Conditions: Hepatocellular Carcinoma
Keywords: hepatocellular carcinoma E7080 lenvatinib pembrolizumab Japan
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 104
Healthy volunteers: no

Brief summary:
This is an open-label Phase 1b study designed to evaluate the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with hepatocellular carcinoma (HCC). The study will evaluate objective response rate and duration of response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).

Detailed description:

Arms:
arm 1: Participants will receive oral lenvatinib at a starting dose of 8 or 12 milligrams (mg) once a day (QD) in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle. The starting dose of lenvatinib will be based on Baseline body weight. Participants weighing greater than or equal to 60 kilograms (kg) will receive 12 mg QD; participants weighing less than 60 kg will receive 8 mg QD.

Interventions: intervention 1: lenvatinib intervention 2: pembrolizumab (200 mg)
Intervention descriptions: intervention 1: 4 mg capsules intervention 2: 30-minute intravenous infusion

Protocol document:
Prot_002.pdf: 
Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 1 of 169
1
TITLE PAGE
Clinical Study Protocol
Study Protocol Number:
E7080-J081-116
Study Protocol Title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subjects with Hepatocellular Carcinoma
Sponsor:
Eisai Co., Ltd.
4-6-10 
Koishikawa, 
Bunkyo-ku, 
Tokyo 112 8088
Japan
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Eisai Ltd.
European Knowledge 
Centre
Mosquito Way
Hatfield, 
Hertfordshire 
AL10 9SN UK
Investigational Product 
Name:
Lenvatinib (E7080/LENVIMA™/ KISPLYX®) and 
Pembrolizumab (MK-3475/KEYTRUDA®)
Indication:
Hepatocellular carcinoma
Phase:
Phase 1b
Approval Date:
V1.0
V2.0
V3.0
V4.0
V5.0
V6.0
21 Sep 2016 (Original Protocol)
10 Mar 2017 (Amendment 01)
13 Jul 2017 (Amendment 02)
12 Feb 2018 (Amendment 03)
13 Aug 2018 (Amendment 04)
17 Jan 2019 (Amendment 05)
IND Number:
115650
EudraCT Number:
2018-000522-55
GCP Statement:
This study is to be performed in full compliance with 
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use (ICH) and all applicable local Good Clinical Practice 
(GCP) and regulations.  All required study documentation will 
be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary 
information of Eisai (the sponsor).  Any viewing or disclosure 
of such information that is not authorized in writing by the 
sponsor is strictly prohibited.  Such information may be used 
solely for the purpose of reviewing or performing this study.


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 2 of 169
Summary of Changes
Revisions to Amendment 01
Date: 10 Mar 2017
Change
Rationale
Affected Protocol Sections
Delete “Investigators: To be 
determined ”
No need to be included based on 
the protocol template.

Clinical Protocol synopsis
Exclusion Criterion #17
Change to “Therapy for HCV 
must be completed at least 4 
weeks prior to first dose of study 
drug in case of Hepatitis C 
subjects who are on active HCV 
treatment.”
Changed in order to avoid possible 
confounding toxicity by the 
therapy for HCV, which was 
based on the discussion with 
Merck. 

Clinical Protocol synopsis

Section 9.3.2
New Exclusion Criterion was 
added (as #18) “Has dual active 
HBV infection (HBsAg (+) and 
/or detectable HBV DNA) and 
HCV infection (anti-HCV Ab(+) 
and detectable HCV RNA) at 
study entry.”
Added to exclude patients who 
have dual active HBV and HCV 
infection, which was based on the 
discussion with Merck.

Clinical Protocol synopsis

Section 9.3.2
New Exclusion Criterion was 
added (as #32) “Has severe 
hypersensitivity (≥Grade 3) to 
pembrolizumab and/or any of its 
excipients.”
Updated based on the latest 
pembrolizumab protocol standard 
text provided by Merck.

Clinical Protocol synopsis

Section 9.3.2
Study Treatment Dose 
Modification
2. Cycle 2 and onward (and 
applies to Cycle 1 and onward  of 
Expansion part)
Underlined words were added to 
make the language clear.

Clinical Protocol synopsis

Section 9.4.1.3.2
Add requirement that 
pembrolizumab treatment is to be 
discontinued for subjects with 
recurrent Grade 2 pneumonitis. 
Updated based on the latest 
pembrolizumab protocol standard 
text provided by Merck.

Clinical Protocol synopsis

Section 9.4.1.3.2 (Table 4)
Guidance for Management of 
Hepatic Events of Clinical 
Interest
d.
Regardless of laboratory 
values, hepatic decompensation 
diagnosed clinically – i.
Changed to “New onset ascites 
uncontrollable with diuretic”
Changed to make the criteria clear 
and clinically reasonable.

Clinical Protocol synopsis

Section 9.4.1.3.2

Section 9.5.1.5.2
Add “Antiplatelet agents and 
anticoagulants that require INR 
monitoring” and “herbal 
supplements or alternative 
medicines” into Prohibited 
Description Adjustment 
(corresponding to Section 
9.4.7.2.1)

Clinical Protocol synopsis


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 3 of 169
Concomitant Medications
Update the introduction of 
pembrolizumab
Updated based on the latest 
pembrolizumab protocol standard 
text provided by Merck. 

Section 7.1.3
Update the information of the 
nonclinical study
Updated the information of the 
new nonclinical study of 
combination of lenvatinib plus 
anti-PD-1 mAb.

Section 7.2.1

Section 10
Update the information of the 
study E7080-G000-304 (Phase 3 
of Lenvatinib Monotherapy for 
HCC)
Updated based on the news release
by Eisai.

Section 7.2.2.2
Update the information of the 
study E7080-J081-115 (Phase 1b 
of Lenvatinib Plus 
Pembrolizumab for Selected Solid 
Tumors in Japan)
Updated that the study is ongoing.

Section 7.2.2.4
Update the language of 
completion of “The 
Discontinuation From Treatment 
CRF page”
Updated based on the latest 
protocol standard text of Eisai.

Section 9.3.3
Update the language of reporting
of “AEs leading screen failure”
Updated based on the latest 
protocol standard text of Eisai.

Section 9.5.1.5.1
Add T3 or free T3 levels 
assessment at Screening and 
Baseline
Description Adjustment 
(corresponding to Inclusion 
criterion #12)

Section 9.5.1.5.3

Section 9.5.2.1
Add Child-Pugh score at each 
cycle Day1 and Off-Treatment 
Visit as well as Pre-treatment 
Phase
Added based on the necessity of 
data of Child-Pugh score.

Section 9.5.2.1
Update the language of Subject 
Disposition CRF
Updated based on the latest 
protocol standard text of Eisai.

Section 9.5.5


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 4 of 169
Summary of Changes
Revisions to Amendment 02
Date: 13 Jul 2017
Change
Rationale
Affected Protocol Sections
Add the language as follows;
“For determination of the 
recommended phase 2 dose, all 
episodes of Grade 3 or 4 
thrombocytopenia and 
neutropenia beyond Cycle 1 will 
be taken into consideration.”
Added based on the FDA’s 
feedback

Clinical Protocol synopsis

Section 9.1
Revise the language for the DLT 
of "Hematologic" Toxicity 
Category so that the DLT 
criteria for thrombocytopenia is 
more conservative as follows; 
"Grade 4 thrombocytopenia 
lasting >/=7 days or Grade 3 
thrombocytopenia associated 
with clinically significant 
hemorrhage or bleeding and/or 
requiring platelet transfusion"
Revised based on the FDA’s 
feedback

Clinical Protocol synopsis

Section 9.1
Revise the Exclusion 
Criterion#11 as follows so that 
patients with therapeutic anti-
factor X treatment are excluded;
"11.Bleeding or thrombotic 
disorders or use of factor X 
inhibitors or anticoagulants 
requiring therapeutic INR 
monitoring, eg, warfarin or 
similar agents.  Treatment with 
low molecular weight heparin is 
permitted.  Antiplatelet agents 
are prohibited throughout the 
study. "
Revised based on the FDA’s 
feedback

Clinical Protocol synopsis

Section 9.3.2
Revise the language in 
“Prohibited Concomitant 
Medications” as follows; 
“Antiplatelet agents, factor X 
inhibitors, and anticoagulants 
that require INR monitoring, 
such as warfarin. (Treatments 
that do not require INR 
monitoring, such as low 
molecular weight heparin are 
Revised based on the FDA’s 
feedback

Clinical Protocol synopsis

Section 9.4.7.2.1


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 5 of 169
Summary of Changes
Revisions to Amendment 02
Date: 13 Jul 2017
Change
Rationale
Affected Protocol Sections
permitted)”
Add the language “Monitor 
subjects with Grade 4 
thrombocytopenia every 48 
hours until resolution to baseline 
or Grade 1.”
Added based on the FDA’s 
feedback

Section 9.5.2.1


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 6 of 169
Summary of Changes
Revisions to Amendment 03
Date: 12 Feb 2018
Change
Rationale
Affected Protocol Sections
Add name and address of Eisai 
Ltd. as sponsor for the European 
Union (EU), and added EudraCT 
number to Title Page.
To accommodate opening of 
sites in the EU to enrollment.

Section 1
Add KISPLYX® as the product 
name of lenvatinib
To accommodate opening of 
sites in the EU to enrollment.

Section 1
Add IND number
Information of IND number is 
reflected.

Section 1
Revise “Study Regions 
(Country) or Center” 
To accommodate opening of 
sites in North America and 
Europe to enrollment in 
Expansion part.

Clinical Protocol synopsis

Section 6
Add the following language into 
Primary Objectives; “(Expansion 
part) To evaluate objective 
response rate (ORR) and 
duration of response (DOR) by 
modified Response Evaluation 
Criteria In Solid Tumors for 
HCC (mRECIST) and RECIST 
1.1 based on independent 
imaging review (IIR)”.  
Revised the Primary Objectives 
to add ORR and DOR by 
mRECIST and RECIST1.1 
based on IIR in Expansion part, 
considering the importance and 
necessity of these efficacy 
endpoints in Expansion part.

Clinical Protocol synopsis

Section 7

Section 8.1
Revise the languages for ORR 
/DOR of DLT evaluation Part, 
and for ORR/DOR of Expansion 
Part by mRECIST based on 
investigator review in Secondary 
Objectives
Description adjustment to clarify 
that they are Secondary 
Objectives.

Clinical Protocol synopsis

Section 8.2
Delete PFS, TTP, TTR and OS 
from Exploratory Objectives and 
add them into Secondary 
Objectives
Transferred PFS, TTP, TTR and 
OS from Exploratory Objectives 
to Secondary Objectives, 
considering the importance of 
these efficacy endpoints.

Clinical Protocol synopsis

Section 8.2

Section 8.3
Delete to evaluate the efficacy 
endpoints and assessments by 
irRECIST and irmRECIST 
(optional, Expansion Part) and 
delete it from Exploratory 
Objectives
Deleted the related languages, 
considering the necessity of 
these efficacy endpoints.

Clinical Protocol synopsis

Section 8.3

Section 9.5.1.3
Add to evaluate HRQoL using 
EORTC QLQ-C30, QLQ-
Added them into Exploratory 
Objectives considering the 

Clinical Protocol synopsis

Section 8.3


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 7 of 169
Summary of Changes
Revisions to Amendment 03
Date: 12 Feb 2018
Change
Rationale
Affected Protocol Sections
HCC18 and EQ-5D-5L for the 
subjects in Expansion Part added 
as of the Protocol Amendment 
03, and add the languages into 
Exploratory Objectives, Study 
Endpoints and Assessments 
necessity of the endpoint.

Section 9.5.1.6
Add the option to increase 
enrollment in Expansion part to 
up to approximately 94 subjects 
based on the results of 2 interim 
analyses after 20 and 56 subjects 
have sufficient follow-up to be
evaluated for response, and 
revise Sample Size Rationale in 
alignment with this revision
To obtain additional efficacy and 
safety data for the combination 
in Expansion part based on 
clinical results.

Clinical Protocol synopsis

Section 9.1

Section 9.3

Section 9.7.2

Section 9.7.3
Add the following language to 
Inclusion Criterion#12; “As of 
Amendment 03, subjects with 
T3, free T3 or free T4 
abnormalities at screening who 
are asymptomatic can be 
eligible”
Changed to make the criterion 
more clinically reasonable.

Clinical Protocol synopsis

Section 9.3.1
Revise the language for 
Exclusion Criterion #15 as 
follows; “Active infection (any 
infection requiring systemic 
treatment).  Hepatitis B or C 
[HBV/HCV] is allowed.”
Revised to make the language 
clear.

Clinical Protocol synopsis

Section 9.3.2
Revise the language of 
Exclusion Criterion#20 as 
“Change to “Subjects with CNS 
metastases are not eligible, 
unless they have completed local 
therapy (eg, whole brain 
radiation therapy [WBRT], 
surgery or radiosurgery) and 
have discontinued the use of 
corticosteroids for this indication 
for at least 4 weeks before 
starting treatment in this study. 
Any signs (eg, radiologic) or 
symptoms of brain metastases 
must be stable for at least 4 
weeks before starting study 
Revised based on the standard 
language of lenvatinib.

Clinical Protocol synopsis

Section 9.3.2


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 8 of 169
Summary of Changes
Revisions to Amendment 03
Date: 12 Feb 2018
Change
Rationale
Affected Protocol Sections
treatment.”
Delete the following Exclusion 
Criterion #26; “Subjects being 
treated with drugs that strongly 
inhibit or induce CYP3A4 and 
that may be possibly used during 
this study”
Deleted since the criterion is no 
longer necessary for the subjects 
in Expansion part added as of 
Protocol Amendment 03.

Clinical Protocol synopsis

Section 9.3.2
Revise the language of footnote 
b of Lenvatinib Dose Reduction 
and Interruption Instructions
Revised based on the standard 
language of lenvatinib.

Clinical Protocol synopsis

Section 9.4.1.3.2
Update “Dose Interval 
Modification Guidelines for 
Non-Hepatic Drug-Related 
Adverse Events Associated with 
Pembrolizumab”
Updated based on the latest 
pembrolizumab protocol 
standard text provided by Merck.

Clinical Protocol synopsis

Section 9.4.1.3.2
Update “Guidance for 
Management of Hepatic Events 
of Clinical Interest” and related 
languages including “Permanent 
Discontinuation Criteria for 
Subjects With Non-overdose 
Hepatic Events of Clinical 
Interest” and “Diagnosis and 
Management of Non-Overdose 
Hepatic Events of Clinical 
Interests”
Updated to make the language 
clear and clinically reasonable 
based on the discussion with 
Merck.

Clinical Protocol synopsis

Section 9.4.1.3.2

Section 9.5.1.5.2
Add the language to clarify that 
images acquired for tumor 
assessments both in DLT 
evaluation part and Expansion 
part will be sent to an ICL for 
archiving and independent 
analysis
Added considering the necessity 
of IIR of tumor assessments in 
DLT evaluation part as well as 
Expansion part.

Clinical Protocol synopsis

Section 9.5.1.3
Delete ORR(week24) from study 
endpoints and analysis
Deleted the related languages, 
considering the necessity of the 
endpoint.

Clinical Protocol synopsis

Section 9.7.1.1.3

Section 9.7.1.6
Add the expected study duration
Added as required by some 
regulatory agencies

Section 5.1

Section 9.1
Add the following languages: 
“European Good Clinical 
Practice Directive 2005/28/EC 
To accommodate opening of 
sites in the EU to enrollment.

Section 5.2


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 9 of 169
Summary of Changes
Revisions to Amendment 03
Date: 12 Feb 2018
Change
Rationale
Affected Protocol Sections
and Clinical Trial Directive 
2001/20/EC for studies 
conducted within any EU 
country.  All SUSARs will be 
reported, as required, to the 
Competent Authorities of all 
involved EU member states.”
Revise “Management of 
Hypertension” and 
“Management of Proteinuria“ in 
“Supportive Care Guidelines for 
Lenvatinib”
Revised based on the standard 
language of lenvatinib.

Section 9.4.1.4.1

Section 9.4.1.4.2
Revise the language of “Rescue 
Medications and Supportive 
Care for Pembrolizumab” 
including “Infusion Reaction 
Treatment Guidelines”
Updated based on the 
pembrolizumab protocol 
standard text provided by Merck.

Section 9.4.1.5
Revise the language of 
“Prohibited Concomitant 
Medications”
Updated to make the language 
clear regarding concomitant 
medications which are allowed.

Section 9.4.7.2.1
Add the following language:  
“Discontinuation of 
pembrolizumab treatment may 
be considered for subjects who 
have attained a confirmed 
complete response (CR) and 
have been treated for at least 8 
cycles (at least 24 weeks), 
receiving 2 cycles of the 
combination including 2 doses 
of pembrolizumab beyond the 
date when the initial CR was 
declared.”  
Updated based on the 
pembrolizumab protocol 
standard text provided by Merck.

Section 9.5.1.3
Add the sparse sampling scheme 
of collecting blood samples for 
lenvatinib pharmacokinetic 
assessments for the subjects in 
Expansion part added as 
Protocol Amendment 03
Added the language considering 
that the sparse sampling scheme 
is reasonable for the subjects in 
Expansion part added as this 
Protocol Amendment.

Section 9.5.1.4.1
Add urine protein-to-creatinine 
ratio (UPCR) into Clinical 
Laboratory Tests as optional 
measurement
Added based on the revision of 
“Management of Proteinuria“ in 
“Supportive Care Guidelines for 
Lenvatinib”

Section 9.5.1.5.3


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 10 of 169
Summary of Changes
Revisions to Amendment 03
Date: 12 Feb 2018
Change
Rationale
Affected Protocol Sections
Revise the language of “Vital 
Signs and Weight 
Measurements” particularly 
regarding measurements and 
assessments of blood pressure
Updated based on the revision of  
“Management of Hypertension” 
in “Supportive Care Guidelines 
for Lenvatinib”

Section 9.5.1.5.4
Update the Schedule of 
Procedures/Assessments
Added assessments of HRQoL 
and lenvatinib PK blood samples 
for the subjects in Expansion 
part added as of this 
Amendment.

Section 9.5.2.1
Update Study Endpoints based 
on the changes of Study 
Objectives
Updated primary endpoints,
secondary endpoints and 
exploratory endpoints based on 
the revision of Study Objectives 
(Section 8).

Section 9.7.1.1
Updated Reference list
Description adjustment

Section 10
Update KEYTRUDA® Package 
Insert and Summary of Product 
Characteristics
To include updated information

Appendix 11


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 11 of 169
Summary of Changes
Revisions to Amendment 04
Date: 13 Aug 2018
Change
Rationale
Affected Protocol Sections
Add reference to main protocol 
section on supportive care 
guidelines in the synopsis.
To provide specific location of 
supportive care guidelines in 
the main protocol.

Clinical Protocol Synopsis
Added symbol “≤” to specify 
acceptable blood pressure for 
inclusion criterion 7.
Clarification per request from 
AEMPS.

Clinical Protocol Synopsis 

Section 9.3.1
Add hypersensitivity to 
lenvatinib and/or any of its 
excipients to exclusion 
criterion 31.
Added as per MHRA request.

Clinical Protocol Synopsis

Section 9.3.2
Added exclusion criterion 32, 
“any subjects with non-GI 
fistula.”
Added as per ANSM request.

Clinical Protocol Synopsis

Section 9.3.2
Added a statement that subjects 
who stop study treatment after 
receiving 35 administrations of 
pembrolizumab (approximately 
2 years) for reasons other than 
progressive disease or 
intolerability, or subjects who 
attain a complete response and 
stop study treatment, may be 
eligible to receive a second 
course of treatment of up to 17 
additional administrations of 
pembrolizumab (approximately 
1 year).  
Added as per ANSM request.

Clinical Protocol Synopsis 

Section 9.4.1.2

Section 9.5.2.1 (Table 9, 
footnote “dd”)
Added sections 9.1.4 and
9.5.1.3.1.
Added Table 10 in section 
9.5.2.1, schedule of 
procedures/assessments in the 
second course of treatment.
To describe conditions for the 
second course of treatment 
with pembrolizumab.

Clinical Protocol Synopsis 

Section 9.1.4

Section 9.5.1.3.1

Section 9.5.2.1


Clinical Study Protocol
Amendment 05
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FINAL: 17 Jan 2019
Confidential
Page 12 of 169
Added footnote “i” to Table 2, 
indicating that Grade 4 is 
applicable to hematologic 
toxicities only, not to 
proteinuria.
Per ANSM request, Table 2 has 
been clarified with an 
additional footnote so that 
Grade 4 is applicable to
hematologic toxicities only.  
This is because Grade 4 
proteinuria does not exist 
in the CTCAE classification.

Clinical Protocol Synopsis

Section 9.4.1.3.2
In the event of first recurrence 
Grade 3 colitis, pembrolizumab 
treatment is to be permanently 
discontinued. 
Added as per ANSM request.  

Clinical Protocol Synopsis

Section 9.4.1.3.2
Updated information for Study
E7080-G000-304.
Study was completed.

Section 7.2.2.2
Request a discussion with 
sponsor in case investigator is 
considering starting HCV anti-
viral therapy. 
Added in response to ANSM.  
The language is consistent with 
other pembrolizumab protocols 
in the same indication.  

Section 9.4.1.3.2
Add treatment discontinuation 
in case of nephrotic syndrome.
Added as per MHRA request.

Section 9.4.1.4.2
Add treatment discontinuation 
in case of any grade of arterial 
thromboembolism.
Added as per MHRA request.

Section 9.4.1.4.4
Tables 8 and 9 have been 
amended to more clearly 
reflect the protocol's 
requirement for a pregnancy 
test either monthly, or before 
each administration of 
pembrolizumab.
Clarification has been added 
per ANSM request.

Section 9.5.1.5.3

Section 9.5.2.1


Clinical Study Protocol
Amendment 05
E7080-J081-116
Eisai
FINAL: 17 Jan 2019
Confidential
Page 13 of 169
Summary of Changes
Revisions to Amendment 05
Date: 17 Jan 2019
Change
Rationale
Affected Protocol Sections
Exclusion criterion #27 updated to 
allow use of systemic steroids up to 
10 mg/d of prednisone.
Changed to clarify the 
physiologic dose of 
prednisone. 

Synopsis

Section 9.3.2
The Follow-up Period for collecting
SAE data was changed from 90 
days to 120 days.
Changed to be consistent with 
other protocols in the 
lenvatinib + pembrolizumab 
development program.

Synopsis

Section 9.5.1.5.1

Section 9.5.4.1
Added “(date of first study dose)” to 
the OS endpoint description.
Clarified timing to be 
consistent with description of 
other endpoints.

Synopsis

Section 9.7.1.1.2
Added “at least” to the data cutoff 
date for the primary analysis to 
clarify the minimal time allowed for 
the duration of follow up.
Changed to clarify the data 
cutoff for the primary 
analysis to be done.

Synopsis

Section 9.7.1.6
RECIST 1.1 changed to mRECIST.
Corrected to show that the 
investigator assessment is 
performed using mRECIST.

Section 9.1.4
Table 6 modified to clarify subject’s 
blood samples for PK assessments.
Clarified to be consistent with 
protocol text.

Section 9.5.1.4.1
Table 10 and table footnotes 
corrected to more clearly reflect the 
main text of the protocol.
Made consistent with the 
main text of the protocol.

Section 9.5.2.1


Clinical Study Protocol
Amendment 05
E7080-J081-116
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FINAL: 17 Jan 2019
Confidential
Page 14 of 169
2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: E7080, MK-3475
Name of Active Ingredient: Lenvatinib, Pembrolizumab
Study Protocol Title
An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects with Hepatocellular 
Carcinoma
Study Regions (Country) or Center
DLT evaluation part: Two centers in Japan
Expansion Part:  multiple centers in Japan, North America, and Europe
Study Period and Phase of Development
Approximately 30 months
Phase 1b
Objectives
Primary Objectives

To evaluate the tolerability and safety for combination of lenvatinib plus pembrolizumab in 
subjects with hepatocellular carcinoma (HCC)

(Expansion part) To evaluate objective response rate (ORR) and duration of response (DOR)
by modified Response Evaluation Criteria In Solid Tumors for HCC (mRECIST) and RECIST 
1.1 based on independent imaging review (IIR)
Secondary Objectives

(DLT evaluation Part) To evaluate ORR and DOR by mRECIST (based on investigator review
and IIR), and by RECIST1.1 based on IIR

(Expansion Part) To evaluate ORR and DOR by mRECIST based on investigator review

To evaluate the following efficacy endpoints by mRECIST (based on investigator review and 
IIR) and RECIST1.1 (based on IIR) :
-
Progression-free survival (PFS)
-
Time to progression (TTP)
-
Time to response (TTR)

Overall survival (OS)

To assess the pharmacokinetic (PK) profile of lenvatinib and pembrolizumab 

To detect anti-drug antibodies for pembrolizumab (ADA)
Exploratory Objectives

To evaluate the following efficacy endpoints by mRECIST (based on investigator review and 
IIR) and RECIST1.1 (based on IIR) :
-
Disease control rate (DCR)
-
Clinical benefit rate (CBR)

To evaluate the impact of treatment on Health Related Quality of Life (HRQoL) for subjects 
treated using the European Organisation for Research and Treatment of Cancer (EORTC) 
QLQ-C30, HCC-specific EORTC QLQ-HCC18 questionnaire and European Quality of Life 


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questionnaire.  
For the subjects in Expansion part added as of the protocol Amendment 03, HRQoL will be 
evaluated using the EORTC QLQ-C30 and the HCC specific supplement QLQ-HCC18. 
HRQoL will also be evaluated using the generic EuroQuol five dimension five level (EQ-5D-
5L) questionnaire. 

To investigate the relationship between candidate biomarkers and anti-tumor activity of 
lenvatinib in combination with pembrolizumab:
-
To explore blood and tumor markers (such as PD-L1 expression levels, cytokine and 
angiogenic factor profiling), and immune cell profiling and evaluate their relationship with 
clinical outcomes including anti-tumor activity of lenvatinib in combination with 
pembrolizumab
Study Design
Overall Design
This is an open-label Phase 1b study.  This study will evaluate the tolerability and safety of 
lenvatinib in combination with pembrolizumab in subjects with HCC. 
This study will begin with lenvatinib 12 mg (Body Weight [BW] ≥60 kg) or 8 mg (BW <60 kg) 
/day orally and pembrolizumab 200 mg (every 3 weeks [Q3W], intravenous [IV]) in subjects with 
HCC. Tolerability of this dose level will be evaluated by dose-limiting toxicities (DLTs) during 
the first cycle (21-day treatment cycle). 
In this dose level, 3 subjects will be enrolled first. If 0 or 1 of 3 subjects in a given dose level 
cohort experiences a DLT, then 3 more subjects will be enrolled into that dose level. If 0 or 1 of 6
subjects in a given dose level cohort experiences a DLT, the dose level will be considered 
tolerable. Additional 4 subjects can be enrolled without DLT evaluation if further safety 
information is considered necessary based on the discussions between the sponsor and 
investigators.  
Enrollment will be interrupted if 2 or more DLTs are observed in this dose level, and after sponsor 
and investigators’ review, enrollment may continue for up to 6 subjects based on the nature and 
severity of the DLTs. Once 6 subjects are enrolled, after sponsor and investigators’ review
regarding the nature and severity of the DLTs, an additional 4 subjects (10 subjects in total for 
DLT evaluation) will be enrolled, and that dose level will be considered to be tolerable if DLT is 
observed in 3 or less of the 10 subjects in total. An independent medical advisor as third party may
be consulted for the review as needed. 
In this dose level, at least 3 subjects treated with lenvatinib 12 mg once daily (QD) and 
pembrolizumab 200 mg Q3W IV (BW ≥60 kg) need to be included in the 6 subjects for DLT 
evaluation. (In case of the 10 subjects for DLT evaluation, at least 5 subjects (BW ≥60 kg) treated 
with lenvatinib 12 mg QD and pembrolizumab 200 mg Q3W IV need to be included.) 
Cohort of reduction to lower dose level (lenvatinib) or study discontinuation will be considered, if 
this dose level (12 mg [BW ≥60 kg] or 8 mg [BW <60 kg] lenvatinib plus 200 mg pembrolizumab)
is not tolerable, upon discussions between the sponsor and investigators, and the protocol will be 
amended as necessary. An independent medical advisor as third party maybe consulted for the 
consideration as needed. 
If there is a potential subject who is not evaluable for DLT (eg, subject who fails to administer 
≥75% of the planned dosage of lenvatinib due to a reason other than treatment related toxicity 
during Cycle 1), the investigator and sponsor will discuss whether or not to include the subject in 
the DLT Analysis Set. If subject is not evaluable for DLT then the subject will be replaced.  
For determination of the recommended phase 2 dose, all episodes of Grade 3 or 4 


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thrombocytopenia and neutropenia beyond Cycle 1 will be taken into consideration.
If the dose level is confirmed to be tolerable, an additional (approximately) 20 subjects will be 
enrolled for consolidation of PK data and safety and efficacy as the Expansion part. As of 
Amendment 03, the Expansion part may be further expanded up to approximately 94 subjects.  The 
decision to expand enrollment will be based on the results of 2 interim analyses that will take place 
when 20 (6 subjects for DLT evaluation part plus 14 subjects for Expansion part) and 56 subjects  
(6 subjects for DLT evaluation part plus 50 subjects for Expansion part) have sufficient follow-up 
to be evaluated for response.  The decision to expand enrollment will be assessed by mRECIST 
based on investigator review.  At the first interim analysis (N = 20), if there are more than 5
responses, then approximately 36 additional subjects will be enrolled. At the second interim 
analysis (N = 56), if there are more than 16 responses, approximately 44 additional subjects will be 
enrolled. If there are 5 or fewer responses at the first interim analysis (N = 20) or 16 or fewer 
responses at the second interim analysis (N=56), the sponsor may decide whether to expand 
enrollment based on other clinical outcome (eg, DOR). At least 5 subjects (BW ≥60 kg) treated 
with Lenvatinib 12 mg QD and at least 5 subjects (BW <60 kg) treated with Lenvatinib 8 mg QD
will be included in Expansion part.  
A DLT is defined as any of the following:

Any of the hematological or nonhematological toxicities noted in the table below considered to 
be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1

Failure to administer ≥75% of the planned dosage of lenvatinib as a result of treatment-related 
toxicity during Cycle 1

Subjects who discontinue treatment due to treatment-related toxicity in Cycle 1

Greater than 2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-related 
toxicity, even if the toxicity does not meet DLT criteria
Dose-Limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic
Grade 4 neutropenia for ≥7 days
Grade 3 or above febrile neutropenia
Grade 4 thrombocytopenia lasting ≥7 days
or 
Grade 3 thrombocytopenia associated with clinically significant 
hemorrhage or bleeding and/or requiring platelet transfusion
Nonhematologic 
toxicity
Grade 4 or Grade 5 toxicity
Grade 3 toxicities lasting >3 days excluding:
Nausea, vomiting, and diarrhea controlled by medical intervention 
within 72 hours
Grade 3 rash in the absence of desquamation, no mucosal 
involvement, does not require steroids, and resolves to Grade 1 by 
the next scheduled dose of pembrolizumab.
Grade 3 hypertension not able to be controlled by medication 
Grade 3 gastrointestinal perforation
Grade 3 wound dehiscence requiring medical or surgical 
intervention
Grade 3 thromboembolic event
Any Grade 3 nonhematologic laboratory value (except AST/ALT) 
if:


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Medical intervention is required to treat the subject, or the 
abnormality leads to hospitalization
Note: Abnormal laboratory values to which treatment and 
hospitalization is not required can be deemed a non-DLT
AST/ALT >10.0×ULN, which does not resolve within 1 week, or 
else is clinically symptomatic.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTCAE = Common Terminology 
Criteria for Adverse Events v4.03, DLT = dose-limiting toxicity, ULN = upper limit of normal.
Adverse events (AEs) with a clear alternative explanation (eg, due to disease progression) can be 
deemed a non-DLT.  
Study Phases
The study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase.
The Pretreatment Phase will last no longer than 28 days and includes:
A Screening Period, to obtain informed consent and establish protocol eligibility, and a Baseline 
Period, to confirm protocol eligibility prior to treatment. 
The Treatment Phase consists of the first cycle (21 days) for each subject. The Treatment Phase
for each subject ends after completing Cycle 1 of treatment or if they discontinue early. Those 
subjects who discontinue study treatment in Cycle 1 transition to the Off Treatment (Off-Tx) Visit 
of the Follow-up Period of the Extension Phase. Those who complete Cycle 1 transition to the 
Treatment Period of the Extension Phase.  
Extension Phase
The Extension Phase consists of a Treatment Period and a Follow-up Period.
Treatment Period (Extension Phase): Subjects still receiving study treatment at the end of the 
Treatment Phase will continue to receive the same treatment. Those subjects who discontinue 
study treatment transition to the Off-Tx Visit of the Follow-up Period of the Extension Phase. 
Follow-up Period (Extension Phase): The Follow-up Period consists of the Off-Tx Visit and the 
Follow-up. The Off-Tx Visit will occur within 30 days following the last dose of study treatment. 
Following the completion of the Off-Tx Visit, subjects will transition to the Follow-up. The 
Follow-up will continue as long as the study subject is alive unless the subject withdraws consent 
or until the sponsor terminates the study. In the Follow-up, subjects will be treated by the 
investigator according to the prevailing local standard of care. For survival and subsequent 
anticancer treatments, subjects will be followed every 12 weeks (±1 week) or at sponsor’s request.
If a clinic visit is not feasible, follow-up information may be obtained via telephone or email. The 
survival follow-up will be continued for up to 2 years after Cycle 1/Day 1 (C1D1) of the last 
subject enrolled in the Expansion part. The sponsor may decide to terminate survival follow-up 
anytime during the Extension Phase or when all subjects have discontinued study treatment.  All 
AEs will be captured for 30 days after the last dose of study drug.  Serious AEs regardless of 
causality assessment must be collected through the last visit and for 120 days after the subject’s last 
dose or for 30 days following the last dose if the subject initiates new anticancer therapy, 
whichever is earlier.
Second Course (Pembrolizumab Retreatment) Phase:  Subjects who stop study treatment after 
receiving 35 administrations of pembrolizumab for reasons other than progressive disease (PD) or 
intolerability, or subjects who attain a complete response (CR) and stop study treatment, may be 
eligible to receive a second course of treatment of up to 17 additional administrations of 


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pembrolizumab (approximately 1 year).
Number of Subjects
This study will enroll approximately 30 evaluable subjects with HCC (N=6 to 10 for DLT 
evaluation part and N=20 for Expansion part).  As of Amendment 03 the enrollment for Expansion 
part may be further expanded up to approximately 94 evaluable subjects.
Inclusion Criteria
1.
Subjects must have confirmed diagnosis of HCC with any of the following criteria:

Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, 
sarcomatoid or mixed cholangio-HCC tumors

Clinically confirmed diagnosis of HCC according to American Association for the Study 
of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology and/or chronic 
hepatitis B or C infection
2.
HCC for which no other appropriate therapy is available
Note:  Subjects basically should receive prior standard therapy including sorafenib.  
However, if the investigator judges the therapy is not appropriate for the subject, 
the prior standard therapy is not necessarily mandated for the eligibility.
Expansion Part: No prior systemic therapy for advanced/unresectable HCC
Note:  Subjects who have received local hepatic injection chemotherapy are eligible.
3.
Subjects categorized to stage B (not applicable for transarterial chemoembolization 
[TACE]), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system
4.
At least 1 measurable target lesion according to mRECIST meeting the following criteria.

