitis. (See Immune-mediated adverse reactions below.)
Immune-Mediated Colitis
Colitis (including microscopic colitis) occurred in 4 (1%) of 411 patients, including 
Grade 2 or 3 cases in 1 (0.2%) and 2 (0.5%) patients, respectively, receiving 
KEYTRUDA in Trial 1. The median time to onset of colitis was 6.5 months (range 
2.3-9.8). The median duration was 2.6 months (range 0.6 weeks-3.6 months). All 
three patients with Grade 2 or 3 colitis were treated with high-dose corticosteroids 
(greater than or equal to 40 mg prednisone or  equivalent per day) with a median 
initial dose of 70 mg/day of prednisone or equivalent; the median duration of initial 
treatment was 7 days (range 4-41), followed by a corticosteroid taper. One patient 
(0.2%) required permanent discontinuation of KEYTRUDA due to colitis. All four 
patients with colitis experienced complete resolution of the event. Monitor patients 
for signs and symptoms of colitis. Administer corticosteroids for Grade 2 or greater 
colitis. Withhold KEYTRUDA for moderate (Grade 2) or severe (Grade 3) colitis, 
and permanently discontinue KEYTRUDA for life-threatening (Grade 4) colitis.
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Immune-Mediated Hepatitis
Hepatitis (including autoimmune hepatitis) occurred in 2 (0.5%) of 411 patients, 
including a Grade 4 case in 1 (0.2%) patient, receiving KEYTRUDA in Trial 1. The 
time to onset was 22 days for the case of Grade 4 hepatitis which lasted 1.1 months. 
The patient with Grade 4 hepatitis permanently discontinued KEYTRUDA and was 
treated with high-dose (greater than or equal to 40 mg prednisone or equivalent per 
day) systemic corticosteroids followed by a corticosteroid taper. Both patients with 
hepatitis experienced complete resolution of the event. 
Elevated transaminases and alkaline phosphatase may be seen during treatment.  
Treatment should be interrupted when transaminase or alkaline phosphatase 
increases are accompanied by Grade 3 total bilirubin, and/or Grade 3 coagulation 
tests (e.g., International Normalized Ratio [INR]), or if subjects are clinically 
symptomatic.  
Evaluation of subjects with elevated transaminases, bilirubins, and alkaline 
phosphatase should involve a workup to assess for infection (SBP or other), viral 
reactivation (if relevant), vascular thrombosis, biliary obstruction, possible 
hepatotoxic medications, tumor progression, alcohol toxicity, and effects of 
pembrolizumab.  At baseline, all subjects should be assessed for HBsAg, HBsAb, 
anti-HBc antibody, HBeAg, and anti-HCV.  As described above, a viral load <100 
IU/mL is required for study entry, and with active HBV must have also been treated 
with antiviral therapy for ≥3 months before initiation of study treatment.  Subjects 
with controlled HBV on therapy should stay on this same therapy throughout 
pembrolizumab treatment.  Subjects who are positive for HBsAg or anti-HBc (but 
negative for HBsAg and HBV DNA), should be assessed for HBV viral load,  
HBsAg, HBsAb, anti-HBc antibody, HBeAg  every 3 weeks, independent of 
treatment delays.  
Subjects with chronic infection by hepatitis C virus (HCV) with successful 
treatment (defined as SVR12 or SVR24) may be included. HCV genotype should 
also be recorded at baseline.  Untreated HCV positive subjects are eligible, and if 
stable after 6 months on pembrolizumab, additional antiviral treatment for HCV 
may be considered per local standard of care. Viral loads should be assessed for 
those with an underlying viral etiology q 3 weeks.  They should also be checked if 
there is an elevation in ALT >3× baseline, a tenfold or greater increase in HBV or 
HCV DNA > baseline, or an absolute increase in HBV or HCV DNA > 105 c/mL.  
If evidence of reactivation is present, the Sponsor should be consulted within 
24 hours, and pembrolizumab treatment should be interrupted.  A hepatology 
consult should be obtained.

For Grade 2 AST/ALT or alkaline phosphatase events (if normal or Grade 
1 at baseline) and no other etiology is found, monitor liver function tests 
weekly. 
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
For Grade 3-4 AST/ALT, alkaline phosphatase events if normal at 
baseline), or >3× baseline (if greater than 2×ULN at baseline) and no other 
underlying etiology is found, consider treatment with intravenous 
corticosteroids 
for 
24–48 hours.  When improved to baseline (for those with levels ≥2×ULN 
at baseline) or Grade 1 or less (for those with normal baseline values), a 
steroid taper should be started and continued over no less than 4 weeks.  

For Grade 2-3 total bilirubin or PT/INR, pembrolizumab should be 
interrupted and steroids given as above. If values don’t improve within 12 
weeks from date of diagnosis of grade 3 toxicity to baseline or Grade 0-1, 
pembrolizumab should be permanently discontinued.

