Conditions: Carcinoma, Hepatocellular
Keywords: Unresectable hepatocellular carcinoma Lenvatinib E7080
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 8
Healthy volunteers: no

Brief summary:
The primary objective of this study is to assess the safety and tolerability of subsequent systemic treatment of physician's choice (TPC) following the first-line lenvatinib treatment in unresectable hepatocellular carcinoma (uHCC) participants.

Detailed description:

Arms:
arm 1: Participants will receive lenvatinib 12 or 8 milligrams (mg) once daily in continuous 28-day cycles until disease progression, development of unacceptable toxicity, participant request, withdrawal of consent, or study termination by the sponsor. Upon completion of lenvatinib treatment, eligible participants will receive commercially available systemic TPC for hepatocellular carcinoma in the subsequent treatment period.

Interventions: intervention 1: Lenvatinib
Intervention descriptions: intervention 1: Lenvatinib capsules will be administered orally, once daily in continuous 28-day cycles.

Body weight (BW) ≥60 kilograms (kg) - Lenvatinib 12 mg (taken as three 4-mg capsules); BW \<60 kg - Lenvatinib 8 mg (taken as two 4-mg capsules)

Protocol document:
Prot_SAP_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-M001-222
Study Protocol 
Title:
A Single-Arm, Multicenter, Phase 2 Trial to Evaluate Safety and 
Efficacy of Treatment of Physician Choice (TPC) Following 
First-Line Treatment of Lenvatinib in Subjects With Unresectable 
Hepatocellular Carcinoma (uHCC)
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
US
Investigational 
Product Name:
LENVIMA® (E7080/Lenvatinib)
Indication:
Hepatocellular Carcinoma (HCC)
Phase:
2
Approval Date(s):
20 Dec 2017
Original Protocol
26 Jan 2018 
Amendment 01
15 Mar 2018
Amendment 02
24 Sep 2018
Amendment 03
IND Number:
115650
GCP Statement:
This study is to be performed in full compliance with International 
Council on 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.


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REVISION HISTORY
Revisions per Amendment 03
Date: 24 Sep 2018
Change
Rationale
Affected Protocol Sections
The term “systemic” was added to 
Treatment of Physician’s choice 
(TPC) to specify and add clarity 
that only systemic treatment 
following lenvatinib treatment will 
be considered as subsequent TPC.
The update was made to highlight 
that only “systemic” treatment will 
be considered as subsequent TPC 
for the study and that locoregional 
procedures will not be considered 
as subsequent TPC.
Synopsis: Objectives, Study 
Design, Study Treatments, 
Subsequent Treatment of Physician 
Choice (TPC), Endpoints
Section 7.1
Section 8.1
Section 8.2
Section 9.1
Section 9.1.2.2
Section 9.1.2.3
Section 9.2
Section 9.4.1.2
Section 9.7.1.1.1
Section 9.7.1.1.2
It was clarified that any 
locoregional therapies (ie, 
chemoembolization /
radioembolization, etc.) will not be 
considered as second line treatment 
following lenvatinib.
The update was made to highlight 
that locoregional procedures will 
not be considered as subsequent 
TPC for the study.
Synopsis: Study Design
Section 9.1.2.2
Section 9.4.1.2
Remove ambiguous wording in the 
protocol to make clear that the TPC 
period is not optional.  The 
continuation to second line 
treatment is expected as long as 
commercially available systemic 
second line treatment is deemed by 
the physician to be clinically 
appropriate. The choice of which 
second line treatment is used is at 
the discretion of the physician.
The change was made to highlight 
that the subsequent TPC period 
following lenvatinib is not 
optional, and that if eligible, 
subjects should receive systemic 
TPC as second line treatment.
Synopsis:  Subsequent Treatment 
of Physician Choice (TPC)
Section 9.1
Section 9.4.1.2
Study rationale was updated to 
further clarify the purpose of the 
study with focus on addressing the 
unmet medical need for data for 
safety and efficacy on the 
subsequent sequential therapies 
after 1st line therapy with 
lenvatinib in uHCC patients, 
The study rationale was updated to 
provide additional clarity for the 
purpose of the study. 
Section 7.1


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US package insert was replaced 
with the lenvatinib Global 
Investigator’s Brochure (GIB) as a 
reference for the dose adjustments 
and drug-drug interactions for 
lenvatinib.
The US package insert was 
replaced with the GIB as the 
source of reference for the 
drug-drug interaction section since 
the GIB is provided to all 
investigators for reference and 
includes all information presented 
in the section on drug-drug 
interactions in the protocol. Also, 
the GIB would be an appropriate 
reference for sites in Canada.
Section 9.4.7.1
Updated information for lenvatinib 
interactions with other 
co- administered drugs which are 
CYP3A4/Pgp substrates:  “In a 
formal drug-drug interaction study, 
lenvatinib did not alter plasma 
concentrations of midazolam (a 
sensitive CYP3A and Pgp 
substrate).  Thus, lenvatinib is not 
expected to alter the metabolism of 
other co administered drugs which 
are CYP3A4/Pgp substrates”.
The information was updated to 
present the latest information on 
lenvatinib drug-drug interactions. 
Section 9.4.7.1
Clarified that echocardiograms 
(ECHO) should be performed 
locally in accordance with the 
institution’s standard practice.  The 
requirement to submit ECHO and 
MUGA scans to the central 
laboratory for analysis and 
archiving was deleted.
Reference to central laboratory in 
previous protocol versions was an 
error, and was removed to reflect 
that the study does not require a 
central laboratory for these 
assessments (ECHO and MUGA 
scans).
Section 9.5.1.5.7
Clarified that a gastroenterological 
endoscopy at screening is 
necessary only if more than 3 
months have passed since the 
previous assessment.  
Gastroenterological endoscopy 
must have been performed within 3 
months prior to receiving first dose 
of the study treatment.
Added to emphasize the 
requirement of a 
gastroenterological endoscopy 
within 3 months prior to receiving 
the first dose of the study 
treatment. 
Section 9.5.2.1 (Table 3 –
Footnote e)


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Revisions per Amendment 02
Date: 15 Mar 2018
Change
Rationale
Affected Protocol Sections
Secondary objective was updated 
as follows:

Evaluation of objective 
response rate (ORR) and 
clinical benefit rate (CBR) in 
both the first-line lenvatinib 
treatment period and the 
subsequent TPC period was 
deleted.

Progression-free survival 
(PFS) and time to progression 
(TTP) will be evaluated for the 
subsequent treatment of 
physician choice (TPC) 
starting from the first dose of
first-line lenvatinib treatment.
The changes to the secondary 
objective were made because there 
is no meaningful way to 
summarize the ORR for the 
duration of the study.
Clarify that PFS and TTP will be 
evaluated for the subsequent 
treatment of physician choice 
(TPC) starting from the first dose 
of first-line lenvatinib treatment
Synopsis:  Secondary Objectives
Section 7.1
Section 8.2
Secondary endpoints were updated 
in line with changes in the 
secondary objective as follows:

Progression-free survival 
(PFS), defined as the time 
from the date of first dose of 
first-line lenvatinib treatment 
to the date of first 
documentation of disease 
progression, or date of death 
during the subsequent TPC, 
whichever occurs first.  

Time to progression (TTP), 
defined as the time from the 
date of first dose of first-line 
lenvatinib treatment to the date 
of first documentation of 
disease progression during 
subsequent TPC.  

Evaluation of ORR and CBR 
was deleted.
Secondary endpoints were updated 
to align with the changes in the 
secondary objective.
Synopsis:  Secondary Endpoints
Section 9.7.1.1.2
Efficacy analysis:  

Evaluation of PFS and TTP for 
both treatment periods was 
deleted since PFS and TTP 
will be evaluated for the 
subsequent TPC period 
following first-line lenvatinib 
treatment.