Hepatic lesion
i.
The lesion can be accurately measured in at least 1 dimension as ≥1.0 cm (viable 
tumor for typical; and longest diameter for atypical), and
ii.
The lesion is suitable for repeat measurement

Nonhepatic lesion
i.
Lymph node (LN) lesion that measures at least 1 dimension ≥1.5 cm in the short 
axis, except for porta hepatis LN that measures ≥2.0 cm in the short axis
ii.
Non-nodal lesion that measures ≥1.0 cm in the longest diameter
Lesions previously treated with radiotherapy or locoregional therapy must show radiographic 
evidence of disease progression to be deemed a target lesion. Subjects whose only target 
lesion(s) is in bone will be excluded.
5.
Child-Pugh score A
6.
Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 to 1
7.
Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications 
within 1 week prior to the C1D1
8.
Adequate renal function defined as creatinine ≤1.5 times the upper limit of normal (ULN) or 
calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with 
creatinine levels >1.5×ULN
9.
Adequate bone marrow function: 


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
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5×103/μL)

Platelets ≥75,000/mm3 (≥75×109/L)

Hemoglobin ≥8.5 g/dL
10. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤2.3
11. Adequate liver function, defined as:

Bilirubin ≤2.0 mg/dL

Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine 
aminotransferase (ALT) ≤5×ULN
12. Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within normal limits.
(control by thyroid replacement therapy is acceptable.)  As of Amendment 03, subjects with 
T3, free T3 or free T4 abnormalities at screening who are asymptomatic can be eligible.  
13. Males or females age ≥18 years at the time of informed consent  
14. Life expectancy of 12 weeks or more
15. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol
16. Expansion Part: Archival tumor tissue or a newly obtained biopsy must be available prior 
to the first dose of study drug for biomarker analysis.

Subjects without archival tumor tissue and with inaccessible tumors for biopsy 
specimens can be enrolled without a biopsy.

In case of submitting unstained cut slides, freshly cut slides should be submitted to the 
testing laboratory within 14 days from when the slides are cut.
Note: Collection of archival tumor tissue or a newly obtained biopsy prior to the first dose 
of study treatment will be optional in the patients who are not enrolled in Expansion cohort.
Exclusion Criteria
1.
Imaging findings for HCC corresponding to any of the following:

HCC with ≥50% liver occupation

Clear invasion into the bile duct

Portal vein invasion with Vp4
2.
Prior anticancer treatment within 28 days (or within 14 days in case of sorafenib) or any 
investigational agent within 28 days prior to the first dose of study drugs. All toxicities 
related to prior treatments must be resolved to Grade ≤1 (except alopecia and controlled 
stable cases).
Note: Refer to inclusion criteria regarding hypertension. 
3.
Any blood enhancing treatment (including blood transfusion, blood products, or agents that 
stimulate blood cell production, eg, granulocyte colony-stimulating factor [G-CSF]) within 
28 days prior to the first dose of study drugs
4.
Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
5.
Subjects must have recovered adequately from any complications from major surgery prior 
to starting therapy.
6.
Subjects having ≥2+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24-hour will be 


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ineligible.
7.
Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib
8.
New York Heart Association congestive heart failure of grade II or above, unstable angina, 
myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated 
with significant cardiovascular impairment within the past 6 months
9.
Prolongation of QTc (Fridericia formula) interval to >480 ms
10. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 
teaspoon) within 3 weeks prior to the first dose of study drug
11. Bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring 
therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with low molecular 
weight heparin is permitted. Antiplatelet agents are prohibited throughout the study.
12. Gastric or esophageal varices that require interventional treatment within 28 days prior to 
first dose of study drug are excluded. Prophylaxis with pharmacologic therapy (eg, 
nonselective beta-blocker) is permitted.
13. Surgical arterial-portal venous shunt or arterial-venous shunt
14. Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 
36 months
15. Active infection (any infection requiring systemic treatment). Hepatitis B or C [HBV/HCV] 
is allowed. 
16. In case of HBsAg (+) subjects: Antiviral therapy for HBV must be given for at least 3 
months prior to first dose of study drug, and HBV viral load must be less than 100 IU/mL 
prior to first dose of study drug.  

Subjects who are HBsAg (+) and on active HBV therapy with viral loads under
100 IU/mL should stay on the same therapy throughout study treatment. 

Subjects without HBV prophylaxis who are anti-HBcAb (+) and/or anti- HBsAb (+) but
negative for HBsAg and HBV DNA do not require prophylaxis  

Subjects with HBV prophylaxis who are anti-HBcAb (+) and/or anti- HBsAb (+) but
negative for HBsAg and HBV DNA should continue the prophylaxis.

In all the subjects above, they need monitoring with HBV DNA every 3 weeks during 
the study treatment.
17. Therapy for HCV must be completed at least 4 weeks prior to first dose of study drug in 
case of Hepatitis C subjects who are on active HCV treatment. Hepatitis C subjects who are 
untreated or uncured may also be enrolled.
18. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
19. Meningeal carcinomatosis
20. Subjects with CNS metastases are not eligible, unless they have completed local therapy (eg, 
whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the 
use of corticosteroids for this indication for at least 4 weeks before starting treatment in this 
study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 
4 weeks before starting study treatment.
21. Subject is known to be positive for Human Immunodeficiency Virus (HIV).


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22. History of clinically significant hepatic encephalopathy
23. Serious nonhealing wound, ulcer, or bone fracture
24. History of solid organ or hematologic transplant
25. Any subject who cannot be evaluated by either triphasic liver computed tomography (CT) or 
triphasic liver magnetic resonance imaging (MRI) because of allergy or other 
contraindication to both CT and MRI contrast agents
26. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical trial
27. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.  
The use of physiologic doses of corticosteroids (up to 10 mg/d of prednisone or equivalent) 
may be approved after consultation with the sponsor. The use of steroids in prophylaxis of 
allergic reaction by CT contrast agents will be allowed.
28. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (eg, thyroxine [T4], insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 
29. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis, 
or has a history of interstitial lung disease.  
30. Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted.
31. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or lenvatinib and/or any of their
excipients.
32. Any subjects with non-GI fistula.
33. Subjects who meet any of the following criteria will be excluded from this study:
1) Females who are breastfeeding or pregnant at Screening or Baseline (as documented by 
a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic 
gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-
hCG [or hCG]).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug. 
2) Females of childbearing potential* who:

do not agree to use a highly effective method of contraception for the entire 
study period and for 120 days after study drug discontinuation ie:
o
total abstinence (if it is their preferred and usual lifestyle) 
o
an intrauterine device (IUD) or hormone releasing system (IUS) 
o
a contraceptive implant
o
an oral contraceptive** (with additional barrier method) 
OR

do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the European Union (EU), it is permissible that if a highly effective 
method of contraception is not appropriate or acceptable to the subject, then the subject 
must agree to use a medically acceptable method of contraception, ie double barrier 
methods of contraception such as condom plus diaphragm or cervical/vault cap with 


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spermicide.
NOTES:
* All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically [ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing]
** Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 
weeks before dosing with study drug and for the duration of the study.
34. Male subjects who are partners of women of childbearing potential must use a condom + 
spermicide and their female partners if of childbearing potential must use a highly effective 
method of contraception (see methods described in Exclusion Criterion #32) beginning at 
least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, 
and for 120 days after the last dose of study drug, unless the male subjects are totally 
sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia 
or unless the female partners have been sterilized surgically or are otherwise proven sterile.
Study Treatments
Lenvatinib
Lenvatinib is provided as 4-mg capsule. Lenvatinib will be administered with water orally once a 
day (with or without food) in 21-day cycles at approximately the same time each day.  On Day 1 of 
each cycle, in case concomitantly administered, it will be administered approximately within 
1 hour after completion of pembrolizumab administration.
Pembrolizumab
Pembrolizumab will be provided as a sterile, preservative-free, white to off-white lyophilized 
powder in single-use vials.  Each vial is reconstituted and diluted for intravenous infusion.  Each 
2 mL of reconstituted solution contains 50 mg of pembrolizumab.  
Alternatively, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for IV infusion. Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution.  Each 1 mL of solution contains 25 mg of 
pembrolizumab. 
Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, Q3W 
(25 minutes to 40 minutes are acceptable).  The Pharmacy Manual contains specific instructions for 
the preparation of the pembrolizumab infusion and administration of infusion solution.  
Pembrolizumab will be administered for up to 2 years after C1D1 at the longest.  Subjects who stop 
study treatment after receiving 35 administrations of pembrolizumab for reasons other than 
progressive disease (PD) or intolerability, or subjects who attain a complete response (CR) and stop 
study treatment, may be eligible to receive a second course of treatment of up to 17 additional 
administrations of pembrolizumab (approximately 1 year).  
Study Treatment Dose Modification
1.
Cycle 1 (except for Expansion part)
a.
If DLT occurs:
Lenvatinib and infusion of pembrolizumab should be interrupted immediately. Treatment may be 
resumed in Cycle 2 of pembrolizumab (except for toxicity which requires permanent 
discontinuation according to the guidance) and at 1 lower dose level of lenvatinib if toxicity is 
resolved to Grade 0–1 (or tolerable Grade 2 for Hematologic Toxicities and Proteinuria in case of 


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lenvatinib treatment-related toxicity) or baseline and investigators decide to continue the study.  
b.
No DLT
Lenvatinib will be interrupted if judged to be clinically needed by investigators, and may be 
resumed at the same dose level at appropriate timing. 
2.
Cycle 2 and onward (and applies to Cycle 1 and onward of Expansion part)
Lenvatinib
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-pembrolizumab 
combination therapy-related toxicity will be in accordance with the dose reduction instructions 
shown in the tables below for this study, respectively.  
See Section 9.4.1.4 of the main protocol for supportive care guidelines, including the management 
of hypertension and proteinuria, for instructions before consulting the table below, as appropriate. 
Any dose reduction below 4 mg/day (4 mg every other day) must be discussed with the sponsor. 
Once the dose has been reduced, it cannot be increased at a later date. 
Starting dose of lenvatinib will be based on baseline BW as follows:

BW ≥60 kg — 12 mg QD. Study subjects will be orally administered lenvatinib as three 4-mg 
capsules

BW <60 kg — 8 mg QD. Study subjects will be orally administered lenvatinib as two 4-mg 
capsules
Dose adjustments for management of intolerable toxicities will be made according to the guidelines 
provided in the table below.
Lenvatinib Dose Reduction and Interruption Instructions
Dose reductions occur in succession based on the previous dose level (12, 8, and 4 mg/day, and 4 mg every other day 
[QOD]).  Any dose reduction below 4 mg every other day must be discussed with the sponsor.  Once the dose has been 
reduced, it cannot be increased at a later date.
Nonhematologic Toxicities
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatmentc
No change
Intolerable Grade 2c or Grade 3d,e,h
First occurrence
Interrupt until resolved to Grade 0-1 or baseline
Reduce lenvatinib by 1 dose level
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 or baseline
Reduce lenvatinib by 1 more dose 
level
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 or baseline
Discuss with sponsor
Grade 4g,h:  Discontinue Lenvatinib
Hematologic Toxicities and Proteinuria
Treatment-Related Toxicitya
Management
Dose Adjustment
Grade 1 or Grade 2e


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Continue treatmentc
No change
Grade 3e
First occurrence
Interrupt until resolved to Grade 0-2 or baseline
No change
Second occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 dose level
Third occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence f
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Fifth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Discuss with sponsor
Grade 4i
First occurrence
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 dose level
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 or baseline
Discuss with sponsor
Note:  Grading according to CTCAE v4.03.
AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMI = body mass index, γ-GTP 
= γ-glutamyltransferase, CTCAE v4.03 = Common Terminology Criteria for Adverse Events Version 4.03, Na = sodium, 
ULN = upper limit of normal, QD = once daily.
a:
An interruption of lenvatinib for more than 21 days (due to lenvatinib treatment-related toxicities) will require 
sponsor's approval before treatment can be resumed.  During treatment interruption, repeat AEs assessment at least 
every 7 days (until restarting administration). 
b:
Excluding alopecia. Initiate optimal medical management for nausea, vomiting, diarrhea, and/or hypothyroidism 
prior to any lenvatinib treatment, interruption, or dose reduction. For treatment-related hypertension, refer to 
Management of Hypertension (Section 9.4.1.4.1) for dose modification guidelines.
c:
Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and investigator.  If Grade 2 
toxicity is determined to be intolerable, the dose of study drug will be reduced with or without dose interruption.  
Interruption for Grade 3 toxicities is mandatory. 
d:
Obese subjects with weight loss do not need to return to baseline or Grade 1 weight loss to restart lenvatinib.  There 
should be no weight loss for at least 1 week, and subjects should be started at the lower dose and normal BMI should 
be used for future dose reductions. 
e:
Not applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of the 
investigator (eg, ALT, AST, γ-GTP values <10×ULN, and Na).  
f:
Not applicable for subjects who start at 8 mg QD.
g:
Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3. 
h:
For asymptomatic Grade ≥3 elevations of amylase and lipase, sponsor should be consulted to obtain permission to 
continue treatment.
i:
Only applicable to Hematologic Toxicities.  
Dose Reduction for Lenvatinib Treatment-Related 
Toxicity Initial Lenvatinib Dose (mg, QD)
Adjusted Dose To Be Administered (mg, QD)
Reduction 1
Reduction 2
Reduction 3
12
8
4
4a
8
4
4a
QD = once daily.


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a:
4 mg every other day [QOD]. Any dose reduction below 4 mg every other day must be discussed with the sponsor.  
General Guidelines for Holding Periods of Lenvatinib due to Procedures:
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 
2 days after, once there is evidence of adequate healing and no risk of bleeding.  
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the procedure and 
then restarted once there is clear wound healing and no risk of bleeding, but at least 1 week after 
the procedure. It is up to the investigator to determine if it is a major or minor procedure.  Usually 
a major procedure implies general anesthesia.
Pembrolizumab
AEs (both nonserious and 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 the table below regarding non-hepatic drug-related AEs or the 
following guidance for hepatic events of clinical interest.  See Section 9.4.1.5 for supportive care 
guidelines, including use of corticosteroids, and Guidance for Management of Hepatic Events of 
Clinical Interest below for dose modification and management of hepatic events of clinical 
interest. 


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Dose Interval Modification Guidelines for Non-Hepatic Drug-Related Adverse Events 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 
Pneumonitis 
Grade 2
Withhold 

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
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
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 and electrolytes should be 
substituted via IV infusion.
Recurrent Grade 3
Permanently 
discontinue at the 
first recurrence of 
Grade 3 colitis
Grade 4
Permanently 
discontinue
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
Withhold

Initiate insulin replacement 
therapy for participants with 
T1DM 

Administer anti-hyperglycemic in 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.


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associated with 
evidence of -cell 
failure
participants with hyperglycemia 
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
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. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 


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limited to:  
Guillain-Barré 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
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).  
See Table 5 for Infusion Reaction Treatment Guidelines in Section 9.4.1.5 for subjects who experience an infusion reaction associated with 
administration of pembrolizumab.


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Dosing interruptions are permitted in the case of medical/surgical events or for logistical reasons 
not related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, and/or 
holidays). Subjects should be placed back on study treatment within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the sponsor.  The reason for interruption should be 
documented in the subject's study record.
Guidance for Management of Hepatic Events of Clinical Interest
Hepatic events of clinical interest will include any of the following events. All of these events will 
require holding pembrolizumab treatment. All cases of retreatment and permanent discontinuation 
must be reported to the sponsor. Refer to Protocol for further details. 
a.
ALT:
i.
Among subjects with baseline ALT <2×ULN:  ALT ≥5×ULN
ii.
Among subjects with baseline ALT ≥2×ULN:  ALT >3× the Baseline level
iii.
ALT >500 U/L regardless of baseline level
b.
AST:
i.
Among subjects with baseline AST <2×ULN:  AST ≥5×ULN
ii.
Among subjects with baseline AST ≥2×ULN:  AST >3× the Baseline level
iii.
AST >500 U/L regardless of baseline level
c.
Total Bilirubin:
i.
Among subjects with baseline levels <1.5 mg/dL:  a value of >2.0 mg/dL
ii.
Among subjects with baseline levels that are ≥1.5 mg/dL:  a value ≥2× the baseline level 
iii.
Total bilirubin >3.0 mg/dL regardless of baseline level
d.
Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
i.
New onset ascites uncontrollable with diuretic
ii.
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)
iii.
Hepatic Encephalopathy
Note: See Immediate Assessment of Section 9.4.1.3.2.  
Permanent Discontinuation Criteria for Subjects With Non-overdose Hepatic Events of 
Clinical Interest
Pembrolizumab should also be permanently discontinued for: 

ALT >20×ULN

Child-Pugh (CP) score of ≥9 points

Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric varices)a

Hepatic Encephalopathya

Recurrence of a severe or life-threatening event, or of any of the laboratory abnormalities listed 
above, that are presumed to be immune-related.


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a: Pembrolizumab is not necessarily discontinued if it is judged by Investigator that the AE is not 
associated with pembrolizumab (eg, lenvatinib treatment-related toxicity) after discussion with 
sponsor. 
Other subjects may be eligible for treatment interruption (and potential re-start) of pembrolizumab 
after discussion with the sponsor.  
See Diagnosis and Management of Non-Overdose Hepatic Events of Clinical Interests of 
Section 9.4.1.3.2 for management details of hepatitis B flare, hepatitis C recurrence or flare, 
immune-related hepatitis, and other hepatic events of clinical interest.  
Duration of Study
Study duration for each subject is estimated to be:

Pretreatment Phase: 4 weeks

Treatment Phase: 3 weeks (1 cycle)

Extension Phase: Subjects will continue to receive study treatment until disease progression, 
development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the 
study.
Concomitant Drug/Therapy
Prohibited Concomitant Medications
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies this will be judged to represent evidence of disease progression, and 
continuation of the study medication and further participation in the study must be discussed and 
agreed upon with the sponsor.
Subjects are prohibited from receiving the following therapies during this study:

Anticancer therapies such as chemotherapy, tyrosine kinase inhibitors (TKIs), local therapy, 
antitumor interventions (surgical resection, thoracocentesis, etc.), or immunotherapy other than 
study drugs

Investigational agents other than lenvatinib and pembrolizumab

Radiation therapy
Note:  Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases 
without being considered progressive disease may be considered on an exceptional case by 
case basis after consultation with the sponsor.  

Live vaccines within 30 days prior to the first dose of study treatment and while participating 
in the study.  Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed. However, 
intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are not allowed.

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.
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies. The use 
of steroids in prophylaxis of allergic reaction by CT contrast agents will be allowed.

Antiplatelet agents, factor X inhibitors, and anticoagulants that require INR monitoring, such 
as warfarin. (Treatments that do not require INR monitoring, such as low molecular weight 


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heparin are permitted.)

No herbal supplements or alternative medicines are allowed during this study.
For subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication and 
further participation in the study must be discussed and agreed upon with the sponsor.  Subjects 
may receive other medications that the investigator deems to be medically necessary.  
The Exclusion Criteria describes other medications that are prohibited in this clinical study. See 
the related Exclusion Criteria regarding antiviral therapy for HBV and HCV.  
Assessments
Efficacy
Tumor assessments will be performed by the investigators using mRECIST for HCC (Lencioni
and Llovet, 2010). All scans for tumor assessments performed during the study should be archived 
in accordance with the standard local practice. The scans from subjects for DLT evaluation must 
be accessible in the event of a sponsor request to submit them for central review. For the
Expansion part, images acquired for tumor assessments will be sent to an imaging core laboratory 
(ICL) for archiving and potential independent analysis including RECIST 1.1 (Eisenhauer, et al.,
2009), and mRECIST for HCC. As of Amendment 03, images acquired for tumor assessments 
both in DLT evaluation part and Expansion part will be sent to an ICL for archiving and 
independent analysis.   
Tumor assessments will be carried out during the Pretreatment Phase and then every 6 weeks 
(±1 week counting from C1D1) until Week 24, then every 9 weeks (±1 week) during treatment 
cycles in the Extension Phase. The tumor assessment schedule should not be affected by 
interruptions in study treatment.  Historical standard of care scans that are performed with scanning 
parameters consistent with the requirements for this protocol within 28 days prior to dosing are 
acceptable. 
Screening tumor assessments using triphasic liver CT/MRI (optimized for pre-contrast, arterial, and 
portal venous phase), contrast-enhanced CT of the chest, and contrast-enhanced CT or MRI of 
abdomen, pelvis, and other areas of known disease plus suspected disease should be performed 
within 28 days prior to C1D1. 
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should be 
performed within 28 days prior to C1D1.  During the Treatment Phase and the Extension Phase, 
CT/MRI of the brain should be performed if clinically indicated.  The same methodology and scan 
acquisition techniques used at Screening should be used throughout the study to ensure 
comparability.
During the Treatment Phase and Extension Phase, tumor assessments of the chest, abdomen, pelvis, 
and other areas of known disease at Screening plus newly suspected disease should be performed 
every 6 weeks (±1 week, starting from the date of C1D1) until Week 24 and every 9 weeks 
thereafter, or sooner, if clinically indicated.  The same methodology (CT or MRI) and scan 
acquisition techniques including use and timing of IV contrast should be used as for the screening 
assessments.  Tumor assessment at the Off-Tx Visit is only necessary if more than 4 weeks have 
passed since the previous assessment (window for these assessments is within 1 week of the Off-Tx
Visit).
Subjects going off treatment without disease progression will also undergo tumor assessments per 
the Schedule of Procedures/Assessments until disease progression is documented or another 


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anticancer therapy is initiated.  
All subjects are required to undergo chest, abdomen, and pelvis imaging at baseline and at all 
follow-up time points.  Contrast-enhanced CT of the chest and contrast-enhanced CT or MRI of the 
abdomen, pelvis, and any other areas of disease, as clinically indicated, will be acquired at 
Screening and at all imaging time points.  Liver CT or MRI must be performed using triphasic 
scanning technique optimized to capture pre-contrast, arterial, and portal venous phase.  Contrast-
enhanced CT or MRI (pre-and post-gadolinium) of the brain will be acquired at Screening and as 
clinically indicated.  
Treatment decisions by the investigator will be based on mRECIST for HCC. If the time point
tumor assessment is progressive disease (PD) per mRECIST, the investigator will consider whether 
the subjects should discontinue from study treatment. The decision to continue study treatment 
after the initial progression per mRECIST is at the investigator’s discretion based on the clinical 
status of the subject. Subjects will be considered to discontinue study treatment upon evidence of 
further radiologic progression as judged by the investigator. However, subjects will be permitted 
to continue treatment beyond initial progression per mRECIST as long as the investigator judges
that the subject is clinically stable and still receiving clinical benefit and is tolerating study drug 
treatment. Clinically stable is defined by the following criteria:  

Absence of signs and symptoms (including worsening of laboratory values) indicating disease 
progression

No decline in ECOG-PS

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring 
urgent alternative medical intervention
The assessment of clinical benefit should take into account the potential efficacy benefit versus the 
safety risk of continuation of treatment. All decisions to continue treatment beyond initial 
progression determined by the investigator will need to be discussed with sponsor and documented 
in the study records.
In order for stable disease (SD) to be considered the best overall response (BOR), it must occur 
≥5 weeks following the first dose of study drug.
The first radiological assessment of tumor response status will be performed at Week 6 (±1 week), 
unless there is clinical indication warranting earlier radiologic imaging. Responses of (partial 
response [PR] or complete response [CR]) should be confirmed no less than 4 weeks after the 
initial response, but generally at the next scheduled tumor assessment time point.
Pharmacokinetic
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be measured, 
and serum ADA will also be measured.  
Pharmacodynamic/Pharmacogenomic
Blood and Tissue Biomarkers:  Blood samples for the development of exploratory predictive
biomarkers will be collected from consented subjects prior to the first dose of study drug, on 
Cycle 1/Day 15 (C1D15), and predose on Day 1 of subsequent cycles up to and including 
Cycle 18, and at the off-treatment assessment.  Subjects will provide an archival tumor tissue 
sample and/or a fresh biopsy of tumor before treatment for biomarker analyses (see the Inclusion 
Criteria). Biomarker discovery and/or validation will be performed to identify blood or tumor 
biomarkers that may be useful to predict subject response to lenvatinib and/or pembrolizumab, as 


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determined by evaluation of response-related and/or safety-related outcomes as well as for 
potential use in diagnostic development.  Blood serum samples from subjects receiving lenvatinib
and pembrolizumab may be analyzed using global proteomic methods, enzyme-linked 
immunosorbent assay (ELISA), multiplex bead-based immunoassay, or other assays/methods or
new technology.  In addition, biomarkers identified in other lenvatinib clinical studies may also be 
assessed in the biomarker samples collected from subjects enrolled in this study.  The decision to 
perform exploratory biomarker analysis may be based on the clinical outcome of this study and/or 
the signals observed in other clinical studies or other information available at that time.
Archived, formalin-fixed paraffin-embedded (FFPE) tissue or a newly obtained biopsy will be 
collected from all consented subjects for potential assessment of mutations and other genetic 
alterations or genes and/or proteins including PD-L1/PD-L2 status and other relevant biomarkers 
(eg, tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid [RNA] signature profiles, 
mutational load) which may be important in the development and progression of cancer as well as 
for potential use in diagnostic development. Appropriate technology/methodologies will be used 
based on the amount of tumor tissue available.
Optional fresh tumor biopsies will be collected from consented subjects to examine markers 
including markers of target engagement, relevant pharmacodynamic biomarkers, and potential 
markers of response.  
A blood plasma sample to isolate circulating cell free nucleic acids (cf-nucleic acids) and a whole 
blood sample for immune cell profiling will be collected from consented subjects prior to the first 
dose of study drug (C1D1), and then predose on C1D15 and Day 1 of subsequent cycles up to and 
including Cycle 18 and at the off-treatment assessment. Cf-nucleic acids isolated from plasma 
samples may be used to obtain circulating tumor DNA (ctDNA) and explore tumor genetic 
alterations such as mutations observed in archival tumor samples as well as those which develop 
during drug treatment. Genomic DNA extracted from blood samples may be used to confirm 
whether the DNA sequence variants observed in DNA extracted from tumor material are limited to 
the tumor and to assess the immune response.  
Data obtained will be used for research to assist in developing safer and more effective treatments 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject. The 
DNA will not be used to determine or predict risks for diseases that an individual subject does not 
currently have.  Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 
15 years to assist in any research scientific questions related to lenvatinib/pembrolizumab, cancer, 
and/or for potential diagnostic development. 
Data will be used to explore pharmacokinetics/pharmacodynamic (PK/PD) relationships for effects 
of lenvatinib in combination with pembrolizumab on ORR, other efficacy-related parameters 
including PFS and OS, AEs/dose reductions, and blood-borne and tumor biomarkers.  
Exploratory/graphical analyses will be conducted for PK/PD evaluations and may be followed by 
model-based analyses. PK/PD results will be provided in a separate report.
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Manual.
Safety
Safety assessments will consist of monitoring and recording all AEs and serious adverse events 
(SAEs), using Common Terminology Criteria for Adverse Events (CTCAE) v4.03; regular 
laboratory evaluation for hematology, blood chemistry, and urine values; regular performance of 
physical examinations, periodic measurement of vital signs, and electrocardiograms (ECGs); and 