For Grade 4 total bilirubin or PT/INR, pembrolizumab should be 
permanently discontinued. 
Immune-Mediated Hypophysitis
Hypophysitis occurred in 2 (0.5%) of 411 patients, consisting of one Grade 2 and 
one Grade 4 case (0.2% each), in patients receiving KEYTRUDA in Trial 1. The 
time to onset was 1.7 months for the patient with Grade 4 hypophysitis and 1.3 
months for the patient with Grade 2 hypophysitis. Both patients were treated with 
high-dose (greater than or equal to 40 mg prednisone or equivalent per day) 
corticosteroids followed by a corticosteroid taper and remained on a physiologic 
replacement dose. Monitor for signs and symptoms of hypophysitis. Administer 
corticosteroids for Grade 2 or greater hypophysitis. Withhold KEYTRUDA for 
moderate (Grade 2) hypophysitis, withhold or discontinue KEYTRUDA for severe 
(Grade 3) hypophysitis, and permanently discontinue KEYTRUDA for 
lifethreatening (Grade 4) hypophysitis.
Renal Failure and Immune-Mediated Nephritis
Nephritis occurred in 3 (0.7%) patients, consisting of one case of Grade 2 
autoimmune nephritis (0.2%) and two cases of interstitial nephritis with renal 
failure (0.5%), one Grade 3 and one Grade 4. The time to onset of autoimmune 
nephritis was 11.6 months after the first dose of KEYTRUDA (5 months after the 
last dose) and lasted 3.2 months; this patient did not have a biopsy. Acute interstitial 
nephritis was confirmed by renal biopsy in two patients with Grades 3-4 renal 
failure. All three patients fully recovered renal function with treatment with high-
dose corticosteroids (greater than or equal to 40 mg prednisone or equivalent per 
day) followed by a corticosteroid taper.
Monitor patients for changes in renal function. Administer corticosteroids for 
Grade 2 or greater nephritis. Withhold KEYTRUDA for moderate (Grade 2) 
nephritis, and permanently discontinue KEYTRUDA for severe (Grade 3), or life-
threatening (Grade 4) nephritis.
Immune-Mediated Hyperthyroidism and Hypothyroidism
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Hyperthyroidism occurred in 5 (1.2%) of 411 patients, including Grade 2 or 3 cases 
in 2 (0.5%) and 1 (0.2%) patients, respectively, receiving KEYTRUDA in Trial 1. 
The median time to onset was 1.5 months (range 0.5-2.1). The median duration was 
2.8 months (range 0.9 to 6.1). One of two patients with Grade 2 and the one patient 
with Grade 3 hyperthyroidism required initial treatment with high-dose 
corticosteroids (greater than or equal to 40 mg prednisone or equivalent per day) 
followed by a corticosteroid taper. One patient (0.2%) required permanent 
discontinuation of KEYTRUDA due to hyperthyroidism. All five patients with 
hyperthyroidism experienced complete resolution of the event. Hypothyroidism 
occurred in 34 (8.3%) of 411 patients, including a Grade 3 case in 1 (0.2%) patient, 
receiving KEYTRUDA in Trial 1. The median time to onset of hypothyroidism was 
3.5 months (range 0.7 weeks-19 months). All but two of the patients with 
hypothyroidism were treated with long-term thyroid hormone replacement therapy. 
The other two patients only required short-term thyroid hormone replacement 
therapy. No patient received corticosteroids or discontinued KEYTRUDA for 
management of hypothyroidism. Thyroid disorders, including thyroiditis, 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. 
Administer corticosteroids for Grade 3 or greater hyperthyroidism, withhold 
KEYTRUDA for severe (Grade 3) hyperthyroidism, and permanently discontinue 
KEYTRUDA 
for 
life-threatening 
(Grade 
4) 
hyperthyroidism. 
Isolated 
hypothyroidism may be managed with replacement therapy without treatment 
interruption and without corticosteroids.
Other Immune-Mediated Adverse Reactions
Other clinically important immune-mediated adverse reactions can occur. The 
following clinically significant, immune-mediated adverse reactions occurred in 
less than 1% of patients treated with KEYTRUDA in Trial 1: exfoliative dermatitis, 
uveitis, arthritis, myositis, pancreatitis, hemolytic anemia, partial seizures arising 
in a patient with inflammatory foci in brain parenchyma, Guillain-Barré syndrome, 
vitiligo, encephalitis, and adrenal insufficiency.  Across clinical studies with 
KEYTRUDA in approximately 2000 patients, the following additional clinically 
significant, immune-mediated adverse reactions were reported in less than 1% of 
patients: myasthenic syndrome, optic neuritis, rhabdomyolysis and sarcoidosis in 
parts of the lymph nodes, skin, or lungs. 
For suspected immune-mediated adverse reactions, ensure adequate evaluation to 
confirm etiology or exclude other causes. Based on the severity of the adverse 
reaction, 
withhold 
KEYTRUDA 
and 
administer 
corticosteroids. 
Upon 
improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper 
over at least 1 month. Based on limited data from clinical studies in subjects whose 
immune-related adverse reactions could not be controlled with corticosteroid use, 
administration of other systemic immunosuppressants can be considered. Restart 
KEYTRUDA if the adverse reaction remains at Grade 1 or less. Permanently 
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discontinue KEYTRUDA for any severe or Grade 3 immune-mediated adverse 
reaction that recurs and for any life-threatening immune-mediated adverse reaction.
9.1.5 Serious Adverse Reactions Considered Expected for pembrolizumab
SOC
Adverse Reaction (MedDRA Preferred 
Terms)
Cardiac disorders
Autoimmune myocarditis
Myocarditis
Endocrine disorders
Adrenal insufficiency
Adrenocortical insufficiency acute
Autoimmune thyroiditis
Hyperthyroidism
Hypophysitis
Hypopituitarism 
Hypothyroidism
Lymphocytic hypophysitis
Secondary adrenocortical insufficiency
Thyroid disorder
Thyroiditis
Eye disorders
Autoimmune uveitis
Iridocyclitis
Iritis
Ocular myasthenia
Ocular sarcoidosis
Uveitis
Gastrointestinal disorders
Autoimmune pancreatitis
Colitis
Colitis microscopic
Diarrhoea
Enterocolitis
Enterocolitis haemorrhagic
Oral lichen planus
Pancreatitis
Pancreatitis acute
Pancreatitis necrotising
General disorders and administration
Pyrexia
Hepatobiliary disorders
Autoimmune hepatitis
Drug-induced liver injury
Hepatitis
Hepatitis acute
Hepatitis fulminant
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Immune system disorders
Anaphylactic reaction
Anaphylactoid reaction
Cytokine release syndrome
Drug hypersensitivity
Hypersensitivity
Sarcoidosis
Serum sickness
Infections and infestations
Encephalitis
Rash pustular
Injury, poisoning and procedural complications
Infusion related reaction
Metabolism and nutritional disorders
Diabetic ketoacidosis
Fulminant type 1 diabetes mellitus
Latent autoimmune diabetes in adults
Type 1 diabetes mellitus
Musculoskeletal and connective tissue disorders
Immune-mediated necrotising myopathy
Myopathy
Myositis
Psoriatic arthropathy
Necrotising myositis
Polymyositis
Rhabdomyolysis
Nervous system disorders
Axonal neuropathy
Demyelinating polyneuropathy
Diabetic ketoacidotic hyperglycaemic coma
Encephalitis autoimmune
Guillain-Barre syndrome
Limbic encephalitis
Miller Fisher syndrome
Myasthenia gravis
Myasthenia gravis crisis
Myasthenic syndrome
Renal and urinary disorders
Autoimmune nephritis
Glomerulonephritis
Glomerulonephritis membranous
Nephritis
Nephrotic syndrome
Tubulointerstitial nephritis
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease*
Pneumonitis*
Pulmonary sarcoidosis
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Skin and subcutaneous tissue disorders
Acute febrile neutrophilic dermatosis
Cutaneous sarcoidosis
Dermatitis
Dermatitis bullous
Dermatitis exfoliative
Drug eruption
Drug reaction with eosinophilia and systemic symptoms
Eczema
Erythema multiforme
Lichen planus
Palmar-plantar erythrodysaesthesia syndrome
Pemphigoid
Perivascular dermatitis
Pruritus
Psoriasis
Rash
Rash erythematous
Rash generalised
Rash macular
Rash maculo-papular  
Rash morbilliform
Rash papular
Rash pruritic
Skin disorder Skin 
necrosis
Skin toxicity
Stasis dermatitis
Stevens-Johnson syndrome (SJS)*
Subacute cutaneous lupus erythematosus
Toxic epidermal necrolysis (TEN)*
For the purpose of safety reporting in clinical trials, only serious adverse reactions are considered expected. 
*Term also considered expected with fatal outcome.
9.1.6 Composition
50 mg, lyophilized powder in single-use vial for reconstitution. 
9.1.7 Storage Recommendations and Dosage Forms
Two Drug Product (DP) dosage forms are available for MK-3475:a white to off-
white lyophilized powder, 50 mg/vial, and a liquid, DP 100 mg/vial, both in Type 
I glass vials intended for single use only.
o
MK-3475 Powder for Solution for Infusion, 50 mg/vial (manufactured using 
the partially formulated DS), is reconstituted with sterile water for injection 
prior to use. MK-3475 DP is formulated with L-histidine as buffering agent, 
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polysorbate 80 as surfactant, sucrose as stabilizer/tonicity modifier, and 
hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for pH adjustment 
(if necessary).
o
MK-3475 Solution for Infusion 100 mg/vial is a liquid DP (manufactured 
using the fully formulated DS with L-histidine as buffering agent, polysorbate 
80 as surfactant, and sucrose as stabilizer/tonicity modifier), and has the 
identical formulation as that of the reconstituted lyophilized vial.  
Both drug product dosage forms are stored under refrigerated conditions (2°C 
- 8°C).  The product after reconstitution with sterile water for injection and the 
liquid drug product are a clear to opalescent solution which may contain 
proteinaceous and extraneous particulates. The reconstituted lyophilized 
product and the liquid product are intended for IV administration. The 
reconstituted DP solution or the liquid DP can be further diluted with normal 
saline or 5% dextrose in the concentration range of 1 to 10 mg/mL in IV 
containers made of polyvinyl chloride (PVC) or non-PVC material. 
Reconstituted vials should be immediately used to prepare the infusion 
solution in the IV bag and the infusion solution should be immediately 
administered. If not used immediately, vials and/or IV bags may be stored at 
2-8 °C for up to a cumulative time of 20 hours. If refrigerated, the vials and/or 
IV bags should be allowed to equilibrate to room temperature prior to 
subsequent use. MK-3475 solutions may be stored at room temperature for a 
cumulative time of up to 4 hours. This includes room temperature storage of 
reconstituted or liquid DP solution in vials, room temperature storage of 
infusion solution in the IV bag and the duration of infusion. This 
recommendation is based on up to 24 hours of room temperature and up to 24 
hours of refrigerated stability data of diluted pembrolizumab solutions in the 
IV bags.
9.1.8 Dispensation and Accountability
For this study, pembrolizumab (Keytruda®) will be provided by Merck as 
Pembrolizumab 50 mg (lyophilized powder for injection) or pembrolizumab 100 
mg/ 4mL (solution for injection).   Please see Appendix J for Preparation and 
Administration/ Reconstitution of Pembrolizumab (Keytruda®) for Injection 
(lyophilized powder)
(See also Section 8.3 Treatment Dispensation, Compliance and Accountability 
for Pembrolizumab) 
10.0 TREATMENT/ DOSE MODIFICATIONS
10.1Unacceptable Toxicity
Causality for all adverse events should be assessed and if deemed attributable, attempts 
should be made toward proper attribution.  
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Drug-related grade 4 toxicities will require subject to discontinue all study treatment.  
Intolerable grade 2 and grade 3 toxicities should be managed as per dose modification 
guidelines listed in the table below.  Pembrolizumab therapy may be continued providing 
the residual adverse events are within permissible ranges for pembrolizumab dosing.    
10.2Dose Modification Guidelines for Pembrolizumab 
Adverse events (AEs) both serious and non-serious associated with pembrolizumab 
exposure may represent an immunologic etiology.  These AEs 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 10 
below.  See also Section 8.4 for supportive care guidelines and Appendix I.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (e.g. elective surgery, unrelated medical events, patient vacation, and/or 
holidays).  Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the PI.  The reason for the interruption should be 
documented in the patient’s study record. 
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Table 10.2 Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Steven-Johnson 
Syndrome (SJS)
Any
Permanently discontinue
Refer patient for specialized 
care for assessment and 
treatment.
If SJS confirmed, permanently discontinue 
pembrolizumab
Toxic Epidermal 
Necrolysis 
(TEN)
Any
Permanently discontinue
Refer patient for specialized 
care for assessment and 
treatment.
If TEN confirmed, permanently discontinue 
pembrolizumab
Grade 2
Withhold 
Pneumonitis 
Grade 3 or 4, or 
recurrent Grade 2
Permanently discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic 
infections
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus).
Participants with ≥ Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid 
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Grade 4
Permanently discontinue
infusion.
3
Withhold
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper
AST / ALT 
elevation
4
Permanently discontinue 
--see exception below2
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value returned 
to baseline or is stable
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisone or equivalent) 
followed by taper
Increased 
bilirubin
Grade 3 or 4 
Permanently discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value returned 
to baseline or is stable
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
Initiate insulin replacement 
therapy for participants with 
T1DM 
Administer anti-
hyperglycemic in participants 
with hyperglycemia 
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes.
Grade 2
Withhold
Hypophysitis
Grade 3 or 4 
Withhold or 
permanently 
discontinue1 
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated.  
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
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Grade 2
Continue 
Hyperthyroidism 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
Monitor for signs and symptoms of thyroid 
disorders. 
Hypothyroidism
Grade 2-4
Continue 
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyroinine) per standard 
of care
Monitor for signs and symptoms of thyroid 
disorders. 
Grade 2
Withhold 
Nephritis and 
Renal 
dysfunction
Grade 3 or 4 
Permanently discontinue
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.
Monitor changes of renal function
Grade 1 or 2
Withhold
Myocarditis
Grade 3 or 4
Permanently discontinue
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Intolerable/ 
persistent Grade 2
Withhold
Grade 3
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Gullain-Barre 
Syndrome, encephalitis
All other 
immune-related 
AEs3
Grade 4 or 
recurrent Grade 3 
Permanently discontinue
Based on type and severity of 
AE administer corticosteroids 
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. 
2.  For grade 3 liver toxicity with elevated AST and/or ALT. Since HCC patients may have grade 1-2 elevation of AST/ALT at baseline, if these patients have Grade 3 
elevation of AST/ALT, hold therapy and resume treatment when AST/ALT return to baseline or Grade ≤1. The AST/ALT should return to baseline or < 5 x ULN within 
12 weeks from start of grade 3, otherwise patient should be discontinued from study.
3. 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.
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  


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10.2.1Hepatic Toxicity 
At baseline, all subjects should be assessed for HBsAg, HBsAb, anti-HBc antibody, 
HBeAg, and anti-HCV.  Patients who test negative for these hepatitis labs do not need 
to repeat these lab tests again, unless clinically indicated.  Evidence of prior HBV 
should also prompt a viral load measurement at baseline.  A viral load <100 IU/mL is 
required for study entry.  Those with active HBV must have been treated with antiviral 
therapy for ≥3 months before initiation of study treatment.  Subjects with controlled 
HBV on therapy should stay on this therapy throughout pembrolizumab.  Subjects who 
are positive for HBsAg, or anti-HBc (but negative for HBsAg and HBV DNA), should 
be assessed for viral loads, anti-HBs, anti-HBc and HBsAg every 3 weeks (Q3W), 
independent of treatment delays.
Viral loads and HBsAg should also be assessed if there is an elevation in ALT >3× 
baseline, a tenfold or greater increase in HBV or HCV DNA over baseline, or an 
absolute increase in HBV or HCV DNA over 105 c/mL.  If evidence of reactivation is 
present, the Sponsor should be consulted within 24 hours, and pembrolizumab 
treatment should be interrupted. 
If there is a 5X or greater elevation in ALT (if normal at baseline), workup should be 
undertaken to rule out SBP, obstruction, medication, or vascular injury. If these are 
unrevealing, consideration of pembrolizumab toxicity should be undertaken. Steroids 
may be considered if viral flare and other etiologies are ruled out. 
Table 1: Hepatitis Treatment Guidelines
Test(s)
Patient Status
Included in KN-0224
Any HBV 
Treatment Needed?
HBsAg (-)
Total anti-HBc (+)
Anti-HBs (+)
Immune after natural 
infection
YES
NO
HBsAg (-)
Total anti-HBc (-)
Anti-HBs (+)
Immune after 
vaccination
YES
NO
HBsAg (+)
Total anti-HBc (+)
IgM anti-HBc (+)
Anti-HBs (-)
Acute Infection
NO 
--
HBsAg (+)
Total anti-HBc (+)
IgM anti-HBc (-)
Anti-HBs (-)
Chronic Infection
YES
YES, need to be on a 
NI for at for at least 
12 week prior to start 
of Pembro without 
evidence of a flare 
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during that period (ie, 
has been on chronic 
NI therapy)
EXCLUDE IF: (a) 
<12 weeks of 
therapy; (b) HBV 
DNA not under 
control during this 
time frame; (c) 
Documented HBV 
flare in the past 12 
weeks
HBsAg (-)
Total anti-HBc (+)
IgM anti-HBc (-)
Anti-HBs (-)
HBV DNA 
(negative)
Unclear. Could be:
(1)    Resolved 
infection (most 
common)
(2)    False positive 
anti-HBc (so actually 
NOT HBV infected)
(3)    Low Level 
infection
(4)    Resolving Acute 
infection 
YES
NO
HBsAg (-)
Total anti-HBc (+)
IgM anti-HBc (-)
Anti-HBs (-)
HBV DNA (+)
(5)    Low Level 
infection
(6)    Resolving Acute 
infection 
YES
YES (as above)
11.0TREATMENT DISCONTINUATION
Treatment may be discontinued for any of the following reasons:

The patient demonstrates progression of disease by RECIST v1.1 (Exception: Patients 
may remain on the study if in the opinion of the Investigator, he/she is deriving clinical 
benefit from study treatment)

The patient withdraws consent from the study

The patient has not received study treatment for 21 days due to a medical/surgical 
events or logistical reasons not related to study therapy (e.g. elective surgery, unrelated 
medical events, patient vacation, and/or holidays).  
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
The patient experiences an adverse event that in the opinion of the Investigator makes 
continued study treatment an unacceptable risk

Intercurrent illness prevents further treatment administration

The patient has 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. 

The patient has confirmed Complete Response (CR) following 24 weeks of 
pembrolizumab; see Section 8.5.1 for full details

The patient becomes pregnant (also see Section 15.6 and Appendix A for Expedited 
Adverse Event Reporting Requirements)

The patient requires continuous treatment with a prohibited concomitant drug(s) for 
which no safe alternatives can be substituted

The patient is significantly noncompliant with the requirements of the protocol
Should discontinuation of study therapy occur, all efforts should be made to execute/ report 
End-of-Treatment and Follow-up Evaluations as completely as possible and to determine/ 
document the reason for discontinuation (unless the patient withdraws consent for follow-
up). 
If a patient wishes to withdraw consent from the study, the PI must be notified.  The 
information regarding withdrawal (i.e. subject identifiers and date of withdrawal) should be 
documented in the subject’s record and updated within any other research database(s). 
12.0 SCHEDULE OF CLINICAL & LABORATORY EVALUATIONS
Prior to performing any study-specific procedures or evaluations, written informed consent 
and authorization for the use of protected health information (HIPAA) must be obtained in 
accordance with all applicable policies, regulations and laws.  
Correlative evaluations (optional) will also be performed at specified visits.  Please refer to 
Section 1.5 and 13.0 CORRELATIVE STUDIES for details. 
Imaging studies should be done every 3 cycles (every 9 weeks, ±9 days) from the date of 
Enrollment timed to coincide with the end of the prior treatment cycle; assessing all known 
sites of disease using the same type(s) of scan(s) that was/were performed at baseline.
All evaluations should be completed as detailed below, prior to the administration of trial 
treatment on Day 1 of each cycle. All evaluations will be administered on an outpatient 
basis.
12.1Pre-Treatment Evaluations (Screening)
The following must be collected/ performed within 28 days prior to Cycle 1, day 1 of 
treatment.  Clinical and laboratory evaluations performed as part of routine standard of 
care do not need to be repeated if performed within the appropriate window. 
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
Complete medical history, disease history and prior medical treatments

Demographic data (age, gender, and race)

Height

Weight

Vital signs (V/S)
o
Oral temperature
o
Blood pressure
o
Heart rate

Complete physical examination (PE)

ECOG Performance Status (PS)

12-Lead Electrocardiogram (ECG)

Urine or serum pregnancy test for women of child-bearing potential 
(WoCBP)

Complete Blood Count (CBC) with differential (diff)

Coagulation studies:
o
PT/INR, 
o
aPTT  

Comprehensive Serum Chemistry Panel (see Section 10.2.1 for hepatic 
toxicity guidelines)
o
Albumin, 
o
Alkaline phosphatase (alk phos),
o
Total bilirubin,
o
Calcium (Ca),
o
Chloride (Cl),
o
Creatinine,
o
Potassium (K), 
o
Total Protein,
o
SGOT (AST),
o
SGPT (ALT),
o
Sodium (Na),
o
Blood urea nitrogen (BUN),
o
Liver function tests (LFTs),

Thyroid Tests 
o
T3
o
T4
o
TSH

Alpha-fetoprotein (AFP)

Lipase,

Amylase and,

Hepatitis B Virus (HBV) Testing (see Section 10.2.1 for hepatic toxicity 
guidelines)
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o
HBsAg,
o
HBsAb,
o
anti-HBc antibody,
o
HBeAg

Hepatitis C Virus (HCV) Testing (see Section 10.2.1 for hepatic toxicity 
guidelines)
o
anti-HCV 

Urinalysis (U/A)

Correlative Studies (See Section 1.5 and 13.0)

Imaging Studies: Imaging studies for tumor assessment for all known sites of 
disease, (including triple phase CT or MRI of abdomen with contrast)

Baseline symptoms
12.2Evaluations on Treatment
Collection of Concomitant Medications and Adverse Events (AEs) should occur 
throughout the study, as described.  Any SAE, or follow up to a SAE, including death 
due to any cause other than progression of the cancer under study that occurs to any 
subject from the time the consent is signed through 90 days following end of treatment, 
or the initiation of new anti-cancer therapy, whichever is earlier, 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.  All subjects with SAEs must be followed up for 
outcome.  (See Section 15.0 and Appendix A for details).
12.2.1Day 1 (±3 days, unless otherwise specified), all Cycles: Trial Treatment 
Administration  

Medical History

Complete PE

ECOG PS

V/S
o
Oral temperature
o
Blood pressure
o
Heart rate

Weight

CBC with diff

Comprehensive Serum Chemistry Panel (see Section 10.2.1 for hepatic toxicity 
guidelines)
o
Albumin, 
o
Alkaline phosphatase (alk phos),
o
Total bilirubin,
o
Calcium (Ca),
o
Chloride (Cl),
o
Creatinine,
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o
Potassium (K), 
o
Total Protein,
o
SGOT (AST),
o
SGPT (ALT),
o
Sodium (Na),
o
Blood urea nitrogen (BUN),
o
Liver function tests (LFTs),

Alpha-fetoprotein (AFP)

Lipase and amylase, only if clinically indicated

Thyroid Tests 
o
T3
o
T4
o
TSH

HBV/ HCV Testing (if tested positive at screening)
o
See Section 10.2.1 for hepatic toxicity guidelines

Correlative Studies (Optional, See Section 1.5 and 13.0)

(Imaging studies for tumor assessment for all known sites of disease (including 
CT or MRI of abdomen with contrast): the same method of assessment and 
technique used at baseline will be used during treatment and follow-up. Imaging 
studies will be done every 3 cycles (after every 9 weeks, ±9 days) from the date 
of Enrollment, timed to coincide with the end of the prior treatment cycle.)
12.3  Off-Treatment Evaluations 
The following assessments must be performed at the Off-Treatment visit (±5 days). 

Medical History

Complete PE

V/S

Weight

ECOG PS

CBC with diff

Comprehensive Serum Chemistry Panel 
o
Albumin, 
o
Alkaline phosphatase (alk phos),
o
Total bilirubin,
o
Calcium (Ca),
o
Chloride (Cl),
o
Creatinine,
o
Potassium (K), 
o
Total Protein,
o
SGOT (AST),
o
SGPT (ALT),
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o
Sodium (Na),
o
Blood urea nitrogen (BUN),
o
Liver function tests (LFTs),

Alpha-fetoprotein (AFP)

Lipase and amylase, only if clinically indicated

Thyroid Tests 
o
T3
o
T4
o
TSH

Correlative Studies (Optional, See Section 1.5 and 13.0)

Imaging studies for tumor assessment for all known sites of disease (including 
CT or MRI of abdomen with contrast): the same method of assessment and 
technique used at baseline will be used during treatment and follow-up. 
12.4 30 Days After Off Treatment (OT) Safety Evaluations 
The following safety assessments must be performed at 30-days (+ 5 days) after Off 
Treatment date. 

Coagulation studies:
o
PT/INR, 
o
aPTT  

Comprehensive Serum Chemistry Panel 
o
Albumin, 
o
Alkaline phosphatase (alk phos),
o
Total bilirubin,
o
Calcium (Ca),
o
Chloride (Cl),
o
Creatinine,
o
Potassium (K), 
o
Total Protein,
o
SGOT (AST),
o
SGPT (ALT),
o
Sodium (Na),
o
Blood urea nitrogen (BUN),
o
Liver function tests (LFTs),

Alpha-fetoprotein (AFP)

Lipase and amylase, only if clinically indicated

Thyroid Tests 
o
T3
o
T4
o
TSH

Correlative Studies (Optional, See Section 1.5 and 13.0)
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
(Any SAE, or follow up to a SAE, including death due to any cause other than 
progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following end of treatment, 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.  All subjects with SAEs must 
be followed up for outcome.  (See Section 15.0 and Appendix A for details).)
12.5Follow-up Evaluations 
For patients without documented evidence of objective disease progression the 
following assessments should be performed every 12 weeks until documented disease 
progression, death, withdrawal of consent, or end of study, whichever occurs first.   A 
telephone call to the patient and/or the patient’s family may be made to evaluate the 
patient’s status on the following:

Post-study anticancer therapy status

Survival status 

Following confirmed disease progression or initiation of new anti-cancer 
therapy, survival will be assessed (at a minimum) by telephone contact every 
12 weeks (±2 weeks).”
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12.6Calendar of Clinical and Laboratory Evaluations
Screening
Treatment Cycle(s) q21 
days
Safety Evaluation
Follow-Up 
≤28 days prior A
Day 1 (±3 days unless 
specified) 
Off Treatment 
±5 days
30-days (+5 days) after  
Off Treatment
every 12 weeks 
K
ICF
X
Eligibility
X
Demographics B  
X
Complete Medical History C  
X
X
X
Height
X
Weight
X
X
X
X
Vital Signs D  
X
X
X
X
Complete PE
X
X
X
X
ECOG PS
X
X
X
X
12-Lead ECG
X
CBC with diff
X
X
X
X
Comp Serum Chemistry Panel E
X
X
X
X
Alpha-fetoprotein (AFP)
X
X
X
X
Lipase & Amylase
X
(X, repeat only if clinically indicated)
T3, T4 and TSH
X
X
X
X
PT/INR, aPTT
X
X
HBV and HCV Testing 
X (Section 12.1)
X (Section 10.2.1)
Urine or serum pregnancy test F  
X
Urinalysis
X
Correlative Studies: Tissue Sample G 
(Archival or newly obtained)
X
Correlative Studies: Peripheral Blood H 
(Serum ) 
X
X H
X H
X H
Imaging studies I 
X
(X) 
X
Pembrolizumab IV administration
X
Baseline Symptoms
X
Adverse Events   
X
(X) J 
Concomitant Medications
X
Telephone Call L 
X
A Screening evaluations should be done within 28-days prior unless otherwise specified. 
B Demographic data includes age, gender and racial/ethnic background.
C Complete Medical History includes disease history and prior medical treatments.
D Vital signs include oral temperature, blood pressure and heart rate.
E Comprehensive Serum Chemistry Panel includes albumin, alkaline phosphatase, total bilirubin, sodium, calcium, chloride, creatinine, potassium, total protein, 
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F Urine or serum (beta-HCG) pregnancy test is required for women of childbearing potential within 3-days prior to Day 1 of trial treatment. 
G Tissue sample (either archival or newly obtained) is optional and for correlative studies (see Section 1.5 and 13.0 for details).
H Serum collection for correlative studies is optional (see Section 1.5 and 13.0 for details).  Samples will be collected at baseline, during treatment and/or at the 
time of documented disease progression, whichever occurs first.
I Imaging studies for tumor assessment for all known sites of disease (including CT or MRI of abdomen with contrast): the same method of assessment and 
technique used at baseline will be used during treatment and follow-up. Imaging studies will be done every 3 cycles (after every 9 weeks, ±9 days) from the date 
of Enrollment, timed to coincide with the end of the prior treatment cycle.)
J AE/SAE collections should continue for at least 90-days post EoT visit.  All subjects with SAEs must be followed up for outcome.  (See Section 15.0 and 
Appendix A for details).
K Follow-up for patients without documented objective disease progression shall occur every 12 weeks (+/- 2 weeks) until documented disease progression, death, 
withdrawal of consent, or EoS, whichever occurs first. 
L Telephone call may be made to patient or patient’s family to follow-up on patients’ post-study anticancer therapy and survival status.   Following confirmed disease 
progression or initiation of new anti-cancer therapy, survival will be assessed (at a minimum) by telephone contact every 12 weeks (±2 weeks).


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13.0 SCHEDULE OF CORRELATIVE EVALUATIONS 
The following optional samples may be collected (at the discretion of the PI) at the specified 
time points if the patient consents to them:
13.1Pre-Treatment Specimen Collection (Screening)

Tissue sample (archival or newly obtained)

Approximately up to 30 mL peripheral blood (2 green top tubes + 1 red top tube + 1 
EDTA tube)
13.2On Treatment Specimen Collection  
13.2.1Every 12 weeks (3 months), all Cycles: Trial Treatment Administration

Approximately up to 30 mL peripheral blood (serum for biomarkers)
13.2.2At Week 9 and Week 18: Trial Treatment Administration

Approximately up to 30 mL peripheral blood 
13.3Off-Treatment Specimen Collection (or at time of documented disease 
progression)
The following must be performed at the Off-Treatment visit (±5 days):

Approximately up to 30 mL peripheral blood (serum for biomarkers)

Additional 7 mL peripheral blood, only if prior to Week 9 or Week 18
13.4     30 Days after Off Treatment Safety visit
The following must be performed at the EOT safety visit and should occur 30-days (+5 
days) after the last dose of study treatment. 

Approximately up to 30 mL peripheral blood (serum for biomarkers)
13.5Calendar of Specimen Collection for Correlative Studies 
Timepoints
Tissue Sample
Peripheral Blood
Screening
X
X (Up to 30 mL)
Week 9
X (Up to 30 mL)
Every 12 weeks (3 months), all Cycles
 
X (Up to 30 mL)
Week 18
X (Up to 30 mL)
Off Treatment (or at time of documented 
disease progression)
X (Up to 30 mL)
(plus additional  
7mL, only if prior to 
Week 9 or 18)
30 Days after Off Treatment Safety Visit
X (Up to 30 mL)
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14.0 MEASUREMENT OF EFFECT
14.1Antitumor Effect in Solid Tumors
For the purposes of this study, patients should be re-evaluated for response every 9 
weeks (± 9 days) which corresponds to the 3 week cycles of therapy.  In addition to a 
baseline scan, confirmatory scans should also be obtained >4 weeks following initial 
documentation of objective response.  (Note:  Lesions are either measurable or non-
measurable using the criteria provided below.  The term “evaluable” in reference to 
measurability will not be used because it does not provide additional meaning or 
accuracy.)
Response and progression will be evaluated in this study using the international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) 
version 1.1 guideline(s). Changes in the largest diameter (unidimensional measurement) 
of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are 
used in RECIST. 
The following general principles must be followed: 
1. To assess objective response, it is necessary to estimate the overall tumor burden at 
baseline to which subsequent measurements will be compared. All baseline evaluations 
should be performed as closely as possible to the beginning of treatment and never 
more than four weeks before registration. 
2. Measurable disease is defined by the presence of at least one measurable lesion. 
3. All measurements should be recorded in metric notation by use of a ruler or calipers. 
4. The same method of assessment and the same technique must be used to characterize 
each identified lesion at baseline and during follow-up. 
14.2Definitions
Evaluable for Objective Response
Only those patients who have measurable disease present at baseline, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for response. These patients will have their response classified according to 
the definitions stated below. (Note: Patients who exhibit objective disease progression 
prior to the end of cycle 1 will also be considered evaluable.)
Evaluable Non-Target Disease Response  
Patients who have lesions present at baseline that are evaluable but do not meet the 
definitions of measurable disease, have received at least one cycle of therapy, and have 
had their disease re-evaluated will be considered evaluable for non-target disease.  The 
response assessment is based on the presence, absence, or unequivocal progression of 
the lesions. 
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14.3Disease Parameters
 Measurable Disease
Measurable lesions are defined as those that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥ 20 mm by chest x-ray, as ≥ 10 mm with 
CT scan, or ≥ 10 mm with calipers by clinical exam. All tumor measurements must be 
recorded in millimeters. 
NOTE: Tumor lesions that are situated in a previously irradiated area may be 
considered measurable if they have grown subsequent to previous radiation.
Malignant Lymph Nodes 
To be considered pathologically enlarged and measurable, a lymph node must be ≥ 15 
mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be no greater than 5 mm). At baseline and in follow-up, only the short axis will be 
measured and followed.
Non-measurable Disease
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm 
or pathological lymph nodes with ≥10 to < 15 mm short axis), are considered non-
measurable disease. Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal 
masses (not followed by CT or MRI), are considered as non-measurable. 
NOTE: Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions.
Target Lesions
All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline. Target lesions should be selected on the basis of their size 
(lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It 
may be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
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reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for 
all target lesions will be calculated and reported as the baseline sum diameters. If lymph 
nodes are to be included in the sum, then only the short axis is added into the sum. The 
baseline sum of the diameters will be used as reference to further characterize any 
objective tumor regression in the measurable dimension of the disease.
Non-target Lesions
All other lesions (or sites of disease) including any measurable lesions over and above 
the 5 target lesions should be identified as non-target lesions and should also be recorded 
at baseline. Measurements of these lesions are not required, but the presence or absence 
of unequivocal progression of each should be noted throughout follow-up.
14.4Methods for Evaluation of Disease
All measurements should be taken and recorded in metric notation using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks (28 days) before the beginning of 
treatment. 
The same method of assessment and the same technique must be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥10 mm in diameter as assessed using calipers 
(e.g., skin nodules). In the case of skin lesions, documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. 
Chest X-ray 
Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung. However, CT is preferable.
Conventional CT and MRI 
This guideline has defined measurability of lesions on CT scan based on the assumption 
that CT slice thickness is 5 mm or less. If CT scans have slice thickness greater than 5 
mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI 
is also acceptable in certain situations (e.g. for body scans).
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
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resolution; however, there are many image acquisition variables involved in MRI which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of 
the type and site of disease. Furthermore, as with CT, the modality used at follow-up 
must be the same as was used at baseline and the lesions should be measured/assessed on 
the same pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe 
specific MRI pulse sequence parameters for all scanners, body parts, and diseases. 
Ideally, the same type of scanner should be used and the image acquisition protocol 
should be followed as closely as possible to prior scans. Body scans should be performed 
with breath-hold scanning techniques, if possible. 
Ultrasound 
Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment 
to the next. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT or MRI is advised. If there is concern about radiation exposure at 
CT, MRI may be used instead of CT in selected instances.
Endoscopy, Laparoscopy  
The utilization of these techniques for objective tumor evaluation is not advised.  
However, such techniques may be useful to confirm complete pathological response 
when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint.
Tumor markers  
Tumor markers alone cannot be used to assess response.  If markers are initially above 
the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian 
cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  
In addition, the Gynecologic Cancer Intergroup has developed CA-125 progression 
criteria which are to be integrated with objective tumor assessment for use in first-line 
trials in ovarian cancer [JNCI 92:1534-1535, 2000].
Cytology, Histology 
These techniques can be used to differentiate between partial responses (PR) and 
complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain).
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
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stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease.
14.5Response Criteria
14.5.1Evaluation of Target Lesions 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR)
At least a 30% decrease in the sum of the diameters of target lesions, taking as reference 
the baseline sum diameters 
Progressive Disease (PD) 
At least a 20% increase in the sum of the diameters of target lesions, taking as reference 
the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm.  (NOTE: the appearance of one or more new lesions is also 
considered progression).
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, 
taking as reference the smallest sum diameters while on study. 
14.5.2Evaluation of Non-Target Lesions
Complete Response (CR) 
Disappearance of all non-target lesions. All lymph nodes must be non-pathological in 
size (<10 mm short axis). Note: If tumor markers are initially above the ULN, they must 
normalize for a patient to be considered in complete CR.  
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level 
above the normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-
target lesions. Unequivocal progression should not normally trump target lesion status. 
It must be representative of overall disease status change, not a single lesion increase. 
When the patient also has measurable disease, there must be an overall level of 
substantial worsening in non-target disease such that, even in the presence of SD or PR 
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in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest “increase” in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The 
designation of overall progression solely on the basis of change in non-target disease in 
the face of SD or PR of target disease will therefore be extremely rare. 
When the patient only has non-measurable disease, the increase in overall disease burden 
should be comparable in magnitude to the increase that would be required to declare PD 
for measurable disease: i.e., an increase in tumor burden from “trace” to “large”, an 
increase in nodal disease from “localized” to “widespread”, or an increase sufficient to 
require a change in therapy. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator).
14.5.3Evaluation of New Lesions 
The appearance of new lesions constitutes Progressive Disease (PD). 
A growing lymph node that did not meet the criteria for reporting as a measurable or non-
measurable lymph node at baseline should only be reported as a new lesion (and therefore 
progressive disease) if it: 
a) increases in size to ≥15 mm in the short axis or; 
b) there is new pathological confirmation that it is disease (regardless of size). 
14.5.4Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence or non-protocol therapy (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). The 
patient’s best response assignment will depend on the achievement of measurement 
criteria.
Target
Lesions
Non-Target Lesions
New
Lesions*
Best Overall
Response
Remarks
CR
CR
No
CR
CR
Non-CR/Non-PD***
No
PR
CR
Not evaluated
No
PR
PR
Non-PD***/not evaluated
No
PR
Confirm by repeat 
assessments ≥4 weeks after 
criteria for response are first 
met.
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SD
Non-PD***/not evaluated
No
SD
Follow-up assessments 
must have met SD criteria 
at least once ≥8 weeks 
from study entry.
PD
Any
Yes or No
PD
Any
PD**
Yes or No
PD***
Any
Any
Yes
PD
No prior SD, PR
or CR
*   See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
** In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression.
*** PD in non-target lesions should not normally trump target lesion status. It must be 
representative of overall disease status change, not a single lesion increase. Please refer to 
the Evaluation of Non-Target Lesions – Progressive Disease section for further explanation.

Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.” Every effort should be made to document the 
objective progression even after discontinuation of treatment.

In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before confirming the CR status.
14.5.5Duration of Response 
Duration of Overall Response 
The duration of overall response is measured from the time measurement criteria are met 
for CR or PR (whichever is first recorded) until the first date that recurrent or progressive 
disease is objectively documented (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
Duration of Stable Disease 
Stable disease is measured from the start of the treatment until the criteria for progression 
are met, taking as reference the smallest measurements recorded since the treatment 
started, including the baseline measurements. 
14.6Disease Control Rate (DCR)
DCR is the proportion of patients whose best overall response per RECIST criteria is 
complete response (CR), partial response (PR), or stable disease (SD).  Disease control 
must be confirmed by repeat assessments performed at an interval of no less than 4 weeks 
for CR and PR.  For SD, disease control must be confirmed by repeat assessments 
performed at an interval of no less than 8 weeks.
14.7Overall Response Rate (ORR)
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ORR is the proportion of patients whose best overall response per RECIST criteria is 
complete response (CR) or partial response (PR).  
14.8Progression-Free Survival (PFS)
PFS is defined as the elapsed time from the date of first study treatment to the earliest 
date of documented disease progression or death from any cause, whichever is earlier. 
For patients who remain alive without progression, follow up time will be censored at 
the date of last disease assessment.
14.9Overall Survival (OS)
OS is defined as the elapsed time from start of treatment to death or date of censoring.  
Patients alive or those lost to follow-up will be censored at the last date of contact (or last 
date known to be alive).
15.0 ADVERSE EVENTS
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for   Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting.
15.1Purpose
Adverse event data collection and reporting, which are required as part of every clinical 
trial, are done to ensure the safety of patients enrolled in the studies, as well as those who 
will enroll in future studies using similar agents.  Adverse events are reported in a routine 
manner at scheduled times during a trial.  Additionally, certain adverse events must be 
reported in an expedited manner for timelier monitoring of patient safety and care. 
15.2 Adverse Event
Adverse Event (AE): Can be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a drug, 
medical treatment, or procedure without judgment about causality.  An adverse event 
can arise from any use and from any route of administration, formulation, or dose 
including an overdose. This includes any newly occurring event or a previous condition 
that has increased in severity or frequency since initiation of a drug, medical treatment, 
or procedure. 
Abnormal Findings
In any clinical assessment, a value outside the normal or reference range (such as a 
clinical laboratory, vital sign, or ECG) will not be reported or assessed as an AE unless 
that value is considered to be of clinical significance by the investigator.  A value of 
clinical significance is one that leads to discontinuation or delay in protocol treatment, 
dose modification, therapeutic intervention*, or is considered to be a clinically 
significant new finding or change from baseline by the investigator. 
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*Transfusion support administered to offset clinical symptoms of anemia or 
thrombocytopenia will not be considered therapeutic intervention.
Signs and Symptoms
Signs/symptoms resulting from an underlying clinical diagnosis should be documented 
as one comprehensive AE.  If no underlying clinical diagnosis can be identified, each 
sign/symptom should be reported as a separate independent event.  (A new or worsening 
event resulting from an underlying clinical diagnosis or a reaction to concurrent 
medications should be documented as a separate independent AE unless it is within the 
normal range of fluctuation for that patient.)  
Grade Changes/Fluctuations
AEs will be reported at the maximum grade/severity experienced for the duration of the 
event.  Should one particular event warrant further investigation, additional details may 
be collected at the discretion of the Principal Investigator.  
Progression of Disease
Progression of disease, if documented in accordance to standard of care, should not be 
reported as an AE.
Tests and Procedures
Tests and procedures should not be reported as AEs.  The underlying clinical diagnosis 
(or sign/symptom in the event an underlying clinical diagnosis is not known) requiring 
testing or a procedure, should be reported as an adverse event if it meets criteria for 
reporting.
15.3Serious Adverse Events (see also Appendix A)
Serious AE (SAE) means any untoward medical occurrence that occurs at any dose:
1. Results in death. 
2. Is life-threatening. 
The term "life-threatening" in the definition of "serious" refers to an event in which 
the patient was at risk of death at the time of the event; it does not refer to an event 
which hypothetically might have caused death if it were more severe).
3. Requires inpatient hospitalization or prolongation of present hospitalization. 
Elective hospitalization to simplify protocol treatment/evaluations or to treat a 
baseline condition that did not worsen from baseline will not be considered an SAE.   
4. Results in persistent or significant disability/incapacity. 
Disability is defined as a substantial disruption of a person’s ability to conduct 
normal life functions.
5. Is a congenital anomaly/birth defect. 
6. Is a medically important event.
A medically important event may not be immediately life threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention to 
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prevent one of the other outcomes listed in the definition above, or involves suspected 
transmission via a medicinal product of an infectious agent.   Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse; any 
organism, virus, or infectious particle (e.g., prion protein transmitting Transmissible 
Spongiform Encephalopathy), pathogenic or nonpathogenic, is considered an 
infectious agent. 
Additional SAE classification(s) for AEs occurring at any dose or during any use 
of Merck product(s): 
1. Is a new cancer (that is not a condition of the study);
2. Is associated with an overdose (whether accidental or intentional): Any adverse 
event associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a non-serious 
event of clinical interest and must be reported within 24 hours.
15.4Adverse Event Collection Period
In this protocol, adverse events include only treatment-emergent adverse events.  A 
treatment-emergent adverse event (TEAE) is defined as any event that begins or worsens 
after the start of protocol treatment.  All baseline-emergent adverse events, any event that 
begins or worsens after completion of the informed consent but prior to the start of 
protocol treatment, should be reported as a Baseline/Comorbid Condition. 
All adverse events that occur within ≤ 30 days of the last dose of study therapy will be 
reported and followed until resolution.  Resolution is defined as a return to baseline status 
or the stabilization of an event with the expectation that it will remain chronic.  
(Exception: If a patient begins an alternative therapy that confounds accurate assessment 
of AEs within ≤ 30 days of the last dose of study therapy, all adverse event collection 
will stop and any ongoing events will be left open.)
15.5Adverse Event Reporting Requirements
The information to be reported in AEs will be assessed by and assigned severity using 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03.   The NCI CTCAE provides descriptive terminology and a 
grading scale for each adverse event listed.  A copy of the NCI CTCAE v4.03 can be 
downloaded from the CTEP home page 
(http://evs.nci.nih.gov/ftp1/CTCAE/About.html).   
Information to be reported in the description of each adverse event may be included, 
but is not limited to:
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1. Clinical Diagnosis of the event as determined by NCI CTCAE, Version 4.03 
descriptive terminology.  If no clinical diagnosis can be identified, each 
sign/symptom should be reported as a separate independent event.
2. Date of onset of the AE (start date).
3. Date of resolution of the AE (end date). 
4. Severity of the event determined by NCI CTCAE, Version 4.0 grading scale.    
5. Relationship of the AE to study therapy.  Categorized as follows:
Definite
The adverse event is clearly related to the investigational agent(s)
Probable
The adverse event is likely related to the investigational agent(s)
Possible
The adverse event may be related to the investigational agent(s)
Unlikely
The adverse event is doubtfully related to the investigational agent(s)
Unrelated
The adverse event is clearly not related to the investigational agent(s)
6. Whether or not the AE is Serious or Not Serious as defined in Section 15.3 Serious 
Adverse Events.
7. Whether the AE is Suspected and/or Unexpected.
Suspected
Any AE for which there is a reasonable possibility that the drug caused 
the AE. For the purposes of expedited safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE.
Unexpected
Any AE for which the nature or severity of the event is not consistent 
with the applicable product information, e.g., the Investigator’s 
Brochure or Package Insert.
8. Action taken as a result of the AE. 
9. Outcome.
15.6Expedited Adverse Event Reporting Requirements
All AEs, regardless if serious or not, will be described in the source documents, 
reported on the applicable AE page of the CRFs, and entered into Velos.  However, 
certain adverse events must also be reported in an expedited manner for more timely 
monitoring of patient safety and care.  Appendix A provides information about these 
expedited reporting requirements.
16.0 STATISTICAL CONSIDERATIONS
16.1Objectives and Endpoints 
This is a single-arm phase II trial of Pembrolizumab (Keytruda®) in patients with 
advanced, unresectable hepatocellular carcinoma.  The primary objective is to assess its 
therapeutic efficacy in patients with unresectable hepatocellular carcinoma (HCC).  The 
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primary endpoint is disease-control rate (DCR) defined as the proportion of patients 
achieving a best overall response of either a CR, PR or SD (that is maintained for at 
least 8 weeks).
Secondary endpoints include progression-free survival (PFS), overall survival (OS), 
objective response rate (ORR), duration of response (DOR), and toxicity profile of 
Pembrolizumab.  We will also evaluate the expression levels of PD-L-1 in tumor tissue, 
as well as serum titers of hepatitis B or C in patients with hepatitis B or C, respectively, 
for whom specimens are available. 
16.2Study Design and Sample Size Justification
The primary endpoint for this single arm phase II trial is disease control rate (CR, PR, or 
SD).  The rationale for using disease control rate (DCR) as the primary endpoint is 
derived from the clinical experience with Sorafenib (SHARP trial 2008), which was 
approved as the first and only therapeutic agent definitively proven to prolong survival 
in patients with advanced HCC.  The disease control rate of Sorafenib was 43% in the 
SHARP trial [7].  We hypothesize that Pembrolizumab will achieve a similar or higher 
disease control rate.  We set a null hypothesis rate of 18% disease control, since standard 
chemotherapy regimens generally result in a DCR of 15-20%.
We propose study size based on the Simon 2-stage MiniMax design [39] with a one-sided 
significance level of 5% and 90% power.  Assuming that Pembrolizumab therapy will 
not be of further interest if DCR were no better than 18% (null hypothesis) while a rate 
of 43% would merit further investigation, the Simon MiniMax design requires at most 
28 patients: 14 patients to be enrolled in the first stage and possibly an additional 14 in 
the second stage.  If no more than 2 of the 14 patients in stage 1 achieve CR/PR/SD, the 
trial will stop and Pembrolizumab will be considered ineffective.  If 3 or more of the 
stage 1 patients achieve CR/PR/SD, our study will continue to a second stage and enroll 
an additional 14 patients for a total of 28.  If 9 or more out of 28 study patients achieve 
CR/PR/SD, we will report an observed DCR of at least 32% and conclude that the true 
DCR significantly exceeds a null rate of 18%.  With this design, the chance of early 
stopping at the end of stage 1 is 53% if the null hypothesis of 18% DCR is true, whereas 
there is a very small chance, 2%, of early termination if the true DCR is 43%.
16.3Analysis Set
Patients who are study eligible and receive at least one dose of Pembrolizumab will be 
considered evaluable for efficacy and toxicity, and will comprise the main analysis set.  
Any patient who is enrolled on study but does not receive study treatment will be 
excluded from all analyses.  Any patient who receives study treatment but is later found 
to be ineligible (e.g. protocol violation) will be withdrawn from study but will be 
followed for response, toxicity, and survival.  The experience of such patients will be 