Evaluation of ORR was
deleted.
Efficacy analyses were updated
based on changes in secondary 
objectives and secondary 
endpoints.
Synopsis:  Efficacy Analyses
Section 9.7.1.6


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Change
Rationale
Affected Protocol Sections
Sample size rationale was updated.
The rationale was updated to be 
consistent with the primary 
objective.
Synopsis:  Sample Size Rationale
Section 9.7.2
Study rationale was updated for 
further clarity.  Data presented 
formerly in Introduction section 
regarding survival follow-up 
period in Study E7080-G000-304 
was moved to Study Rationale 
section to provide additional clarity 
for rationale of the study.
To provide more clarity for the 
rationale of the study.
Section 7
Section 7.1
Study design text was updated to 
clarify that the study will evaluate 
safety and efficacy of subsequent 
TPC (commercially available) 
following first-line lenvatinib 
treatment.
Text was updated to align with the 
primary objective.
Synopsis:  Study Design
Section 7.1
Section 9.1
Section 9.2
Criterion for non-hepatic target 
lesion in the inclusion criteria was 
updated to delete specifications for 
porta hepatis lymph node.
To avoid confusion for the 
inclusion criteria for non-hepatic 
lesions.
Synopsis:  Inclusion criteria
Section 9.3.1
Appendix 2
Information on treatment included 
in TPC was added in the section 
for study treatments.
To provide TPC information in 
synopsis.
Synopsis:  Study Treatments 
For the TPC, the following 
sentence was deleted ‘Once the 
dose has been reduced, it cannot be 
increased at a later date’.
To emphasize that decisions on 
dosing reduction/interruptions will 
be based on the prescribing 
information for the TPCs.
Synopsis:  Subsequent Treatment 
of Physician Choice (TPC) - Dose 
Reduction and Interruption
Section 9.4.1.2
Definition of concomitant 
medications was updated to include 
medications up to 28 days after last 
dose of TPC if subject does not 
stay in the TPC period for the 
8 weeks of safety monitoring.
To align data collection.
Section 9.4.7
Section 9.5.2.1 (Table 3)
Section 9.7.1.5
Appendix 2 for mRECIST was 
updated to include additional 
examples for non-target lesions.
To provide additional examples for 
selection of non-target lesions.
Appendix 2
Table in Appendix 8 for CYP3A4 
substrates, inhibitors, and inducers 
was deleted and it was clarified 
that the 
http://medicine.iupui.edu/clinphar
m/ddis/ website should be referred 
to for most updated information on 
CYP3A4 substrates, inhibitors, and 
inducers.
To refer to most updated 
information on CYP3A4 
substrates, inhibitors, and inducers.
Appendix 8


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Revisions per Amendment 01
Date: 26 Jan 2018
Change
Rationale
Affected Protocol Sections
Title of the protocol was reworded 
to “A Single-Arm, Multicenter, 
Phase 2 Trial to Evaluate Safety 
and Efficacy of Treatment of 
Physician Choice (TPC) Following 
First-Line Treatment of Lenvatinib 
in Subjects With Unresectable 
Hepatocellular Carcinoma (uHCC).
The title of the protocol was 
reworded to add clarity and to 
align with the updated text for the 
primary objective and the primary 
endpoint.
Title page
Synopsis: Study Protocol Title
Primary objective and primary 
endpoint were reworded as 
assessment of safety and 
tolerability of subsequent TPC 
following the first-line lenvatinib 
treatment in uHCC subjects.
Updated to add clarity.

Synopsis: Primary Objective, 
Primary Endpoint

Section 8.1

Section 9.7.1.1.1
The schedule for safety data 
collection during TPC (ie, 
Treatment Period 2 [TP2]) was
specified with updates made in 
Table 3.  
It was also specified that AEs will 
be reported until 28 days after the 
last dose of lenvatinib treatment if 
subjects do not enter TPC period, 
or for 8 weeks after the start of 
TPC period.  SAE information 
should be collected for 8 weeks 
after the start of the TPC, or for at 
least 28 days after the last dose of 
lenvatinib/TPC if subjects do not 
continue into the TPC period or do 
not stay in the TPC period for the 
8 weeks of safety monitoring 
(Table 3, footnote “z”, 
Section 9.5.1.5.1, and
Section 9.5.4.1).
The following footnote (footnote 
“aa”) was added in Table 3 to 
clarify assessments after week 16:  
After week 16, only tumor 
assessment and TPC dose 
information will be collected until 
the end of TPC (disease 
progression, development of 
unacceptable toxicity, subject 
request, withdrawal of consent, or 
study termination by the sponsor).
The schedule for data collection 
during TPC was specified to allow 
systematic collection of safety data 
during TPC period following 
1st line lenvatinib treatment of 
uHCC.

Synopsis: Study Design, 
Safety Assessments

Section 9.1.2.2

Section 9.5.1.5

Section 9.5.2.1 (Table 3)


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For TP2, it was clarified that 
subjects starting subsequent TPC 
≥8 weeks after lenvatinib 
off-treatment visit may be 
considered after discussion with 
sponsor.
To add clarity about the TPC 
period duration.

Synopsis: Study Design

Section 9.1.2.2
For subsequent TPC definition, it 
was clarified that the first treatment 
of a single agent or combination of 
multiple drugs after lenvatinib
treatment will be considered as the 
subsequent TPC.  
Chemoembolization procedures 
will not be considered as a second 
line treatment following lenvatinib.  
If commercially available TPC is 
not used as the subsequent 
treatment following lenvatinib 
treatment, subjects will be followed 
in the survival follow up period.
To provide clarity of definition of 
TPC.
Added in 1 to provide clarity on 
chemoembolization procedures.

Section 9.4.1.2

Section 9.1.2.2
For the duration of TPC, it was 
clarified that subjects will continue 
to receive TPC treatment until 
disease progression, development 
of unacceptable toxicity, subject 
request, withdrawal of consent, or 
study termination by the sponsor.

Synopsis:  Duration of 
Treatment

Section 9.4.1.2
For concomitant medications, it 
was clarified that concomitant 
medications will be recorded until 
28 days after last dose of lenvatinib 
treatment if subjects do not enter 
TPC period, or for 8 weeks after 
the start of TPC period.  All 
anticancer therapy will be recorded 
until time of death or termination 
of survival follow-up.
Updated to adjust the assessment 
schedule.

Section 9.4.7

Section 9.7.1.5

Section 9.5.2.1 (Table 3)
Assessment of special chemistries 
was added at Baseline and C1D15.
Pregnancy test at the Treatment 
Period 1 off -treatment visit was 
deleted.
Also, it was clarified that NYHA 
cardiac disease classification 
should only be performed at 
Screening if needed.
Updated to adjust the assessment 
schedule.

Section 9.5.2.1 (Table 3)


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For the pharmacodynamic blood 
(serum/plasma) biomarkers and 
pharmacogenetic biomarkers 
assessments, it was clarified that 
samples will be collected at week 8 
and week 16 (±1 week), and that 
subjects entering the subsequent 
TPC period should have TPC 
baseline sample collected unless 
the lenvatinib Off-Treatment visit 
in the lenvatinib treatment period is 
≤28 days before the subsequent 
treatment starts, in which case 
those samples may be used as the 
TPC period baseline.
This was added for clarity on
biomarker data collection during 
TPC period.

Synopsis: Pharmacodynamic 
Blood Biomarkers, 
Pharmacogenetic Biomarker 
Assessments.

Section 9.5.1.4.2

Section 9.5.2.1 (Table 3)
Blood (whole blood) sample 
collection for potential genetic 
analysis from all enrolled subjects 
was added to evaluate whether 
genetic variation within a clinical 
study population correlates with 
response to the study treatment.  
The following was additionally 
added: Biomarker correlative 
analyses may be performed to 
explore blood or tumor biomarkers 
that may be useful to predict 
subject’s response in a 
retrospective manner.  The results 
of these studies are to gain further 
insight into the clinical mechanism 
of action for study drug but not 
foreseen to result in commercially 
valuable products.
This study will collect biomarker 
samples in all enrolled subjects 
who have consented for 
participation of the biomarker 
assessments.  Participation of any 
future exploratory research of left 
over material will be optional. 
This was added to allow potential 
genetic analysis from all enrolled 
subjects, to evaluate whether 
genetic variation within a clinical 
study population correlates with 
response to the study treatment.

Synopsis: Pharmacogenetic 
Biomarker Assessments

Section 9.5.1.4.2

Section 9.5.2.1 (Table 3)
It was specified that in TPC period, 
PRO-CTCAE questionnaires will 
be collected 2 weeks for the first 
4 weeks, and then at week 8, and 
week 16 (±1 week).  A TPC 
baseline assessment should be 
performed unless the lenvatinib 
Off-Treatment visit is completed 
within 7 days prior to the first TPC 
treatment.
Updated to adjust the assessment 
schedule.