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echocardiograms or multigated acquisition (MUGA) scans including left ventricular ejection 
fraction (LVEF).
Other Assessments
For the subjects in Expansion part added as of Protocol Amendment 03, assessments of HRQoL 
scores will be performed using the generic cancer HRQoL instrument (EORTC QLQ-C30), the 
HCC-specific module (EORTC QLQ-HCC18), and the generic HRQoL instrument, EQ 5D-5L.  
Subjects will be asked to complete each of the three questionnaires at the Baseline Visit, on Day 1 
of each subsequent cycle, and at the Off-Treatment Visit.  Validated translations of questionnaires 
will be used according to EORTC and FDA guidelines.
Bioanalytical Methods
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be measured 
by using validated methods.  Serum ADA will be detected by using validated methods.  
Statistical Methods
Study Endpoints
The following endpoints will be defined based on mRECIST and RECIST 1.1 except for OS.  
ORR is defined as the proportion of subjects who have BOR of CR or PR at the time of data 
cutoff.
DOR is defined as the time from the first documentation of CR or PR to the date of first 
documentation of disease progression or death (whichever occurs first).
PFS is defined as the time from the first study dose date to the date of first documentation of 
disease progression or death (whichever occurs first). 
TTP is defined as the time from the first study dose date to the date of first documentation of 
disease progression.
TTR is defined as the time from the date of first study dose to the date of first documentation of 
CR or PR.
DCR is defined as the proportion of subjects who have BOR of CR or PR or SD (minimum 
duration from C1D1 to SD ≥5 weeks).
CBR is defined as the proportion of subjects who have BOR of CR or PR or durable SD (duration 
of SD ≥23 weeks).
OS is measured from the start date of the Treatment Phase (date of first study dose) until date of 
death from any cause. Subjects who are lost to follow-up and the subjects who are alive at the date 
of data cutoff will be censored at the date the subject was last known alive or the cut-off date, 
whichever comes earlier.
As Exploratory Endpoints, HRQoL will be assessed using EORTC QLQ-C30 and the HCC-
specific supplemental questionnaire (HCC-18) for the subjects in Expansion part added as of 
Protocol Amendment 03. The generic EQ-5D-5L will be used for the expanded subjects added as 
of Protocol Amendment 03.
Analysis Sets
DLT Analysis Set will include all subjects (except for the Expansion part) who have completed 
Cycle 1 without major protocol deviation with at least 75% of study drug compliance and are
assessed for DLT, and subjects who have experienced DLT during Cycle 1.  This will be the 


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analysis set to determine tolerability.
Safety Analysis Set/Efficacy Analysis Set will include all subjects who received at least 1 dose of 
study drug.
PK Analysis Set will include all subjects who have received at least 1 dose of lenvatinib and 
pembrolizumab, and have evaluable concentration data.
Efficacy Analyses
Efficacy analyses will be based on the Efficacy Analysis Set. BOR will be summarized, and ORR
and their corresponding exact 2-sided 95% confidence interval (CI) will be calculated. DOR will 
also be summarized and plotted over time by Kaplan-Meier method. Likewise, PFS, OS, TTP and 
TTR will be analyzed as needed. If applicable, DCR, CBR and their corresponding exact 2-sided 
95% CI will also be calculated. If applicable, a waterfall plot will be presented for the percent 
changes from baseline in the sum of the diameters of target lesions at post-baseline nadir (ie,
maximum tumor shrinkage).
Data cutoff for the primary analysis will be done after all subjects in the Expansion part finish at 
least Cycle 8 assessment and have a tumor assessment for at least Week 24, or discontinue if before
Cycle 8.
Pharmacokinetic and/or Pharmacodynamic Analyses
Pharmacokinetic
The primary PK parameters of lenvatinib in the combination will be calculated using 
noncompartmental analysis and compared with historical data after a single dose using the PK 
analysis set. If warranted, additional analyses may be performed.  PK data for lenvatinib and 
pembrolizumab is planned to be analyzed using nonlinear mixed effects modeling.  Based on PK 
data obtained in this study and from other studies, a population PK analysis may be performed to 
characterize PK parameters to support the proposed dosing regimen.  PK data for lenvatinib and 
pembrolizumab may also be used to explore the exposure-response relationships for antitumor 
activity/efficacy as well as biomarkers and safety in the proposed subject population, if feasible. 
The results of these analyses, if performed, will be reported separately.  For serum ADA levels, a 
listing of results will be made.
Pharmacodynamic
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic and/or 
imaging biomarkers will be summarized using descriptive statistics. PK/PD relationships will be 
explored graphically and may be investigated by model-based analyses. Details of the analysis will 
be provided in a separate analysis plan. The results of these analyses, if performed, will be 
reported separately.
Tolerability/Safety Analyses
All tolerability analyses will be performed on the DLT Analysis Set. The number and percentage 
of subjects with DLT will be calculated. Safety analyses will be performed on the Safety Analysis
Set. The number (percentage) of subjects with treatment-emergent AEs (TEAEs) and treatment-
emergent SAEs will be summarized by system organ class (SOC) and preferred term (PT). 
Summary statistics will be presented for laboratory test values, vital signs, and 12-lead ECG 
parameters. If needed, the changes from baseline will also be summarized.


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Sample Size Rationale
A sample size of approximately 30 subjects (N=6 to 10 for DLT evaluation part and N=20 for 
Expansion part) will be enrolled in this study. This is not based on statistical power considerations. 
As of Amendment 03, Expansion part may be further expanded up to approximately 94 evaluable 
subjects.  For this expansion decision, 2 interim analyses will take place when 20 (6 subjects for 
DLT evaluation part plus 14 subjects for Expansion part) and 56 subjects (6 subjects for DLT 
evaluation part plus 50 subjects for Expansion part) have sufficient follow-up to be evaluated for 
response.  The decision to expand enrollment will be based on the results of 2 interim analyses, 
which will spend β = 0.012 and β = 0.024 at the first and second interim analyses, respectively.  
The decision to expand enrollment will be assessed by mRECIST based on investigator review. 
Based on an assumption of H0:  25% ORR and H1:  45% ORR, the 100-subject design with two 
futility analyses has approximately 96% statistical power at 2-sided α = 0.02 (that corresponds to 1-
sided α = 0.01). At the first interim analysis (N = 20), if there are more than 5 responses, then 
approximately 36 additional subjects will be enrolled.  At the second interim analysis (N = 56), if 
there are more than 16 responses, approximately 44 additional subjects will be enrolled.  If there 
are 5 or fewer responses at the first interim analysis (N=20) or 16 or fewer responses at the second 
interim analysis (N=56), the sponsor may decide whether to expand enrollment based on clinical 
outcome (eg, DOR).  


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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS.............................................................................14
3
TABLE OF CONTENTS.................................................................................................37
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................42
5
ETHICS............................................................................................................................47
5.1
Institutional Review Boards/Independent Ethics Committees ..............................47
5.2
Ethical Conduct of the Study.................................................................................48
5.3
Subject Information and Informed Consent...........................................................48
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................49
7
INTRODUCTION ...........................................................................................................49
7.1
Indication ...............................................................................................................49
7.1.1
Hepatocellular Carcinoma (HCC)................................................................49
7.1.2
Lenvatinib ....................................................................................................50
7.1.3
PD-1 Inhibitors and Pembrolizumab ...........................................................51
7.2
Combination of Lenvatinib Plus Pembrolizumab..................................................52
7.2.1
Nonclinical...................................................................................................52
7.2.2
Clinical Studies............................................................................................53
7.2.2.1
E7080-J081-202 (Phase 1/2 of Lenvatinib Monotherapy for HCC)....53
7.2.2.2
E7080-G000-304 (Phase 3 of Lenvatinib Monotherapy for HCC) .....54
7.2.2.3
E7080-A001-111 (Phase 1b/2 of Lenvatinib Plus Pembrolizumab 
for Selected Solid Tumors in US)........................................................54
7.2.2.4
E7080-J081-115 (Phase 1b of Lenvatinib Plus Pembrolizumab for 
Selected Solid Tumors in Japan)..........................................................55
7.3
Study Rationale......................................................................................................55
8
STUDY OBJECTIVES....................................................................................................58
8.1
Primary Objectives.................................................................................................58
8.2
Secondary Objectives.............................................................................................58
8.3
Exploratory Objectives ..........................................................................................58
9
INVESTIGATIONAL PLAN..........................................................................................59
9.1
Overall Study Design and Plan..............................................................................59
9.1.1
Pretreatment Phase.......................................................................................63
9.1.1.1
Screening Period..................................................................................63
9.1.1.2
Baseline Period ....................................................................................64
9.1.2
Treatment Phase...........................................................................................64
9.1.3
Extension Phase ...........................................................................................64


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9.1.3.1
Treatment Period..................................................................................64
9.1.3.2
Follow-Up Period.................................................................................64
9.1.4
Second Course Phase (Pembrolizumab Retreatment Period)......................65
9.2
Discussion of Study Design...................................................................................66
9.3
Selection of Study Population................................................................................66
9.3.1
Inclusion Criteria .........................................................................................66
9.3.2
Exclusion Criteria ........................................................................................68
9.3.3
Removal of Subjects From Therapy or Assessment....................................71
9.3.3.1
Discontinuation Criteria by Subject.....................................................72
9.4
Treatments..............................................................................................................72
9.4.1
Treatments Administered.............................................................................72
9.4.1.1
Lenvatinib ............................................................................................72
9.4.1.2
Pembrolizumab ....................................................................................73
9.4.1.3
Criteria for Interruption of Treatment, Dose Reduction, and 
Resumption of Treatment ....................................................................73
9.4.1.4
Supportive Care Guidelines for Lenvatinib.........................................87
9.4.1.5
Rescue Medications and Supportive Care for Pembrolizumab ...........90
9.4.2
Identity of Investigational Products.............................................................92
9.4.2.1
Chemical Name, Structural Formula of Lenvatinib.............................92
9.4.2.2
Information of Pembrolizumab............................................................93
9.4.2.3
Labeling for Study Drug......................................................................93
9.4.2.4
Storage Conditions...............................................................................93
9.4.3
Method of Assigning Subjects to Treatment Groups...................................93
9.4.4
Selection of Doses in the Study ...................................................................93
9.4.5
Selection and Timing of Dose for Each Subject..........................................94
9.4.6
Blinding........................................................................................................94
9.4.7
Prior and Concomitant Therapy...................................................................94
9.4.7.1
Drug–Drug Interactions .......................................................................95
9.4.7.2
Prohibited Concomitant Medications/Vaccinations ............................95
9.4.8
Treatment Compliance.................................................................................97
9.4.9
Drug Supplies and Accountability...............................................................97
9.5
Study Assessments.................................................................................................99
9.5.1
Assessments.................................................................................................99
9.5.1.1
Demography.........................................................................................99
9.5.1.2
Baseline Assessments ..........................................................................99
9.5.1.3
Efficacy Assessments.........................................................................100


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9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments...........................................................103
9.5.1.5
Safety Assessments............................................................................107
9.5.1.6
Other Assessments.............................................................................113
9.5.2
Schedule of Procedures/Assessments ........................................................114
9.5.2.1
Schedule of Procedures/Assessments ................................................114
9.5.2.2
Description of Procedures/Assessments Schedule.............................126
9.5.3
Appropriateness of Measurements.............................................................126
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated With Special Situations ...........................................................126
9.5.4.1
Reporting of Serious Adverse Events................................................126
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .....................................................................................127
9.5.4.3
Reporting of Events Associated with Special Situations...................127
9.5.4.4
Expedited Reporting ..........................................................................128
9.5.4.5
Breaking the Blind.............................................................................129
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................129
9.5.5
Completion/Discontinuation of Subjects...................................................129
9.5.6
Abuse or Diversion of Study Drug ............................................................129
9.5.7
Confirmation of Medical Care by Another Physician ...............................130
9.6
Data Quality Assurance .......................................................................................130
9.6.1
Data Collection ..........................................................................................130
9.6.2
Clinical Data Management ........................................................................130
9.7
Statistical Methods...............................................................................................130
9.7.1
Statistical and Analytical Plans..................................................................131
9.7.1.1
Study Endpoints.................................................................................131
9.7.1.2
Definitions of Analysis Sets...............................................................133
9.7.1.3
Subject Disposition............................................................................133
9.7.1.4
Demographic and Other Baseline Characteristics .............................133
9.7.1.5
Prior and Concomitant Therapy.........................................................133
9.7.1.6
Efficacy Analyses ..............................................................................134
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses.................................................................134
9.7.1.8
Tolerability/Safety Analyses..............................................................135
9.7.2
Determination of Sample Size ...................................................................137
9.7.3
Interim Analysis.........................................................................................138
9.7.4
Other Statistical/Analytical Issues .............................................................139


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9.7.5
Procedure for Revising the Statistical Analysis Plan.................................139
10
REFERENCE LIST .......................................................................................................140
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....146
11.1
Changes to the Protocol .......................................................................................146
11.2
Adherence to the Protocol....................................................................................146
11.3
Monitoring Procedures.........................................................................................146
11.4
Recording of Data................................................................................................147
11.5
Identification of Source Data...............................................................................147
11.6
Retention of Records............................................................................................148
11.7
Auditing Procedures and Inspection....................................................................148
11.8
Handling of Study Drug.......................................................................................148
11.9
Publication of Results ..........................................................................................149
11.10 Disclosure and Confidentiality ............................................................................149
11.11 Discontinuation of Study .....................................................................................149
11.12 Subject Insurance and Indemnity.........................................................................150
12
APPENDICES ...............................................................................................................151
LIST OF IN-TEXT TABLES
Table 1
Dose-Limiting Toxicities...........................................................................62
Table 2
Lenvatinib Dose Reduction and Interruption Instructions.........................75
Table 3
Dose Reduction for Lenvatinib Treatment-Related Toxicity ....................76
Table 4
Dose Interval Modification Guidelines for Non-Hepatic Drug-Related 
Adverse Events Associated With Pembrolizumab ....................................78
Table 5
Infusion Reaction Treatment Guidelines ...................................................91
Table 6
Blood Sampling Schedule for Pharmacokinetic Assessments.................103
Table 7
Blood Sampling Schedule for Anti-pembrolizumab Antibodies
(ADAs).....................................................................................................105
Table 8
Clinical Laboratory Tests.........................................................................111
Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, 
and Extension Phases...............................................................................115
Table 10
Schedule of Procedures/Assessments in the Second Course 
(Pembrolizumab Retreatment) Phase.......................................................123
Table 11
2-Sided 95% Confidence Interval for the ORR of 10% to 90% (20 
Subjects)...................................................................................................138
Table 12
Boundaries for the Decision to Expand Enrollment in the Expansion 
Part...........................................................................................................138


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LIST OF IN-TEXT FIGURES
Figure 1
Confirmation of the Tolerability................................................................61
Figure 2
Study Design..............................................................................................63
LIST OF APPENDICES
Appendix 1
American Association for the Study of Liver Diseases (AASLD) 
Criteria .....................................................................................................152
Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (mRECIST) ...153
Appendix 3
Barcelona Clinic Liver Cancer (BCLC) Staging System ........................156
Appendix 4
Child-Pugh Classification........................................................................157
Appendix 5
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 158
Appendix 6
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03.............................................................................................159
Appendix 7
New York Heart Association (NYHA) Cardiac Disease Classification..160
Appendix 8
Clinical Studies Evaluating Drug–Drug Interactions with Lenvatinib....161
Appendix 9
Tumor, Node, and Metastasis Staging of Hepatocellular Carcinoma......162
Appendix 10
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 164
Appendix 11
KEYTRUDA® Package Insert.................................................................167


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AASLD
American Association for the Study of Liver Diseases
ADA
anti-drug antibody
AE
adverse event
AFP
α-fetoprotein
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
AUC
area under the concentration-time curve
BCLC
Barcelona Clinic Liver Cancer
β-hCG
beta-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BOR
best overall response
BP
blood pressure 
BW
body weight
C#/D#
Cycle#/Day#
CA
competent authority
CBC
complete blood count
CBR
clinical benefit rate
cf-nucleic acid
cell free nucleic acid
CFR
Code of Federal Regulations
CI
confidence interval
CLIA
clinical laboratory improvement amendments
Cmax
maximum concentration
CP
Child-Pugh
CPMP
Committee for Proprietary Medicinal Products
CR
complete response
CRA
clinical research associate


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Abbreviation
Term
CRF
case report form
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events 
ctDNA
circulating tumor DNA
CV
curriculum vitae
CYP
cytochrome P450
Dbil
direct bilirubin
DCR
disease control rate
DKA
diabetic ketoacidosis
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
DVT
deep vein thrombosis
ECG
electrocardiogram
EDC
electronic data capture
ECOG
Eastern Cooperative Oncology Group
ELISA
enzyme-linked immunosorbent assay
EORTC
European Organisation for Research and Treatment of Cancer
EU
European Union
FDA
United States Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FGFR
fibroblast growth factor receptor
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
γ-GTP
gamma-glutamyltransferase
GI
gastrointestinal
hCG
human chorionic gonadotropin
HBcAb
hepatitis B core antibody
HBeAg
hepatitis B e antigen
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen


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Abbreviation
Term
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HIV Ab
human immunodeficiency virus antibody
HNSCC
squamous cell carcinoma of head and neck
HRQoL
Health Related Quality of Life
HU
Hounsfield Units
HUVEC
human umbilical vein endothelial cell
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
ICL
imaging core laboratory
IEC
independent ethics committee
IIR
independent imaging review
INR
international normalized ratio
irAE
immune-related adverse event
IRB
institutional review board
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
IxRS
interactive voice/web response system
KIT
a stem cell factor receptor
LC/MS/MS
liquid chromatography with tandem mass spectrometry
LLT
lower level term
LMWH
low-molecular-weight heparin
LN
lymph node
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mRECIST
modified RECIST
MRI
magnetic resonance imaging
MTD
maximum tolerated dose


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Abbreviation
Term
MUGA
multigated acquisition
NCI
National Cancer Institute
NE
not evaluable
NN
Non-CR/Non-PD
NSAIDs
nonsteroidal antiinflammatory drugs
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
Off-Tx
Off Treatment
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein 1
PDGFR
platelet-derived growth factor receptor
PD-L1 (or 2)
PD-1 ligand 1 (or 2)
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetics
PK/PD
pharmacokinetics/pharmacodynamic
PO
per os, orally
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PS
performance status
PT
preferred term
Q3W
every 3 weeks
QD
once daily
QOD
every other day
QT
time from the beginning of the QRS complex to the end of the T wave
QTc
QT interval corrected for heart rate
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RET
ret proto-oncogene
RNA
ribonucleic acid


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Abbreviation
Term
RP2D
recommended Phase 2 dose
RTK
receptor tyrosine kinase
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SI
Système International
SOC
system organ class
SOD
sum of diameter
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
SVR
sustained virological response
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
T4
thyroxine
TAM
tumor-associated macrophage
Tbil
total bilirubin
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TKI
tyrosine kinase inhibitor
tmax
time to maximum concentration
TNM
tumor-node-metastasis
TSH
thyroid stimulating hormone
TTP
time to progression
TTR
time to response
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
US
United States
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell
WHO DD
World Health Organization Drug Dictionary


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with International Council for
Harmonisation (ICH) E6 (Good Clinical Practice [GCP]), Section 3, and any local 
regulations.  Any protocol amendment or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval, except for changes involving only logistical or 
administrative aspects of the study (eg, change in Clinical Research Associate [CRA], change 
of telephone number).  Documentation of IRB/IEC compliance with the ICH E6 and any 
local regulations regarding constitution and review conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (or if regionally required, the head of the medical institution) with a copy to the 
sponsor before study start and the release of any study drug to the site by the sponsor or its 
designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  The end of the study will be the date of the last study visit for the last 
subject in the study.  It is estimated that the study duration will be 36 months. The sponsor 
should also provide the IRB/IEC with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.


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5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceuticals, Medical Devices and 
Other Therapeutic Products Act (Law No. 145, 1960) for studies conducted in Japan, in 
addition to Japan’s GCP

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All SUSARs will be reported, 
as required, to the Competent Authorities of all involved EU member states. 

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF before any 
study-specific procedures are performed.  No subject can enter the study before his/her 
informed consent has been obtained.


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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.  
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
For pharmacogenomic assessments, subjects will be asked to sign an additional consent for 
these assessments (see Section 9.5.1.4.2).
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 2 investigational sites in Japan for DLT evaluation part, and 
multiple centers in Japan, North America, and Europe in Expansion part.
The name and telephone and fax numbers of the sponsor’s responsible medical officer and 
other contact personnel at the sponsor and, if applicable, of the contract research 
organization(s) (CRO(s)) are listed in the Investigator Study File provided to each site.
7
INTRODUCTION
Study E7080-J081-116 is planned to evaluate the tolerability and safety of a combination of 
lenvatinib plus pembrolizumab in subjects with hepatocellular carcinoma (HCC). The 
primary objective is to confirm the tolerability and safety for the combination regimen. The 
tolerability and safety of lenvatinib 12 mg (Body Weight [BW] ≥60 kg) or 8 mg (BW 
<60 kg) once daily (QD) orally and pembrolizumab 200 mg every 3 weeks (Q3W)
intravenous (IV) will be evaluated in this study. As secondary objectives, the 
pharmacokinetic (PK) profile and the efficacy of the regimen will be assessed. As of 
Amendment 03, ORR and DOR in Expansion part by mRECIST and RECIST 1.1 based on 
IIR analysis are added in primary objective. 
7.1
Indication
7.1.1
Hepatocellular Carcinoma (HCC)
Liver cancer is the 6th most common cancer (782,000 new cases; 554,000 cases in men and 
228,000 cases in women) and the 2nd cause of cancer related death (745,000 cases) which 
accounted for 9.1% of all cancers in 2012 (Ferlay, et al, 2015). HCC represents more than 
90% of primary liver cancers and is a major global health problem. The majority of the HCC 
occur in Asia or Africa, however, the incidence has been rising in a number of low-rate areas 
including Europe and United States (EASL-EORTC Clinical Practice Guidelines, 2012).


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HCC is associated with chronic liver disease, in particular cirrhosis. Major causes of 
cirrhosis include hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver 
disease. Hepatitis B is the most frequent underlying cause of HCC, with an estimated 300 
million persons with chronic infection worldwide. Chronic HBV carriers have a 5- to 15-
fold increased risk of HCC compared with the general population (El-Serag and Rudolph, 
2007).  Chronic HCV infection is also a major risk factor for HCC.  The risk of HCC was 
increased 17-fold in one study of HCV-infected patients compared with HCV-negative 
controls (Donato, et al., 2002).
The prognosis for advanced HCC is very poor.  Although therapies including arterial infusion 
and radiation therapy have been tried, none has proven highly successful (Llovet, et al., 
2003). Sorafenib is the current standard of therapy for advanced HCC patients following 
clinical results from the 2 pivotal trials in Western and Asian patients (Llovet, et al., 2008;
Cheng, et al., 2009).  
7.1.2
Lenvatinib
Vascular endothelial growth factor receptor (VEGFR) is expressed in vascular endothelial 
cells, playing a vital role for physiological and pathological angiogenesis and lymphogenesis 
or in the malignant cells led by vascular endothelial growth factor (VEGF) ligand stimulation 
(Ellis and Hicklin, 2008; Ferrara, et al., 2003; Hattori, et al., 2002; Laakkonen, et al., 2007;
Tammela and Alitalo, 2010).  Fibroblast growth factor receptor (FGFR), platelet-derived 
growth factor receptor-α (PDGFRα), RET, and KIT are also known to be associated with 
angiogenesis, proliferation, or both (St Bernard, et al., 2005; Turner and Grose, 2010; Matsui, 
et al., 2004; Hirota, et al., 1998; Williams, 2002; Kondo, et al., 2006; Phay and Shah, 2010;
Gild, et al., 2011; Hirota, et al., 2003; Oseini and Roberts, 2009) and anticancer treatment 
may be improved if their receptor tyrosine kinases (RTKs) are inhibited simultaneously.
Lenvatinib mesilate was developed at Eisai Tsukuba Research Laboratories to explore agents 
that inhibit RTKs activities associated with tumor angiogenesis.  It is a multikinase inhibitor 
that exhibits potent inhibitory effects not only on VEGFR1 to VEGFR 3 at the level of 
inhibition constant Ki 1 nmol/L, but also on FGFR 1 to FGFR4 and KITs.
In preclinical studies, lenvatinib showed inhibitory activities dose-dependently in VEGFR2-
driven phosphorylation, tube formation and proliferation in human vascular endothelial cells 
(human umbilical vein endothelial cell – HUVEC) induced by VEGF.  In in vivo studies
where human cancer cells were transplanted in immune deficient mouse models, lenvatinib 
also demonstrated high anticancer effect in a wide variety of cancers. In addition, safety 
results in nonclinical studies showed lenvatinib to be well tolerated within the therapeutic 
range.
HCC stimulates the development of arterial vessels in the process of progression, and it also 
expresses high levels of VEGF (Yamaguchi, et al., 1998; Poon, et al., 2004). An 
angiogenesis inhibitor, therefore, which selectively inhibits VEGF receptors, could be a 
therapeutic agent that selectively treats HCC with little effect on background hepatic disease. 


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While lenvatinib is expected to induce tumor necrosis and suppression of progression by 
inhibiting angiogenesis and blocking blood flow in HCC with high expression of VEGF, an 
additional incremental benefit (compared with conventional anticancer agents) is that 
lenvatinib may have the potential for lower levels of toxicity in patients with HCC who have 
chronic hepatic disease.  Because it selectively affects blood vessels, lenvatinib may also be
less likely to induce resistance after long-term treatment since endothelial cells are unlikely 
to become resistant.  
Lenvatinib is currently being evaluated in several clinical trials including patients with HCC, 
renal cell carcinoma, non-small cell lung cancer (NSCLC), endometrial cancer, glioma, 
melanoma, and ovarian cancer. 
Use of lenvatinib 24 mg QD for the treatment of differentiated thyroid cancer has been 
approved by United States (US) FDA, European Union (EU) and Japan regulatory agencies.  
In addition, the once daily combination of 18 mg lenvatinib and 5 mg everolimus for patients 
with advanced renal cell carcinoma following 1 prior anti-angiogenic therapy was approved 
by the US FDA, and approved by EU for advanced renal cell carcinoma following one prior 
VEGF targeted therapy.  
Concerning HCC, a Phase 1/2 study (E7080-J081-202) has been conducted, which showed 
clinical activity of lenvatinib monotherapy in patients with advanced HCC.  Based on review 
of the safety and pharmacokinetic data derived from this Phase 1/2 study, lenvatinib 12 mg 
(BW ≥60 kg) or 8 mg (BW <60 kg) QD orally was established for Phase 3 study of 
lenvatinib monotherapy in patient with unresectable HCC (E7080-G000-304) (see 
Section 7.2.2.1 and 7.2.2.2).
7.1.3
PD-1 Inhibitors and Pembrolizumab
Antitumor immunity is often ineffective due to the tight regulation associated with the 
maintenance of immune homeostasis (Stagg and Allard, 2013). Recent studies have shown 
that cancer cells, as well as stromal cells and immune cells in the cancer microenvironment 
can upregulate expression of the B7 family of inhibitory molecules.  These are peripheral 
membrane proteins found on activated antigen presenting cells (Coico, et al., 2003). 
Compelling evidence indicates that B7 proteins can suppress T-cell responses (Chen, 2004;
Sharpe and Freeman, 2002) aiding tumor immune evasion.  These negative signals are 
largely provided by 2 members of the B7-family.  One of these is programmed cell death 
protein 1 (PD-1, also known as B7-H1). PD-1 limits T cell effector functions within tissues
by negatively regulating antitumor CD8 T cell responses.  By upregulating ligands for PD-1, 
tumor cells block antitumor immune responses in the tumour microenvironment. Indeed, 
expression of the PD-1 ligand, programmed cell death protein 1 ligand (PD-L1), has been 
shown to be associated with poor prognosis in melanoma and hepatocellular carcinoma 
(Gadiot, et al., 2011; Gao, et al., 2009; Topalian, et al., 2012).
Clinically, blockade of PD-1 or PD-L1, using monoclonal antibodies, has demonstrated 
substantial clinical activity in patients with metastatic melanoma, renal cell carcinoma, 


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NSCLC, bladder, head and neck cancers (HNSCC), and other tumors (Brahmer, et al., 2012;
Hamid and Carvajal, 2013; Philips and Atkins, 2015; Robert, et al., 2014; Motzer, et al., 
2015).
HCC is reported to be typically inflammation-associated and can be immunogenic (Hato, et
al., 2014). Infection with HBV and HCV is associated with up-regulation of PD-1 (Xu, et al., 
2014; Barathan, et al., 2015) and upregulation of circulating PD-L1/PD-1 is associated with 
poor prognosis in patients with HBV-related HCC (Zeng, et al., 2011). Concerning HCC, 
recently it was also reported that nivolumab (fully human IgG4 PD-1 antibody) showed anti-
cancer effects in the interim data of phase 1/2 trial (El-Khoueiry, et al., 2015). Therefore, it 
is expected that PD-1 blockade with pembrolizumab, another anti-PD-1 antibody with similar 
efficacy and toxicity as nivolumab, may improve clinical outcomes in HCC patients as well.
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  For more details on specific indications refer to the 
Investigator brochure.
Concerning HCC, studies of Phase 2 (MK-3475-224/KEYNOTE-224) and Phase 3 (MK-
3475-240/KEYNOTE-240) of pembrolizumab 200 mg Q3W for previously systemically 
treated advanced HCC are on-going. (Clinicaltrials.gov; KEYNOTE-224, KEYNOTE-240)
7.2
Combination of Lenvatinib Plus Pembrolizumab
7.2.1
Nonclinical
It is reported that VEGF/VEGFR signaling exhibits proangiogenic properties but also may
contribute to an immunosuppressive microenvironment (Gabrilovich, et al., 1996; Huang, et 
al., 2007; Terme, et al., 2013; Voron, et al, 2015).  Therefore, it is expected that lenvatinib 
which inhibits VEGFR, may also have immune modulating activity.
The effect of combining lenvatinib with PD-1/L1 (programmed death, ligand 1) monoclonal 
antibodies (mAbs) has been investigated in the CT26 murine colorectal cancer syngeneic 
model (PD-L1 mAb) as well as the LL/2 murine lung cancer syngeneic model (PD-1 mAb).  
Combination treatment with lenvatinib and PD-1/L1 mAb was more effective than either 
compound alone. Tumor-associated macrophage (TAM) cells express PD-L1 at a higher 
level than cancer cells in the CT26 syngeneic model, and lenvatinib significantly decreased 
the TAM population (Kato and Matsui, 2015).  Because TAM cells produced interleukin 10 
(IL-10) and transforming growth factor, beta 1 (TGFβ) (Noy and Pollard, 2014), lenvatinib 