characterized separately from that of evaluable patients. Reasons for all exclusions will 
be characterized, such as eligibility subsequently not confirmed, or failure to receive 
treatment.  
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16.4Patient Enrollment and Study Duration
We plan to enroll up to 35 patients, to ensure that we have a minimum of 28 patients who 
are evaluable for the primary efficacy endpoint for this study, disease control rate (DCR).  
We expect to enroll 10-12 patients per year based on our institution’s enrollment 
capacity.  
Accrual will be suspended after 14 evaluable patients (stage 1) in order to assess DCR in 
accordance with the two-stage design of this trial.
16.5Statistical Analysis
Demographics and baseline disease and treatment characteristics will be summarized 
using descriptive statistics such as counts and percentages, mean, standard deviation, 
median and range, as appropriate.  This will include age, sex, race/ethnicity, performance 
status, prior systemic therapy, laboratory parameters (bone marrow function, liver 
function, etc.), and disease characteristics such as site (visceral, non-visceral), Child-
Pugh classification and stage.
The number of Pembrolizumab injections received and reasons for treatment 
discontinuation will be summarized descriptively.  Safety data, including toxicities, 
reasons for withdrawal from study treatment and laboratory data will also be summarized 
descriptively.  Toxicities will be tabulated by type, grade, duration and attribution to 
treatment.  A patient-level summary by worst grade toxicity will be included.
Efficacy analysis will include the primary study endpoint disease control rate (DCR), as 
well as the secondary endpoints,   which include objective response rate (CR+PR), 
progression-free survival and overall survival.  Disease control rate and overall response 
rate will be estimated by the percentage of patients achieving these criteria and the 
corresponding 95% confidence interval using the exact binomial method [40].  
In addition, we will report median and range for the time to onset and duration of response 
for patients who achieve CR or PR. For patients whose best response is SD, we will report 
the median and range of SD duration.
The Kaplan-Meier method will be used to estimate progression-free and overall survival 
rates and corresponding median times, if attained.  Point estimates with corresponding 
95% confidence intervals based on Greenwood’s variance and the log-log transform 
method will be given for the proportion of progression-free/surviving patients at selected 
times, such as 3, 6, 12, 18, and 24 months following the initiation of treatment, as well 
as for median times, if attained [41].  For purposes of these analyses, progression-free 
survival will be measured from start date of treatment to date of documented disease 
progression, or death from any cause, whichever occurs first.  Patients who are alive and 
progression-free will be censored at their date of last documented progression-free status.  
Overall survival will be measured from start date of treatment to date of death from any 
cause.  Patients who are alive will be censored at their date of last contact.  To the extent 
possible with 28 patients, we will explore the effect of baseline characteristics on 
progression-free and overall survival using Cox regression [42]. The objective response 
rate (ORR) will be estimated by the percentage of patients and corresponding 95% 
confidence interval using the exact binomial method.
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To the extent that biomarker data are available, we will summarize expression levels of 
PD-L- 1 in tumor tissue, and serum titers of hepatitis B and/ hepatitis C in patients with 
hepatitis B or C, respectively, using descriptive statistics. A descriptive analysis will be 
done for hypothesis-generating purposes but a statistical analysis will not be done as there 
may not be enough tumor tissue and blood samples collected (to conduct a formal 
statistical analysis).
17.0DATA REPORTING
Data must be submitted according to the protocol requirements for all patients registered.  
Patients for whom documentation is inadequate to determine eligibility will generally be 
deemed ineligible. 
17.1Data and Safety Monitoring 
The Sylvester Comprehensive Cancer Center (SCCC) Data and Safety Monitoring 
Committee (DSMC) will monitor this clinical trial according to the Cancer Center’s 
DSM Plan.  In its oversight capacity, the DSMC bears responsibility for suspending or 
terminating this study.  DSMC oversight of the conduct of this trial includes ongoing 
review of accrual and adverse event (AE) data, and periodic review of the study therapy.  
The guidelines appearing in this section are offered for DSMC consideration in assessing 
AEs and response to study treatment.  In addition, the DSMC will review reports from 
all audits, site visits, or study reviews pertaining to this clinical trial and take appropriate 
action.  The SCCC DSM Plan to which this study is subject can also be found at 
www.sylvester.org. 
17.2Stopping Rules (for the study as a whole)
17.2.1Early Stopping Guidelines
We propose the following guidelines for the DSMC in its review of accumulating 
data. For safety, we propose early stopping guidelines based on a Bayesian 
method.  Early stopping guidelines for lack of efficacy are built into the Simon 2-
stage design for this trial.  Specific details are presented in the remainder of this 
section.
17.2.2Safety: Early Stopping Due to Excessive Toxicity
We propose the following guidelines for the DSMC in its review of accumulating 
data on toxicity.  The proposed guidelines were developed using Bayesian 
methods, which can be applied at any stage of enrollment without advance 
specification of the number of interim analyses to be performed, or the number of 
patients evaluable for toxicity, at the time such assessments are made [43-44].
Under the Bayesian method, we assign a prior probability (level of belief at the 
start of the trial) to a range of possible values for the true toxicity rate.  As data on 
treated patients become available, each of these probability distributions is revised 
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and the resulting posterior probability becomes the basis for recommending either 
early termination or continuation of the study.  Specific stopping guidelines and 
details on the prior distribution assumptions, and the resulting posterior 
probabilities are presented below. 
For purposes of safety monitoring, we define an unacceptable toxicity to be any 
treatment-related (i.e., possible, probable, or definite) grade 3 or higher toxicity 
excepting nausea, reversible elevation of liver function tests and reversible 
myelosuppression. Prolonged (defined as >12 weeks,) grade 3 or higher elevation 
of liver function tests or myelosuppression will be considered unacceptable. 
Patients with hepatitis may take longer to recover their counts but it is considered 
justifiable given their poor prognosis. Early stopping (suspension and possibly 
termination) will be considered if there is evidence that the proportion of patients 
experiencing unacceptable toxicity exceeds 20%. 
Specifically, we suggest as a guideline for early termination, a posterior 
probability of 90% or higher that the rate of unacceptable toxicity exceeds 20%.  
The table below shows specific instances where this guideline is met, thus 
suggesting early termination due to evidence of excessive toxicity.
For example, if 8 evaluable patients have been assessed for toxicity, the second 
row of the above table indicates that early stopping should be considered if 4 (or 
more) of these patients have experienced unacceptable toxicity. Note that 4 of 8 
patients with unacceptable toxicity is an observed toxicity rate of 50%. 
Posterior probabilities used to derive the preceding table are calculated under a 
prior beta distribution with parameters 1 = 0.4 and 2 = 1.6, which corresponds to 
an expected rate of 20% based on very limited information, roughly equivalent to 
having studied two patients.  This prior distribution implies an a priori chance of 
36% that the rate of unacceptable toxicity is 20% or greater.
Number of patients with 
unacceptable toxicity*
Total patients 
evaluated
Observed toxicity rate
3
4 to 6
≥ 50%
4
7 to 10
≥ 40%
5
11 to 13
≥ 39%
6
14 to 17
≥ 35%
7
18 to 21
≥ 33%
8
22 to 25
≥ 32%
9
26 to 27
≥ 32%
*Possibly, probably or definitely treatment-related, grade 3+ toxicity excepting nausea, 
reversible elevation of liver function tests and reversible myelosuppression.
17.2.3Early Stopping for Lack of Efficacy
The Simon two-stage design of this trial, described in Section 16.2, provides for a 
single interim analysis of the primary study endpoint, disease control rate (DCR).  
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After enrollment of the first 14 evaluable patients in stage 1, accrual will be 
suspended and a decision to terminate the study early or continue accrual will be 
made.  DCR of this cohort of 14 evaluable patients from stage 1 will be determined 
as a best overall response of either a CR, PR, or SD (as detailed in section 14.5).  If 
no more than 2 of the first 14 patients achieve DCR, the trial will stop and 
pembrolizumab will be considered ineffective, as this suggests that the DCR is no 
better than the null hypothesis rate of 18%.  If DCR is achieved in 3 or more of the 
first 14 patients, the trial will continue to a second stage and enroll an additional 14 
patients for a total evaluable number of 28 patients.  The findings of interim analysis 
of DCR from the first 14 patients of stage 1 will be reported to the Sylvester DSMC.
17.2.4No Early Stopping for Treatment Efficacy
We do not intend to stop the study early if the proposed study treatment appears 
to be effective.  Under such circumstance, continuation of the trial will yield 
additional information regarding the magnitude of the true DCR.  Moreover, if 
results from this study are promising, further studies will be needed to fully assess 
the benefits and risks of Pembrolizumab therapy in the treatment of patients with 
advanced unresectable hepatocellular carcinoma.
18.0STUDY AUDITING AND MONITORING
This study will be audited and monitored according to 
http://uresearch.miami.edu/regulatory-compliance-services/rcqa and the Office of Research 
Integrity Assurance, respectively. 
19.0INVESTIGATOR RESPONSIBILITIES
19.1Investigator Responsibility/Performance
The investigator will ensure that this study is conducted in accordance with all 
regulations governing the protection of human subjects. The investigator will ensure that 
all work and services described in or associated with this protocol will be conducted in 
accordance with the investigational plan, applicable regulations, and the highest 
standards of medical and clinical research practice.
19.2Confidentiality
The investigator must ensure that each subject’s anonymity will be maintained and each 
subject’s identity will be protected from unauthorized parties.  A number will be assigned 
to each subject upon study entry and the number and the subject’s initials will be used to 
identify the subject for the duration of the study.  The investigator will maintain all 
documents related to this study in strict confidence.
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19.3Informed Consent and Permission to Use Protected Health Information 
It is the responsibility of the investigator to obtain written informed consent from each 
subject participating in this study after adequate explanation, in lay language, of the 
methods, objectives, anticipated benefits, and potential hazards of the study.  The 
investigator must also explain that the subject is completely free to refuse to enter the 
study or to discontinue participation at any time (for any reason) and receive alternative 
conventional therapy as indicated.  Prior to study participation, each subject will sign an 
IRB approved informed consent form and receive a copy of same (and information 
leaflet, if appropriate).  For subjects not qualified or able to give legal consent, consent 
must be obtained from a parent, legal guardian, or custodian. The investigator or designee 
must explain to the subject before enrollment into the study that for evaluation of study 
results, the subject’s protected health information obtained during the study may be 
shared with the study sponsor, regulatory agencies, and the IRB.  It is the investigator’s 
(or designee’s) responsibility to obtain permission to use protected health information 
per HIPAA from each subject, or if appropriate, the subjects’ parent or legal guardian.
19.4Source Documentation and Investigator Files
The investigator must maintain adequate and accurate records to fully document the 
conduct of the study and to ensure that study data can be subsequently verified.  These 
documents should be classified into two separate categories:  (1) investigator study file 
and (2) subject clinical source documents that corroborate data collected on the CRF’s.  
Subject clinical source documents may include hospital/clinic patient records; physician's 
and nurse's notes; appointment book; original laboratory, ECG, EEG, radiology, 
pathology, and special assessment reports; pharmacy dispensing records; subject diaries; 
signed informed consent forms; and consultant letters.  When the CRF or any form is 
used as the source document, this must be clearly stated in the investigator study file. 
Minimally, the following be documented in source documents:

Medical history/physical condition and diagnosis of the subject before involvement 
in the study sufficient to verify protocol entry criteria

Study number, assigned subject number, and verification that written informed 
consent was obtained (each recorded in dated and signed notes on the day of entry 
into the study)

Progress notes for each subject visit

Documentation of treatment

Laboratory test results

Adverse events (action taken and resolution)

Condition and response of subject upon completion of or early termination from 
the study
19.5Recording and Processing of Data
If using hard copies of CRF’s, study center personnel will complete individual CRF’s in 
black ink.  All corrections to entered data will be made by drawing a single line through 
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the information to be corrected without obscuring it.  All corrections will be initialed, 
dated and explained, if necessary.  The use of “white-out” or obscuring correction tape 
will be prohibited.  A CRF is required for every patient who received any amount of 
study treatment.  The investigator will ensure that the CRF’s are accurate, complete, 
legible and timely. Separate source records are required to support all CRF entries except 
those for which use of the CRF as source document is clearly allowed per note in the 
investigator study file.
Data must be submitted according to the protocol requirements for ALL patients 
registered.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
19.6Non-Protocol Research
No investigative procedures other than those described in this protocol will be 
undertaken on the enrolled subjects without the agreement of the IRB.
19.7Ethics
The investigator agrees to conduct the study in compliance with the protocol, current 
good clinical practices, and all applicable (local, FDA) regulatory guidelines and 
standard of ethics.
UM Ethics Programs’ Research Ethics Consultation Service (RECS) is a free resource 
for UM Researchers.  See the website for further information: 
http://www.miami.edu/index.php/ethics/projects/recs/ 
19.8Essential documents for the conduct of a clinical trial
Essential documents are those documents with individually and collectively permit 
evaluation of the conduct of a trial and the quality of the data produced. The following 
documents should be on file: 1) 1572 or investigator’s agreement (for studies involving 
IND drugs or devices, respectively); 2) CV’s and license of all Investigators; 3) IRB 
documentation/correspondance and 4) Documentation of IRB certification
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REFERENCES
1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: GLOBOCAN 
2000. Int J Cancer 2001; 94: 153–56.
2. Deuffic S, Poynard T, Buffat L, Valleron AJ. Trends in primary liver cancer. Lancet 1998; 
351: 214–15.
3. El Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. 
N Engl J Med 1999; 340: 745–50.
4. Altekruse SF, Henley SJ, Cucinelli JE, McGlynn KA. Am J Gastro 109(4):542-53, 2014
5. 5    Fattovich G, Giustina G, Degos F, et al. Morbidity and mortality in compensated 
cirrhosis type C:    a retrospective follow-up study of 384 patients. Gastroenterology 1997; 
112: 463–72.
6. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003; 362: 1907-17.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N 
Engl J Med 2008; 359: 378–390.
8. Mizukoshi E, Nakamoto Y, Arai K, Yamashita T, Sakai A, Sakai Y, et al. Comparative 
analysis of various tumor associated antigen-specific t-cell responses in patients with 
hepatocellular carcinoma. Hepatology 2011; 53: 1206-16.
9. Korangy F, Ormandy LA, Bleck JS, Klempnauer J, Wilkens L, Manns MP et al. 
Spontaneous tumor-specific humoral and cellular immune responses to NY-ESO-1 in 
hepatocellular carcinoma. Clin Cancer Res  2004;10:4332-41.
10. Shiina S, Tagawa K, Unuma T,Takanashi R,Yoshiura K, Komatsu Y et al. Percutaneous 
ethanol injection therapy for hepatocellular carcinoma. A histo-Pathologic study. Cancer 
1991; 68: 1524-1530.
11. Hato T, Goyal L,Greten TF, Duda DG, Zhu AX.  Immune checkpoint blockage in 
hepatocellular carcinoma: Current progress and future directions. Hepatology, 2014; 
60:1776-1782, 2014.
12. Chen KJ, LinSZ, Zhou L, Xie HY, Zhou WH, Taki-EldinA, et al. Selective recruitmentof 
regulatory T cells through CCR6-CCL20 in hepatocelllar carcinoma fosters 
tumorprogression and predicts poor prognosis.  PloS One 2011; 6:e24671.\
13. Flecken T, Schmidt N,Hild S, Gostick E, Drognitz O, Zeiser R et al. Immunodominance and 
functional alterations of tumor-associated antigen-specific CD8+  T-cell responses in 
hepatocellular carcinoma. Hepatology 2014;59:1415-1426
14. Ilkovitch D, Lopez DM. The liver is a site for tumor-induced myeloid-derived Suppressor 
cell accumulation and immunosuppression.  Cancer Res 2009;69:5514- 5521.
15. Alias A, Ives A, Pathan AA, Navarrete CV, Williams R, Bertoletti A. et al. Analysis of CD4 
+  T-cell responses to a novel alpha-fetoprotein-derived epitope in hepatocellular carcinoma 
patients.  Clin CanRes 2005;11:6686-6694.
16. Watanabe T, Bertoletti A, Tanoto TA.   PD1/PDL1 pathway and T cell exhaustion in 
chronic hepatitis virus infection.    Journal of Viral Hepatitis 2010; 17:453-458.
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17. Nobuhiro N, Cho H, Shaked A, Olthoff K, Valiga ME, Kaminski M,Gostick E, et al. 
Synergistic reversal of intrahepatic HCV-specific CD8  T cell exhaustion by combined PD-
1/CTLA-4 Blockade.    PloS Pathog 5(2):e1000313, 2009.
18. Sangro B, Gomez-Martin C, Mata M, InarrairaeguiM, Garralda E, et al. A clinical trial of 
CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic 
hepatitis C.     J of Hep  2013 , 59: 81-88.
19. El-Khoueiry AB, Melero I, Crocenzi TS, Welling TH, Yau TC, Yeo W, et al. Phase I/II 
safety and antitumor activity of nivolumab in patients with advanced Hepatocellular 
carcinoma (HCC) CA 209-040.  Proc ASCO  2015.   
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APPENDIX A: EXPEDITED ADVERSE EVENT (AE) REPORTING REQUIREMENTS
For all AEs that meet criteria for expedited reporting, the Principal Investigator (PI) is obligated 
to pursue and provide follow-up reporting information until the event has resolved or until an 
acceptable medical endpoint has been reached (i.e. for the duration specified in the protocol), or 
the patient is lost to follow-up.
The PI and all applicable research study team members should become familiar with the safety 
profile of the investigational agent(s) and/or intervention at the start of the study and for the 
duration of the research, e.g. by reviewing the Investigator’s Brochure (IB) and any Safety 
Reports released, by the Sponsor as applicable.  
A. FDA Expedited Reporting
a.
Sponsor-Investigators i.e. IND Holders, have additional reporting requirements to the 
FDA and other committees, and should consult the applicable regulations and agency 
guidelines for these requirements.  
b. Since this protocol involves the use of FDA IND agent(s), completion of the FDA 
MedWatch 3500A Reporting Form is required for Sponsor-Investigators.  The Form 
can be obtained electronically at: 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf 
i. All serious, unexpected (unanticipated) and suspected adverse events must be 
directly reported to the FDA within 15 calendar days of being made known to the 
Principal Investigator (PI).  
ii. All fatal or life-threatening AEs must be directly reported to the FDA within 7 
calendar days of being made known to the PI.
c.
For more information regarding reporting to the FDA, please refer to the FDA 
website for REPORTING GUIDELINES:  
http://www.fda.gov/Safety/MedWatch/HowToReport/default.htm
B. IRB Expedited Reporting
a.
All Investigators should also be aware of local Institutional requirements for AE 
reporting.  For more information regarding the IRB policy, please refer to the UM 
HSRO’s Investigator Manual: http://hsro.med.miami.edu/documents/HRP-103_-
_INVESTIGATOR_MANUAL_4.11.2014.docx and the UM HSRO SOP on New 
Information (HRP-024) 
https://eprost.med.miami.edu/eProst/Doc/0/HLJ5OTJVQEH419E0I6QPT3B199/HRP
-024%20-%20SOP%20-%20New%20Information.docx
b. All AEs that are serious, unanticipated and possibly related will be reported to the 
IRB within ten (10) working days of being made known to the PI.  
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c.
Events that are more frequent than anticipated or more severe than expected must be 
reported to the IRB within ten (10) working days of being made known to the PI.
d. All unanticipated deaths must be reported to the IRB within 24 hours of being made 
known to the PI.
C. Merck Expedited Reporting, (Events of Clinical Interest or ECIs)
a.
In addition to the mandatory MedWatch 3500A Form, the PI is also required to 
comply with all reporting requirements as supplied by the Investigational Drug 
Sponsor: Merck. 
b. Any serious adverse event, or follow up to a serious adverse event, including 
death due to any cause other than progression of the cancer under study that 
occurs to any subject from the time the consent is signed through 90 days 
following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, must be reported 
within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. 
c.
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety 
and will be handled in the same manner as SAEs. 
d. Additionally, any serious adverse event, considered by an investigator who is a 
qualified physician, to be related to Merck product that is brought to the attention 
of the investigator at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck.
e.
SAE reports and any other relevant safety information are to be forwarded to 
the Merck Global Safety facsimile number:  +1-215-993-1220
f.
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.
g.
All subjects with serious adverse events must be followed up for outcome. 
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APPENDIX B: DATA SUBMISSION SCHEDULE
CASE REPORT FORM(S)
TIMEPOINT TO BE COMPLETED
Pre-Treatment
ICF, including HIPAA signed/dated
Eligibility Checklist 
SCCC Protocol Enrollment Form
Prior to registration
On-study Form
Within 30 days of registration
On Treatment
Treatment Form Cycle X, Day Y
Due every cycle for phase II-IV studies
End of Treatment
Off Treatment Form
Within 14 days of discontinuation/completion of 
protocol therapy
Follow-Up (for studies with long term follow-up)
Follow-up Form
Every 3 months until documented disease 
progression, death, withdrawal of consent, or EoS, 
whichever occurs first.
Progression/Relapse
Within 4 weeks of knowledge of progression/relapse
Notice of Death Form
Within 4 weeks of knowledge of death
Subsequent Malignancy
Within 4 weeks of knowledge of another malignancy
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APPENDIX C: PERFORMANCE STATUS SCALES
As published in Am J Clin Oncol: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, 
McFadden ET, Carbone PP. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982;5:649-655. The Eastern Cooperative Oncology Group, 
Robert Comis, MD, Group Chair. 
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APPENDIX D: NYHA CLASSIFICATION OF HEART DISEASE
New York Heart Association (NYHA) classification of heart disease
NYHA Class
Symptoms
I
No symptoms and no limitation in ordinary physical activity, e.g. shortness of 
breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients.
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APPENDIX E: INFORMATION ON POSSIBLE DRUG INTERACTIONS
(NO formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab.)
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APPENDIX F: OPTIONAL BIOMARKER, CORRELATIVE AND SPECIAL STUDIES  
Tumor tissue (obtain either from archival tissue or newly obtained at time of biopsy) may be 
stained for PD-L1 expression. Obtaining tumor tissue for correlative studies is optional and will 
only be performed at Screening for patients who consent. We will assess PD-L1 tumor expression 
with clinical outcome. This is exploratory and there is no formal statistical analysis planned. PD-
L1 testing will be performed by Dr Monica Garcia-Buitrago at Jackson Memorial Hospital. 
Peripheral blood will have serum obtained for biomarkers. Immunologic markers including ctDNA 
(approximately up to 30 mL using 2 green top tubes + 1 red top tube + 1 EDTA tube) will be 
performed.  Hepatitis B and C viral titers (7 mL) will also be performed.  Blood will be drawn at 
baseline, during treatment and/or at the time of documented disease progression and at treatment 
discontinuation, only on those patients who consent.  Please refer to Section 13.0 for details.
The purpose is to determine if viral titers change with treatment. This is exploratory and no 
formal statistical analysis is planned.  Biomarker testing will be performed by Dr. Niramol 
Savaraj at the following location:
University of Miami
1201 NW 16th St, Room D1010
Miami, FL 33125
Telephone: 305-575-3143
Email: nsavaraj@med.miami.edu      
Several representative cytokines associated with T cell activation and suppression in serum, tumor 
biopsy and PBMCs from patients will also be analyzed pre-and post- anti-PD-1 treatment. T cell 
proliferation and activation in response to T cell receptor (TCR) and CD28 signals require IL-2, 
IL-12, IFN-r stimulation, but can be suppressed by immunosuppressive cytokines such as IL-10 
and TGF-β. 
1) Patient serum and peripheral blood myeloid cells (PBMCs) preparation:
We will collect the blood samples from patients including pre-treatment and post-treatment (30 
cases). The whole blood samples will be centrifuged at 1, 200 rpm, and then supernatant (serum) 
will be collected and stored at -80 degree for biomarker screening. The rest of blood samples 
(pellets) will be mixed with phosphate-buffered saline (PBS, 1:1) and added on top of Ficoll-Paque 
(GE Healthcare Life Science); PBMC will be separated by centrifuging at 100 x g.  
2)  Detection of IL-12, IL-10, and TGF-β in patent serum:
As mentioned, patient serum (including pretreatment and post-treatment) will be stored at -80 
degree and TGF-β, IL-12 and IL-10 levels in serum will be detected using ELISA. Thereafter, we 
will correlate the levels of these cytokines with tumor progression, T cell activity in PBMCs, and 
activation of tumor infiltrating lymphocytes (TILs, CD3+ cells), and PD-L1 expression. The 
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detection of T cell activation will be based on IFN-r, IL-2, and IL-12 expressions in PBMC (or 
CD3+ T cells).  
3) Detection of IFN-r, IL-2, and IL-10 expressions in PBMCs using intracellular staining:
After we obtain PBMC, we will plate PBMC (1 x105) in 96-well plate and incubate them with 
brefeldinA overnight, and then fixed with 4% formalin and permeabilized by 0.5% saponin. 
Thereafter, cell will be incubated with anti-CD3, INF-r, IL-2, or IL-10 antibodies conjugated with 
fluorescence, and then analyzed by FACS. Positive control will be PBMCs treated with ionomycin 
and PMA to promote T cell activation, such IFN-r production.  
4) Detection of IL-10, CD3, PD-L1, IFN-r, and IL-2 in tumor biopsy using IHC staining: 
In this regard, we will obtain tumor biopsy from patients, either archived or fresh tumor if available 
(and patient is willing) and stain these markers to clarify that they express in TILs or cancer cells. 
Therefore, we will do single staining for each marker and double staining to co-localize CD3 and 
IL-2 /or IFN-r. 
This testing will be performed by Dr. Niramol Savaraj at the following location:
University of Miami
1201 NW 16th St, Room D1010
Miami, FL 33125
Telephone: 305-575-3143
Email: nsavaraj@med.miami.edu      
Approximately 10 ml blood in one EDTA tube will be collected along with the immunologic 
markers at the same time. The blood will be centrifuged, plasma and cells separated and sent for  
sent to Merck for tDNA testing.
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APPENDIX G: CHILD-PUGH CLASSIFICATION 
Reference: The U.S. Department of Veterans Affairs 
http://www.hepatitis.va.gov/provider/tools/child-pugh-calculator.asp 
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APPENDIX H: PROTOCOL APPROVED METHODS OF CONTRACEPTION
Pembrolizumab 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or are 
considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) surgically 
sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually active for the 
duration of the study.  The two birth control methods can be either two barrier methods or a 
barrier method plus a hormonal method to prevent pregnancy. Subjects should start using birth 
control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period defined in the protocol.  If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should not 
be entered into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the subject 
will immediately be removed from the study.  The site will contact the subject at least monthly 
and document the subject’s status until the pregnancy has been completed or terminated.  The 
outcome of the pregnancy will be reported to the Sponsor and to Merck without delay and within 
24 hours to the Sponsor 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 Sponsor.   If a male subject 
impregnates his female partner the study personnel at the site must be informed immediately and 
the pregnancy reported to the Sponsor and to Merck and followed as described above.
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the nursing 
infant, subjects who are breast-feeding are not eligible for enrollment.
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APPENDIX I: EVENTS OF CLINICAL INTEREST & SUPPORTIVE CARE 
GUIDELINES FOR PEMBROLIZUMAB 
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology.  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.  These guidelines are intended to be applied when the 
Investigator determines the events to be related to pembrolizumab.  