Synopsis: Other assessments

Section 9.5.1.6

Section 9.5.2.1 (Table 3)


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The analysis of extent of exposure 
was updated to include 
summarization of percentage of 
subjects that receive TPC, average 
dose intensity and relative dose 
intensity of lenvatinib treatment 
and TPC, and feasibility rate.
To obtain comprehensive 
information about the extent of 
exposure.

Section 9.7.1.8.1


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
A Single-Arm, Multicenter, Phase 2 Trial to Evaluate Safety and Efficacy of Treatment of Physician 
Choice (TPC) Following First-Line Treatment of Lenvatinib in Subjects With Unresectable 
Hepatocellular Carcinoma (uHCC)
Investigators
United States (US), Canada
Sites
Approximately 20 to 25 sites 
Study Period and Phase of Development
Approximately 30 months from first subject enrolled to end of last subject in TPC.
Phase 2  
Objectives
Primary Objective

To assess the safety and tolerability of subsequent systemic TPC following first-line lenvatinib
treatment in uHCC subjects.
Secondary Objectives

To evaluate overall survival (OS) in uHCC subjects treated with lenvatinib as the first-line 
treatment followed by systemic TPC.

To evaluate progression-free survival (PFS) and time to progression (TTP) of subsequent 
systemic TPC starting from the first dose of first-line lenvatinib treatment using modified 
Response Evaluation Criteria in Solid Tumors (mRECIST).

To evaluate OS by subgroups of systemic TPC.
Exploratory Objectives

To measure the patient perceived burden by Patient-Reported Outcomes version of the Common 
Terminology Criteria for Adverse Events (PRO-CTCAE) in the subsequent TPC period.

To explore biomarkers based on availability of serum and tissue samples.
Study Design
This study is a single-arm, open-label, multicenter, phase 2 trial to evaluate safety and efficacy of 
subsequent systemic TPC (commercially available) following first-line lenvatinib treatment in 
subjects with uHCC. 
The study will consist of a Pretreatment Phase and a Treatment Phase.  The pretreatment phase will 
last up to 21 days and will include the Screening Period to obtain informed consent and establish 
protocol eligibility, and the Baseline Period to confirm protocol eligibility and disease characteristics. 
The Treatment Phase consists of 2 treatment periods (Lenvatinib Treatment Period [Treatment Period
1] and the Subsequent TPC Treatment Period [Treatment Period 2]) and a Follow-Up Period. The 
Lenvatinib Treatment Period (Treatment Period 1) for each subject will begin at the time of the first 
dose of lenvatinib study treatment and will consist of lenvatinib treatment on 28-day cycles until 


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completion of the lenvatinib Off-Treatment Visit that will occur within 30 days after the final 
administration of lenvatinib.  
Lenvatinib treatment cycles will be counted continuously regardless of dose interruptions.  Subjects 
will undergo safety and efficacy assessments as defined in the Schedule of Procedures/Assessments.  
Subjects will continue to receive study treatment until disease progression, development of 
unacceptable toxicity, subject request, withdrawal of consent, or study termination by the sponsor.  
Subjects will be permitted to continue lenvatinib treatment beyond mRECIST defined disease 
progression as long as the treating investigator considers that there is clinical benefit and, the subject 
is tolerating study treatment. The assessment of clinical benefit should take into account whether the 
subject is clinically deteriorating and unlikely to receive further benefit from continued treatment. 
All decisions to continue treatment beyond initial progression must be discussed with the Eisai 
Medical Monitor. Subjects will discontinue study treatment upon evidence of further progression 
and/or loss of clinical benefit, as judged by the investigator.
The Subsequent Treatment Period (TPC period, Treatment Period 2) will begin upon the completion 
of lenvatinib Off-Treatment Visit in first-line treatment of lenvatinib.  Subjects will be treated by 
commercially available systemic TPC for uHCC. Locoregional therapies (ie, 
chemoembolization/radioembolization, etc.) will not be considered as a second line treatment 
following lenvatinib. If the investigator deems a subject inappropriate for commercially 
available systemic TPC as the subsequent treatment following lenvatinib, subjects will be followed in 
the survival Follow-Up period.  All treatment following lenvatinib will be captured in the case report 
form. Data will be collected from the start of TPC, then at intervals as indicated in Schedule of 
Procedures/Assessments (Table 3). 
Subjects starting subsequent systemic TPC ≥8 weeks after lenvatinib off-treatment visit may be 
considered after discussion with sponsor.
The Follow-Up Period will begin immediately after the final visit in the subsequent treatment period
(Treatment Period 2).  Subjects will be followed every 12 weeks for survival and will continue as 
long as the study subject is alive, unless the subject withdraws consent.  If the investigator deems a 
subject inappropriate for commercially available subsequent systemic TPC, the subject will be
followed for survival every 12 weeks after the lenvatinib Off-Treatment Visit in the lenvatinib 
treatment period (Treatment Period 1).  Subjects’ survival status and all additional anticancer 
treatments received will be recorded.
The sponsor may decide to terminate survival follow-up of subjects after the completion of the 
primary analysis or when all subjects have discontinued study treatment.
Number of Subjects
Approximately 100 subjects with uHCC will be enrolled to the first-line treatment of lenvatinib. 
Inclusion Criteria
1.
Subjects must have confirmed diagnosis of uHCC with any of the following criteria:
a.
Histologically or cytologically confirmed diagnosis of uHCC
b.
Clinically confirmed diagnosis of uHCC according to American Association for the Study of
Liver Diseases (AASLD) criteria, including cirrhosis of any etiology or with chronic 
hepatitis B or C infection criteria
2.
At least one measurable target lesion regardless if hepatic or non-hepatic according to mRECIST 
meeting the following criteria:
a.
Hepatic lesion
•
The lesion can be accurately measured in at least one dimension as ≥1.0 cm (viable tumor 


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for typical; and longest diameter for atypical), and
•
The lesion is suitable for repeat measurement, 
b.
Nonhepatic lesion
•
Lymph node lesion that measures at least one dimension as ≥1.5 cm in the short axis
•
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.
3.
Subjects categorized on the Barcelona Clinic Liver Cancer (BCLC) staging system to Stage B 
(not applicable for transarterial chemoembolization [TACE]) or Stage C
4.
Adequate bone marrow function, defined as:
•
Absolute neutrophil count (ANC) ≥1.5 × 109/L
•
Hemoglobin ≥8.5 g/dL
•
Platelet count ≥75 × 109/L
5.
Adequate liver function, defined as:
•
Albumin ≥2.8 g/dL
•
Bilirubin ≤3.0 mg/dL
•
Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine aminotransferase
(ALT) ≤5 × the upper limit of normal (ULN)
6.
Adequate blood coagulation function, defined as international normalized ratio (INR) ≤2.3
7.
Adequate renal function defined as creatinine clearance >30 mL/min calculated per the Cockcroft
and Gault formula
8.
Adequate pancreatic function, defined as lipase ≤1.5 × ULN
9.
Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents, defined as BP 
≤150/90 mmHg at Screening and no change in antihypertensive therapy within 1 week prior to
Cycle 1/Day 1
10. Child-Pugh A
11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
12. Survival expectation of 12 weeks or longer before starting study drug
13. Males or females aged at least 18 years at the time of informed consent
14. Provide written informed consent
15. Willing and able to comply with all aspects of the protocol
Exclusion Criteria
1.
Imaging findings for HCC corresponding to any of the following:
a.
HCC with ≥50% liver occupation
b.
Clear invasion into the bile duct
c.
Portal vein invasion at the main portal branch (Vp4)
2.
Subjects who have received any systemic chemotherapy, including sorafenib, regorafenib or 
other anti-vascular endothelial growth factor (VEGF) therapy, nivolumab, or any systemic 
investigational anticancer agents, including lenvatinib, for advanced/uHCC.  Note:  Subjects who 
have received local hepatic injection chemotherapy (if not within 28 days prior to the first dose of 
lenvatinib study treatment) are eligible
3.
Subjects who have received any anticancer therapy (including surgery, percutaneous ethanol 
injection, radio frequency ablation, transarterial [chemo] embolization, hepatic intra-arterial 