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might increase antitumor immunity in the CT26 model and up-regulate the effects of the PD-
1 signal inhibitors.  
Antitumor activity of combination treatment of lenvatinib with anti-PD-1 mAb was also 
examined in H22 murine hepatocellular carcinoma cell syngeneic model. The result showed 
that combination treatment with lenvatinib and PD-1 mAb was more effective than single-
agent treatment in this model (Kato, et al., 2016).
Thus, in addition to the direct anti-angiogenic effects of lenvatinib, the immune-modulating 
effect of lenvatinib may also result in potent combination effect with PD-1 signal inhibitors
in multiple syngeneic tumor models.  
7.2.2
Clinical Studies
7.2.2.1
E7080-J081-202 (Phase 1/2 of Lenvatinib Monotherapy for HCC)
A Phase 1/2 clinical study (E7080-J081-202) has been conducted in subjects with advanced 
HCC for which effective therapeutic methods have not been established.  This was a 
multicenter, open-label study of lenvatinib (8 to 16 mg QD for 4 weeks per cycle) consisting 
of a Dose Escalation Component (Phase 1 part) and an Expansion Component (Phase 2 part) 
in subjects with advanced HCC in Asia (Japan and Korea). Based on the results of Phase 1, 
the recommended dose for Phase 2 was determined to be 12 mg for HCC subjects with 
Child-Pugh A (CP-A, score 5–6).  A total of 46 subjects were enrolled in Phase 2 part.  
In the Phase 2 part, efficacy assessment based on the independent imaging review (N=46)
indicated that 17 (37.0%) subjects had PR by mRECIST for HCC. Nineteen (41.3%) 
subjects had SD (ie, lasting ≥7 weeks) with durable SD (ie, lasting ≥16 weeks) reported in 15
(32.6%) subjects.  Based on the independent imaging review, the median time to progression
(TTP) was 7.4 months. An overall survival (OS) analysis with a minimum follow-up period 
of 12 months indicated a median OS of 18.7 months.  
All the 46 subjects enrolled in Phase 2 part experienced at least 1 treatment-emergent adverse 
event (TEAE), and 44 subjects experienced treatment-related TEAEs. Twenty-two of 46 
subjects reported a serious TEAE, and in 14 subjects the serious TEAEs were considered 
treatment-related.  Grade 3 or above TEAEs were reported for 45 subjects and were 
considered treatment-related in 40 subjects. Sixteen subjects experienced AEs that led to 
discontinuation of study treatment, and 10 AEs were considered to be related to treatment 
medication.  Thirty-two subjects experienced treatment-related TEAEs that resulted in dose 
reduction and 20 subjects had treatment-related TEAEs that led to interruption of study drug 
administration.
Overall, the most common TEAEs (occurring in ≥30% of subjects overall) were hypertension 
(76.1%; 35/46 subjects), palmar-plantar erythrodysaesthesia syndrome (65.2%; 30/46 
subjects), decreased appetite, proteinuria (each in 60.9%; 28/46 subjects), fatigue (54.3%; 
25/46 subjects), diarrhoea (43.5%; 20/46 subjects), constipation (41.3%; 19/46 subjects), 


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nausea, dysphonia (each in 37.0%; 17/46 subjects), thrombocytopenia, oedema peripheral 
(each in 34.8%; 16/46 subjects), and weight decreased (30.4%; 14/46 subjects). The most 
frequently occurring Grade 3 or above TEAEs were hypertension (54.3%; 25/46 subjects), 
thrombocytopenia (21.7%; 10/46 subjects), proteinuria (19.6%; 9/46 subjects), platelet count 
decreased, hepatic encephalopathy, diarrhoea (each in 13.0%; 6/46 subjects), and palmar-
plantar erythrodysaesthesia syndrome (8.7%; 4/46 subjects).  Thrombocytopenia and cardiac 
tamponade were reported at Grade 4 (each in 2.2%; 1/46 subject).  
Although most AEs were controllable by dose interruption and dose reduction, 20 subjects 
had dose reduction within the first treatment cycle, and 17 of these subjects weighed less than 
60 kg. Subsequent analysis of the study results indicated a relationship between area under 
the concentration × time curve (AUC)/body weight (BW) and dose reduction/discontinuation 
within the first treatment cycle. In order to reduce the number of dose reductions and 
withdrawals due to AEs within the first treatment cycle, a weight-based dosing schedule has 
been established with 2 categories. The starting lenvatinib dose will be 12 mg administered 
orally QD in HCC subjects who weigh 60 kg or more, and the lenvatinib dose will be 8 mg 
administered orally QD in subjects who weigh less than 60 kg.
Based on the above analysis from the Phase 1/2 study, lenvatinib is expected to be a 
promising treatment for advanced HCC patients.  
7.2.2.2
E7080-G000-304 (Phase 3 of Lenvatinib Monotherapy for HCC)
E7080-G000-304 is a multicenter, randomized, open-label, Phase 3 trial designed to compare 
the safety and efficacy of lenvatinib versus sorafenib in subjects with Child-Pugh A, 
unresectable HCC.  The purpose of this study is to compare the OS of subjects with 
unresectable HCC treated with lenvatinib versus sorafenib.  Subjects were randomized 1:1 to 
receive either of the following treatment groups: “Lenvatinib group: 12 mg (BW ≥60 kg) or 
8 mg (BW <60 kg) QD” and “Sorafenib group: 400 mg twice daily (BID)”. This study was 
completed on 13 November 2016 (data cutoff for the primary analysis). According to the 
results of the study, lenvatinib met the statistical criteria for non-inferiority of OS compared 
to sorafenib, and showed statistically significant and clinically meaningful improvement for 
PFS, TTP and ORR.
7.2.2.3
E7080-A001-111 (Phase 1b/2 of Lenvatinib Plus Pembrolizumab for Selected 
Solid Tumors in US)
E7080-A001-111 is an open-label Phase 1b/2 study in subjects with selected solid tumors 
(NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial 
carcinoma, HNSCC or melanoma [excluding uveal melanoma]), which is being conducted in 
the US. 
In Phase 1b, subjects were to enroll in 1-3 dose levels to determine and confirm the 
maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of lenvatinib in 
combination with pembrolizumab.  The dose of pembrolizumab did not change during the 


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MTD phase, while lenvatinib started at 24 mg and then was reduced, if necessary, to either 
20 mg or 14 mg.  In the lenvatinib 24 mg cohort, 2 dose-limiting toxicities (DLTs) were 
observed in the first 3 subjects (2 renal cell carcinoma and 1 NSCLC): Grade 3 fatigue and 
Grade 3 arthralgia.  The dose was de-escalated to 20 mg QD lenvatinib and 10 additional 
subjects (total of 6 renal cell carcinoma, 1 NSCLC, 1 Melanoma and 2 Endometrial) started 
treatment. There were no DLTs in the 2nd cohort and the MTD and RP2D were determined
at 20 mg lenvatinib QD in combination with 200 mg Q3W of pembrolizumab.  
In Phase 2, subjects are assigned by tumor type to up to 6 cohorts (10 or 20 evaluable 
subjects per cohort) to receive the MTD to assess the safety and efficacy of the combination 
in the selected tumor-types.  This phase is ongoing.
7.2.2.4
E7080-J081-115 (Phase 1b of Lenvatinib Plus Pembrolizumab for Selected 
Solid Tumors in Japan)
Study E7080-J081-115 is being conducted for subjects with selected solid tumors in Japan.
Basically the design of this study will be the mirror of the Phase 1b part of E7080-A001-111 
conducted in US. The tolerability and safety of lenvatinib 20 mg QD and pembrolizumab 
200 mg Q3W IV, which was determined as MTD and RP2D in Study 111, will be confirmed 
in Japanese subjects in this Study 115. The primary objective is to confirm the tolerability 
and safety for combination regimen of lenvatinib plus pembrolizumab in subjects with 
selected solid tumors.  
7.3
Study Rationale
This multicenter, open-label Phase 1b study will evaluate the tolerability and safety of 
lenvatinib in combination with pembrolizumab in subjects with advanced/unresectable HCC. 
This study will begin with lenvatinib 12 mg (BW ≥60 kg) or 8 mg (BW <60 kg) QD and 
pembrolizumab 200 mg Q3W in subjects with HCC on a 21-day treatment cycle. For the 
confirmation of the tolerability of the dose level, DLTs will be evaluated during the first 
cycle (21 days). Treatment will continue until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or discontinuation of this study by the sponsor.  
HCC stimulates development of arterial vessels in the process of progression and it shows 
high expression of VEGF (Yamaguchi, et al., 1998; Poon, et al., 2004). Lenvatinib, an 
angiogenesis inhibitor which selectively inhibits VEGF receptors, could be a therapeutic 
agent that treats HCC with little effect on background hepatic disease. 
Likewise, HCC is reported to be typically inflammation-associated and can be immunogenic 
(Hato, et al., 2014). Infection with HBV and HCV is associated with up-regulation of PD-1 
(Xu, et al., 2014; Barathan, et al., 2015) and upregulation of circulating PD-L1/PD-1 is 
associated with poor prognosis in patients with HBV-related HCC (Zeng, et al., 2011). 
Clinically, it has been reported that an anti-PD-1 antibody showed anti-cancer effects
(El-Khoueiry, et al., 2015). Therefore, it is expected that PD-1 blockade with 
pembrolizumab may improve clinical outcomes in HCC patients.


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In preclinical studies, the effect of combining lenvatinib with PD-1/L1 mAbs has been 
investigated utilizing multiple kinds of cancer cells including an H22 murine hepatocellular 
carcinoma cell syngeneic model. In the model, the combination treatment with lenvatinib 
and PD-1 mAb showed superior antitumor effects compared with either compound alone.
Lenvatinib significantly decreased the TAM population and it was suggested that lenvatinib 
might increase antitumor immunity in the CT26 model and up-regulate the effect of the PD-1 
signal inhibitors (Kato and Matsui, 2015).
Therefore, the combination therapy of lenvatinib plus pembrolizumab might become a 
potential treatment for HCC.  
The starting dose of lenvatinib for the combination trial will be 12 mg (BW ≥60 kg) or 8 mg 
(BW <60 kg). These doses are based on the review of the safety and pharmacokinetic data 
derived from the Phase 1/2 study of lenvatinib in subjects with HCC (E7080-J081-202), 
which is adopted in the ongoing Phase 3 study of lenvatinib monotherapy in subjects with 
unresectable HCC (E7080-G000-304). While the recommended dose for the Phase 2 part
was determined to be 12 mg for HCC subjects with CP-A based on the results of Phase 1
part, in order to reduce the number of dose reductions and withdrawals due to AEs within the 
first treatment cycle, a weight-based dosing schedule has been established with the 2
categories of 12 mg QD (BW ≥60 kg) and 8 mg QD (BW <60 kg) (see Section 7.2.2.1). 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W, which is the 
recommended dose of pembrolizumab based on the well-established safety and efficacy 
profile in other solid tumors. 
In KEYNOTE-001, an open-label Phase I study was conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, and anti-tumor activity of single agent 
pembrolizumab. The dose escalation portion of this trial evaluated 3 dose levels, 1 mg/kg, 
3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts 
evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors. All 
dose levels were well tolerated and no dose-limiting toxicities were observed.  This first-in-
human study of pembrolizumab showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels. No maximum tolerated dose has been 
identified. In addition, 2 randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, and 1
randomized cohort evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
completed. The clinical efficacy and safety data demonstrate a lack of important differences 
in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures for 
200 mg Q3W are expected to lie within this range and will be close to those obtained with 
2 mg/kg Q3W dose.  


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A population PK model, which characterized the influence of BW and other patient 
covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a low clearance 
and a limited volume of distribution. The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure range established 
in melanoma as associated with maximal clinical response.  PK properties of pembrolizumab, 
and specifically the weight-dependency in clearance and volume of distribution are 
consistent with no meaningful advantage to weight-based dosing relative to fixed dosing.  
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested 
doses among tumor types.  Thus the 200 mg Q3W fixed-dose regimen is considered an 
appropriate fixed dose for other tumor indications as well.  
There has been no significant difference in tolerability and PK profile noted between 
Japanese and non-Japanese patients.
While the pembrolizumab 200 mg Q3W fixed-dose regimen is considered an appropriate 
fixed dose for other tumor indications as above, safety of single agent pembrolizumab in 
subjects with HCC is being investigated. The studies of Phase 2 (MK-3475-224/KEYNOTE-
224) and Phase 3 (MK-3475-240/KEYNOTE-240) for previously systemically treated 
advanced HCC are ongoing (Clinicaltraials.gov; KEYNOTE-224, KEYNOTE-240). 
Based on above, this study was considered scientifically rational and designed based on the 
previous findings to evaluate the tolerability, safety, and pharmacokinetics of lenvatinib plus 
pembrolizumab combination therapy.


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8
STUDY OBJECTIVES
8.1
Primary Objectives

To evaluate the tolerability and safety for combination of lenvatinib plus pembrolizumab 
in subjects with hepatocellular carcinoma (HCC)

(Expansion part) To evaluate objective response rate (ORR) and duration of response 
(DOR) by modified Response Evaluation Criteria in Solid Tumors for HCC (mRECIST) 
and RECIST 1.1 based on independent review (IIR)
8.2
Secondary Objectives

(DLT evaluation Part) To evaluate ORR and DOR by mRECIST (based on investigator 
review and IIR), and by RECIST1.1 based on IIR

(Expansion Part) To evaluate ORR and DOR by mRECIST based on investigator review

To evaluate the following efficacy endpoints by mRECIST (based on investigator review 
and IIR) and RECIST1.1 (based on IIR) :
-
Progression-free survival (PFS)
-
Time to progression (TTP)
-
Time to response (TTR)

Overall survival (OS)

To assess the pharmacokinetic (PK) profile of lenvatinib and pembrolizumab 

To detect anti-drug antibodies for pembrolizumab (ADA)
8.3
Exploratory Objectives

To evaluate the following efficacy endpoints by mRECIST (based on investigator review 
and IIR) and RECIST1.1 (based on IIR):
-
Disease control rate (DCR)
-
Clinical benefit rate (CBR)

To evaluate the impact of treatment on Health Related Quality of Life (HRQoL) for 
subjects treated using the European Organisation for Research and Treatment of Cancer 
(EORTC) QLQ-C30, HCC-specific EORTC QLQ-HCC18 questionnaire and European 
Quality of Life questionnaire.  
For the subjects in Expansion part added as of the protocol Amendment 03, HRQoL will 
be evaluated using the EORTC QLQ-C30 and the HCC specific supplement QLQ-
HCC18. HRQoL will also be evaluated using the generic EuroQuol five dimension five 
level (EQ-5D-5L) questionnaire.

To investigate the relationship between candidate biomarkers and anti-tumor activity of 
lenvatinib in combination with pembrolizumab:
-
To explore blood and tumor markers (such as PD-L1 expression levels, cytokine and 
angiogenic factor profiling), and immune cell profiling and evaluate their 


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relationship with clinical outcomes including anti-tumor activity of lenvatinib in 
combination with pembrolizumab
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is an open-label Phase 1b study.  This study will evaluate the tolerability and safety of 
lenvatinib in combination with pembrolizumab in subjects with HCC. 
This study will begin with lenvatinib 12 mg (Body Weight [BW] ≥60 kg) or 8 mg (BW 
<60 kg) /day orally and pembrolizumab 200 mg (every 3 weeks [Q3W], intravenous [IV]) in 
subjects with HCC. Tolerability of this dose level will be evaluated by dose-limiting 
toxicities (DLTs) during the first cycle (21-day treatment cycle). 
In this dose level, 3 subjects will be enrolled first.  If 0 or 1 of 3 subjects in a given dose level 
cohort experiences a DLT, then 3 more subjects will be enrolled into that dose level. If 0 or 
1 of 6 subjects in a given dose level cohort experiences a DLT, the dose level will be 
considered tolerable (Figure 1). Additional 4 subjects can be enrolled without DLT 
evaluation if further safety information is considered necessary based on the discussions 
between the sponsor and investigators.  
Enrollment will be interrupted if 2 or more DLTs are observed in this dose level, and after 
sponsor and investigators’ review, enrollment may continue for up to 6 subjects based on the 
nature and severity of the DLTs.  Once 6 subjects are enrolled, after sponsor and 
investigators’ review regarding the nature and severity of the DLTs, an additional 4 subjects 
(10 subjects in total for DLT evaluation) will be enrolled, and that dose level will be 
considered to be tolerable if DLT is observed in 3 or less of the 10 subjects in total (Figure 1).  
An independent medical advisor as third party may be consulted for the review as needed. 
In this dose level, at least 3 subjects treated with lenvatinib 12 mg once daily (QD) and 
pembrolizumab 200 mg Q3W IV (BW ≥60 kg) need to be included in the 6 subjects for DLT 
evaluation. (In case of the 10 subjects for DLT evaluation, at least 5 subjects (BW ≥60 kg)
treated with lenvatinib 12 mg QD and pembrolizumab 200 mg Q3W IV need to be included.)  
Cohort of reduction to lower dose level (lenvatinib) or study discontinuation will be 
considered, if this dose level (12 mg [BW ≥60 kg] or 8 mg [BW <60 kg] lenvatinib plus
200 mg pembrolizumab) is not tolerable, upon discussions between the sponsor and 
investigators, and the protocol will be amended as necessary (Figure 1). An independent 
medical advisor as third party maybe consulted for the consideration as needed. 
If there is a potential subject who is not evaluable for DLT (eg, subject who fails to 
administer ≥75% of the planned dosage of lenvatinib due to a reason other than treatment 
related toxicity during Cycle 1), the investigator and sponsor will discuss whether or not to 


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include the subject in the DLT Analysis Set. If subject is not evaluable for DLT then the 
subject will be replaced.  
For determination of the recommended phase 2 dose, all episodes of Grade 3 or 4 
thrombocytopenia and neutropenia beyond Cycle 1 will be taken into consideration.
If the dose level is confirmed to be tolerable, an additional (approximately) 20 subjects will 
be enrolled for consolidation of PK data and safety and efficacy as the Expansion part. As 
of Amendment 03, the Expansion part may be further expanded up to approximately 94 
subjects.  The decision to expand enrollment will be based on the results of 2 interim 
analyses that will take place when 20 (6 subjects for DLT evaluation part plus 14 subjects for 
Expansion part) and 56 subjects (6 subjects for DLT evaluation part plus 50 subjects for 
Expansion part) have sufficient follow-up to be evaluated for response.  The decision to 
expand enrollment will be assessed by mRECIST based on investigator review.  At the first 
interim analysis (N = 20), if there are more than 5 responses, then approximately 36
additional subjects will be enrolled. At the second interim analysis (N = 56), if there are more 
than 16 responses, approximately 44 additional subjects will be enrolled. If there are 5 or 
fewer responses at the first interim analysis (N = 20) or 16 or fewer responses at the second 
interim analysis (N=56), the sponsor may decide whether to expand enrollment based on 
other clinical outcome (eg, DOR). At least 5 subjects (BW ≥60 kg) treated with Lenvatinib 
12 mg QD and at least 5 subjects (BW <60 kg) treated with Lenvatinib 8 mg QD will be 
included in Expansion part.  


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Figure 1
Confirmation of the Tolerability
DLT = dose-limiting toxicity, IV = intravenous, PO = per os (orally), Q3W = every 3 weeks.  
a:  After sponsor and investigators’ review, enrollment may continue for up to 6 subjects based on the nature and severity of 
the DLTs.  
b:  After sponsor and investigators’ review regarding the nature and severity of the DLTs, an additional 4 subjects 
(10 subjects in total for DLT evaluation) will be enrolled.  
c:  Expansion part may be expanded to enroll up to approximately 94 evaluable subjects.
A DLT is defined as any of the following:

Any of the hematological or nonhematological toxicities noted in Table 1 considered to 
be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1

Failure to administer ≥75% of the planned dosage of lenvatinib as a result of treatment-
related toxicity during Cycle 1

Subjects who discontinue treatment due to treatment-related toxicity in Cycle 1

Greater than 2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-
related toxicity, even if the toxicity does not meet DLT criteria
Not tolerable upon discussions between 
the sponsor and investigators
Review by the sponsor and 
investigators
Additional
3 Subjects
≤1/6 DLT
Dose Level:  
12 mg lenvatinib (BW≥60 kg or 8 mg (BW<60 kg) (PO, daily)
+ 200 mg pembrolizumab (IV, Q3W)
≤1/3 DLT
≥2 DLTs
Additional
4 Subjectsb
≤3/10 DLTs
Enrollment
Up to 6 Subjectsa
Tolerable
First Enrolled 
3 Subjects
Lower dose level (lenvatinib) or study discontinuation 
will be considered.  
First Enrolled 
3 Subjects
Tolerable
Expansion 
Part
(N=94-c)
Expansion 
Part
(N=94 c)


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Table 1
Dose-Limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic

Grade 4 neutropenia for ≥7 days

Grade 3 or above febrile neutropeniaa

Grade 4 thrombocytopenia lasting ≥7 days
or 
Grade 3 thrombocytopenia associated with clinically significant hemorrhage 
or bleeding and/or requiring platelet transfusion
Nonhematologic 
toxicity

Grade 4 or Grade 5 toxicity

Grade 3 toxicities lasting >3 days excluding:

Nausea, vomiting, and diarrhea controlled by medical intervention within 
72 hours

Grade 3 rash in the absence of desquamation, no mucosal involvement, 
does not require steroids, and resolves to Grade 1 by the next scheduled 
dose of pembrolizumab.

Grade 3 hypertension not able to be controlled by medication 

Grade 3 gastrointestinal perforation

Grade 3 wound dehiscence requiring medical or surgical intervention

Grade 3 thromboembolic event
Any Grade 3 nonhematologic laboratory value (except AST/ALT) if:

Medical intervention is required to treat the subject, or the abnormality 
leads to hospitalization
Note: Abnormal laboratory values to which treatment and hospitalization is 
not required can be deemed a non-DLT

AST/ALT >10.0×ULN, which does not resolve within 1 week, or else is 
clinically symptomatic.
ANC = absolute neutrophil count, ALT = alanine aminotransferase, AST = aspartate aminotransferase, CTCAE = 
Common Terminology Criteria for Adverse Events v4.03, DLT = dose-limiting toxicity, ULN = upper limit of normal.  
a:
Febrile neutropenia Grade 3 or Grade 4:  
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of 
≥38 °C (100.4 °F) for more than 1 hour.
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of 
≥38 °C (100.4 °F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated.
Adverse events (AEs) with a clear alternative explanation (eg, due to disease progression) 
can be deemed a non-DLT.  
The study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase (Figure 2).  


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Figure 2
Study Design
BW = body weight, DLT = dose-limiting toxicity, IV = intravenous, Q3W = every 3 weeks.  
9.1.1
Pretreatment Phase
The Pretreatment Phase will last no longer than 28 days and will include a Screening Period 
and a Baseline Period.
9.1.1.1
Screening Period
Screening will occur between Day –28 and Day –3.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.  Tumor assessments performed up to 28 days 
prior to dosing are acceptable as screening tumor assessments if they are consistent with the 
requirements for this protocol.  
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable.
21 days per cycle
First dose
Pretreatment
Treatment
Extension
Screening
Informed consent
Enrollment
Baseline
≤28 days
≤3 days
Final dose
Off-Treatment Visit
Follow-up
Cycle 1
Treatment 
(Cycle 2, Cycle 3 & onward)
≤30 days
DLT observation
(except for Expansion part)
Administer lenvatinib 12 mg/day (BW≥60 kg) 
or 8 mg/day (BW<60 kg) orally and 
pembrolizumab 200 mg Q3W IV
Follow-up Visit
Every 12 weeks


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9.1.1.2
Baseline Period
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria.  Baseline assessments may be performed from Day –3 to Day –1 
or on Cycle 1/Day 1 (C1D1) prior to dosing.  
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase.  
9.1.2
Treatment Phase
The Treatment Phase consists of the first cycle (21 days) for each subject. The Treatment 
Phase for each subject ends after they complete Cycle 1 of treatment or if they discontinue 
early.  Those subjects who discontinue study treatment in Cycle 1 transition to the Off 
Treatment (Off-Tx) Visit of the Follow-up Period of the Extension Phase.  Those who
complete Cycle 1 transition to the Treatment Period of the Extension Phase.  
Subjects will be required to stay at the site during Cycle 1 in principle except for the 
Expansion part; however, they may be allowed to receive treatment as outpatient at the 
investigators’ discretion based on the safety of the subject.  
9.1.3
Extension Phase
The Extension Phase consists of 2 periods, the Treatment Period and the Follow-up Period.  
9.1.3.1
Treatment Period
Subjects still receiving study treatment at the end of the Treatment Phase will continue to 
receive the same study treatment in the Treatment Period of the Extension Phase. Subjects 
will continue to receive study treatment until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or sponsor termination of the study.  Those 
subjects who discontinue study treatment transition to the Off-Tx Visit of the Follow-up 
Period of the Extension Phase. 
9.1.3.2
Follow-Up Period
The Follow-up Period consists of the Off-Tx Visit and the Follow-up.

The Off-Tx Visit will occur within 30 days following the last dose of study treatment. 
Following the completion of the Off-Tx Visit, subjects will transition to the Follow-up. 

The Follow-up will continue as long as the study subject is alive unless the subject 
withdraws consent or until the sponsor terminates the study. In the Follow-up, subjects 
will be treated by the investigator according to the prevailing local standard of care. For 
survival and subsequent anticancer treatments, subjects will be followed every 12 weeks 
(±1 week) or at sponsor’s request. If a clinic visit is not feasible, follow-up information 
may be obtained via telephone or email. The survival follow-up will be continued for up 


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to 2 years after Cycle1/Day1 (C1D1) of the last subject enrolled in the Expansion part. 
The sponsor may decide to terminate survival follow-up anytime during the Extension 
Phase or when all subjects have discontinued study treatment.  
As required by some regulatory agencies, the following estimates are provided: 
- The study began in February 2017 and will end on or before February 2020.
- The maximum estimated period for the study is anticipated to be approximately 36 
months.  However, subjects will continue to receive study treatment as long as they 
demonstrate clinical benefit.  Refer to Section 9.3.3.1 Discontinuation Criteria by Subject 
for details.
9.1.4
Second Course Phase (Pembrolizumab Retreatment Period)
All subjects who stop treatment with lenvatinib plus pembrolizumab and have SD or better 
may be eligible to receive up to 1 additional year of treatment with pembrolizumab 
(17 cycles), with or without lenvatinib, if they develop PD after stopping study treatment 
during the initial treatment period.  This retreatment period is termed the Second Course 
Phase of this study and is only available if the study remains open and the subject meets the 
following conditions.
Either:

Stopped initial treatment with lenvatinib plus pembrolizumab after attaining an 
investigator-determined confirmed CR according to mRECIST
-
Was treated for at least 8 cycles with lenvatinib plus pembrolizumab before 
discontinuing therapy
-
Received at least 2 treatment cycles of lenvatinib plus pembrolizumab beyond the 
date when the initial CR was declared
Or:

Had SD, PR, or CR and stopped lenvatinib plus pembrolizumab treatment after 
completion of 35 administrations (approximately 2 years) of study treatment for 
reasons other than disease progression or intolerability
AND
All of the following:

Develops investigator-determined radiographic disease progression,  per mRECIST 
after stopping initial treatment with pembrolizumab

No new anticancer treatment was administered after the last dose of study treatment 


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
The subject meets all of the safety parameters listed in the inclusion criteria and none 
of the safety parameters listed in the exclusion criteria

The study is ongoing
The investigator should perform tumor assessments for all subjects who are retreated 
according to the local standard of care, but not less frequently than every 12 weeks (see 
Section 9.5.1.3.1 for details).  During the Second Course (Pembrolizumab Retreatment) 
Phase, scans will no longer be sent to the imaging core lab.  If the subject has an objective 
response or disease progression during retreatment, it will not be counted as an event for the 
primary analysis of PFS or ORR in this study.
Visit requirements for the Second Course Phase are outlined in Table 10 in Section 9.5.2.1.
9.2
Discussion of Study Design
This open-label Phase 1b study was designed to evaluate the tolerability and safety of 
lenvatinib in combination with pembrolizumab in subjects with HCC. The study design 
follows well-established designs for Phase 1b oncology studies, including ongoing studies 
featuring co-administration of oncology drugs with different mechanisms of action and PD-1 
inhibitors.  Subjects with HCC to be studied in this study have shown response to lenvatinib 
and/or a PD-1 inhibitor in other studies where the drug products were individually 
administered.  
9.3
Selection of Study Population
Approximately 30 subjects will be enrolled in Japan and US (N=6 to10 for DLT evaluation 
part and N=20 for Expansion part).  As of Amendment 03 the enrollment for Expansion part 
may be further expanded up to approximately 94 evaluable subjects. Subjects who do not 
meet all of the inclusion criteria or who meet any of the exclusion criteria will not be eligible 
to receive study drug.  
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:  
1. Subjects must have confirmed diagnosis of HCC with any of the following criteria:

Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, 
sarcomatoid or mixed cholangio-HCC tumors

Clinically confirmed diagnosis of HCC according to American Association for the 
Study of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology and/or 
chronic hepatitis B or C infection
2. HCC for which no other appropriate therapy is available


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Note:  Subjects basically should receive prior standard therapy including sorafenib.  
However, if the investigator judges the therapy is not appropriate for the 
subject, the prior standard therapy is not necessarily mandated for the 
eligibility.
Expansion Part: No prior systemic therapy for advanced/unresectable HCC
Note:  Subjects who have received local hepatic injection chemotherapy are eligible.
3. Subjects categorized to stage B (not applicable for transarterial chemoembolization 
[TACE]), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system
4. At least 1 measurable target lesion according to mRECIST meeting the following criteria.

Hepatic lesion
i.
The lesion can be accurately measured in at least 1 dimension as ≥1.0 cm (viable 
tumor for typical; and longest diameter for atypical), and
ii.
The lesion is suitable for repeat measurement

Nonhepatic lesion
i.
Lymph node (LN) lesion that measures at least 1 dimension ≥1.5 cm in the short 
axis, except for porta hepatis LN that measures ≥2.0 cm in the short axis
ii.
Non-nodal lesion that measures ≥1.0 cm in the longest diameter
Lesions previously treated with radiotherapy or locoregional therapy must show 
radiographic evidence of disease progression to be deemed a target lesion. Subjects 
whose only target lesion(s) is in bone will be excluded.
5. Child-Pugh score A
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 to 1
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive 
medications within 1 week prior to the C1D1
8. Adequate renal function defined as creatinine ≤1.5 times the upper limit of normal (ULN)
or calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with 
creatinine levels >1.5×ULN
9. Adequate bone marrow function: 

Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5×103/μL) 

Platelets ≥75,000/mm3 (≥75×109/L) 

Hemoglobin ≥8.5 g/dL
10. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤2.3
11. Adequate liver function, defined as:

Bilirubin ≤2.0 mg/dL

Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine 
aminotransferase (ALT) ≤5×ULN


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12. Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within normal limits
(control by thyroid replacement therapy is acceptable).  As of Amendment 03, subjects 
with T3, free T3, or free T4 abnormalities at screening who are asymptomatic can be 
eligible.
13. Males or females age ≥18 years at the time of informed consent  
14. Life expectancy of 12 weeks or more
15. Voluntary agreement to provide written informed consent and the willingness and ability 
to comply with all aspects of the protocol
16. Expansion Part: Archival tumor tissue or a newly obtained biopsy must be available 
prior to the first dose of study drug for biomarker analysis.

Patients without archival tumor tissue and with inaccessible tumors for biopsy 
specimens can be enrolled without a biopsy.

In case of submitting unstained cut slides, freshly cut slides should be submitted to 
the testing laboratory within 14 days from when the slides are cut.
Note: Collection of archival tumor tissue or a newly obtained biopsy prior to the first 
dose of study treatment will be optional in the patients who are not enrolled in Expansion 
cohort
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Imaging findings for HCC corresponding to any of the following:

HCC with ≥50% liver occupation

Clear invasion into the bile duct

Portal vein invasion with Vp4
2. Prior anticancer treatment within 28 days (or within 14 days in case of sorafenib) or any 
investigational agent within 28 days prior to the first dose of study drugs. All toxicities 
related to prior treatments must be resolved to Grade ≤1 (except alopecia and controlled 
stable cases).  
Note: Refer to inclusion criteria regarding hypertension. 
3. Any blood enhancing treatment (including blood transfusion, blood products, or agents 
that stimulate blood cell production, eg, granulocyte colony-stimulating factor [G-CSF]) 
within 28 days prior to the first dose of study drugs.
4. Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
5. Subjects must have recovered adequately from any complications from major surgery 
prior to starting therapy.
6. Subjects having ≥2+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24-hour will be 
ineligible.