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 that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus or T1DM (if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
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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 3 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 4 events, treat with intravenous corticosteroids for 24 to 48 hours (or 
longer if clinically indicated). Monitor LFTs labs at least weekly until Grade 0-1 or 
baseline at Investigator discretion. 
o
When symptoms improve to Grade 2 or less, a steroid taper should be started and 
continued over no less than 4 weeks.
o
Hold drug if an elevated AST or ALT lab value that is ≥ 5X the upper limit of 
normal (ULN) and an elevated total bilirubin lab value that is ≥ 2X the ULN and, 
at the same time, an alkaline phosphatase lab value that is < 2X the ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.* Monitor labs tests more frequently until AST, ALT and total 
bilirubin values return to baseline or <grade 3.
*Note:  These criteria are based upon available regulatory guidance documents. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that 
may require an additional evaluation for an underlying etiology.  The trial site 
guidance for assessment and follow up of these criteria can be found in the 
Investigator Trial File Binder (or equivalent).

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
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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. 

Overdose: An overdose that is not associated with clinical symptoms or abnormal 
laboratory results.
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.”

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. 
The table below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
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 
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).
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NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
(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.
Grades 3 or 4
Grade 3:
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 
drug administration.
REFERENCE: Merck. Pembrolizumab Program (MK-3475) Event of Clinical Interest 
Guidance Document. Version 5.0. 18-Dec-2014. 
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APPENDIX J: PREPARATION AND ADMINISTRATION/ RECONSTITUTION OF 
PEMBROLIZUMAB (KEYTRUDA®) FOR INJECTION (LYOPHILIZED 
POWDER)*
Reconstitution
 Add 2.3 mL of Sterile Water for Injection, USP by injecting the water along the walls of the 
vial and not directly on the lyophilized powder (resulting concentration 25 mg/mL). 
 Slowly swirl the vial. Allow up to 5 minutes for the bubbles to clear. Do not shake the vial. 
Preparation for Intravenous Infusion 
 Visually inspect the solution for particulate matter and discoloration prior to administration. 
The solution is clear to slightly opalescent, colorless to slightly yellow. Discard the vial if visible 
particles are observed. 
 Dilute KEYTRUDA injection (solution) or reconstituted lyophilized powder prior to 
intravenous administration. 
 Withdraw the required volume from the vial(s) of KEYTRUDA and transfer into an 
intravenous (IV) bag containing 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, 
USP. Mix diluted solution by gentle inversion. The final concentration of the diluted solution 
should be between 1 mg/mL to 10 mg/mL. 
 Discard any unused portion left in the vial. 
Storage of Reconstituted and Diluted Solutions 
The product does not contain a preservative. Store the reconstituted and diluted solution from the 
KEYTRUDA 50 mg vial either: 
 At room temperature for no more than 6 hours from the time of reconstitution. This includes 
room temperature storage of reconstituted vials, storage of the infusion solution in the IV bag, 
and the duration of infusion. 
 Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. 
Store the diluted solution from the KEYTRUDA 100 mg/4 mL vial either: 
 At room temperature for no more than 6 hours from the time of dilution. This includes room 
temperature storage of the infusion solution in the IV bag, and the duration of infusion. 
 Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of 
dilution. If refrigerated, allow the diluted solution to come to room temperature prior to 
administration. Do not freeze.
*Reference: Prescribing Information for pembrolizumab injection (Keytruda®). 
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