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chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or 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 lenvatinib study treatment
4.
Subjects who have not recovered from toxicities as a result of prior anticancer therapy such as the 
local hepatic injection chemotherapy or any prior therapy for other cancer types.  Recovery is 
defined as <Grade 2 severity per Common Terminology Criteria for Adverse Events 
Version 4.03 (CTCAE v4.03), except alopecia and infertility
5.
Significant cardiovascular impairment within 6 months of the first dose of study drug: history of 
congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable 
angina, myocardial infarction or stroke, cardiac arrhythmia associated with hemodynamic 
instability, or a left ventricular ejection fraction (LVEF) below the institutional normal range as 
determined by multigated acquisition (MUGA) scan or echocardiogram
6.
Prolongation of QTcF (QT interval corrected for heart rate using Fridericia’s correction) interval 
to >480 ms
7.
Gastrointestinal malabsorption or any other condition that might affect the absorption of 
lenvatinib in the opinion of the investigator
8.
Bleeding or thrombotic disorders or use of anticoagulants such as, warfarin or similar agents 
requiring therapeutic INR monitoring.  (Treatment with low molecular weight heparin is 
allowed.)
9.
Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least half teaspoon) 
within 28 days prior to the first dose of lenvatinib study treatment 
10. Gastric or esophageal varices that require treatment
11. 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
12. Any history of, or current brain or subdural metastases
13. Subjects having >1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection 
for quantitative assessment of proteinuria.  Subjects with urine protein ≥1 g/24 h will be 
ineligible.
14. Arterial-portal venous shunt or arterial-venous shunt preventing proper diagnosis of tumor
15. Any medical or other condition that in the opinion of the investigator would preclude the 
subject’s participation in a clinical study
16. Known intolerance to lenvatinib or any of the excipients
17. Human immunodeficiency virus (HIV) positive or active infection requiring treatment (except 
for hepatitis virus)
18. Any history of drug or alcohol dependency or abuse within the prior 2 years
19. 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
20. Major surgery within 3 weeks prior to the first dose of lenvatinib study treatment or scheduled 
for surgery during the study
21. Subject has had a liver transplant
22. 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 


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baseline assessment is required if a negative screening pregnancy test was obtained more than 
72 hours before the first dose of study drug
23. Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of contraception, which 
includes any of the following:
-
total abstinence (if it is their preferred and usual lifestyle)
-
an intrauterine device or intrauterine hormone-releasing system (IUS)
-
a contraceptive implant
-
an oral contraceptive (with additional barrier method) (Subject must be on a stable dose of 
the same oral contraceptive product for at least 28 days before dosing and throughout the 
study and for 28 days after study drug discontinuation).
-
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) throughout 
the entire study period and for 28 days after study drug discontinuation.
For sites outside of the 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 latex or 
synthetic condom plus diaphragm or cervical/vault cap with spermicide.
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).
24. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period and for 96 days after study drug 
discontinuation).  No sperm donation is allowed during the study period and for 96 days after 
study drug discontinuation. 
Study Treatments
Test Drug:  Lenvatinib is provided as 4 mg capsules.
Starting dose of lenvatinib will be based on baseline body weight (BW) as follows:

BW ≥60 kg — Lenvatinib 12 mg (three 4 mg capsules) once daily (QD) will be taken orally.

BW <60 kg — Lenvatinib 8 mg (two 4 mg capsules) QD will be taken orally.
Study medication should be taken at approximately the same time each day.
If a dose is missed and cannot be taken within 12 hours, then that dose should be skipped and the 
next dose should be taken at the usual time of administration.
Study medication may be taken in a fasting state or following a meal.
Treatment of Physician Choice (TPC): TPC is limited to commercially available systemic 
products for uHCC.
Dose adjustments for management of toxicities will be made according to the guidelines 
provided in the table below.


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Study Treatment Dose Reduction and Interruption Instructions
Dose reductions occur in succession based on the previous dose level (eg, 12, 8, and 4 mg/day, and 4 mg every 
other day for the subjects with initial BW ≥60 kg).  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.
Non-Hematologic Toxicities
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d or Grade 3e,d
First occurrence
Interrupt until resolved to Grade 0-1 
or baseline
One-level reduction
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
One-level reduction
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
One-level reduction
Fourth occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
Discuss with sponsor
Grade 4g:  Discontinue Study Treatment
Hematologic Toxicities and Proteinuria
Treatment-Related Toxicitya
Management
Dose Adjustment
Grade 1 or Grade 2
Continue treatment
No change
Grade 3
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
One-level reduction
Third occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Fourth occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Fifth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Discuss with sponsor
Grade 4
First occurrence
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Fourth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Discuss with sponsor
Note:  Grading according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
AEs = adverse events, ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal
a:
An interruption of study treatment for more than 28 days (due to treatment-related toxicities) will require a discussion 
with the sponsor before treatment can be resumed.  During treatment interruption, repeat AEs assessment at least every 7 days 
(until restarting administration).
b:
Initiate optimal medical management for nausea, vomiting, diarrhea and/or hypothyroidism prior to any study treatment, 
interruption, or dose reduction.
c:
Applicable only to Grade 2 toxicities judged by the subject and physician to be intolerable.
d;
For proteinuria, interrupt until Grade 0-2.
e:
Not applicable to abnormal clinical laboratory values that require no treatment (eg, sodium).  Manage ALT, AST, and 
gamma-glutamyltransferase values 10 × ULN or higher as Grade 3.  
f:
Please ignore this step for subjects who start at 8 mg once daily.


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g:
Excluding laboratory abnormalities judged to be non-life-threatening, which should be managed as Grade 3.
Management of Hypertension and Proteinuria
Management of Hypertension
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 ≤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 Cycle 1/Day 1.  Early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions.  
Regular assessment of BP should be conducted as detailed in the Schedule of Procedures/Assessments.  
Hypertension will be graded using CTCAE v4.03, based on BP measurements only (and not on the 
number of antihypertensive medications).
Only one 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 (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg), the BP measurement should be repeated at least 5 minutes later.  The mean value of these 
2 measurements done at least 5 minutes apart is defined as one 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 mmHg or diastolic BP ≥90 mmHg), a confirmatory BP assessment should be obtained at least 30 
minutes later by performing 2 measurements at least 5 minutes apart (to yield a mean value).
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mmHg or diastolic 
BP ≥90 mmHg) is confirmed on 2 assessments at least 30 minutes apart.  One BP assessment is defined 
as the mean value of 2 measurements at least 5 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, monotherapy with one of the classes of antihypertensives should 
be started when systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg is first observed on 2 assessments 
at least 30 minutes apart.  For those subjects already on antihypertensive medication, the dose of the 
current agent may be increased, if appropriate, or one or more agents of a different class of 
antihypertensive should be added.  For subjects with hypertension and proteinuria, treatment with an 
angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist is preferred.
Study drug should be withheld in any instances 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 comorbidities).  Once the subject has been on same hypertensive 
medications for at least 48 hours and the BP is controlled, study drug should be resumed as 
described below.
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored 
every 2 weeks (on Day 15 or more frequently as clinically indicated) until systolic BP has been 
≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment cycles.  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 
2 consecutive treatment cycles.
The following guidelines should be followed for the management of systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg confirmed on repeat measurements after 30 minutes:
•
Continue study drug and institute antihypertensive therapy for subjects not already receiving 
antihypertensive medication.
•
For those subjects already on antihypertensive medication, the dose of the current agent may be 
increased, if appropriate, or one or more agents of a different class of antihypertensive should be 