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7. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib.
8. New York Heart Association congestive heart failure of grade II or above, unstable 
angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia 
associated with significant cardiovascular impairment within the past 6 months.
9. Prolongation of QTc (Fridericia formula) interval to >480 ms.
10. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 
teaspoon) within 3 weeks prior to the first dose of study drug.
11. Bleeding or thrombotic disorders or use of factor X inhibitors or anticoagulants requiring 
therapeutic INR monitoring, eg, warfarin or similar agents. Treatment with low 
molecular weight heparin is permitted. Antiplatelet agents are prohibited throughout the 
study.
12. Gastric or esophageal varices that require interventional treatment within 28 days prior to 
first dose of study drug are excluded. Prophylaxis with pharmacologic therapy (eg, 
nonselective beta-blocker) is permitted.
13. Surgical arterial-portal venous shunt or arterial-venous shunt.
14. Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past 
36 months.
15. Active infection (any infection requiring systemic treatment).  Hepatitis B or C 
[HBV/HCV] is allowed. 
16. In case of HBsAg (+) subjects: Antiviral therapy for HBV must be given for at least 3 
months prior to first dose of study drug, and HBV viral load must be less than 100 IU/mL 
prior to first dose of study drug.  

Subjects who are HBsAg (+) and on active HBV therapy with viral loads under
100 IU/mL should stay on the same therapy throughout study treatment. 

Subjects without HBV prophylaxis who are anti-HBcAb (+) and/or anti- HBsAb (+) 
but negative for HBsAg and HBV DNA do not require prophylaxis.  

Subjects with HBV prophylaxis who are anti-HBcAb (+) and/or anti- HBsAb (+) but
negative for HBsAg and HBV DNA should continue the prophylaxis.

In all the subjects above, they need monitoring with HBV DNA every 3 weeks during 
the study treatment.
17. Therapy for HCV must be completed at least 4 weeks prior to first dose of study drug in 
case of Hepatitis C subjects who are on active HCV treatment. Hepatitis C subjects who 
are untreated or uncured may also be enrolled.
18. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab(+) and detectable HCV RNA) at study entry.
19. Meningeal carcinomatosis.
20. Subjects with CNS metastases are not eligible, unless they have completed local therapy 
(eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have 


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discontinued the use of corticosteroids for this indication for at least 4 weeks before 
starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain 
metastases must be stable for at least 4 weeks before starting study treatment.
21. Subject is known to be positive for Human Immunodeficiency Virus (HIV).
22. History of clinically significant hepatic encephalopathy.
23. Serious nonhealing wound, ulcer, or bone fracture.
24. History of solid organ or hematologic transplant.
25. Any subject who cannot be evaluated by either triphasic liver computed tomography (CT)
or triphasic liver magnetic resonance imaging (MRI) because of allergy or other 
contraindication to both CT and MRI contrast agents.
26. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical trial.
27. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment.  The use of physiologic doses of corticosteroids (up to 10 mg/d of prednisone 
or equivalent) may be approved after consultation with the sponsor. The use of steroids 
in prophylaxis of allergic reaction by CT contrast agents will be allowed.
28. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine [T4], insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment. 
29. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis, or has a history of interstitial lung disease.  
30. Has received a live-virus vaccination within 30 days of planned treatment start. 
Seasonal flu vaccines that do not contain live virus are permitted. 
31. Has severe hypersensitivity (≥Grade 3) to pembrolizumab or lenvatinib and/or any of 
their excipients.
32. Any subjects with non-GI fistula.  
33. Subjects who meet any of the following criteria will be excluded from this study:
1) Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic 
gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of 
ß-hCG [or hCG]).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug. 
2) Females of childbearing potential* who:

do not agree to use a highly effective method of contraception for the entire 
study period and for 120 days after study drug discontinuation ie:
o
total abstinence (if it is their preferred and usual lifestyle) 


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o
an intrauterine device (IUD) or hormone releasing system (IUS) 
o
a contraceptive implant
o
an oral contraceptive** (with additional barrier method) 
OR

do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the European Union (EU), it is permissible that if a highly 
effective method of contraception is not appropriate or acceptable to the subject, then 
the subject must agree to use a medically acceptable method of contraception, ie 
double barrier methods of contraception such as condom plus diaphragm or 
cervical/vault cap with spermicide.
NOTES:
* All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [ie, bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing].
** Must be on a stable dose of the same oral hormonal contraceptive product for at 
least 4 weeks before dosing with study drug and for the duration of the study.
34. Male subjects who are partners of women of childbearing potential must use a condom + 
spermicide and their female partners if of childbearing potential must use a highly 
effective method of contraception (see methods described in Exclusion Criterion #32) 
beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire 
study period, and for 120 days after the last dose of study drug, unless the male subjects 
are totally sexually abstinent or have undergone a successful vasectomy with confirmed 
azoospermia or unless the female partners have been sterilized surgically or are otherwise 
proven sterile.  
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.   
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-up Period and complete protocol-specified off-
treatment visits, procedures, and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, the 
date will be documented in the source documents.  The Discontinuation From Treatment 
CRF page will be completed indicating the primary reason for discontinuation from 


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treatment.  In addition, the date of last dose of study drug(s) will be recorded on the Study 
Drug Dosing CRF page.
During the Follow-up Period, subjects who have discontinued study treatment without 
progression should have disease assessments until disease progression is documented or 
another anticancer therapy is initiated. The investigator will discontinue the study of the 
subject in the event of the sponsor request to discontinue the study for medical reasons or any 
other reason (see Section 11.11).  
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to halt survival follow-up after completion of the primary 
study analysis.  The survival follow-up will be continued for up to 2 years after C1D1 of the 
last subject enrolled in the Expansion part.  
9.3.3.1
Discontinuation Criteria by Subject
If a subject meets any of the following criteria, the investigator will discontinue treating a 
subject with study treatment or withdraw the subject from the study.  
1. Evidence of disease progression or emergence of new lesion(s).  (Treatment decisions by 
the investigator will be based on mRECIST.) If progressive disease (PD) is confirmed 
and the subject is experiencing extraordinary clinical benefit, site must contact sponsor to 
discuss continuing treatment (see Section 9.5.1.3).
2. Withdrawal of consent by subject
3. Presence of adverse event that prohibits continuation with therapy
4. Pregnancy
5. Subject is determined to be non-compliant with the protocol and ineligible in view of 
safety issue.
6. Study discontinuation is appropriate judged by the investigator or subinvestigator.
7. Subject is found to be ineligible after the enrollment.
9.4
Treatments
9.4.1
Treatments Administered
9.4.1.1
Lenvatinib
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  On Day 1 of each cycle, in case 
concomitantly administered, it will be administered approximately within 1 hour after 
completion of pembrolizumab administration.


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9.4.1.2
Pembrolizumab
Pembrolizumab (200 mg) will be administered as a 30-minute IV infusion, Q3W (infusions 
lasting between 25 minutes to 40 minutes are acceptable).  The Pharmacy Manual contains 
specific instructions for the preparation of the pembrolizumab infusion and administration of 
infusion solution.  
Pembrolizumab will be administered for up to 2 years after C1D1 at the longest. Subjects 
who stop study treatment after receiving 35 administrations of pembrolizumab for reasons 
other than progressive disease (PD) or intolerability, or subjects who attain a complete 
response (CR) and stop study treatment, may be eligible to receive a second course of 
treatment of up to 17 additional administrations of pembrolizumab (approximately 1 year).  
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
Study treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle (except for Cycle 2 in the subjects of DLT evaluation part) 
due to administrative reasons.  Study treatment with pembrolizumab of Cycle 3 should be 
skipped if pembrolizumab is administered on Day 4 or later in Cycle 2 due to treatment-
related toxicity or any other reason in the subjects of DLT evaluation part. 
9.4.1.3
Criteria for Interruption of Treatment, Dose Reduction, and Resumption of 
Treatment
9.4.1.3.1
CYCLE 1 (EXCEPT FOR EXPANSION PART)
Dose Modification in the Event of DLT
Lenvatinib and infusion of pembrolizumab should be interrupted immediately. Treatment 
may be resumed in Cycle 2 of pembrolizumab (except for toxicity which requires permanent 
discontinuation according to the guidance) and at 1 lower dose level of lenvatinib if toxicity 
is resolved to Grade 0–1 (or tolerable Grade 2 for Hematologic Toxicities and Proteinuria in 
case of lenvatinib treatment-related toxicity) or baseline and investigators decides to continue 
the study.  
Dose Modification in the Event of No DLT
Lenvatinib will be interrupted if judged to be clinically needed by investigators, and may be 
resumed at the same dose level at appropriate timing. 


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9.4.1.3.2
CYCLE 2 AND ONWARD (AND APPLIES TO CYCLE 1 AND ONWARD OF EXPANSION 
PART)
Lenvatinib
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-
pembrolizumab combination therapy-related toxicity will be in accordance with the 
guidelines provided in Table 2 and Table 3, respectively, for this study.  
For management of hypertension and proteinuria, refer to the main protocol text for 
instructions before consulting the table below, as appropriate. See Table 3 for dose 
reductions.  Any dose reduction below 4 mg/day (4 mg every other day) must be discussed 
with the sponsor. Once the dose has been reduced, it cannot be increased at a later date. 
Starting dose of lenvatinib will be based on baseline BW as follows:

BW ≥60 kg — 12 mg QD. Study subjects will be orally administered lenvatinib as three 
4-mg capsules

BW <60 kg — 8 mg QD. Study subjects will be orally administered lenvatinib as two 4-
mg capsules
Dose adjustments for management of intolerable toxicities will be made according to the 
guidelines provided in the table below.


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Table 2
Lenvatinib Dose Reduction and Interruption Instructions
Dose reductions occur in succession based on the previous dose level (12, 8, and 4 mg/day, and 4 mg 
every other day [QOD]).  Any dose reduction below 4 mg every other day must be discussed with the 
sponsor.  Once the dose has been reduced, it cannot be increased at a later date.
Nonhematologic Toxicities
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatmentc
No change
Intolerable Grade 2c and Grade 3d,e,h
First occurrence
Interrupt until resolved to Grade 0-1 
or baseline
Reduce lenvatinib by 1 dose level
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
Reduce lenvatinib by 1 more dose 
level
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
Discuss with sponsor
Grade 4g,h:  Discontinue Lenvatinib
Hematologic Toxicities and Proteinuria
Treatment-Related Toxicitya
Management
Dose Adjustment
Grade 1 or Grade 2e
Continue treatmentc
No change
Grade 3e
First occurrence
Interrupt until resolved to Grade 0-2 
or baseline
No change
Second occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Reduce lenvatinib by 1 dose level
Third occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence f
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Reduce lenvatinib by 1 more dose 
level
Fifth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Discuss with sponsor
Grade 4i
First occurrence
Interrupt until resolved to Grade 0-2 
or baseline
Reduce lenvatinib by 1 dose level
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2
or baseline
Reduce lenvatinib by 1 more dose 
level
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Discuss with sponsor
Note:  Grading according to CTCAE v4.03.
AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BMI = body mass index, γ-
GTP = γ-glutamyltransferase, CTCAE v4.03 = Common Terminology Criteria for Adverse Events Version 4.03, Na = 


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Table 2
Lenvatinib Dose Reduction and Interruption Instructions
sodium, ULN = upper limit of normal, QD = once daily.
a:
An interruption of lenvatinib for more than 21 days (due to lenvatinib treatment-related toxicities) will require 
sponsor's approval before treatment can be resumed.  During treatment interruption, repeat AEs assessment at 
least every 7 days (until restarting administration). 
b:
Excluding alopecia. Initiate optimal medical management for nausea, vomiting, diarrhea, and/or hypothyroidism 
prior to any lenvatinib treatment, interruption, or dose reduction. For treatment-related hypertension, refer to 
Management of Hypertension (Section 9.4.1.4.1) for dose modification guidelines.
c:
Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and investigator.  If 
Grade 2 toxicity is determined to be intolerable, the dose of study drug will be reduced with or without dose 
interruption.  Interruption for Grade 3 toxicities is mandatory. 
d:
Obese subjects with weight loss do not need to return to baseline or Grade 1 weight loss to restart lenvatinib.  
There should be no weight loss for at least 1 week, and subjects should be started at the lower dose and normal 
BMI should be used for future dose reductions. 
e:
Not applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of the 
investigator (eg, ALT, AST, γ-GTP values <10×ULN, and Na).  
f:
Not applicable for subjects who start at 8 mg QD.
g:
Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3. 
h:
For asymptomatic Grade ≥3 elevations of amylase and lipase, sponsor should be consulted to obtain permission 
to continue treatment.
i:
Only applicable to Hematologic Toxicities.
Table 3
Dose Reduction for Lenvatinib Treatment-Related Toxicity  
Initial Lenvatinib
Dose (mg, QD)
Adjusted Dose To Be Administered (mg, QD)
Reduction 1
Reduction 2
Reduction 3
12
8
4
4a
8
4
4a
QD = once daily.
a:
4 mg every other day [QOD]. Any dose reduction below 4 mg every other day must be discussed with the 
sponsor.  
General Guidelines for Holding Periods of Lenvatinib Due to Procedures:
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 
2 days after, once there is evidence of adequate healing and no risk of bleeding.  
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the 
procedure and then restarted once there is clear wound healing and no risk of bleeding, but at 
least 1 week after the procedure. It is up to the investigator to determine if it is a major or 
minor procedure.  Usually a major procedure implies general anesthesia.
Pembrolizumab
AEs (both nonserious and 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 4 below regarding non-hepatic drug-related 


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AEs or the following guidance for hepatic events of clinical interest.  See Section 9.4.1.5 for 
supportive care guidelines, including use of corticosteroids, and Guidance for Management 
of Hepatic Events of Clinical Interest of Section 9.4.1.3.2 for dose modification and 
management of hepatic events of clinical interest. 


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Table 4
Dose Interval Modification Guidelines for Non-Hepatic Drug-Related Adverse Events 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 
Pneumonitis 
Grade 2
Withhold 

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
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
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 and electrolytes should be 
substituted via IV infusion.
Recurrent Grade 3
Permanently 
discontinue at the 
first recurrence of 
Grade 3 colitis
Grade 4
Permanently 
discontinue


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Table 4
Dose Interval Modification Guidelines for Non-Hepatic Drug-Related Adverse Events 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 
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.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 

Monitor for signs and symptoms of thyroid 


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Table 4
Dose Interval Modification Guidelines for Non-Hepatic Drug-Related Adverse Events 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 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 


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Table 4
Dose Interval Modification Guidelines for Non-Hepatic Drug-Related Adverse Events 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 
limited to:  
Guillain-Barré 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
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).  
See Table 5 for Infusion Reaction Treatment Guidelines in Section 9.4.1.5 for subjects who experience an infusion reaction associated 
with administration of pembrolizumab.  


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Dosing interruptions are permitted in the case of medical/surgical events or for logistical 
reasons not related to study therapy (eg, elective surgery, unrelated medical events, subject 
vacation, and/or holidays).  Subjects should be placed back on study treatment within 
3 weeks of the scheduled interruption, unless otherwise discussed with the sponsor.  The 
reason for interruption should be documented in the subject's study record.  
Guidance for Management of Hepatic Events of Clinical Interest:  
Hepatic events of clinical interest will include any of the following events. All of these 
events will require holding pembrolizumab treatment. All cases of retreatment and 
permanent discontinuation must be reported to the sponsor. Refer to Sections 9.5.1.5.2 and
9.5.4.3.2 for further details. 
a.
ALT:
i.
Among subjects with baseline ALT <2×ULN:  ALT ≥5×ULN
ii.
Among subjects with baseline ALT ≥2×ULN:  ALT >3× the baseline level
iii.
ALT >500 U/L regardless of baseline level
b. AST:
i.
Among subjects with baseline AST <2×ULN:  AST ≥5×ULN
ii.
Among subjects with baseline AST ≥2×ULN:  AST >3× the baseline level
iii.
AST >500 U/L regardless of baseline level
c.
Total Bilirubin:
i.
Among subjects with baseline levels <1.5 mg/dL:  a value of >2.0 mg/dL
ii.
Among subjects with baseline levels that are ≥1.5 mg/dL:  a value ≥2× the Baseline
level 
iii.
Total bilirubin >3.0 mg/dL regardless of baseline level
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
i.
New onset ascites uncontrollable with diuretic
ii.
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or 
gastric varices) 
iii.
Hepatic Encephalopathy
Immediate Assessment
All subjects

All subjects should be evaluated according to directions below within 72 hours of alert 
for non-overdose events of clinical interest  

Procedures:
-
Consider a consultation with a hepatologist


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-
Obtain a work-up for hepatitis if there is no underlying hepatitis, including hepatitis A, 
B,C, D, E, Epstein-Barr virus, and cytomegalovirus
-
Assess for ingestion of drugs/supplements with hepatotoxic potential
-
Assess for alcohol ingestion
-
Assess for potential bacterial infection, biliary obstruction, or occult gastrointestinal 
bleeding
-
Repeat ALT, AST, Tbil, Dbil, ALP, γ-glutamyl transpeptidase, INR, and CBC with 
differential
-
Other laboratories or imaging studies as clinically indicated
-
Consider liver biopsy if indicated by hepatologist
Hepatitis C-infected Subjects (including subjects who previously achieved SVR 12)

In addition to the above, measure HCV RNA viral load
Hepatitis B-infected Subjects

HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe antibody, and anti-HBs 
antibody

Subjects should be questioned about compliance with the use of anti-viral agents.
Permanent Discontinuation Criteria for Subjects With Non-Overdose Hepatic Events of 
Clinical Interest:  
Pembrolizumab should also be permanently discontinued for: 

ALT >20×ULN

Child-Pugh (CP) score of ≥9 points

Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)a 

Hepatic Encephalopathya 

Recurrence of a severe or life-threatening event, or of any of the laboratory abnormalities 
listed above, that are presumed to be immune-related.
a: Pembrolizumab is not necessarily discontinued if it is judged by Investigator that the AE 
is not associated with pembrolizumab (eg, lenvatinib treatment-related toxicity) after 
discussion with sponsor
Other subjects may be eligible for treatment interruption (and potential re-start) of 
pembrolizumab after discussion with the sponsor.  
Diagnosis and Management of Non-Overdose Hepatic Events of Clinical Interests:  


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HCC subjects are at risk for a range of complications that can cause hepatic laboratory
abnormalities with or without clinical decompensation. Those with a history of chronic HCV 
or HBV infection also have the potential to experience virologic flares. The following 
section provides further guidance on the diagnosis and management of potential hepatic 
complications among HCC subjects.  
Hepatitis B Flare
Hepatitis B flares are characterized by rapid elevations of ALT and AST to >5×ULN and/or 
>3× baseline. ALT elevation to ≥10×ULN is common. In the absence of hepatic 
decompensation, ALT/AST elevations are typically isolated (ie, limited/no elevations of 
bilirubin/ALP). Subjects who are compliant with anti-viral therapy should have continued 
suppression of HBV DNA at the time of flare; thus, detection of HBV DNA should prompt 
questioning of subjects for compliance. Laboratory abnormalities secondary to flare are 
typically observed for 3-5 weeks.
Among subjects with HBV, a flare should be considered if this pattern is observed and there 
is no evidence of an alternative etiology. Guidelines for subjects with a diagnosis of HBV 
flare are as follows:  

Care should be instituted in consultation with a hepatologist.

For subjects who have detectable HBV DNA, re-institute anti-viral therapy.

If the subject is clinically stable, pembrolizumab dosing may be interrupted for up to 
12 weeks. Subjects should undergo weekly laboratory tests including: AST, ALT, ALP, 
Tbil, Dbil, INR, HBsAg, HBV DNA (if detected at the onset of the flare). Obtain anti-
HBe antibody, anti-HBs antibody, and HBV DNA levels (if not detected at the onset of 
the flare) every 2-3 weeks.  

If ALT returns to normal or Grade 1 (if normal at baseline), or to baseline grade (if Grade 
2 at baseline) within 12 weeks, and subjects are clinically stable, subjects may restart 
pembrolizumab treatment. If these conditions are not met, then pembrolizumab treatment 
should be permanently discontinued.  
Hepatitis C Recurrence or Flare
Subjects who achieved SVR 12 and subjects with ongoing HCV infection are eligible for 
enrollment. In rare circumstances, HCV subjects who achieve SVR 12 may relapse at later 
time points. Relapse is characterized by detection of HCV RNA, often accompanied by ALT 
elevations to >5×ULN. In the absence of hepatic decompensation, ALT/AST elevations are 
typically isolated (ie, limited/no elevations of bilirubin/ALP).  
Among subjects with uncontrolled hepatitis C, virologic flares are possible. Hepatitis C
flares are characterized by rapid elevations of ALT and AST to >5×ULN and/or >3× baseline 
along with a rise in HCV RNA. ALT elevation to ≥10×ULN and a 1 log elevation in HCV 
RNA level are common. In the absence of hepatic decompensation, ALT/AST elevations are 


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typically isolated (ie, limited/no elevations of bilirubin/ALP). Laboratory abnormalities 
secondary to flare or recurrence are typically observed for 3-5 weeks.  
Guidelines for subjects with recurrent HCV infection or an HCV flare are described below:  
Recurrent HCV infection
If the subject entered the study with an HCV RNA test of “Target not Detected” and has 
confirmed detectable HCV RNA (2 specimens, 1 week apart), then the subject has 
experienced a late HCV relapse or a recurrent infection.  

Question the subject about use of injection or inhalation drugs

At the time of first detection of HCV RNA, send a specimen for HCV genotyping

Measure AST, ALT, ALP, Tbil, Dbil, and INR weekly

Measure HCV RNA levels every 2 weeks

Please discuss risk-benefit with Sponsor prior to starting HCV anti-viral therapy.  
HCV Flare

At the time of first detection of HCV RNA, send a specimen for HCV genotyping

Measure AST, ALT, ALP, Tbil, Dbil, INR weekly

Measure HCV RNA levels every 2 weeks

Please discuss risk-benefit with Sponsor prior to starting HCV anti-viral therapy.
For both recurrent infection and HCV flare: if ALT returns to normal or Grade 1 (if normal at 
baseline), or to baseline grade (if Grade 2 at baseline) within 12 weeks, and the subjects are 
clinically stable, subjects may restart pembrolizumab treatment. If these conditions are not 
met, then pembrolizumab treatment should be permanently discontinued.  
Immune-related hepatitis
Description: Immune-related hepatitis due to pembrolizumab should be suspected if:

AST or ALT baseline values are less than 2×ULN, and AST or ALT laboratory values 
increase to ≥5×ULN

Among subjects with baseline ALT or AST ≥2×ULN, levels increase to >3× the baseline
level

AST/ALT >500 U/L regardless of baseline level

Among subjects with baseline Tbil levels <1.5 mg/dL: a value of >2.0 mg/dL

Among subjects with baseline Tbil levels that are ≥1.5 mg/dL: a value of ≥2× the 
baseline level, OR

Total bilirubin >3.0 mg/dL regardless of baseline level.


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Immune-related hepatitis is a diagnosis made after excluding other possible etiologies for the 
change. Viral flare (if applicable), biliary or vascular obstruction, infection, medications, and 
alcohol use must be ruled out (see below).  
Management

Interrupt pembrolizumab treatment and alert the sponsor as per events of clinical interest
criteria above for ALT, AST, bilirubin, and hepatic decompensation.

Start IV corticosteroid (methylprednisolone 125 mg) followed by oral corticosteroid (1-2 
mg/kg/day). Steroid taper should be started and continued for 28 days until symptoms 
improve to Grade 1 or less.

Monitor with biweekly laboratory tests including AST, ALT, Tbil, Dbil, ALP, and INR.

If symptoms and laboratory tests resolve to Grade ≤1 or baseline (if abnormal at baseline), 
taper steroids over 28 days. Pembrolizumab treatment may be restarted after steroid 
treatment has been tapered to prednisone ≤10 mg/day (or equivalent dose of another 
agent). Treatment and laboratory results must be reported on a CRF.  

If laboratory abnormalities do not resolve within 3 weeks, or steroids cannot be lowered 
to ≤10 mg/day (or prednisone equivalent) within 12 weeks, or subjects show evidence of 
decompensation to CP C status or have esophageal or variceal bleeding at any point, 
treatment must be permanently discontinued.  This must be reported on a CRF.  
Other Hepatic Events of Clinical Interest

Infection needs to be ruled out with cultures of blood, urine, and ascites (if possible), as 
well as chest x-ray and abdominal imaging if relevant. If an infection is found, 
antibiotics should be started.  

If Tbil is elevated above imaging should be obtained to rule out vascular compromise, 
biliary obstruction, and/or tumor progression. If biliary obstruction is present, 
consultation with a gastroenterologist and/or an interventional radiologist should be 
obtained to see if the obstruction may be relieved.  

A careful review of drugs, including herbal and alternative medications, should be 
obtained, and alcohol use should be ruled out. See Section 9.4.7.2.1 for drugs which may 
interfere with hepatic function.  

For all of these cases, subjects may resume pembrolizumab treatment if they are
clinically stable after appropriate therapy or discontinue the causative agent, as long as 
laboratory values have returned to Grade 1 or baseline (if normal or Grade 1 at start) or to 
baseline grade within 3 weeks.  Dose interruption of pembrolizumab is allowed up to 12 
weeks at most, and discussion with sponsor is needed before restarting pembrolizumab.

Treatment must be permanently discontinued if the subject is off pembrolizumab therapy 
for infection, obstruction, or drug/alcohol-related toxicity for more than 3 weeks, or if 
they have esophageal bleeding, or become CP C at any point.  


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9.4.1.4
Supportive Care Guidelines for Lenvatinib
9.4.1.4.1 MANAGEMENT OF HYPERTENSION
Regular assessment of BP should be conducted as detailed in the Schedule of 
Procedures/Assessments. CTCAE v4.03 grading for hypertension will be based on BP 
measurements only (and not on the number of antihypertensive medications).
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling.  
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mmHg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before C1D1.  Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.  
Per Amendment 03, if BP is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), 
BP measurement should be repeated at least 5 minutes apart.  One BP assessment is defined 
as the mean value of 2 measurements at least 5 minutes apart. Antihypertensive agents 
should be started as soon as elevated BP (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg) is confirmed on 2 assessments a minimum of 30 minutes apart.  The choice of 
antihypertensive treatment should be individualized to the subject’s clinical circumstances 
and follow standard medical practice.  For previously normotensive subjects, appropriate 
antihypertensive therapy should be started when systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg is first observed on 2 assessments a minimum of 30 minutes apart.  For those 
subjects already on antihypertensive medication, treatment modification may be necessary if 
hypertension persists.  For subjects with hypertension and proteinuria, appropriate therapy, 
eg, angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist, is 
preferred (Kilfoy, et al., 2009).  
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop 
a hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mmHg, significant risk factors for cardiac disease, 
intracerebral hemorrhage, or other significant co-morbidities).  Once the subject has been on 
the same antihypertensive medications for at least 48 hours and the BP is controlled, 
lenvatinib should be resumed as described below.
During the Treatment Phase and the Treatment Period in the Extension Phase, subjects with 
systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on 
Day 15 or more frequently as clinically indicated until systolic BP has been ≤150 mmHg and 
diastolic BP has been ≤95 mmHg for 3 consecutive months.  If a repeat event of systolic BP 
≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must resume the Day 15 
evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 
3 consecutive months.


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The following guidelines should be followed for the management of systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg confirmed on repeat measurements after at least 30 minutes:

Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving antihypertensive medication.

For those subjects already on antihypertensive medication, the dose of current agent may 
be increased, if appropriate, 1 or more agents of a different class of antihypertensive
should be used.

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 lower dose level as specified in Table 3 only when systolic BP ≤150 mmHg 
and diastolic BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):

Institute appropriate medical management.

Discontinue lenvatinib.
9.4.1.4.2 MANAGEMENT OF PROTEINURIA
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria are 
summarized as follows:

Grading according to CTCAE v4.03 will be based on the 24-hour urinary protein result if 
one has been obtained. Grade 3 proteinuria must be confirmed by 24-hour urine protein. 
Management of lenvatinib administration will be based on the grade of proteinuria 
according to the “Lenvatinib Dose Reduction and Interruption Instructions”.

A 24-hour urine collection initiated as soon as possible and at least within 72 hours or an
immediate spot urine protein-to-creatinine ratio [UPCR] test to verify the grade of 
proteinuria for protein quantitation is required in the following situations:
- The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on lenvatinib
- A subsequent increase in severity of urine dipstick proteinuria occurring on the same
  lenvatinib dose level
- When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is 3+ or 4+

A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.

Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 2 
weeks (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 2 consecutive treatment cycles.


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In the event of nephrotic syndrome, lenvatinib must be discontinued.
9.4.1.4.3 MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (eg, ALT, AST, bilirubin levels) should be 
conducted as detailed in the Schedule of Procedures/Assessments and as clinically indicated.  
If signs occur indicating a decrease in liver function by 1 grade or more from baseline, the 
instructions contained in Table 2 of the protocol should be followed.  Appropriate supportive 
care should be provided together with close monitoring.  If hepatic failure occurs, lenvatinib
must be discontinued.
9.4.1.4.4 MANAGEMENT OF THROMBOEMBOLIC EVENTS
Subjects should be advised to pay attention to the symptoms suggestive of venous 
thromboembolic events, which include acute onset of dyspnea, chest pain, cough, 
hemoptysis, tachypnea, tachycardia, cyanosis, deep vein thrombosis (DVT) signs including 
lower-extremity swelling, redness and warmth to touch or tenderness.  In case any of these 
signs or symptoms appear, subjects should be instructed to report such signs and symptoms 
promptly to the treating physician.  If a thromboembolic event is confirmed, instructions 
contained in Table 2 of the protocol should be followed. Appropriate supportive care should 
be provided together with close monitoring.  If a subject experiences life-threatening (Grade 
4) thromboembolic reactions, including pulmonary embolism, the lenvatinib must be 
discontinued.  If a subject experiences an arterial thromboembolism event of any grade, 
lenvatinib must be discontinued.
9.4.1.4.5
MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES)
In clinical studies with lenvatinib, events of posterior reversible encephalopathy syndrome 
(PRES) were reported in less than 1% of lenvatinib-treated subjects.  PRES is a neurological 
disorder that can present with headache, seizure, lethargy, confusion, altered mental function, 
blindness, and other visual or neurological disturbances.  Mild to severe hypertension may be 
present.  Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of PRES.  
Appropriate measures should be taken to control blood pressure.  In subjects with signs or 
symptoms of PRES, dose interruptions, reductions, or discontinuation may be required per 
instructions included in Table 2.  Please refer to the Investigator's Brochure for further 
information on lenvatinib, including the full set of special warnings and precautions for use.
9.4.1.4.6
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored every 3 weeks per the Schedule of 
Procedures/Assessments.  Hypocalcemia should be treated per institutional guidelines (eg, 
using, as appropriate, calcium, magnesium, and Vitamin D supplementation) until resolution.  
9.4.1.4.7
MANAGEMENT OF GASTROINTESTINAL PERFORATION OR FISTULA FORMATION
Study treatment should be discontinued in any subjects who develop gastrointestinal
perforation or life-threatening fistula.  