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added. 
•
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal antihypertensive 
therapy, then study drug administration should be interrupted and restarted at a dose of 8 mg QD 
(one dose level reduction as specified in table above) 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.
◦
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the 8 mg QD dose despite 
optimal management of hypertension with antihypertensive medications (either by dose 
increase or the addition of a different class of antihypertensive), then study drug administration 
should be interrupted and restarted at a dose of 4 mg QD (one dose level reduction as specified 
in the table above) only when systolic BP ≤150 mmHg and diastolic BP ≤95mmHg and the 
subject has been on a stable dose of antihypertensive medication for at least 48 hours. 
◦
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the 4 mg QD dose despite 
optimal management of hypertension with antihypertensive medications (either by dose 
increase or the addition of a different class of antihypertensive), then study drug administration 
should be interrupted and a restart of study medication should be discussed with the sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):
•
Institute appropriate medical management
•
Discontinue study drug
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 of Proteinuria
•
Grading of proteinuria according to CTCAE v4.03 will be based on the 24-hour urinary protein 
result.  Management of lenvatinib administration will be based on the grade of proteinuria 
according to the Dose Modification Guidelines.
Detection and Confirmation
1.
Perform urine dipstick testing per the Schedule of Assessments
2.
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 is required in the following situations:
a.
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug
b.
A subsequent increase in severity of urine dipstick proteinuria occurring on the same lenvatinib 
dose level
c.
When there has been a lenvatinib dose reduction and at the new dose level the urine protein 
dipstick result is ≥2+
3.
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.
Monitoring
•
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.
Subsequent Treatment of Physician Choice (TPC)


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The Subsequent Treatment Period (TPC period, Treatment Period 2) will begin upon the completion 
of lenvatinib Off-Treatment Visit in first-line treatment with lenvatinib.  Subjects will be treated by 
commercially available, systemic TPC for uHCC.  .
Dose Reduction and Interruption
For subjects who experience TPC-related toxicity, dose reduction and/or interruption will be in 
accordance with the prescribing information for each medication.  
Duration of Treatment
Lenvatinib treatment (Treatment Period 1)
Lenvatinib treatment will continue until disease progression, development of unacceptable toxicity, 
subject requests to discontinue, withdrawal of consent, or sponsor termination of the study.  The 
duration of lenvatinib treatment for each subject is estimated to be 6 to 8 months.
Once disease progression occurs, lenvatinib treatment may not be restarted and subject should be 
considered for subsequent TPC.
Subsequent treatment of physician choice (Treatment Period 2)
Subjects will continue to receive TPC treatment until disease progression, development of 
unacceptable toxicity, subject request, withdrawal of consent, or study termination by the sponsor.
Concomitant Drug/Therapy
The following concomitant therapies will be prohibited from the time of informed consent for this 
study until discontinuation from lenvatinib study treatment. Additional antihypertensive treatment is 
allowed as appropriate if the BP increases once the subject has been enrolled.
1.
Surgery or radiotherapy for the treatment of HCC; Palliative radiotherapy of up to 
2 painful pre-existing, non-target bone metastases will be permitted without being 
considered progressive disease (PD).
2.
Systemic therapy, hepatic intra-arterial chemotherapy, immunological therapy 
(eg, interferon, interferon-type drugs, etc), hormonal therapy, or local therapy of any kind 
(eg, percutaneous ethanol inject [PEI], radiofrequency ablation [RFA], TACE, etc) for the 
treatment of HCC. Subjects who are receiving antiviral therapy for hepatitis B virus (HBV) 
may continue to receive this therapy at the discretion of the investigator.
3.
Other investigational drugs.
4.
Antiplatelet agents and anticoagulants that require INR monitoring, such as warfarin 
(treatments that do not require INR monitoring, such as low molecular weight heparin and 
certain factor X inhibitors are permitted).
Assessments
Efficacy Assessments
All efficacy endpoints, other than OS, will be based on the tumor response evaluation as determined 
by investigator assessment according to mRECIST (and including the RECIST 1.1 conventions for 
non-hepatic lesions).  Tumor assessments will be performed at the site by appropriately qualified 
personnel.  Treatment decisions will be based on tumor response assessments determined by the 
investigator.  
Tumor Assessments
Tumor assessments will be performed during the Screening/Baseline phase (standard of care scans 
performed up to 28 days before the first dose of study treatment are acceptable) and then every 
8 weeks (±1 week), or sooner if clinically indicated, during lenvatinib treatment phase until disease 


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progression. 
Subjects who discontinue lenvatinib treatment without disease progression should have tumor 
assessments performed (within 1 week of the lenvatinib Off-Treatment Visit) if more than 4 weeks 
have passed since the previous assessment and if the subject will not continue with follow-up scans. 
Subjects entering subsequent treatment period (Treatment Period 2) should have TPC baseline tumor 
assessments performed unless the last tumor assessment performed in lenvatinib treatment period is 
less than 28 days before the subsequent treatment starts, in which case those scans may be used as the 
TPC period baseline. A new tumor assessment baseline (selection of target and non-target lesions 
and calculation of a new baseline sum of diameters (SOD) must be established before beginning 
TPC. Subjects will continue tumor assessments during subsequent treatment period every 8 weeks 
(±1 week), or until disease progression, subject death, withdrawal or loss to follow-up.
Tumor assessments will be performed per mRECIST. Copies of all tumor imaging scans will be sent 
to an imaging core laboratory designated by the sponsor for potential future review. All subjects are 
required to undergo chest, abdomen, and pelvis imaging at Baseline and 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 precontrast, arterial and portal venous phase.
The tumor assessment schedule should not be affected by interruptions in therapy, or any other 
events that might lead to imbalance between the treatment groups with regard to the timing of disease 
assessments.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Pharmacodynamic Blood Biomarkers
Blood serum samples for pharmacodynamic and exploratory biomarkers analysis will be collected at 
the following time points: 

Treatment Period 1:  Before dosing (predose) lenvatinib on Cycle 1 Day 1, Cycle 1 Day 15, 
Day 1 of all subsequent cycles, and at the off-treatment assessment. 

Treatment Period 2: Subjects entering the subsequent TPC period should have TPC baseline 
sample collected unless the lenvatinib Off-Treatment visit in the lenvatinib treatment period is 
≤28 days before the subsequent treatment starts, in which case those samples may be used as the 
TPC period baseline.  Samples will then be collected at week 8 and week 16 (±1 week).
A detailed biomarker analysis plan will be prepared separately.
Pharmacogenetic Biomarker Assessments
Archived, fixed tumor tissue from the most recent surgery or biopsy will be collected (if available) 
from all enrolled subjects for potential assessment of mutations and other genetic alterations or genes 
and/or proteins that may be important in the development and progression of cancer as well as in 
response to study drug treatment for potential use in diagnostic development.  Appropriate 
technology/methodologies will be used based on the amount of tumor tissue available. Note that in 
order to understand tumor-specific mutations, it may be necessary to compare the tumor genome with 
the germline genome.
A blood plasma sample to isolate circulating cell-free nucleic acids will be collected at the following 
time points: 

Treatment Period 1: Before dosing (predose) lenvatinib on Cycle 1 Day 1, Cycle 1 Day 15, 
Day 1 of all subsequent cycles, and at the off-treatment assessment. 

Treatment Period 2: Subjects entering the subsequent TPC period should have TPC baseline 
sample collected unless the lenvatinib Off-Treatment visit in the lenvatinib treatment period is 


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≤28 days before the subsequent treatment starts, in which case those samples may be used as the 
TPC period baseline.  Samples will then be collected at week 8 and week 16 (±1 week).
A blood sample will be collected for potential genetic analysis from all enrolled subjects to evaluate 
whether genetic variation within a clinical study population correlates with response to the study 
treatment. Furthermore, it is important to evaluate germline DNA variation across the genome in 
order to interpret tumor-specific DNA mutations. 
A detailed biomarker analysis plan will be prepared separately.
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 study treatment, cancer and/or for 
potential diagnostic development.
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Manual.
Biomarker correlative analyses may be performed to explore blood or tumor biomarkers that may be 
useful to predict subject’s response in a retrospective manner.  The results of these studies are to gain 
further insight into the clinical mechanism of action for study drug but not foreseen to result in 
commercially valuable products.
This study will collect biomarker samples in all enrolled subjects who have consented for 
participation of the biomarker assessments.  Participation of any future exploratory research of 
leftover material will be optional.
Safety Assessments
During lenvatinib treatment period, safety assessments will consist of monitoring and recording all 
adverse events (AEs), including all CTCAE v4.03 grades (for increasing severity), and serious 
adverse events (SAEs); regular laboratory evaluation for hematology, blood chemistry, and urine 
values; periodic measurement of vital signs, electrocardiograms (ECGs), and echocardiograms or 
MUGA scans including LVEF; and the performance of physical examinations.
Safety assessments will be performed at intervals as indicated in Schedule of 
Procedures/Assessments (Table 3) in both treatment periods.
Other Assessments
Subjects perceived burden post lenvatinib treatment in Treatment Period 2 will be measured by 
completed PRO-CTCAE questionnaires. PRO-CTCAE data will be collected only at the lenvatinib 
Off-Treatment Visit during Treatment Period 1, and every 2 weeks for the first 4 weeks, and then at 
week 8, and week 16 ± (1 week) in Treatment Period 2. A TPC baseline assessment should be 
performed unless the lenvatinib Off-Treatment visit is completed within 7 days prior to the first TPC 
treatment.
Bioanalytical Methods
Not Applicable
Statistical Methods
Study Endpoints
Primary Endpoint
The primary endpoint is the safety and tolerability of subsequent systemic TPC following the 
first-line lenvatinib treatment in uHCC subjects, and will be analyzed by summarizing the incidence 
of treatment-emergent adverse events (TEAEs) and SAEs.  


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Secondary Endpoints

Overall survival (OS), measured from the date of first dose of study treatment until date of death 
from any cause.  Subjects who are lost to follow-up will be censored at the last date the subject 
was known to be alive, and subjects who remain alive will be censored at the time of data cutoff.

Progression-free survival (PFS), defined as the time from the date of first dose of first-line 
lenvatinib treatment to the date of first documentation of disease progression, or date of 
death, during the subsequent systemic TPC, whichever occurs first.

Time to progression (TTP), defined as the time from the date of first dose of first-line 
lenvatinib treatment to the date of first documentation of disease progression during the 
subsequent systemic TPC.  
Exploratory Endpoint

Patient-reported outcome (PRO) results from a well-defined PRO instrument will be determined 
by scores in the subsequent TPC period
Analysis Sets
Safety Analysis Set (Full Analysis Set) is the group of subjects who received at least 1 dose of the 
lenvatinib treatment.  This will be the analysis set for all safety and efficacy evaluations. 
The Pharmacodynamic Analysis Set is all the subjects who have received at least 1 dose of 
lenvatinib and had sufficient pharmacodynamic data to derive at least 1 pharmacodynamic 
measurement and with documented dosing history.
Efficacy Analyses
Efficacy analyses will be performed based on Safety Analysis Set (Full Analysis Set
OS
The median OS and the cumulative probability of OS at selected time points will be calculated and 
presented with 2-sided 95% confidence intervals (CIs).  The selected time points will depend on the 
OS times that are observed during the study and will be specified in the SAP.  Kaplan-Meier (KM) 
estimates of OS will be plotted over time.
PFS
Median PFS time and the cumulative probability of PFS at selected time points will be calculated, 
and presented with corresponding 2-sided 95% CIs.  The selected time points will depend on the PFS 
times that are observed during the study and will be specified in the SAP.  KM estimates of PFS will 
be plotted over time.
TTP
TTP (based on the tumor response evaluation as determined by investigator assessment according to 
mRECIST) will be evaluated using same procedure as used for PFS.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
The effect of study treatment on soluble, tissue, genetic and/or other relevant biomarkers will be 
summarized using descriptive statistics using the Pharmacodynamic Analysis Set and correlated with
clinical outcomes-related endpoints for safety and/or efficacy as appropriate. Details will be included
in a separate analysis plan.
Safety Analyses
All safety analyses based on Safety Analysis Set will be performed for each treatment period.  Safety 
data will be summarized on an “as treated” basis.  The incidence of TEAEs and SAEs will be 
summarized.  Laboratory test results, vital signs and their changes from baseline, and 12-lead ECG 
and echocardiogram results including LVEF, will be summarized using descriptive statistics.  
Abnormal values will be flagged.


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Other Analyses
To assess subjects’ perceived burden following lenvatinib treatment, PRO-CTCAE questionnaire 
results will be summarized descriptively.
Interim Analyses
No interim analysis is planned in this study.
Sample Size Rationale
With the sample size of 100 subjects, assuming that more than 50% of subjects will go on to receive 
TPC, and that the rate of TEAE with CTCAE Grade ≥3 is 75%, the half width of the 95% CI for the 
rate of TEAE with CTCAE Grade ≥3 will be no more than 12%.


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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS.............................................................................10
3
TABLE OF CONTENTS.................................................................................................23
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................27
5
ETHICS............................................................................................................................30
5.1
Institutional Review Boards/Independent Ethics Committees ..............................30
5.2
Ethical Conduct of the Study.................................................................................30
5.3
Subject Information and Informed Consent...........................................................31
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................32
7
INTRODUCTION ...........................................................................................................32
7.1
Study Rationale......................................................................................................34
8
STUDY OBJECTIVES....................................................................................................35
8.1
Primary Objective..................................................................................................35
8.2
Secondary Objectives.............................................................................................35
8.3
Exploratory Objectives ..........................................................................................35
9
INVESTIGATIONAL PLAN..........................................................................................36
9.1
Overall Study Design and Plan..............................................................................36
9.1.1
Pretreatment Phase.......................................................................................36
9.1.1.1
Screening Period..................................................................................36
9.1.1.2
Baseline Period/Visit ...........................................................................36
9.1.2
Treatment Phase...........................................................................................37
9.1.2.1
Lenvatinib Treatment Period (Treatment Period 1).............................37
9.1.2.2
Subsequent Treatment Period (TPC Period, Treatment Period 2).......37
9.1.2.3
Follow-Up Period (Survival Follow-Up).............................................38
9.2
Discussion of Study Design, Including Choice of Control Groups.......................38
9.3
Selection of Study Population................................................................................38
9.3.1
Inclusion Criteria .........................................................................................38
9.3.2
Exclusion Criteria ........................................................................................39
9.3.3
Removal of Subjects from Therapy or Assessment.....................................42
9.4
Treatments..............................................................................................................42
9.4.1
Treatments Administered.............................................................................42
9.4.1.1
Test Drug:  Lenvatinib.........................................................................42
9.4.1.2
Subsequent Treatment of Physician Choice (TPC) .............................47
9.4.2
Identity of Investigational Product...............................................................48
9.4.2.1
Chemical Name, Structural Formula of E7080 (Lenvatinib)...............48
9.4.2.2
Comparator Drug .................................................................................48


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9.4.2.3
Labeling for Study Drug......................................................................49
9.4.2.4
Storage Conditions...............................................................................49
9.4.3
Method of Assigning Subjects to Treatment Groups...................................49
9.4.4
Selection of Doses in the Study...................................................................49
9.4.5
Selection and Timing of Dose for Each Subject..........................................50
9.4.6
Blinding........................................................................................................50
9.4.7
Prior and Concomitant Therapy...................................................................50
9.4.7.1
Drug-Drug Interactions........................................................................50
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................51
9.4.8
Treatment Compliance.................................................................................52
9.4.9
Drug Supplies and Accountability...............................................................52
9.5
Study Assessments.................................................................................................53
9.5.1
Assessments.................................................................................................53
9.5.1.1
Demography.........................................................................................53
9.5.1.2
Baseline Assessments ..........................................................................53
9.5.1.3
Efficacy Assessments...........................................................................54
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................56
9.5.1.5
Safety Assessments..............................................................................58
9.5.1.6
Other Assessments...............................................................................63
9.5.2
Schedule of Procedures/Assessments ..........................................................63
9.5.2.1
Schedule of Procedures/Assessments ..................................................63
9.5.2.2
Description of Procedures/Assessments Schedule...............................70
9.5.3
Appropriateness of Measurements...............................................................70
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................70
9.5.4.1
Reporting of Serious Adverse Events..................................................70
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................71
9.5.4.3
Reporting of Events Associated with Special Situations.....................72
9.5.4.4
Expedited Reporting ............................................................................72
9.5.4.5
Breaking the Blind...............................................................................72
9.5.4.6
Regulatory Reporting of Adverse Events ............................................72
9.5.5
Completion/Discontinuation of Subjects.....................................................73
9.5.6
Abuse or Diversion of Study Drug ..............................................................73
9.6
Data Quality Assurance .........................................................................................73
9.6.1
Data Collection ............................................................................................73
9.6.2
Clinical Data Management ..........................................................................74