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9.4.1.4.8
MANAGEMENT OF DIARRHEA
An anti-diarrheal agent should be recommended to the subject at the start of study treatment
and subjects should be instructed and educated to initiate anti-diarrheal treatment at the first
onset of soft bowel movements. The choice of anti-diarrheal agent should be individualized
to the subject’s clinical circumstances and follow standard medical practice. If
signs/symptoms of diarrhea persist despite optimal medical management, instructions
contained in Table 2 of the protocol should be followed.  
9.4.1.5
Rescue Medications and Supportive Care for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of non-
hepatic drug-related adverse events with potential immunologic etiology are outlined in 
Table 4 in Section 9.4.1.3.2.  Where appropriate, these guidelines include the use of oral or 
intravenous treatment with corticosteroids as well as additional antiinflammatory agents if 
symptoms do not improve with administration of corticosteroids.  Note that several courses 
of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased.  For each disorder, attempts should be made to rule out other causes such as 
metastatic disease or bacterial or viral infection, which might require additional supportive 
care.  The treatment guidelines are intended to be applied when the investigator determines 
the events to be related to pembrolizumab.  
Note: If after the evaluation of the event, it is determined not to be related to 
pembrolizumab, the investigator does not need to follow the treatment guidance. Refer to 
Table 4 in Section 9.4.1.3.2 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab.


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Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 h
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 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (eg, from 100 mL/h to 
50 mL/h).  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 study treatment 
administration.
Subject may be premedicated 
1.5h (±30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg 
orally (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
orally (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms following 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, 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:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
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.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Subject is permanently discontinued from 
further study treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of 


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Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
drug administration.
CTCAE = Common Terminology Criteria for Adverse Events v4.03, IV = intravenous, NCI = National Cancer Institute, 
NSAID = nonsteroidal antiinflammatory drug.
9.4.2
Identity of Investigational Products
Lenvatinib and pembrolizumab will be supplied by the sponsor in appropriately labeled 
containers.  
Lenvatinib will be provided as 4-mg capsules. Lenvatinib is formulated with calcium 
carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-substituted 
hydroxypropylcellulose, and talc.
Pembrolizumab may be provided as a sterile, preservative-free, white to off-white 
lyophilized powder in single-use vials.  Each vial will be reconstituted and diluted for 
intravenous infusion.  Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab 
and is formulated in L-histidine (3.1 mg), polysorbate-80 (0.4 mg), sucrose (140 mg).  The 
solution may contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.  
Alternatively, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for intravenous 
infusion.  Each vial contains 100 mg of pembrolizumab in 4 mL of solution.  Each 1 mL of 
solution contains 25 mg of pembrolizumab and is formulated in L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection.  
9.4.2.1
Chemical Name, Structural Formula of Lenvatinib
LENVIMA is the mesylate salt of lenvatinib.  Its chemical name is 4-[3-chloro-4-(N’-
cyclopropylureido)phenoxy]-7-methoxyquinoline-6 carboxamide methanesulfonate.  The 
molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt 
is 522.96.  The chemical structure of lenvatinib mesylate is:


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9.4.2.2
Information of Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab is an IgG4 kappa immunoglobulin 
with an approximate molecular weight of 149 kDa. (See Appendix 11 for KEYTRUDA®
package insert.)
9.4.2.3
Labeling for Study Drug
Lenvatinib and pembrolizumab will be labeled in accordance with text that is in full 
regulatory compliance with each participating country and is translated into the required 
language(s) for each of those countries.
9.4.2.4
Storage Conditions
Study drugs will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee (or if regionally 
required, the pharmacist or its designee) is responsible for ensuring that the temperature is 
monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will receive 
lenvatinib in combination with pembrolizumab.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
The starting dose of lenvatinib will be 12 mg (BW ≥60 kg) or 8 mg (BW <60 kg). This dose 
setting is based on the review of the safety and pharmacokinetic data derived from the 
Phase 1/2 study of lenvatinib in subjects with HCC (E7080-J081-202), which is adopted in 
the ongoing Phase 3 study of lenvatinib monotherapy in subjects with unresectable HCC 
(E7080-G000-304). While the recommended dose for the Phase 2 part was determined to be 
12 mg for HCC subjects with CP-A based on the results of Phase 1 part, however, in order to 
reduce the number of dose reductions and withdrawals due to AEs within the first treatment 
cycle, a weight-based dosing schedule has been established with the 2 categories of 12 mg 
QD (BW ≥60 kg) and 8 mg QD (BW <60 kg). 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W, which is the
recommended dose of pembrolizumab based on the well-established safety and efficacy 
profiles in other solid tumors. The safety of single agent pembrolizumab in subjects with 


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HCC is being investigated; the studies of Phase 2 (MK-3475-224/KEYNOTE-224) and 
Phase 3 (MK-3475-240/KEYNOTE-240) for previously systemically treated advanced HCC
are ongoing (Clinicaltraials.gov; KEYNOTE-224, KEYNOTE-240). 
9.4.5
Selection and Timing of Dose for Each Subject
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  On Day 1 of each cycle, in case 
concomitantly administered, it will be administered approximately within 1 hour after 
completion of pembrolizumab administration.
Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, Q3W 
(infusion durations of 25 minutes to 40 minutes are acceptable).  The Pharmacy Manual 
contains specific instructions for the preparation of the pembrolizumab infusion and its 
administration.  Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting.  Study treatment of pembrolizumab may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle (except for 
Cycle 2 in the subjects of DLT evaluation part) due to administrative reasons.  Study 
treatment with pembrolizumab of Cycle 3 should be skipped if pembrolizumab is 
administered on Day 4 or later in Cycle 2 due to treatment-related toxicity or any other 
reason in the subjects of DLT evaluation part.  
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 30 days after the final 
dose of study drug will be recorded.  A concomitant therapy will not be recorded if other 
anticancer treatment is started.  Any medication that is considered necessary for the subject’s 
health and that is not expected to interfere with the evaluation of or interact with lenvatinib or 
pembrolizumab may be continued during the study.
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) lenvatinib or pembrolizumab.
Nonsteroidal antiinflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  G-CSF or equivalent may be used 
in accordance with American Society of Clinical Oncology (ASCO), institutional, or national 
guidelines.  Erythropoietin may be used according to ASCO, institutional, or national 


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guidelines, but the subject should be carefully monitored for increases in red blood cell 
(RBC) counts.
The investigator will record on the Adverse Event CRF any AE for which the concomitant 
medication/therapy was administered.
9.4.7.1
Drug–Drug Interactions
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 (CYP) 
enzymes (Study No. XT063020) suggests a low risk of lenvatinib interference with the PK of 
other drugs metabolized by CYP enzymes which are co-administered in usual clinic practice.  
Nonclinical studies identify CYP3A4 as an important enzyme responsible for human hepatic 
metabolism of lenvatinib.  However, clinical studies conducted to test these findings showed 
that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp) inhibitors or 
inducers is not of clinical concern (see Appendix 8 for a summary of clinical findings).  
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab.  Pembrolizumab is a monoclonal antibody; pharmacokinetic interactions 
with lenvatinib (and vice-versa) are not expected.
9.4.7.2
Prohibited Concomitant Medications/Vaccinations
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The investigator should discuss any questions regarding this with the 
sponsor. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on study therapy or vaccination schedule requires the mutual agreement of the 
investigator, the sponsor, and the subject.
9.4.7.2.1
PROHIBITED CONCOMITANT MEDICATIONS
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies, this will be judged to represent evidence of disease 
progression, and continuation of the study medication and further participation in the study 
must be discussed and agreed upon with the sponsor.
Subjects are prohibited from receiving the following therapies during this study:  

Anticancer therapies such as chemotherapy, tyrosine kinase inhibitors (TKIs), local 
therapy, antitumor interventions (surgical resection, thoracocentesis, etc.), or 
immunotherapy other than study drugs

Investigational agents other than lenvatinib and pembrolizumab

Radiation therapy


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-
Note:  Palliative radiotherapy of up to 2 painful pre-existing, non-target bone 
metastases without being considered progressive disease may be considered on an 
exceptional case by case basis after consultation with the sponsor.  

Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed. However, intranasal influenza vaccines (eg, Flu-Mist®) 
are live attenuated vaccines, and are not allowed.

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.
-
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies.
The use of steroids in prophylaxis of allergic reaction by CT contrast agents will be 
allowed.

Antiplatelet agents, factor X inhibitors, and anticoagulants that require INR monitoring, such as 
warfarin. (Treatments that do not require INR monitoring, such as low molecular weight heparin 
are permitted.)
For subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with the sponsor.  
Subjects may receive other medications that the investigator deems to be medically necessary.  
It is important for investigators to review each medication (prescription and non-prescription) 
the subject is taking before starting the study and at each study visit. 

At each visit, subjects should be questioned about any new drug they are taking. 

To minimize the risk of adverse drug interactions, every effort should be made to limit 
the number of concomitant drugs to those that are truly essential. 

Drugs known to be hepatotoxic (ie, drugs with a warning of hepatotoxicity in the package 
insert) should be avoided during the dosing period.  Investigators are encouraged to 
review each medication for potential hepatotoxicity by searching the 
www.livertox.nih.gov website.
Listed below are specific restrictions for concomitant therapy during the course of the study.  
The following medications/therapies should be avoided during the dosing period and for 
14 days thereafter:
Known hepatotoxic drugs, including but not limited to:

Etifoxine

Isoniazid

Nitrofurantoin


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
Ketoconazole

Amiodarone

Phenytoin
Herbal Supplements/Alternative Medicines 

No herbal supplements or alternative medicines are allowed during this study.
The Exclusion Criteria describes other medications that are prohibited in this clinical study. 
See the related Exclusion Criteria regarding antiviral therapy for HBV and HCV.  
For clarification, the following concomitant medications are also allowed:

Thyroid hormone suppressive therapy (including therapy to treat hypothyroidism and 
hyperthyroidism)

Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer 

Anticoagulants that do not require INR monitoring, such as low molecular weight 
heparin 

Antiinflammatory agents (Note:  Use of steroids is not permitted except as outlined in 
Section 9.4.1.5 to manage immune-related adverse event [irAEs])

Bisphosphonates or denosumab

Supportive care guidelines for pembrolizumab (see Section 9.4.1.5)

Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the patient has been enrolled)
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the pharmacist or its designee) until the following 
documentation has been received by the sponsor:  

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study


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
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable

Financial Disclosure form(s) for the principal investigator and all subinvestigators listed 
on Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the principal investigator including a copy 
of the principal investigator’s current medical license or medical registration number on 
the CV

A signed and dated clinical studies agreement
The investigator and the study staff (or if regionally required, the pharmacist or its designee)
will be responsible for the accountability of all study drugs (dispensing, inventory, and 
record keeping) following the sponsor’s instructions and adherence to GCP guidelines as 
well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation log, 
(c) study drugs accountability log, and (d) documentation of returns to the sponsor.  All 
forms will be provided by the sponsor.  Any comparable forms that the site wishes to use 
must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority.  As 
applicable, all unused study drugs and empty and partially empty containers from used study 
drugs are to be returned to the investigator (or if regionally required, the pharmacist or its 
designee) by the subject and, together with unused study drugs that were shipped to the site 
but not dispensed to subjects, are to be returned to the sponsor’s designated central or local 
depot(s) during the study or at the conclusion of the study, unless provision is made by the 
sponsor for destruction of study drugs and containers at the site.  Destruction at the site will 
only occur under circumstances where regulation or supply type prohibits the return of study 
drugs to the central or local depot(s).  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and 


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reconciliation procedures by the site’s personnel and documentation procedures by the 
sponsor’s personnel, study drugs that are to be returned to the sponsor’s designated central or 
local depot(s) must be boxed, sealed, and shipped back to the central or local depot(s) 
following all local regulatory requirements.  In some regions, study drugs may be removed 
from the site and hand delivered to the central or local depot by sponsor representatives.  
Where study drugs are approved for destruction at the site, destruction will occur following 
the site’s standard procedures and certificates of destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.  
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography
information includes date of birth (or age), sex, race and ethnicity. Baseline characteristics 
will include ECOG-PS, New York Heart Association (NYHA) cardiac disease classification, 
BCLC staging, and tumor-node-metastasis (TNM) staging at initial diagnosis (Appendix 3, 
Appendix 5, Appendix 7, and Appendix 9); macroscopic invasion, extra hepatic spread, and 
Child-Pugh score (Appendix 4).  
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All clinically significant medical and surgical history and current medical conditions 
must be noted in the Medical History and Current Medical Conditions CRF.  
The following disease characteristics will also be investigated:

Cause of HCC (hepatitis B, C, alcohol, other, unknown)

Specify whether disease is confined to liver or metastatic, and if metastatic, to which
organs

Presence and severity of any symptoms/conditions associated with HCC

Detailed medical history of HCC including:
-
Pathology, if available
-
Date of diagnosis
-
Child-Pugh category at enrollment (Appendix 4)
-
Any surgical procedures
-
Prior treatments administered (including dates and modality) 


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◦
Hepatic intra-arterial chemotherapy
◦
Transarterial [chemo] embolization
◦
Radiofrequency ablation
◦
Cryoablation
◦
Percutaneous ethanol injection
◦
Other treatments
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 9). A comprehensive physical examination will include 
evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), 
abdomen, limbs, skin, and a neurological examination. Documentation of the physical 
examination will be included in the source documentation at the site. Significant findings at 
the Screening Visit will be recorded on the Medical History and Current Medical Conditions 
CRF. Changes from screening physical examination findings that meet the definition of an 
AE will be recorded on the Adverse Events CRF.  
9.5.1.2.2
GASTROENTEROLOGICAL ENDOSCOPY
Gastroenterological endoscopy will be performed at Screening only. Gastroenterological 
endoscopy at Screening Period is necessary only if more than 3 months have passed since the 
previous assessment.  
9.5.1.3
Efficacy Assessments
All efficacy endpoints, other than OS, will be based on tumor assessments performed by the 
investigators using mRECIST for HCC (Lencioni and Llovet, 2010; see Appendix 2 for 
further details). All scans for tumor assessments performed during the study should be 
archived in accordance with the standard local practice. The scans from subjects for DLT 
evaluation must be accessible in the event of a sponsor request to submit them for central 
review. For the Expansion part, images acquired for tumor assessments will be sent to an 
imaging core laboratory (ICL) for archiving and potential independent analysis including 
RECIST 1.1 (Eisenhauer, et al., 2009) and mRECIST for HCC. As of Amendment 03, 
images acquired for tumor assessments both in DLT evaluation part and Expansion part will 
be sent to an ICL for archiving and independent analysis.    
Tumor assessments will be carried out during the Pretreatment Phase and then every 6 weeks 
(±1 week counting from C1D1) until Week 24, then every 9 weeks (±1 week) during 
treatment cycles in the Extension Phase. The tumor assessment schedule should not be 
affected by interruptions in study treatment.  Historical standard of care scans that are 
performed with scanning parameters consistent with the requirements for this protocol within 
28 days prior to dosing are acceptable (scans before informed consent would be acceptable). 
Screening tumor assessments using triphasic liver CT/MRI (optimized for pre-contrast, 
arterial, and portal venous phase), contrast-enhanced CT of the chest, and contrast-enhanced 


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CT or MRI of abdomen, pelvis, and other areas of known disease plus suspected disease 
should be performed within 28 days prior to C1D1. 
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should 
be performed within 28 days prior to C1D1.  During the Treatment Phase and the Extension 
Phase, CT/MRI of the brain should be performed if clinically indicated.  The same 
methodology and scan acquisition techniques used at Screening should be used throughout 
the study to ensure comparability.
During the Treatment Phase and Extension Phase, tumor assessments of the chest, abdomen, 
pelvis, and other areas of known disease at Screening plus newly suspected disease should be 
performed every 6 weeks (±1 week, starting from the date of C1D1) until Week 24 and every 
9 weeks thereafter, or sooner, if clinically indicated.  The same methodology (CT or MRI) 
and scan acquisition techniques including use and timing of IV contrast should be used as for 
the screening assessments.  Tumor assessment at the Off-Tx Visit is only necessary if more 
than 4 weeks have passed since the previous assessment (window for these assessments is 
within 1 week of the Off-Tx Visit).
Subjects going off treatment without disease progression will also undergo tumor 
assessments per the Schedule of Procedures/Assessments until disease progression is 
documented or another anticancer therapy is initiated.  
All subjects are required to undergo chest, abdomen, and pelvis imaging at baseline and at all 
follow-up time points.  Contrast-enhanced CT of the chest and contrast-enhanced CT or MRI 
of the abdomen, pelvis, and any other areas of disease, as clinically indicated, will be 
acquired at Screening and at all imaging time points.  Liver CT or MRI must be performed 
using triphasic scanning technique optimized to capture pre-contrast, arterial, and portal 
venous phase.  Contrast-enhanced CT or MRI (pre-and post-gadolinium) of the brain will be 
acquired at Screening and as clinically indicated.  
Treatment decisions by the investigator will be based on mRECIST for HCC. If the time 
point tumor assessment is progressive disease (PD) per mRECIST, the investigator will 
consider whether the subjects should discontinue from study treatment. The decision to 
continue study treatment after the initial progression per mRECIST is at the investigator’s 
discretion based on the clinical status of the subject.  Subjects will be considered to 
discontinue study treatment upon evidence of further radiologic progression as judged by the 
investigator.  However, subjects will be permitted to continue treatment beyond initial
progression per mRECIST as long as the investigator judges that the subject is clinically 
stable and still receiving clinical benefit and is tolerating study drug treatment. Clinically 
stable is defined by the following criteria:  

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG-PS


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
Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
The assessment of clinical benefit should take into account the potential efficacy benefit 
versus the safety risk of continuation of treatment. All decisions to continue treatment 
beyond initial progression determined by the investigator will need to be discussed with 
sponsor and documented in the study records.
In order for stable disease (SD) to be considered the best overall response (BOR), it must 
occur ≥5 weeks following the first dose of study drug.
The first radiological assessment of tumor response status will be performed at Week 6 
(±1 week), unless there is clinical indication warranting earlier radiologic imaging. 
Responses of (partial response [PR] or complete response [CR]) should be confirmed no less 
than 4 weeks after the initial response, but generally at the next scheduled tumor assessment 
time point.
Discontinuation of pembrolizumab treatment may be considered for subjects who have 
attained a confirmed complete response (CR) and have been treated for at least 8 cycles (at 
least 24 weeks), receiving 2 cycles of the combination including 2 doses of pembrolizumab 
beyond the date when the initial CR was declared. 
Subjects will be followed-up every 12 weeks (±1 week) for survival and subsequent 
anticancer treatments as long as the subject is alive and/or until completion of the primary 
analysis, unless the subject withdraws consent or the sponsor terminates the study.  If a clinic 
visit is not feasible, follow-up information may be obtained via telephone or email.  All 
anticancer therapy will be recorded until time of death or termination of survival follow up.
9.5.1.3.1
TUMOR IMAGING DURING SECOND COURSE PHASE (PEMBROLIZUMAB 
RETREATMENT)
Tumor imaging using the same methodology as during the initial treatment phase must be 
performed within 28 days prior to restarting treatment with pembrolizumab ± lenvatinib.  
Tumor assessments should then be performed by the investigator at a frequency according to 
the local standard of care, but not less frequently than every 12 weeks.  During the Second 
Course (Pembrolizumab Retreatment) Phase, scans will no longer be sent to the imaging core 
lab.
For subjects who discontinue pembrolizumab ± lenvatinib in the Second Course Phase, 
tumor imaging should be performed at the time of treatment discontinuation (±4-week 
window). If previous imaging was obtained within 4 weeks prior to the date of 
discontinuation, then imaging at treatment discontinuation is not mandatory. For subjects
who discontinue study treatment because of documented disease progression, this is the final 
required tumor imaging.


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For subjects who discontinue pembrolizumab ± lenvatinib in the Second Course Phase
without documented disease progression, the investigator should make every effort to 
continue monitoring their disease status as clinically indicated thereafter until the subject 
either starts a new anticancer treatment, has disease progression, withdraws consent, or dies, 
or the study ends, whichever occurs first.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
A schedule of lenvatinib and pembrolizumab PK, pharmacodynamic, and pharmacogenomic
sampling is shown in the Schedule of Procedures/Assessments (Table 9).
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Plasma Lenvatinib and Serum Pembrolizumab Concentrations
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be 
measured.  
Blood samples will be collected as specified in Table 9.  Table 6 presents the detailed blood 
sampling schedule for pharmacokinetic assessments.  As of Amendment 03, the enrollment 
for Expansion part may be further expanded up to approximately 94 evaluable subjects. For 
the subjects in Expansion part added as of Protocol Amendment 03, blood samples for 
lenvatinib will be collected as the sparse sampling scheme (Table 6).  See the Laboratory 
Manual for a description of collection, handling, and shipping procedures for PK samples.  
Samples from all subjects will be analyzed.  Plasma lenvatinib concentrations of analytes will 
be quantified by liquid chromatography with tandem mass spectrometry (LC/MS/MS) 
methodology using a previously validated assay.  Serum concentrations of pembrolizumab
will be measured by using validated methods.
The actual time and date of PK blood collection will be recorded on the CRF.  The actual 
time, date, and dose of lenvatinib administered on Days 1, 14, and 15 of Cycle 1 will be 
recorded in the CRF.  For the subjects in Expansion part added as of Protocol Amendment 03, 
the actual time, date, and dose of lenvatinib administered on Day 1 of Cycle 2, 4, 6, and the
day before of Day 1 of Cycle 2, 4 and 6 will be additionally recorded in the CRF. The actual
start/stop time of infusion, date, and dose of pembrolizumab administered will be recorded in 
the CRF.  Date and time of last food intake before study drug administration on Days 1 and 
15 of Cycle 1 will also be recorded in the CRF.  
Table 6
Blood Sampling Schedule for Pharmacokinetic Assessments
Lenvatinib – Subjects Enrolled in DLT Evaluation Part and Expansion Part as per Original 
Protocol, Amendment 01, and Amendment 02
Days
Time (on Each Day)
Acceptable Time-window
(approximate)


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C1D1
Predose of pembrolizumab
≤24 h before infusion
1 h postdose of lenvatinib
±15 min
2 h postdose of lenvatinib
±15 min
4 h postdose of lenvatinib
±15 min
8 h postdose of lenvatinib
±60 min
24 h postdose of lenvatinib
≤–60 min
C1D15
Predose of lenvatinib
≤–60 min
1 h postdose of lenvatinib
±15 min
2 h postdose of lenvatinib
±15 min
4 h postdose of lenvatinib
±15 min
8 h postdose of lenvatinib
±60 min
24 h postdose of lenvatinib
≤–60 min
Lenvatinib Sparse Sampling for the Subjects in Expansion Part as per Amendment 03
Onwards 
Days
Time (on each Day)
C1D1
0.5-4 h post dose of lenvatinib
6-10 h post dose of lenvatinib
C1D15
Predose of lenvatinib
0.5-4 h post dose of lenvatinib
6-10 h post dose of lenvatinib
Day 1 of Cycles 2, 4 and 6
Predose of pembrolizumab
Pembrolizumab
Days
Time (on Each Day)
Acceptable Time-window
(approximate)
C1D1
Predose of pembrolizumab
≤24 h before infusion
C2D1
Predose of pembrolizumab
≤24 h before infusion
C4D1
Predose of pembrolizumab
≤24 h before infusion
C6D1
Predose of pembrolizumab
≤24 h before infusion
C8D1
Predose of pembrolizumab
≤24 h before infusion
Day 1 in every 4 
cycles after Cycle 8
Predose of pembrolizumab
≤24 h before infusion
End of treatment
Within 30 days after discontinuation 
or until the initiation of other 
anticancer treatment, whichever earlier
–
C#D# = Cycle #/Day #.


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Serum Anti-pembrolizumab Antibodies (ADA)
Serum ADA will be measured.  
Blood samples will be collected as specified in Table 9.  Table 7 presents the detailed blood 
sampling schedule for anti-pembrolizumab antibodies (ADAs).  See the Laboratory Manual 
for a description of collection, handling, and shipping procedures for blood samples.  
Serum ADA will be detected by using validated methods.  
The actual time and date of blood collection for ADA will be recorded on the CRF.  
Table 7
Blood Sampling Schedule for Anti-pembrolizumab Antibodies
(ADAs)
Anti-pembrolizumab Antibodies (ADA)
Days
Time (on each Day)
Acceptable time-window
C1D1
Predose of pembrolizumab
≤24 h before infusion
C6D1
Predose of pembrolizumab
≤24 h before infusion
C#D# = Cycle #/Day #.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
A schedule of biomarker sampling is shown in the Schedule of Procedures/Assessments
(Table 9).  
Blood samples for the development of exploratory predictive biomarkers will be collected 
from consented subjects prior to the first dose of study drug, on Cycle 1/Day 15 (C1D15), 
and predose on Day 1 of subsequent cycles up to and including Cycle 18, and at the off-
treatment assessment.  Subjects will provide an archival tumor tissue sample and/or a fresh 
biopsy of tumor before treatment for biomarker analyses (see the Inclusion Criteria). An 
archival tumor sample from the most recent surgery or biopsy will be collected.  Biomarker 
discovery and/or validation will be performed to identify blood or tumor biomarkers that may 
be useful to predict subject response to lenvatinib and/or pembrolizumab, as determined by 
evaluation of response-related and/or safety-related outcomes as well as for potential use in 
diagnostic development.  Blood serum samples from subjects receiving lenvatinib and 
pembrolizumab may be analyzed using global proteomic methods, enzyme-linked 
immunosorbent assay (ELISA), multiplex bead-based immunoassay, or other assays/methods 
or new technology.  In addition, biomarkers identified in other lenvatinib clinical studies may 
also be assessed in the biomarker samples collected from subjects enrolled in this study.  The 
decision to perform exploratory biomarker analysis may be based on the clinical outcome of 
this study and/or the signals observed in other clinical studies or other information available 
at that time.


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Archived, formalin-fixed paraffin-embedded (FFPE) tissue or a newly obtained biopsy will 
be collected from all consented subjects for potential assessment of mutations and other 
genetic alterations or genes and/or proteins including PD-L1/PD-L2 status and other relevant 
biomarkers (eg, tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid [RNA] 
signature profiles, mutational load) which may be important in the development and 
progression of cancer as well as for potential use in diagnostic development. Appropriate 
technology/methodologies will be used based on the amount of tumor tissue available.
Note: For PD-L1/PD-L2 status, submission of FFPE tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted 
to the testing laboratory within 14 days from the site slide sectioning date; otherwise, a 
new specimen will be requested.
Optional fresh tumor biopsies will be collected from consented subjects to examine markers 
including markers of target engagement, relevant pharmacodynamic biomarkers, and 
potential markers of response.  
A blood plasma sample to isolate circulating cell free nucleic acids (cf-nucleic acids) and a 
whole blood sample for immune cell profiling will be collected from consented subjects prior 
to the first dose of study drug (C1D1), and then predose on C1D15 and Day 1 of subsequent 
cycles up to and including Cycle 18 and at the off-treatment assessment. Cf-nucleic acids
isolated from plasma samples may be used to obtain circulating tumor DNA (ctDNA) and 
explore tumor genetic alterations such as mutations observed in archival tumor samples as 
well as those which develop during drug treatment. Genomic DNA extracted from blood 
samples may be used to confirm whether the DNA sequence variants observed in DNA 
extracted from tumor material are limited to the tumor and to assess the immune response.  
Data obtained will be used for research to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject. All analyses will be limited to correlations relevant to diseases and clinical 
outcomes related to therapy of lenvatinib and pembrolizumab.  The DNA will not be used to 
determine or predict risks for diseases that an individual subject does not currently have.  
Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 15 years to 
assist in any research scientific questions related to lenvatinib/pembrolizumab, cancer, and/or 
for potential diagnostic development. 
Data will be used to explore pharmacokinetics/pharmacodynamic (PK/PD) relationships for
effects of lenvatinib in combination with pembrolizumab on ORR, other efficacy-related 
parameters including PFS and OS, AEs/dose reductions, and blood-borne and tumor 
biomarkers.  Exploratory/graphical analyses will be conducted for PK/PD evaluations and 
may be followed by model-based analyses. PK/PD results will be provided in a separate 
report.  
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.


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9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE 
v4.03 grades (for both increasing and decreasing severity), and serious adverse events 
(SAEs); regular monitoring of laboratory tests including hematology, blood chemistry, and 
urine values; periodic measurement of vital signs and electrocardiogram (ECGs); 
echocardiograms or multigated acquisition (MUGA) scans including left ventricular ejection 
fraction (LVEF); and performance of physical examinations as detailed in Table 9.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the investigational 
products are lenvatinib and pembrolizumab.  
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, withdrawal of study drug, or 
withholding of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be recorded on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF until 30 days after the last dose of study treatment.  Serious AEs 
regardless of causality assessment must be collected through the last visit and for 120 days 
after the subject’s last dose or for 30 days following the last dose if the subject initiates new 
anticancer therapy, whichever is earlier.  An AE will not be recorded on the Adverse Event 
CRF if other anticancer treatment is started.  All SAEs will be recorded on the Adverse Event 
CRF.


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Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Progression of malignant disease (PD) should not be recorded as an adverse event in studies 
where it is included as an endpoint for underlying disease.  If the progression leads to an 
untoward medical occurrence (increased pain, pleural effusion, etc), then this medical 
occurrence should be the adverse event.
All AEs must be followed for 30 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 6).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event


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Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
Events of clinical interest for this study include:
1.
Hepatic events of clinical interest include any of the following events.  All of these 
events will require holding pembrolizumab, notification of the event(s) to the sponsor 
within 24 hours via electronic media or paper (see Section 9.5.4.3.2), and a 
hepatology consultation.  
For dose interval modification and guidance related to the diagnosis and management of 
hepatic events of clinical interest, refer to Guidance for Management of Hepatic Events of 
Clinical Interest of Section 9.4.1.3.2.  
a.
ALT:
i.
Among subjects with baseline ALT <2×ULN:  ALT ≥5×ULN


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ii.
Among subjects with baseline ALT ≥2×ULN:  ALT >3× the baseline level
iii.
ALT >500 U/L regardless of baseline level
b. AST:
i.
Among subjects with baseline AST <2×ULN:  AST ≥5×ULN
ii.
Among subjects with baseline AST ≥2×ULN:  AST >3× the baseline level
iii.
AST >500 U/L regardless of baseline level
c.
Total Bilirubin:
i.
Among subjects with Baseline levels <1.5 mg/dL:  a value of >2.0 mg/dL
ii.
Among subjects with Baseline levels that are ≥1.5 mg/dL:  a value ≥2× the baseline
level
iii.
Total bilirubin >3.0 mg/dL regardless of baseline level
d. Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
i.
New onset ascites uncontrollable with diuretic
ii.
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or 
gastric varices) 
iii.
Hepatic Encephalopathy
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; and AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be recorded on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry


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9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 8.  The Schedule of Procedures/Assessments (Table 9) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.  Clinical laboratory tests will be performed by the local laboratory.  
If there is ≥Grade 3 clinically significant hematologic or clinical chemistry toxicity, repeat 
laboratory test and AEs assessment at least every 7 days (until improvement to < Grade 3).  
Table 8
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential
INRa
Clinical Chemistry
Electrolytes
Calcium, chloride, magnesium, phosphorus, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function tests
Blood urea nitrogen, creatinine
Thyroid function testsb
TSH, free T4 levels and T3 or free T3 levels
Other
Albumin, cholesterol, glucose, lactate dehydrogenase, total protein, 
triglycerides
Pregnancy test (serum or urine β-hCG)i
Urinalysisf
Glucose, ketones, pH, protein, blood (or hemoglobin), specific 
gravity, UPCRh
Other 
Ammoniac, HIV Abc, HCV Abc, HBsAgc, HBV DNAd
α-fetoprotein (AFP)e
Amylaseg, lipaseg
C#D# = Cycle #/Day #, RBC = red blood cell, WBC = white blood cell, HBcAb = hepatitis B core antibody,
HBsAg = hepatitis B surface antigen, HBsAb = hepatitis B surface antibody, HBV = hepatitis B virus, HCV = 
hepatitis C virus, HIV Ab = human immunodeficiency virus antibody, INR = International Normalized Ratio, 
T3 = triiodothyronine, T4 = thyroxine, TSH = thyroid stimulating hormone, UPCR urine protein-to-creatinine 
ratio.
a:
INR will be assessed on C2D1 and every cycle Day 1 thereafter.  
b:
TSH and free T4 will be assessed at Screening, Baseline, C3D1 and every 2 cycles thereafter (C5D1, 
C7D1, etc) and Off-Treatment Visit. T3 or free T3 levels will be assessed at Screening and Baseline.
c:
Only at Screening.  
d:
Subjects who are HBsAg (+), or anti-HBcAb (+) and/or anti- HBsAb (+) but negative for HBsAg and HBV 
DNA need monitoring with HBV DNA every 3 weeks during study treatment. 
e:
α-fetoprotein (AFP) will be measured on C2D1, C3D1, and every 2 cycles thereafter.
f:
If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity test should be performed at the institution’s laboratory.  