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9.7
Statistical Methods.................................................................................................74
9.7.1
Statistical and Analytical Plans....................................................................74
9.7.1.1
Study Endpoints...................................................................................74
9.7.1.2
Definitions of Analysis Sets.................................................................75
9.7.1.3
Subject Disposition..............................................................................75
9.7.1.4
Demographic and Other Baseline Characteristics ...............................75
9.7.1.5
Prior and Concomitant Therapy...........................................................75
9.7.1.6
Efficacy Analyses ................................................................................75
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................76
9.7.1.8
Safety Analyses....................................................................................76
9.7.1.9
Other Analyses.....................................................................................78
9.7.2
Determination of Sample Size .....................................................................78
9.7.3
Interim Analysis...........................................................................................79
9.7.4
Other Statistical/Analytical Issues ...............................................................79
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................79
10
REFERENCE LIST .........................................................................................................80
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......82
11.1
Changes to the Protocol .........................................................................................82
11.2
Adherence to the Protocol......................................................................................82
11.3
Monitoring Procedures...........................................................................................82
11.4
Recording of Data..................................................................................................83
11.5
Identification of Source Data.................................................................................83
11.6
Retention of Records..............................................................................................84
11.7
Auditing Procedures and Inspection......................................................................84
11.8
Handling of Study Drug.........................................................................................84
11.9
Publication of Results ............................................................................................85
11.10 Disclosure and Confidentiality ..............................................................................85
11.11 Discontinuation of Study .......................................................................................85
11.12 Subject Insurance and Indemnity...........................................................................86
12
APPENDICES .................................................................................................................87
LIST OF IN-TEXT TABLES
Table 1
Dose Modification and Treatment Discontinuation Guidelines for 
Management of Lenvatinib-Related Toxicity............................................43
Table 2
Clinical Laboratory Tests...........................................................................61
Table 3
Schedule of Procedures/Assessments in Study E7080-M001-222............64


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Table 4
Half width of 95% CI estimates for Rate of TEAE with CTCAE 
Grade≥3 for Subjects Receiving TPC (Range from 100% to 50%) ..........78
LIST OF APPENDICES
Appendix 1
American Association for the Study of Liver Diseases (AASLD) 
Criteria .......................................................................................................88
Appendix 2
Modified Response Evaluation Criteria in Solid Tumors (mRECIST) .....89
Appendix 3
Barcelona Clinic Liver Cancer (BCLC) Staging System ..........................92
Appendix 4
Child-Pugh Classification..........................................................................93
Appendix 5
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ..94
Appendix 6
Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.03.............................................................................................................95
Appendix 7
New York Heart Association (NYHA) Cardiac Disease Classification....96
Appendix 8
Clinical Studies Evaluating Drug–Drug Interactions with Lenvatinib......97
Appendix 9
Pharmacogenomic and Biomarker Research .............................................98


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AASLD
American Association for the Study of Liver Diseases 
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ß-hCG
beta-human chorionic gonadotropin
BCLC
Barcelona Clinic Liver Cancer
BOR
best overall response
BP
blood pressure
BW
body weight
CBR
clinical benefit rate
CFR
Code of Federal Regulations
CI
confidence interval
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DLT/DLTs
dose-limiting toxicity/dose-limiting toxicities
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group Performance Status 
ELISA
enzyme-linked immunosorbent assay 
FGF
fibroblast growth factor
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor 
HBV
hepatitis B virus 
HCC
hepatocellular carcinoma
HIV
human immunodeficiency virus 
HR
hazard ratio
ICF
informed consent form


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Abbreviation
Term
ICH
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
INR
international normalized ratio
IRB
Institutional Review Board
KM
Kaplan Meier 
LVEF
left ventricular ejection fraction 
MedDRA
Medical Dictionary for Regulatory Activities
mRECIST
modified Response Evaluation Criteria in Solid Tumors 
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition
NYHA
New York Heart Association 
ORR
objective response rate
OS
overall survival 
PD
progressive disease
PD-1
programmed cell death protein-1
PEI
percutaneous ethanol inject
PFS
progression-free survival
P-gp
P-glycoprotein
PI
principal investigator
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PRO
patient-reported outcome
PRO-CTCAE
Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events
QTcF
corrected QT interval using Fridericia’s correction
RECIST
Response Evaluation Criteria in Solid Tumors
RFA
radiofrequency ablation
RNA
ribonucleic acid 
SAE
serious adverse event
SD
stable disease
SOC
system organ class 
SOD
sum of diameters 
TACE
transarterial chemoembolization 


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Abbreviation
Term
TEAEs
treatment emergent adverse events 
TKI
tyrosine kinase inhibitor
TPC
treatment of physician choice
TTP
time to progression
uHCC
unresectable hepatocellular carcinoma 
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio
VEGF
vascular endothelial growth factor


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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 on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human 
use (ICH) E6 Good Clinical Practice (GCP), Section 3, and any local regulations (eg, Code 
of Federal Regulations, Title 21 CFR Part 56).  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(s) [CRA(s)], change of telephone number[s]).  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 (PI) 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 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 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 
within 90 days.  The definition for end of the study is the date of data cutoff for the final 
analysis or last subject/last visit including discontinuation from the study for any reason, 
whichever occurs later.  Subjects who remain on treatment at the cutoff for the final analysis 
will continue receiving the same treatment in consecutive cycles as long as they do not meet 
any of the study discontinuation criteria as detailed in the protocol.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.
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:


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
Principles of the World Medical Association Declaration of Helsinki, 2013

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 on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use

Title 21 of the United States (US) 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
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or legally authorized representative 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 or the subject’s legally acceptable representative 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 or if a legally acceptable representative 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 or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative 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 at the Screening Visit before any study-specific procedures are performed.  No 
subject can enter the study before his/her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations (eg, Title 21 CFR Part 50).  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 or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study.  The communication of this information 
should be documented.


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6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 20 to 25 investigational sites in the US and Canada.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organizations (CROs) are listed in Investigator 
Study File provided to each site.
7
INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common primary hepatic malignancy and the 
second leading cause of cancer-related deaths globally.  Patients with advanced HCC that is 
not amenable to surgical resection or local treatment have few effective treatment options.  
At present, sorafenib (Nexavar®, Bayer), a small-molecule multikinase inhibitor, is the only 
FDA approved first-line treatment option for patients with advanced HCC (Gosalia, et al., 
2017).  In previously untreated patients with advanced disease, the median overall survival 
(OS) was 10.7 months in those treated with sorafenib and 7.9 months in those who received 
placebo (P<0.001) (Llovet, et al., 2008).
A recent prospective, observational registry study (GIDEON study) evaluated the safety of 
sorafenib and treatment practices in HCC patients.  This large global database allowed for 
assessment of the use and tolerability of sorafenib in patients with liver dysfunction.  Within 
the overall safety population enrolled to this study, 2,708 patients had known Child-Pugh 
status at the start of sorafenib therapy; of these, 73% (n=1968) had Child-Pugh A, 25% 
(n=666) had Child-Pugh B, and 3% (n=74) had Child-Pugh C.  In the intent-to-treat 
population (n=3213), median OS (months [95% confidence interval (CI)]) was longer in 
Child-Pugh A patients (13.6 [12.8-14.7]) compared with Child-Pugh B patients (5.2 
[4.6-6.3]) (Marrero, et al., 2016).
Recent approval of regorafenib (Stivarga®, Bayer) and nivolumab (Opdivo®, BMS) for the 
treatment of patients with HCC who have been previously treated with sorafenib has 
provided clinicians with two standard of care treatment options as the second-line therapy of 
HCC.
In selected HCC subjects who tolerated sorafenib but progressed while on therapy, 
regorafenib has been reported to provide an OS benefit compared with placebo (10.6 months 
vs 7.8 months; P<0.001).  Although structurally similar, regorafenib is more potent than 
sorafenib, with a similar side-effect profile.  In the Phase 3 clinical RESORCE (Regorafenib 
After Sorafenib in Patients With HCC) study, subjects with Child-Pugh Class A cirrhosis and 
advanced HCC who progressed on sorafenib had a significantly longer overall median 
survival of 10.6 months in the regorafenib arm vs 7.8 months in the placebo arm (P<0.001).  
Progression-free survival (PFS) and response to therapy were also significantly higher in 
subjects treated with regorafenib (Bruix, et al., 2017).