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Table 8
Clinical Laboratory Tests
Category
Parameters
g:
Amylase and lipase will be measured at Screening, C2D1 and every cycle thereafter.
h:
UPCR will be measured as needed.
i:
Subjects must have a pregnancy test prior to administration/dispensing of pembrolizumab/lenvatinib at the 
beginning of each treatment cycle.
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to pembrolizumab administration and results reviewed prior 
to administration/dispensing of study drug at the beginning of each treatment cycle.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.  
If AEs were assessed during unscheduled visits, all the data corresponding to the laboratory 
abnormality will be recorded on the CRF.  
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 9) by a 
validated method.  BP and pulse will be measured after the subject has been resting for 5 
minutes.  All BP measurements should be performed on the same arm, preferably by the 
same person.  As of Amendment 03, for subjects with an elevated BP (systolic BP ≥140 
mmHg or diastolic BP ≥90 mmHg), BP measurement should be repeated at least 5 minutes 
apart.  One BP assessment is defined as the mean value of 2 measurements at least 5 minutes 
apart. Elevated BP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) is confirmed on 2 
assessments a minimum of 30 minutes apart. Height will be measured at the Screening Visit 
only.  
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 9).  A comprehensive physical examination will include 
evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and lungs), 
abdomen, limbs, skin, and a neurological examination.  Documentation of the physical 
examination will be included in the source documentation at the site.  Only changes from 
screening physical examination findings that meet the definition of an AE will be recorded 
on the Adverse Events CRF. 


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9.5.1.5.6
ELECTROCARDIOGRAMS
ECGs will be obtained as designated in the Schedule of Procedures/Assessments (Table 9).  
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3×4 lead format 
are to be used.  In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously.  Subjects must be in the recumbent position or 
sitting for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.5.7
ECHOCARDIOGRAM OR MULTIGATED ACQUISITION SCAN 
A MUGA scan (using technetium-99m-pertechnetate) or an echocardiogram to assess LVEF 
will be performed as designated in the Schedule of Procedures/Assessments (Table 9).  
MUGA or echocardiogram scans should be performed locally in accordance with the 
institution’s standard practice.  MUGA scans are the preferred modality; however, whichever 
modality is used for an individual subject at baseline should be repeated for all subsequent 
LVEF assessments for that subject.  LVEFs as assessed by the institution will be entered onto 
the CRF.  
All scans performed during the study should be archived in accordance with the standard 
local practice.  They must be accessible in the event of a sponsor request to submit them for 
central review.
9.5.1.6
Other Assessments
For the subjects in Expansion part added as of Protocol Amendment 03, assessments of 
HRQoL scores will be performed using the generic cancer HRQoL instrument (EORTC 
QLQ-C30), the HCC-specific module (EORTC QLQ-HCC18) (Blazeby, et al., 2004), and 
the generic HRQoL instrument, EQ 5D-5L.  Subjects will be asked to complete each of the 
three questionnaires at the Baseline Visit, on Day 1 of each subsequent cycle, and at the Off-
Treatment Visit.  Validated translations of questionnaires will be used according to EORTC 
and FDA guidelines. Assessments will be performed in English or in the validated local 
language, where available. The subject will complete HRQoL questionnaires.  Site personnel 
should check the forms returned by the subject for completeness before the subject leaves the 
clinic.  If the subject is unable to complete the form, qualified site personnel may administer 
the questionnaires via interview and complete the forms for the subject.
The EORTC QLQ-C30 is a 30-item validated questionnaire that is used in assessing HRQoL 
in cancer patients within the context of clinical trials.  The EORTC QLQ-HCC18 is a 18-item 
validated questionnaire that was developed to assess health-related quality of life among 


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patients with hepatobiliary cancers.  In both assessments, there are four scale scores: 1) Not 
at all, 2) A little, 3) Quite a bit, and 4) Very much.
EQ-5D-5L is a standard instrument for use as a measure of health outcome.  Applicable to a 
wide range of health conditions and treatments, it provides a simple descriptive profile and a 
single index value for health status.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 9 present the schedule of procedures and assessments for the study.  Table 10 presents 
the schedule of procedures/assessments for the Second Course (Pembrolizumab Retreatment) 
Phase for the study.


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Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga Baselinea
Cycle 1b
Treatment
(Cycle 2b)
Treatment
(Cycle 3b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6
7
8, 10, 12, 
etc.
9, 11, 13, 
etc.
Off-Treatment 
Visitv
Follow-up
Day
–28 to –3
–3 to –1
1
8
15
1
15
1
15
Within 30 days 
after last dose
Every 
12 weeksy
Assessments
S
Informed consent
X
S
Inclusion/exclusion
X
X
S
Demographic data
X
S
ECOG-PS/NYHAc
X
X
X
X
X
NS
BCLC staging/TNM staging 
X
NS
Medical/surgical history
X
X
S
Prior medications
X
NS
Gastroenterological endoscopyp
X
NS
Viral tests at Screening (HIV 
Ab, HCV Ab, HBsAg) aa
X
NS
HBV DNAbb
X
X
X
X
S
Vital signsd
X
X
X
X
X
X
X
X
Xw
X
-
Physical examinatione
X
Xf
X
X
X
X
X
X
X
NS
12-lead ECGg
X
X
X
X
X


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Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga Baselinea
Cycle 1b
Treatment
(Cycle 2b)
Treatment
(Cycle 3b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6
7
8, 10, 12, 
etc.
9, 11, 13, 
etc.
Off-Treatment 
Visitv
Follow-up
Day
–28 to –3
–3 to –1
1
8
15
1
15
1
15
Within 30 days 
after last dose
Every 
12 weeksy
Assessments
S
MUGA or echocardiogramx
X
X


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Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga Baselinea
Cycle 1b
Treatment
(Cycle 2b)
Treatment
(Cycle 3b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6
7
8, 10, 12, 
etc.
9, 11, 13, 
etc.
Off-Treatment 
Visitv
Follow-up
Day
–28 to –3
–3 to –1
1
8
15
1
15
1
15
Within 30 days 
after last dose
Every 
12 weeksy
Assessments
S
Clinical chemistry & 
hematologyh, cc
X
X
X
X
X
X
X
X
S
Thyroid function testsh, cc
X
X
Xh
X
S
Urinalysis (Dipstick)i, cc
X
X
X
X
X
X
X
Xw
X
S
Pregnancy testj, cc
X
X
X
X
X
S
Blood coagulation test (INR)h,cc
X
X
X
X
X
NS
α-fetoprotein (AFP)z
X
X
X
X
NS
Ammonia test
X
NS
Child-Pugh score
X
Xee
X
X
X
NS
HRQoLgg
(For the subjects in Expansion 
part added as of Amendment 
03)
X
X
X
X
NS
Amylase and lipase
X
X
X
X
S
Lenvatinib treatment
Throughout


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Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga Baselinea
Cycle 1b
Treatment
(Cycle 2b)
Treatment
(Cycle 3b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6
7
8, 10, 12, 
etc.
9, 11, 13, 
etc.
Off-Treatment 
Visitv
Follow-up
Day
–28 to –3
–3 to –1
1
8
15
1
15
1
15
Within 30 days 
after last dose
Every 
12 weeksy
Assessments
NS
Pembrolizumab treatmentdd
X
X
X
NS
Lenvatinib PK blood samplesk
X
X
NS
Lenvatinib PK blood samplesff
(For the subjects in Expansion 
part added as of Amendment 
03)
X
X
X
Xff
NS
Pembrolizumab PK blood 
samplesl
Xl
Xl
Xl
X


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Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga Baselinea
Cycle 1b
Treatment
(Cycle 2b)
Treatment
(Cycle 3b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6
7
8, 10, 12, 
etc.
9, 11, 13, 
etc.
Off-Treatment 
Visitv
Follow-up
Day
–28 to –3
–3 to –1
1
8
15
1
15
1
15
Within 30 days 
after last dose
Every 
12 weeksy
Assessments
NS
Anti-pembrolizumab antibodies 
(ADA) blood samplesm
Xm
Xm
S
Tumor assessments: CT (MRI)n
X
Counting from C1D1, for the first 24 weeks, every 6 weeks (±1 week), or sooner, if clinically 
indicated, until documentation of disease progression.  After 24 weeks, tumor assessments must 
be performed every 9 weeks counting from C9D1 (±1 week), or sooner if clinically indicated, 
until documentation of disease progression. Responses must be confirmed at least 4 weeks later 
(usually at the next tumor assessment time point). Triphasic CT/MRI of liver is mandatory at 
Screening and all subsequent time points unless it becomes medically contraindicated.
All subjects continuing study treatment after initial mRECIST for HCC-defined progression must 
continue tumor assessments at the same interval (and have copies of all tumor assessments sent to 
the ICL) until further progression and/or loss of clinical benefit as judged by the investigator.
NS
CT or MRI of the braino
X
Brain scans will be performed if clinically indicated and within 
1 week of subject achieving CR.
S
Archival tumor block or slidesq, t
Xq
S
Fresh Tumor Biopsies 
(additional consent required) r
Xr
S
Blood sample (serum) for 
biomarkerss
X
X
X
X
X


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Table 9
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga Baselinea
Cycle 1b
Treatment
(Cycle 2b)
Treatment
(Cycle 3b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6
7
8, 10, 12, 
etc.
9, 11, 13, 
etc.
Off-Treatment 
Visitv
Follow-up
Day
–28 to –3
–3 to –1
1
8
15
1
15
1
15
Within 30 days 
after last dose
Every 
12 weeksy
Assessments
S
Biomarker (plasma) samples
X
X
X
X
X
S
Biomarker (whole blood) 
samples
X
X
X
X
X
S
Concomitant 
medications/therapiesu
Throughout
X
S
AEs/SAEsu
Throughout
S
Survivaly
Throughout
ADA = anti-drug antibody, AE = adverse event, BCLC = Barcelona Clinic Liver Cancer, BP = blood pressure, C#D# = Cycle #/Day #, CRF = case report form, CR = complete 
response, CT = computed tomography, DLT = dose-limiting toxicity, ECG = electrocardiogram, ECOG-PS = Eastern Cooperative Oncology Group Performance Status, HBcAb = 
hepatitis B core antibody, HBsAb = hepatitis B surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, HCC = hepatocellular carcinoma, HCV = hepatitis C 
virus, HIV Ab = human immunodeficiency virus antibody, ICL = imaging core laboratory, INR = international normalized ratio, LVEF = left ventricular ejection fraction, MUGA = 
multigated acquisition, MRI = magnetic resonance imaging, NYHA = New York Heart Association, PD = progressive disease, PK = pharmacokinetics, RR = respiratory rate, SAE = 
serious adverse event, T3 = triiodothyronine, TNM = tumor-node-metastasis.
a.
The Screening Period extends from Day -28 to Day -3.  Subjects must be screened within 28 days prior to C1D1.  The screening assessment can serve as the baseline 
assessment, if performed within 72 hours before C1D1.  The baseline assessment can be performed from Day -3 to C1D1 (prior to the first dose of study drug).  Informed 
consent may be obtained 4 weeks prior to the start of study drug.  The results of all screening assessments and evaluations must be completed and reviewed by the investigator 
prior to the Baseline Visit.
b.
Efforts should be made to conduct study visits on the day scheduled (±3 days).  Clinical laboratory assessments may be conducted anytime within 72 hours prior to the 
scheduled visit, unless otherwise specified.


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c.
ECOG-PS will be evaluated at the Screening and Baseline Visits, on C2D1, and on Day 1 at every subsequent cycle thereafter.  NYHA will only be assessed at the Screening 
Visit.  ECOG and NYHA assessment guidelines are provided in the Appendix of the protocol.
d.
Assessments will include vital signs (resting BP, pulse, RR, and body temperature), weight, and height.  Height will be measured at the Screening Visit only.  Elevated BP 
(systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) should be confirmed by 2 assessments 30 minutes apart.  One BP assessment is defined as the mean value of 2
measurements at least 5 minutes apart.  
e.
A comprehensive physical examination (including a neurological examination) will be performed at the Screening or Baseline Visit, on C1D15, on Day 1 of each subsequent 
cycle, and at the Off-Treatment Visit assessment.  A symptom-directed physical examination will be performed on C1D1, C1D8, and at any time during the study as clinically 
indicated.
f.
Required if screening physical examination was performed >7 days prior to C1D1.
g.
Single, 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 min prior to the ECG.  During the Treatment Period of the Extension Phase, ECGs will be 
collected on Day 1 of every cycle.
h.
Clinical laboratory tests will be performed by the local laboratory.  Clinical chemistry and hematology results must be reviewed prior to administration of study drug on 
C1D1.  If there is ≥ Grade 3 clinically significant hematologic or clinical chemistry toxicity, repeat laboratory test and AEs assessment at least every 7 days (until 
improvement to < Grade 3).  TSH and free T4 will be assessed at Screening, Baseline, C3D1 and every 2 cycles thereafter (C5D1, C7D1, etc.) and Off-Treatment Visit.T3 or 
free T3 levels will be assessed at Screening and Baseline.
i.
Urinalysis will be performed at Screening, Baseline, C1D8, C1D15, and each study visit of every cycle thereafter.  Urinalysis will include glucose, hemoglobin (or blood), 
ketones, pH, protein, specific gravity.  If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and sensitivity test should be 
performed at the institution’s laboratory.  If urine protein is ≥2+ on urinalysis, then see Footnote W.
j.
A serum and/or urine pregnancy test will be performed in women of childbearing potential (ie, premenopausal women and postmenopausal women who have been 
amenorrheic for less than 12 months).
k.
Study Treatment PK blood samples drawn predose, 1 (±0.25), 2 (±0.25), 4 (±0.25), 8 (±1), and 24 (-1) hours after the administration on C1D1 and C1D15.
l.
Pre-dose (trough) PK samples will be collected within 24 hours before infusion in Cycles 1, 2, 4, 6 and 8, and every 4 cycles thereafter; and within 30 days after 
discontinuation of study drug (or until the subject starts new anti-cancer therapy).
m.
Anti-pembrolizumab antibody (ADA) samples will be collected within 24 hours before infusion in Cycles 1 and 6.
n.
Pretreatment Phase:  Tumor assessments using triphasic liver CT/MRI (optimized for pre-contrast, arterial phase, and portal venous phase), contrast-enhanced CT of the chest, 
and contrast-enhanced CT or MRI of the abdomen, pelvis, and other areas of known disease plus suspected disease should be performed within 28 days prior to C1D1.
Treatment/Extension Phase:  Tumor assessments using triphasic liver CT/MRI (optimized for pre-contrast, arterial phase, and portal venous phase), contrast-enhanced CT of 
the chest, and contrast-enhanced CT or MRI of the abdomen, pelvis, and other areas of known disease at Screening plus newly suspected disease should be performed as 
indicated in the Schedule of Procedures/Assessments above (or sooner if there is evidence of progressive disease).  The same methodology (CT or MRI) and scan acquisition 
techniques should be used as for the screening assessments.  Objective responses must be confirmed at least 4 weeks later (eg, generally at the next tumor assessment time 
point). 
Follow-up Period:  Subjects who discontinue treatment without disease progression should continue tumor assessments (every 6 weeks until Week 24, then every 9 weeks as 
needed) until disease progression or beginning another anticancer therapy.  All subjects continuing study treatment after initial mRECIST for HCC-defined progression must 
continue tumor assessments at the same interval (and have copies of all tumor assessments sent to the ICL in the Expansion part) until further progression and/or loss of 
clinical benefit as judged by the investigator.
o.
Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 4 weeks prior to C1D1.  During the Treatment Phase and the Extension 
Phase, CT/MRI of the brain will be performed if clinically indicated, and within a target of 1 week after a subject achieves a CR.  The same methodology and scan acquisition 
techniques used at Screening should be used throughout the study to ensure comparability.
p.
Gastroenterological endoscopy at Screening period is necessary only if more than 3 months have passed since the previous assessment.


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q.
An archival tumor tissue sample should be available prior to first dose. Collection of archival tumor tissue or a newly obtained biopsy prior to the first dose of study treatment 
will be required in Expansion cohort, while it will be optional in the patients who are not enrolled in Expansion cohort. An archival tumor sample from the most recent 
surgery or biopsy will be collected. If archival tumor tissue sample is not available, please see footnote t.
r.
Optional fresh tumor biopsies will be collected at the Screening visit from consented subjects to examine markers including markers of target engagement, relevant 
pharmacodynamic biomarkers, and potential markers of response.
s.
Collection of blood sample from consented subjects to be used for biomarker studies.  Samples will be obtained predose at these time points: C1D1, C1D15, Day 1 of all 
subsequent cycles up to and including Cycle 18, and at the off-treatment assessment.
t.
If an archival tumor sample for biomarker analysis is not available from subjects, then a newly obtained tumor biopsy should be obtained prior to the first dose of study 
treatment.  If a newly obtained biopsy is required, it is preferred that the biopsy is obtained from a non-target lesion.  Subjects must have recovered adequately from the 
biopsy prior to starting therapy.  Subjects without archival tumor tissue and with inaccessible tumors for biopsy specimens can be enrolled without a biopsy.  In case of 
submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from when the slides are cut.
u.
Concomitant medications/therapies are recorded for 30 days after last dose or until the subject initiates new anticancer therapy, whichever is earlier. Collection of AE/SAE 
will be referred to the statement in Safety Assessments.
v.
The off-treatment assessment should occur within 30 days after the final dose of study treatment. Subjects may receive other anti-cancer treatment within 30 days after the 
final administration if his/her cancer conditions necessitate.  In this case, off-treatment observation must be conducted before initiation of other anti-cancer treatment.
w.
Assessments/procedures on Day 15 of Cycle 3 or later can be skipped only if subject’s safety is assured by investigators.
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on Day 15 or more frequently as clinically indicated until systolic BP has 
been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.  If a new event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the 
subject must resume the Day 15 evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.  
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 2 weeks (on Day 1 and Day 15 or more frequently as clinically indicated until the results 
have been 1+ or negative for 2 consecutive treatment cycles).  If a new event of proteinuria ≥2+ occurs, the subject must resume the Day 1 and Day 15 urine dipstick testing 
for evaluation of proteinuria until results are 1+ or negative for 2 consecutive treatment cycles.
Subjects will visit on Day 15 if BP monitoring or urine dipstick testing is required as specified above.
x.
During the Treatment and Extension Phases, MUGA scans or echocardiograms will be performed to assess LVEF every 24 weeks.
y:
Subjects will be followed-up every 12 weeks (±1 week) for survival and subsequent anticancer treatments as long as the subject is alive and/or until completion of the primary 
analysis, unless the subject withdraws consent or the sponsor terminates the study. If a clinic visit is not feasible, follow-up information may be obtained via telephone or 
email. All anticancer therapy will be recorded until time of death or termination of survival follow up.
z:
α-fetoprotein (AFP) will be measured at the Screening Visit, on C2D1, C3D1, every 2 cycles thereafter (C5D1, C7D1, C9D1, etc.), and at the Off-Treatment Visit.
aa:
Viral tests of HIV Ab, HCV Ab and HBsAg (quantitative assay, High-sensitivity) will be done at the Screening visit.
bb: Subjects who are HBsAg (+), or anti-HBcAb (+) and/or anti- HBsAb (+) but negative for HBsAg and HBV DNA need monitoring with HBV DNA every 3 weeks during 
study treatment. 
cc:
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis samples are to be obtained prior to pembrolizumab administration and results 
reviewed prior to administration/dispensing of study drug at the beginning of each treatment cycle.  Monitor subjects with Grade 4 thrombocytopenia every 48 hours until 
resolution to baseline or Grade 1.
dd: Pembrolizumab will be administered until 2 years after C1D1 at the latest.  Study treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle (except for Cycle 2 in the subjects of DLT evaluation part) due to administrative reasons.  Study treatment with pembrolizumab of Cycle 3 
should be skipped if pembrolizumab is administered on Day 4 or later in Cycle 2 due to treatment-related toxicity or any other reason in the subjects of DLT evaluation part. 
Note: Subjects who stop study treatment after receiving 35 administrations of pembrolizumab for reasons other than progressive disease (PD) or intolerability, or subjects 
who attain a complete response (CR) and stop study treatment, may be eligible to receive up to 17 additional administrations of pembrolizumab (approximately 1 year).  This 
will be a second course of treatment (see Table 10 for details).


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ee:   Data of C1D1 can be used for Baseline if it is assessed before treatment of study drugs.
ff:    For the subjects in Expansion part added as of Amendment 03, study Treatment PK blood samples drawn 0.5-4 hours, and 6-10 hours post lenvatinib dose on C1D1, prior to 
dose and 0.5-4 hours, and 6-10 hours post lenvatinib dose on C1D15. Study Treatment PK blood samples drawn prior to pembrolizumab dose only on Day 1 of Cycles 2, 4, 
and 6.
gg:  HRQoL surveys are conducted for the subjects in Expansion part added as of the protocol Amendment 03.  
Table 10
Schedule of Procedures/Assessments in the Second Course (Pembrolizumab Retreatment) Phase
Phase
Retreatment 
Baseline
Second Course Phase (Retreatment)
Period
Treatment Period
Follow-Up 
Period
Visit
100
101-998
102-997
999n
1000
Day
-1
Cycle X (Last Cycle +1) and Beyonda
Off-Treatment 
Visit
1
15
Assessments
Inclusion/exclusion
X
ECOG-PSb
X
X
X
Vital signs and weightc
X
X
Xc
X
Physical examinatione
X
X
X
X
12-lead ECGf
X
X
X
MUGA scan or echocardiogramg
X
X
Hematology and clinical 
chemistryh
X
X
X
Urine dipstick testingd
X
X
Xd
X
Pregnancy testi
X
X
X
X
Tumor assessments: CT (MRI)j
X
Tumor assessments will be performed according to the local 
standard of care.
Brain scan
X
Brain scans will be performed if clinically indicated.
Survivalk
X


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Phase
Retreatment 
Baseline
Second Course Phase (Retreatment)
Period
Treatment Period
Follow-Up 
Period
Study drug treatment
21-day cycle of lenvatinib daily plus pembrolizumab IV once 
every 21 days 
Concomitant medicationsl
X
Throughout
X
AEs/SAEsm
X
Throughout
X
X
AE = adverse event; BP = blood pressure; BW = body weight; CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; eCRF = 
electronic case report form; HR = heart rate; IV = intravenous; ECOG-PS = Eastern Cooperative Oncology Group Performance Status; med = medication(s); 
MRI = magnetic resonance imaging; MUGA = multigated acquisition; RR = respiratory rate; SAE = serious adverse event; ULN = upper limit of normal; w/in = 
within.
a.
Efforts should be made to conduct study visits on the day scheduled (3 days).  Clinical laboratory assessments may be conducted anytime within 72 hours 
prior to the scheduled visit, unless otherwise specified in this Schedule of Procedures/Assessments.
b.
For ECOG-PS assessment, see protocol appendices. 
c.
Assessments will include vital signs (resting BP, HR, RR, and body temperature) and BW.  Only 1 BP measurement is needed for subjects with systolic BP 
<140 mmHg and diastolic BP <90 mmHg.  If the subject’s initial BP measurement is elevated (ie, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg), the 
BP measurement should be repeated at least 5 minutes later.  The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP assessment.  If 
the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is elevated (ie, systolic BP ≥140 mm Hg or diastolic BP ≥90 
mm Hg), a confirmatory assessment should be obtained at least 30 minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean 
value.  Subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg assessment must have their BP monitored on Day 15 (or more frequently as 
clinically indicated) until their systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles.  If a repeat event 
of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the subject must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles.  See Section 9.4.1.4.1, Management of Hypertension, for further details. 
Note:  During Cycle 3 and subsequent cycles, subjects may return to the clinic for the Day 15 visit if BP monitoring is required as specified above.  The Day 
15 visit is mandatory in Cycles 1 and 2.
d.
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 or more frequently as clinically indicated until the results have been 
1+ or negative for 2 consecutive treatment cycles.  Urine dipstick testing should be performed preferably at the investigational site (but may be performed 
locally by the primary care physician or a local laboratory if the subject does not have to come for a visit to the site).  If a new event of proteinuria ≥2+ 
occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 2 consecutive treatment 
cycles.  For subjects with proteinuria ≥2+, see Section 9.4.1.4.2, Management of Proteinuria, for further details.
Note:  During Cycle 3 and subsequent cycles, subjects may return to the clinic for the Day 15 visit if urine dipstick testing is required, as specified above.  
The Day 15 visit is mandatory in Cycles 1 and 2.


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e.
A comprehensive physical examination will be performed on Day 1 of each cycle and at the off-treatment assessment.  A physical examination may also be 
performed on Day 15, or sooner if clinically indicated.
f.
Single 12-lead ECG as clinically indicated. Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.
g.
A MUGA scan or echocardiogram will be performed during or within 1 week following the off-treatment assessment, or sooner if clinically indicated. 
MUGA scans or echocardiograms will be performed in accordance with the institution’s standard practice.  Assessment should use the same methodology 
(MUGA scan or echocardiogram).
h.
Hematology and clinical chemistry results must be reviewed within 2 business days of receipt of results for all subsequent cycles.  Assessments scheduled 
may be performed within 72 hours prior to the visit.  If Grade ≥3 clinically significant hematologic or clinical chemistry toxicities occur, repeat laboratory 
tests and AE assessments at least every 3-7 days until improvement to Grade <3.  For subjects with blood glucose > ULN, a fasting (>6 h, water only) blood 
glucose sample will be obtained. 
i.
A serum or urine pregnancy test will be performed in women of childbearing potential (ie, premenopausal women and postmenopausal women who have 
been amenorrheic for less than 12 months) on Day 1 of each cycle from Cycle 2 onwards, at the Off-Treatment Visit and every 30 days up to 120 days after 
the last dose of the study medication or the start of a new anticancer therapy, whichever comes first.
j.
Tumor imaging using the same methodology as during the initial treatment phase must be performed within 28 days prior to restarting treatment with 
pembrolizumab ± lenvatinib.  Tumor assessments should then be performed by the investigator at a frequency according to the local standard of care, but not 
less frequently than every 12 weeks.  During the Second Course (Pembrolizumab Retreatment) Phase, scans will no longer be sent to the imaging core lab.
k.
Subjects will be followed for survival every 12 weeks (±1 week) after the Off-Treatment Visit unless they withdraw consent or are lost to follow-up.  If a 
clinic visit is not feasible, follow up information may be obtained via telephone or e-mail.
l.
Concomitant medications will be recorded for 30 days after last dose.  All anticancer therapy will be recorded until time of death or termination of survival 
follow up.
m. All AEs will be captured for 30 days after the last dose of pembrolizumab ± lenvatinib.  SAEs must be collected through 120 days after the subject’s last 
dose of pembrolizumab ± lenvatinib, or 30 days after the last dose of pembrolizumab ± lenvatinib if the subject initiates new anticancer therapy, whichever 
is earlier.  Any pregnancy in which the estimated date of conception is either before the last visit or within 120 days of the last dose of pembrolizumab ± 
lenvatinib or 30 days after the last dose of pembrolizumab ± lenvatinib if the subject initiates new anticancer therapy, whichever is earlier, must be reported.  
Also, any exposure to pembrolizumab ± lenvatinib through breastfeeding during the Second Course Phase or within 120 days of the last dose of 
pembrolizumab ± lenvatinib, or 30 days following the last dose of pembrolizumab ± lenvatinib if the subject initiates a new anticancer therapy, whichever is 
earlier, must be reported.
n.
Off-treatment assessments should occur within 30 days of the final dose of pembrolizumab ± lenvatinib.


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9.5.2.2
Description of Procedures/Assessments Schedule
Refer to Table 9 for the description and timing of each procedure and assessment in the 
Pretreatment and Treatment Phase and the Extension Phase, respectively.  
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies involving 
subjects with HCC.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, vital signs, ECGs, echocardiograms or MUGA scans, physical 
examinations and assessment of AEs, are standard evaluations to ensure subject safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
With Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from the date the investigator becomes aware of the event.
Serious AEs regardless of causality must be collected through the last visit and for 120 days 
after the subject’s last dose or for 30 days following the last dose if the subject initiates new 
anticancer therapy, whichever is earlier.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.


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Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
For sites in the United States, the investigator must notify his/her IRB/IEC of the occurrence 
of the SAE in writing, if required by their institution.  A copy of this communication must be 
forwarded to the sponsor to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 120 days of the last study treatment or 30 days following last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported.  Also, any
exposure to study drug through breastfeeding during study treatment or within 120 days of 
the last study treatment, or 30 days following the last study treatment if the subject initiates a 
new anticancer therapy, whichever is earlier, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:


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Overdose
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with the
protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel
or the subject  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
Note:  Overdose for pembrolizumab is defined as a dose greater than 5 times the 200 mg 
dose.
9.5.4.3.2
REPORTING OF EVENTS OF CLINICAL INTEREST
Selected nonserious and serious adverse events are also known as events of clinical interest
and must be reported to the sponsor.
For the time period beginning when the consent form is signed until enrollment, any event of 
clinical interest, or follow up to an events of clinical interest, that occurs to any subject must 
be reported within 24 hours to the Sponsor if it causes the subject to be excluded from the 
trial, or is the result of a protocol-specified intervention, including but not limited to washout 
or discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at enrollment through 30 days following cessation of 
treatment, any events of clinical interest, or follow up to an events of clinical interest, 
whether or not related to the investigational product, must be reported within 24 hours to the 
sponsor, either by electronic media or paper.  Electronic reporting procedures can be found in 
the EDC data entry guidelines.  Paper reporting procedures can be found in the Investigator 
Trial File Binder (or equivalent).
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 


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regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements. 
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 9).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons. 
Subjects except for the Expansion part who discontinue study treatment prior to completing 
the Treatment Phase for any reason other than a DLT will be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Not applicable.


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9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines.  Site audits will be made periodically by the sponsor’s or the 
CRO’s qualified compliance auditing team, which is an independent function from the study 
team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the data cutoff for 
the primary analysis or the study is completed and the database is locked.  Statistical analyses 
will be performed using SAS software or other validated statistical software as required.  
Details of the statistical analyses will be included in a separate statistical analysis plan (SAP).


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9.7.1
Statistical and Analytical Plans
The statistical analyses of the study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINTS
The primary objective is to evaluate the tolerability and safety for combination of lenvatinib 
plus pembrolizumab in subjects with HCC. Thus, the primary endpoints will be safety 
related endpoints including DLT. 
To evaluate ORR and DOR by mRECIST and RECIST 1.1 based on IIR analysis is also 
primary objective and primary endpoint in the Expansion part.  
9.7.1.1.2
SECONDARY ENDPOINTS
In DLT evaluation part, the secondary endpoints related to the efficacy endpoints will be 
ORR and DOR by mRECIST (based on investigator review and IIR) and by RECIST 1.1 
based on IIR.  
In Expansion Part, the secondary endpoints related to the efficacy endpoints will be ORR and 
DOR by mRECIST based on investigator review.
The following efficacy endpoints by mRECIST (based on investigator review and IIR) and 
RECIST1.1 (based on IIR) are also the secondary endpoints in this study:
-
Objective response rate (PFS)
-
Duration of response (TTP)
-
Time to response (TTR)
Overall survival (OS) is also the secondary endpoint in this study.
These efficacy endpoints are defined as follows.  

ORR is defined as the proportion of subjects who have BOR of CR or PR at the time of 
data cutoff.

DOR is defined as the time from the first documentation of CR or PR to the date of first 
documentation of disease progression or death (whichever occurs first).

PFS is defined as the time from the first study dose date to the date of first 
documentation of disease progression or death (whichever occurs first). 

TTP is defined as the time from the first study dose date to the date of first 
documentation of disease progression.


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
TTR is defined as the time from the date of first study dose to the date of first 
documentation of CR or PR.

OS is measured from the start date of the Treatment Phase (date of first study dose) until 
date of death from any cause. Subjects who are lost to follow-up and the subjects who 
are alive at the date of data cutoff will be censored at the date the subject was last known 
alive or the cut-off date, whichever comes earlier.
Determination of the PK profile of lenvatinib and pembrolizumab while subjects are 
receiving combination therapy also is a secondary endpoint.  
Serum ADA will be measured.  
9.7.1.1.3
EXPLORATORY ENDPOINTS
The exploratory endpoints related to the efficacy endpoints will be DCR and CBR.  These
efficacy endpoints are defined as follows.  

DCR is defined as the proportion of subjects who have BOR of CR or PR or SD 
(minimum duration from C1D1 to SD ≥5 weeks).

CBR is defined as the proportion of subjects who have BOR of CR or PR or durable SD 
(duration of SD ≥23 weeks).
For the subjects in Expansion part added as of Protocol Amendment 03, HRQoL will be 
assessed using EORTC QLQ-C30, the HCC-specific questionnaire (HCC-18), and a generic 
instrument EQ-5D-5L.
The QLQ-C30 core questionnaire (version 3.0) is a generic HRQoL measure for cancer 
patients, and comprises a global health status/QoL scale, five multi-item functional scales, 
three multi-item symptom scales, and single items for the assessment of symptoms and the 
financial impact of disease and treatment.
QLQ-HCC-18 is an 18-item HCC-specific supplemental module developed to augment 
QLQ-C30 and to enhance the sensitivity and specificity of HCC-related HRQoL parameters.  
HCC-18 contains six multi-item scales addressing fatigue, body image, jaundice, nutrition, 
pain and fever, as well as two single items addressing sexual life and abdominal swelling.
All of the derived scales for QLQ-C30 and HCC-18 range in score from 0 to 100.  For the 
overall HRQoL and functioning scales, a higher score is correlated with better HRQoL, 
whereas a higher score represents worse HRQoL for symptom scales.
The EQ-5D-5L generic QoL questionnaire comprises of five dimensions:  mobility, self-care, 
usual activities, pain or discomfort, and anxiety or depression.  Each dimension has five 
levels (1) no problems, (2) slight problems, (3) moderate problems, (4) severe problems, and 
(5) extreme problems.  Thus, the final scoring consists of 3125 possible combinations or 


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health states.  The utility value for each state is assigned based on a set of preference weights 
(tariffs) elicited from general population.
Mean (SD) of the derived functional / symptom scales according to the scoring manual and 
global health status scores will be summarized by treatment group at each time point.  A 
separate pre-specified HRQoL analysis following FDA and EMEA PRO Guidelines will be 
performed and detailed in a separate Statistical Analysis Plan (SAP) and HRQoL report.  
Scoring of EQ-5D-5L and derivation of utility for health economic analysis will also be 
accomplished in a separate analysis and described in a separate HRQoL report.
The exploratory objective is to investigate the relationship between candidate biomarkers and 
anti-tumor activity of lenvatinib in combination with pembrolizumab.  Exploratory endpoints 
will be blood and tumor markers (such as PD-L1 expression levels, cytokine and angiogenic 
factor profiling), and immune cell profiling.
9.7.1.2
Definitions of Analysis Sets
DLT Analysis Set will include all subjects (except for the Expansion part) who have 
completed Cycle 1 without major protocol deviation with at least 75% of study drug 
compliance and are assessed for DLT, and subjects who have experienced DLT during Cycle 
1.  This will be the analysis set to determine tolerability.
Safety Analysis Set/Efficacy Analysis Set will include all subjects who received at least 1 
dose of study drug.
PK Analysis Set will include all subjects who have received at least 1 dose of lenvatinib and 
pembrolizumab, and have evaluable concentration data.
9.7.1.3
Subject Disposition
The number (percentage) of treated subjects will be summarized as well as subjects who 
discontinued from the study treatment and reasons for discontinuation from study treatment
by dose level cohort, part, and overall.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Efficacy Analysis Set will be 
summarized for each dose level cohort, part, and overall using descriptive statistics.  
Continuous demographic and baseline variables include age; categorical variables include 
sex, age group, race, region, ECOG-PS, NYHA cardiac disease classification, BCLC staging,
TNM staging, macroscopic invasion, extra hepatic spread, and Child-Pugh score.  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes.  Prior 


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medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose.  All 
medications will be presented in subject data listings.
9.7.1.6
Efficacy Analyses
Efficacy analyses will be based on the Efficacy Analysis Set. Efficacy data will be presented 
for each dose level cohort, part, and/or overall as appropriate.  BOR will be summarized, and 
ORR and their corresponding exact 2-sided 95% confidence interval (CI) will be calculated. 
DOR will also be summarized and plotted over time by Kaplan-Meier method. Likewise, 
PFS, OS, TTP and TTR will be analyzed as needed. If applicable, DCR, CBR and their 
corresponding exact 2-sided 95% CI will also be calculated. If applicable, a waterfall plot 
will be presented for the percent changes from baseline in the sum of the diameters of target 
lesions at post-baseline nadir (ie, maximum tumor shrinkage).
Data cutoff for the primary analysis will be done after all subjects in the Expansion part
finish at least Cycle 8 assessment and have a tumor assessment for at least Week 24, or 
discontinue if before Cycle 8.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The primary PK parameters of lenvatinib in the combination will be calculated using 
noncompartmental analysis and compared with historical data after a single dose using the 
PK analysis set. If warranted, additional analyses may be performed.  PK data for lenvatinib 
and pembrolizumab is planned to be analyzed using nonlinear mixed effects modeling.  
Based on PK data obtained in this study and from other studies, a population PK analysis 
may be performed to characterize PK parameters to support the proposed dosing regimen.  
PK data for lenvatinib and pembrolizumab may also be used to explore the exposure-
response relationships for antitumor activity/efficacy as well as biomarkers and safety in the 
proposed subject population, if feasible. The results of these analyses, if performed, will be 
reported separately.  For serum ADA levels, a listing of results will be made.  
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic 
and/or imaging biomarkers will be summarized using descriptive statistics. PK/PD
relationships will be explored graphically and may be investigated by model-based analyses.
Details of the analysis will be provided in a separate analysis plan. The results of these 
analyses, if performed, will be reported separately.  


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9.7.1.8
Tolerability/Safety Analyses
All tolerability analyses will be performed on the DLT Analysis Set.  The number and 
percentage of subjects with DLT will be calculated.
Safety analyses will be performed on the Safety Analysis Set.  Safety data will be presented 
for each dose level cohort, part, and/or overall as appropriate.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation will be summarized.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA lower level term (LLT) closest to 
the verbatim term.  The linked MedDRA preferred term (PT) and primary system organ class 
(SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during the 
time from the first dose of study drug to 30 days following the last dose of study drug, having 
been absent at pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted only once 
within an SOC and PT, even if the subject experienced more than 1 TEAE within a specific 
SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized by 
highest CTCAE grade.
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT. Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.


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The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT.  A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT.  A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment will be summarized by 
visit and using descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.3 will be 
summarized using frequencies (number and percentage of subjects), and changes from 
baseline to each postbaseline visit and to the end of treatment will be reported using shift 
tables.  Percentages will be based on the number of subjects with both nonmissing baseline 
and relevant postbaseline results.
Laboratory parameters will be categorized according to CTCAE v4.03 grades, and shifts 
from baseline CTCAE grades to maximum and final postbaseline grades will be assessed.  
CTCAE v4.03 will be used to identify subjects with treatment-emergent markedly abnormal 
laboratory values (TEMAV).  A more detailed definition of TEMAV will be specified in the 
SAP.  A summary of TEMAVs will be presented overall study period.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, resting pulse, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit.
9.7.1.8.5
ELECTROCARDIOGRAMS
Change from baseline to each postbaseline visit and to the end of treatment in ECG findings 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant) will be summarized by visit using shift tables.  Descriptive statistics for ECG 
parameters and changes from baseline will be presented.
9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive statistics for LVEF assessed on echocardiogram or MUGA scans and changes 
from baseline will be presented.


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9.7.2
Determination of Sample Size
A sample size of approximately 30 subjects (N=6 to 10 for DLT evaluation part and N=20 
for Expansion part) will be enrolled in this study. This is not based on statistical power 
considerations. 
The sample size in the Expansion part is 20 evaluable subjects.  The associated 2-sided 95% 
CIs for the ORR of 10% to 90% for 20 subjects are provided in Table 11.
As of Amendment 03, Expansion part may be further expanded up to approximately 94 
evaluable subjects.  For this expansion decision, 2 interim analyses will take place when 20
(6 subjects for DLT evaluation part plus 14 subjects for Expansion part) and 56 subjects (6 
subjects for DLT evaluation part plus 50 subjects for Expansion part) have sufficient follow-
up to be evaluated for response.  The decision to expand enrollment will be based on the 
results of 2 interim analyses, which will spend β = 0.012 and β = 0.024 at the first and second 
interim analyses, respectively. The decision to expand enrollment will be assessed by 
mRECIST based on investigator review. 
Based on an assumption of H0:  25% ORR and H1:  45% ORR, the 100-subject design with 
two futility analyses has approximately 96% statistical power at 2-sided α = 0.02 (that 
corresponds to 1-sided α = 0.01). At the first interim analysis (N = 20), if there are more than 
5 responses, then approximately 36 additional subjects will be enrolled.  At the second 
interim analysis (N = 56), if there are more than 16 responses, approximately 44 additional 
subjects will be enrolled.  If there are 5 or fewer responses at the first interim analysis (N=20) 
or 16 or fewer responses at the second interim analysis (N=56), the sponsor may decide 
whether to expand enrollment based on clinical outcome (eg, DOR).   
The boundaries for the decision to expand enrollment in Expansion part are presented in 
Table 12.


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Table 11
2-Sided 95% Confidence Interval for the ORR of 10% to 90% 
(20 Subjects)
ORR (N=20)
95% CI
10%
(0.012, 0.317)
20%
(0.057, 0.437)
30%
(0.119, 0.543)
40%
(0.191, 0.639)
50%
(0.272, 0.728)
60%
(0.361, 0.809)
70%
(0.457, 0.881)
80%
(0.563, 0.943)
90%
(0.683, 0.988)
CI = confidence interval, ORR = objective response rate assessed by mRECIST based on investigator 
review.
95% CI is estimated using Clopper-Pearson method.
Table 12
Boundaries for the Decision to Expand Enrollment in the 
Expansion Part
Analysis Number
Cumulative β Spent
Objective Response Rate
P-value
Interim Analysis 1
(N=20)
0.012
0.258
0.933
Interim Analysis 2
(N=56)
0.024
0.301
0.376
Final Analysis
(N=100)
0.041
0.351
0.020
9.7.3
Interim Analysis
As of Amendment 03, Expansion part may be further expanded up to approximately 94 
evaluable subjects.  For this expansion decision, 2 interim analyses will take place when 20
(6 subjects for DLT evaluation part plus 14 subjects for Expansion part) and 56 subjects (6 
subjects for DLT evaluation part plus 50 subjects for Expansion part) have sufficient follow-
up to be evaluated for response.  The decision to expand enrollment will be based on the 
results of 2 interim analyses, which will spend β= 0.012 and β= 0.024 at the first and second 
interim analyses, respectively.  The decision to expand enrollment will be assessed by 
mRECIST based on investigator review. 
Based on an assumption of H0:  25% ORR and H1:  45% ORR, the 100-subject design with 
two futility analyses has approximately 96% statistical power at 2-sided α = 0.02 (that 


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corresponds to 1-sided α = 0.01).  At the first interim analysis (N = 20), if there are more than 
5 responses, then approximately 36 additional subjects will be enrolled.  At the second 
interim analysis (N = 56), if there are more than 16 responses, approximately 44 additional 
subjects will be enrolled.  If there are 5 or fewer responses at the first interim analysis (N=20) 
or 16 or fewer responses at the second interim analysis (N=56), the sponsor may decide 
whether to expand enrollment based on clinical outcome (eg, DOR).   
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.


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enhanced antitumor activity of a PD-1 blockade agent by potentiating Th1 immune response
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LENVIMA Summary of Product Characteristics: 
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_Product_Information/human/004224/WC500216237.pdf


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor and the IRB/IEC for the site must 
be notified immediately.  The sponsor must notify the health or regulatory authority as 
required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:


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
Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

Recorded data from automated instruments such as IxRS, x-rays, and other imaging 
reports (eg, sonograms, CT scans, magnetic resonance images, radioactive images, ECGs, 
rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of how 
these images are stored, including microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each consented subject by qualified and 
authorized personnel.  All data on the CRF must reflect the corresponding source document, 
except when a section of the CRF itself is used as the source document.  Any correction to 
entries made on the CRF must be documented in a valid audit trail where the correction is
dated, the individual making the correct is identified, the reason for the change is stated, and 
the original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following item(s), the data recorded directly on the CRF are to be considered source data:

Study drug compliance (eg, the reason for any change of dosage)

Indication for prior/concomitant medication (drug/therapy)

Discontinuation information (eg, in the case of lost to follow-up due to the subject 
choice)

Sampling date and time for the drug concentration


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
Sampling date for the clinical laboratory tests

Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome)
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.  
In Japan, pembrolizumab is expected to be designated as a biologic product.  The site in 
Japan will retain and control the sources to identify the name and address of subject, the 
dosing date, and lot number of study drug for 10 years from the date of last dose (or 
shipment) for the purpose of traceability.  
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.


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All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA (or designated contractor) or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.
11.9
Publication of Results
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 
the sponsor’s proprietary information existing either at the date of the commencement of the 
study or generated during the study.
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between each investigator and the sponsor or CRO, as appropriate.
11.10 Disclosure and Confidentiality
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the investigator’s staff, and the IRB/IEC and 
will not be disclosed in whole or in part to others, or used for any purpose other than 
reviewing or performing the study, without the written consent of the sponsor.  No data 
collected as part of this study will be used in any written work, including publications, 
without the written consent of the sponsor.  These obligations of confidentiality and non-use 
shall in no way diminish such obligations as set forth in either the Confidentiality Agreement 
or Clinical Trial Agreement executed between the sponsor/CRO and the 
institution/investigator.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the institution/investigator and the sponsor/CRO.
11.11 Discontinuation of Study
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 


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sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.


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12 APPENDICES


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Appendix 1
American Association for the Study of Liver Diseases 
(AASLD) Criteria
Diagnosis of hepatocellular carcinoma is to be clinically confirmed according to AASLD 
practice guidelines as described in:  Bruix J, Sherman M; American Association for the 
Study of Liver Diseases.  Management of hepatocellular carcinoma: an update. Hepatology. 
2011;53(3):1020-2.  Available from:  http://www.aasld.org/practiceguidelines.
The diagnostic algorithm is shown below.


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Appendix 2
Modified Response Evaluation Criteria in Solid Tumors 
(mRECIST)
Tumor response assessments in this clinical trial will use modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) based on Lencioni and Llovet (2010) and incorporating 
elements of RECIST 1.1 based on Eisenhauer, et al. (2009). 
QUANTITATIVE AND QUALITATIVE ASSESSMENTS OF TUMOR BURDEN
The disease burden at Baseline will be categorized into target and nontarget lesions.  Within 
the target and nontarget categories are typical hepatic lesions, atypical hepatic lesions, and 
nonhepatic lesions.
•
Typical hepatic lesions are lesions that display hypervascularity in the arterial 
phase and “wash-out” in the portal venous phase of contrast-enhanced CT or MRI 
imaging.
•
Atypical hepatic lesions are lesions that are not showing the distinctive 
enhancement pattern but are considered to be malignant.
•
Nonhepatic lesions are all nodal and non-nodal lesions outside of the liver.
SELECTION AND MEASUREMENT OF TARGET LESIONS 
A maximum of 2 target lesions per organ and 5 target lesions in total, representative of all 
involved organs, may be selected.  Target lesions are lesions that can be accurately measured 
in at least 1 dimension and whose minimum lesion size is as follows:
•
Typical hepatic target lesions:  The longest diameter of the viable tumor must 
measure ≥1 cm or ≥two times the slice thickness/reconstruction interval (if the 
slice thickness/reconstruction interval is >5 mm).
•
Atypical hepatic target lesions:  The longest diameter must measure ≥1 cm or 
≥two times the slice thickness/reconstruction interval (if the slice 
thickness/reconstruction interval is >5 mm). 
•
Nonhepatic non-nodal target lesions:  The longest diameter must measure ≥1 cm 
or ≥two times the slice thickness/reconstruction interval (if the slice 
thickness/reconstruction interval is >5 mm). 
•
Nonhepatic nodal target lesions (lymph nodes):  The short axis must measure 
≥1.5 cm with exception of porta hepatis lymph nodes that need to be ≥2.0 cm in 
the short axis (regardless of modality/scanner type and slice 
thickness/reconstruction interval).


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If typical and atypical liver lesions are present, preference should be given to typical liver 
lesions when selecting targets.  Target lesions are measured at every time point and a single 
Sum of Diameters (SOD) will be determined by adding the longest diameters of all non-
nodal lesions and short axes (ie, widest dimensions perpendicular to the long axis) of nodal 
nonhepatic lesions.  For typical hepatic lesions the longest diameters will include only the 
viable tissue, while for all other target lesions all tumor tissue (whether necrotic or not) will 
be included in the SOD.  Note that hypovascular tissue should not be considered as necrotic 
(nonviable) tissue. While hypovascular tissue will still show contrast uptake (although less 
than what would be observed in a hypervascular lesion), necrotic tissue will show complete 
absence of any contrast enhancement. Quantitative determinations of average Hounsfield 
Units (HU) in the tissue of interest both pre-contrast and post-contrast may be used, if needed, 
to support the subjective assessment: necrotic (nonviable) tissue will show no change in HU 
between the phases, while hypovascular tissue will yield an increase in HU (although less 
than what would be observed in a hypervascular lesion) between pre-contrast and post-
contrast images of the same region.  Please refer to the Image Interpretation Guidance 
Manual for the use of mRECIST for HCC for further details regarding differentiating 
hypovascular from necrotic (nonviable) tissue.
Target lesions are assessed as CR, PR, SD, PD, or NE at every time point based on the SOD.
SELECTION AND ASSESSMENT OF NONTARGET LESIONS  
Nontarget lesions are all other lesions, including malignant portal vein thrombosis, 
infiltrative type, and diffuse type HCC with ill-defined lesion borders and truly 
nonmeasurable lesions.  Nontarget lesions will be assessed qualitatively, and the possible 
assessments are CR, Non-CR/Non-PD (NN), and PD. 
If a hepatic nontarget lesion exhibits an enhancement pattern that is consistent with HCC, the 
determination of CR, NN, PD, or NE will be dependent on the enhancing portion of the 
lesion.  All other nontarget lesions will be assessed following the conventional RECIST 1.1 
criteria.
If pleural effusions or ascites selected as nontarget lesions at Baseline are stable in size or 
minimally enlarging, they will be assessed as NN.  A cytopathological confirmation of any 
effusion that appears or worsens on treatment is required when the measurable tumor has met 
criteria for response or SD.
NEW LESIONS
New lesions are defined as:
•
Unequivocally new nonhepatic lesions seen at follow-up, without a corresponding 
lesion on the baseline imaging


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•
New typical hepatic lesions displaying intratumoral arterial enhancement 
(hypervascularization in the arterial phase and washout in the portal venous phase 
on contrast-enhanced CT or MRI) that measure ≥1 cm in the longest diameter
•
New atypical hepatic lesions ≥1 cm in the longest diameter that show interval 
growth in subsequent scans of at least 1 cm
Any lesion that meets the requirements for unequivocal new lesions will trigger PD.  Any 
lesion that does not meet the above criteria (eg, <1 cm in longest diameter and/or does not 
show typical HCC vascular enhancement pattern) should be considered an equivocal new 
lesion.  If an equivocal lesion is later determined to be unequivocal, the time point of 
progression will be the time point the lesion was first noted as equivocal.
OVERALL RESPONSE ASSESSMENTS
Target Lesions
Nontarget Lesions
New Lesions
Overall Time Point Response
CR
CR
No
CR
CR
NN
No
PR
CR
NE
No
PR
PR
NE
No
PR
PR
CR
No
PR
PR
NN
No
PR
SD
NE
No
SD
SD
CR
No
SD
SD
NN
No
SD
PD
Any
Yes/No
PD
Any
PD
Yes/No
PD
Any
Any
Yes
PD
NE
Non-PD
No
NE
CR
No nontarget lesions 
identified
No
CR
PR
No nontarget lesions 
identified
No
PR
SD
No nontarget lesions 
identified
No
SD
CR = complete response, NE = not evaluable, NN = Non-CR/Non-PD, PD = progressive disease, PR = partial 
response, SD = stable disease.


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Appendix 3
Barcelona Clinic Liver Cancer (BCLC) Staging System
European Association for the Study of the Liver; European Organisation for Research and Treatment of Cancer.  
EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.  J Hepatol. 2012 
Apr;56(4):908-43.  Erratum to: ‘‘EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular 
carcinoma’’ [J Hepatol 2012;56:908-43]. J Hepatol. 2012 Jun;56(6):1430.


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Appendix 4
Child-Pugh Classification
Parameter
Scorea
1
2
3
Ascites
Absent
Mild
(Respond to treatment)
Moderate
(Refractory)
Serum bilirubin (mg/dL)
<2.0
2.0–3.0
>3.0
Serum albumin (g/dL)
>3.5
2.8–3.5
<2.8
INR 
<1.7
1.7–2.30
>2.30
Encephalopathyb
0
1–2
3–4
INR = international normalized ratio.
a:  Child-Pugh A: 5 or 6 points; Child-Pugh B: 7–9 points; Child-Pugh C: >9 points.
b: Encephalopathy grades defined as follows:
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram 
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps (cycles per second) 
waves 
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves 
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
Grade 4:  unrousable, coma, no personality/behavior, decerebrate, slow 2–3 cps delta activity


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Appendix 5
Eastern Cooperative Oncology Group Performance 
Status (ECOG-PS)
Scale
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light house work, office work)
2
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.
5
Dead
Adapted from Oken MM, et al. Am J Clin Oncol. 1982;5:649-55.


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Appendix 6
Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03
The Common Terminology Criteria for Adverse Events (CTCAE v4.03, published 14 June 
2010) provides descriptive terminology to be used for adverse event reporting in clinical
trials.  A brief definition is provided to clarify the meaning of each AE term.  To increase the 
accuracy of AE reporting, all adverse event terms in CTCAE v4.03 have been correlated with 
single-concept Medical Dictionary for Regulatory Activities (MedDRA) terms.
The Common Terminology Criteria for Adverse Events v4.03 grading refers to the severity 
of the AE.  The Common Terminology Criteria for Adverse Events grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Grade
CTCAE Status
1
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
2
Moderate:  minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADLb
4
Life-threatening consequences: urgent intervention indicated
5
Death related to adverse event
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03
For further details regarding MedDRA, refer to the MedDRA website at:  
http://www.meddra.org


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Appendix 7
New York Heart Association (NYHA) Cardiac Disease 
Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for cardiac subjects.  Based 
on NYHA definitions, subjects are to be classified as follows:
Class
NYHA Status
Class I:
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II:
Subjects with slight, mild limitation of activity; they are comfortable with rest 
or with mild exertion.
Class III:
Subjects with marked limitation of activity; they are comfortable only at rest.
Class IV:
Subjects who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest.
NYHA = New York Heart Association.
Adapted from The Criteria Committee of the New York Heart Association.  Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels.  9th ed. New York: Little Brown; 1994. p.253-6.


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Appendix 8
Clinical Studies Evaluating Drug–Drug Interactions 
with Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme
responsible for metabolism of lenvatinib.  Clinical studies were conducted to test these 
findings.  
Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly (15% to 
19%) increases systemic exposure to lenvatinib (Shumaker, et al., 2015).  Since no change 
was observed in half-life, tmax, or lag time (tlag), the slight increase in systemic exposure is 
probably related to a decrease in first pass metabolism.  However, since the magnitude of 
change is small, co-administration of lenvatinib with CYP3A4/P-gp inhibitors is not of 
clinical concern.  
The influence of P-gp inhibition on lenvatinib PK has been investigated.  P-gp inhibition was 
accomplished by co-administering a single dose of rifampin with a single dose of lenvatinib.  
Preliminary results suggest P-gp inhibition increases systemic exposure to lenvatinib 26% to 
32%.  Thus, co-administration of lenvatinib with P-gp inhibitors only causes a small increase 
in lenvatinib exposure.  
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been 
investigated.  Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK 
was accomplished by administering rifampin QD for 21 days (Shumaker, et al., 2014).  A 
single dose of lenvatinib was co-administered with the 15th dose of rifampin.  Based on 
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib 
exposure as mean Cmax increased about 8% while AUC decreased about 7%.  Co-
administration of lenvatinib with CYP3A4/P-gp inducers is not of clinical concern.


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Appendix 9
Tumor, Node, and Metastasis Staging of Hepatocellular 
Carcinoma
The TNM (tumor-node-metastasis) classification for staging of hepatocellular carcinoma per 
the American Joint Committee on Cancer (AJCC) is provided below:
Primary tumor (T)
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Solitary tumor without vascular invasion
T2 Solitary tumor with vascular invasion or multiple tumors, none >5 cm
T3a Multiple tumors >5 cm
T3b Single tumor or multiple tumors of any size involving a major branch of the portal or 
hepatic vein
T4 Tumor(s) with direct invasion of adjacent organs other than gallbladder or with visceral 
peritoneum
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Anatomic stage/prognostic groups
Stage
T
N
M
I
T1
N0
M0
II
T2
N0
M0
IIIA
T3a
N0
M0
IIIB
T3b
N0
M0
IIIC
T4
N0
M0
IVA
Any T
N1
M0
IVB
Any T
Any N
M1


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Source:  Cheng CH, Lee CF, Wu TH, Chan KM, Chou HS, Wu TJ, et al. Evaluation of the 
new AJCC staging system for resectable hepatocellular carcinoma. World J Surg Oncol. 
2011;9:114.  Available from:  http://www.wjso.com/content/9/1/114.


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Appendix 10
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic, pharmacogenomic, and other biomarker analysis.  These samples may be 
used for discovery and validation to identify biomarkers that may be used for exploratory 
evaluation of response and/or safety-related outcomes as well as for use in diagnostic 
development.
The pharmacogenomic samples may be used to identify genetic factors that may influence a 
subject’s exposure to the study drug, as well as genetic factors that may have an effect on 
clinical response or potential adverse events related to study treatment, and to explore the 
role of genetic variability in response.  Samples may be analyzed to determine a subject’s 
genotypes or sequence for a number of genes or non-coding regulatory regions.  The research 
may include the investigation of polymorphisms in genes that are likely to influence the 
study drug pharmacokinetics or therapeutic response.
Collection of the pharmacodynamic, pharmacogenomic, and other biomarker samples will be 
bound by the sample principles and processes outlined in the main study protocol.  Sample 
collection for pharmacodynamic, pharmacogenomic, and other biomarker analysis is required 
as per the study protocol unless the collection and use of the samples is prohibited by specific 
country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 


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authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All pharmacodynamic and other biomarker 
samples will be single coded.  Genomic DNA samples used to explore the effects on PK, 
treatment response, and safety will be single coded.  Genomic DNA samples that will be 
stored for long-term use (defined as 15 years after the completion of the study) will be double 
coded.  Double coding involves removing the initial code (subject ID) and replacing with 
another code such that the subject can be re-identified by use of 2 code keys.  The code keys 
are usually held by different parties.  The key linking the sample ID to the subject number 
will be maintained separately from the sample.  At this point, the samples will be double-
coded, the first code being the subject number.  Laboratory personnel performing genetic 
analysis will not have access to the “key.”  Clinical data collected as part of the clinical trial 
will be cleaned of subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:

Clinical research organizations retained by the sponsor 

Independent ethics committees or institutional review boards that have responsibility for 
this research study 

National regulatory authorities or equivalent government agencies


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At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the pharmacodynamic, pharmacogenomic, and other biomarker 
analysis, it will not be possible to return individual data to subjects.  The results that may be 
generated are not currently anticipated to have clinical relevance to the patients or their 
family members.  Therefore, these results will not be disclosed to the patients or their 
physicians.
If at any time, pharmacodynamic, pharmacogenomic, and/or other biomarker results are 
obtained that may have clinical relevance, IRB review and approval will be sought to 
determine the most appropriate manner of disclosure and to determine whether or not 
validation in a Clinical Laboratory Improvement Amendments (CLIA)-certified setting will 
be required.  Sharing of research data with individual patients should only occur when data 
have been validated by multiple studies and testing has been done in CLIA-approved 
laboratories.


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Appendix 11
KEYTRUDA® Package Insert
The latest KEYTRUDA Package Insert is available in the FDA website at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/125514s014lbl.pdf
KEYTRUDA Summary of Product Characteristics is available at: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/003820/WC500190990.pdf


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: 
E7080-J081-116 
E7080-J081-J 16 
Study Protocol Title: 
An Open-Label Phase I b Trial ofLenvatinib Plus 
Pembrolizumab in Subjects with HepatoceJlular Carcinoma 
lnvestigational Product 
Name: 
Lenvatinib (E7080/LENVJMA ™)and Pembrolizumab (MK-
3475/KEYTRUDA ®) 
IND Number: 
115650 
EudraCT Number: 
2018-000522-55 
SIGNATURES 
Authors: 
Eisai 
FINAL: 17 Jan 2019 
Oncology Business Group, Eisai lnc. 
Oncology Business Group, Eisai Inc. 
Confidential 
Z I 't'vv. ZO/lj 
•./ 
Date 
Date 
Page 168 of169 
PPD
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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-J081-116
Study Protocol Title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subjects with Hepatocellular Carcinoma
Investigational Product
Name:
Lenvatinib (E7080/LENVIMA™) and pembrolizumab (MK-
3475/KEYTRUDA®)
IND Number:
115650
EudraCT Number:
2018-000522-55
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date

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