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Immunotherapies that inhibit the immune checkpoint interaction between programmed cell 
death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) have shown substantial 
survival benefit in some patients with metastatic carcinomas of multiple tissue origins.  
Nivolumab is a fully human immunoglobulin G4 monoclonal antibody that disrupts PD-1 
immune checkpoint signaling and thereby restores the antitumor activity of otherwise 
suppressed effector T cells.  CheckMate 040 (NCT 01658878) is a global, open-label, 
Phase 1b/2 study of nivolumab in subjects with advanced HCC with or without chronic viral 
hepatitis who were previously treated or untreated with sorafenib (El-Khoueiry, et al., 2017).  
In September of 2017, FDA approved nivolumab (Opdivo) as the second-line treatment of 
patients with HCC who have been previously treated with sorafenib.  The approval was 
based on a 154-patient subgroup of CheckMate 040, conducted in subjects with HCC and 
Child-Pugh A chronic liver disease who progressed on or were intolerant to sorafenib.  The 
confirmed objective response rate (ORR) by Response Evaluation Criteria in Solid 
Tumors 1.1 (RECIST 1.1), as assessed by blinded independent central imaging review, was 
14.3%, with 3 complete responses (CRs) and 19 partial responses (PRs).  Response duration 
ranged from 3.2 to 38.2+ months; 91% of responders had responses lasting 6 months or 
longer and 55% had responses lasting 12 months or longer 
(https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577166.htm). A 
Phase 3 randomized study of nivolumab monotherapy compared with sorafenib in the 
first-line setting is ongoing.
Lenvatinib (LENVIMA®) is a kinase inhibitor that was approved by FDA for the treatment of 
patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory 
differentiated thyroid cancer as well as for the treatment of advanced renal cell carcinoma in 
combination with everolimus following one prior anti-angiogenic therapy.
The recently concluded Study E7080-G000-304 (REFLECT) [Study 304] investigated the 
effect of lenvatinib vs sorafenib in subjects with HCC.  Sorafenib is the standard of care for 
first-line treatment of advanced HCC.  Study 304 was a multicenter, randomized, open-label, 
noninferiority Phase 3 study comparing the efficacy and safety of lenvatinib versus sorafenib 
as a first-line systemic treatment in subjects with unresectable HCC (uHCC).  Study 304 is a 
positive study with an adequately defined non-inferiority margin and valid assay sensitivity 
that met its primary endpoint showing that OS with lenvatinib was noninferior to sorafenib.  
Lenvatinib also demonstrated statistically significant and clinically meaningful improvement 
for all secondary efficacy endpoints (PFS, time to progression [TTP] and ORR) (Cheng, et al., 
2017).
Post-progression therapy may have affected survival in both arms and especially in the 
sorafenib group as more subjects received post-treatment anticancer therapy in the sorafenib 
arm than in the lenvatinib arm, particularly in the Western region.  After study treatment, 
subjects on the sorafenib arm were eligible for second-line studies targeting enrollment of 
sorafenib failures and/or sorafenib-intolerant subjects, while subjects on the lenvatinib arm 
were not.
Initial clinical experience with lenvatinib in advanced HCC was obtained in a Phase 1/2
clinical study (E7080-J081-202).  The recommended Phase 2 dose was determined to be 


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12 mg for HCC subjects with Child-Pugh Class A.  In subjects with Child-Pugh scores of 
7-8, the maximum tolerated dose (MTD) was 8 mg once daily (QD).  In Study 304, 
lenvatinib had an acceptable safety profile in HCC subjects when treatment was initiated at 
8 mg or 12 mg QD (based on body weight [BW]) and adjusted by a dose-reduction algorithm 
to manage toxicity (Study E7080-G000-304 Clinical Study Report, 2017).  Results from 
Study 304 provide evidence for lenvatinib as a potential effective and safe first-line treatment 
for patients with HCC.
Additionally, all subjects included in Study 304 and the Phase 2 study (Study 202) had 
preserved liver function (Child-Pugh A) (Study E7080-G000-304 Clinical Study Report, 
2017) (Ikeda, et al., 2017), and our knowledge regarding the efficacy of lenvatinib in subjects 
with worse hepatic impairment is limited to very small subgroups of subjects (Ikeda, et al., 
2016).  
7.1
Study Rationale
Since 2007 there has been only 1 approved systemic medication (sorafenib) for patients with 
uHCC.  Because of this fact in the treatment landscape, studies that evaluated second line 
treatment of HCC required prior sorafenib as first line therapy.  Therefore, the currently 
approved second line medications (regorafenib and nivolumab) were studied as subsequent 
sequential therapies to sorafenib.  Results from the phase 3 REFLECT study (Study 304) 
demonstrated the treatment effect of lenvatinib on OS, which was statistically confirmed by 
non-inferiority to sorafenib for first-line treatment for patients with uHCC.  Therefore, it is 
important to address unmet medical need for data for safety and efficacy on the subsequent 
sequential therapies after 1st line therapy with lenvatinib in uHCC patients.  
The safety and efficacy of lenvatinib in first line uHCC has been established in the large 
Phase 3 international REFLECT study.  This has led to the approval of lenvatinib as first line 
treatment in uHCC in Japan, EU and in the US.  In the REFLECT study, upon progression 
with first line lenvatinib, 32.6% of patients received subsequent anticancer medications.  The
information on safety of the subsequent medications after lenvatinib was not captured in the 
REFLECT study, since patients on lenvatinib were followed post-progression only for OS.  
Therefore, the objective of study E7080-M001-222 is to capture the safety and tolerability of 
the subsequent sequential therapy after first-line lenvatinib in patients with uHCC. 
The survival follow-up from Study 304 has shown some preliminary information of 
subsequent treatment following the first-line lenvatinib treatment in HCC subjects during the 
study period (01 Mar 2013 to 13 Nov 2016).  During survival follow-up in Study 304, the 
percentage of subjects receiving post-treatment anticancer medications (not given for a 
procedure) in the lenvatinib arm compared with sorafenib arm was 32.6% vs 38.7%, 
respectively.  Sorafenib was the most common anticancer agent given to lenvatinib-treated 
subjects during survival follow-up, taken by 25.3% of subjects; 11.8% of sorafenib-treated 
subjects restarted or continued sorafenib during survival follow-up.  The percentage of 
subjects who took investigational anticancer drugs during survival follow-up in the lenvatinib 
arm compared with the sorafenib arm was 3.1% vs 9.5%, respectively.  These investigational 
agents were mostly administered within clinical trials (eg, regorafenib, cabozantinib), which 


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required failure of sorafenib therapy as an entry criteria, thus precluding enrollment of 
lenvatinib-treated subjects in these studies (Study E7080-G000-304 Clinical Study Report, 
2017).
This is a single-arm, open-label, multicenter, Phase 2 study to evaluate the safety and 
efficacy of subsequent systemic treatment of physician choice (TPC) (commercially 
available) following first-line lenvatinib treatment for uHCC. 
The primary objective of the study is to evaluate the safety and tolerability of subsequent 
systemic TPC following first-line lenvatinib treatment in uHCC subjects.  The secondary 
objectives include evaluation of OS in uHCC subjects treated with lenvatinib as first-line 
treatment followed by TPC, and evaluation of PFS and TTP of subsequent systemic TPC 
starting from the first dose of first-line lenvatinib treatment.
Approximately 100 subjects will be enrolled to first-line treatment with lenvatinib.  Subjects 
with Child-Pugh A will be included in this study.  Starting dose of lenvatinib will be based 
on baseline BW:  12 mg QD or 8 mg QD will be orally administered for subjects’ BW 
≥60 kg or <60 kg, respectively.  
8
STUDY OBJECTIVES
8.1
Primary Objective
To assess the safety and tolerability of subsequent systemic TPC following the first-line 
lenvatinib treatment in uHCC subjects.
8.2
Secondary Objectives
To evaluate OS in uHCC subjects treated with lenvatinib as the first-line treatment 
followed by systemic TPC
To evaluate PFS and TTP of subsequent systemic TPC starting from the first dose of 
first-line lenvatinib treatment using modified RECIST (mRECIST)
To evaluate OS by subgroups of systemic TPC
8.3
Exploratory Objectives
To measure the patient perceived burden by Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE) in the subsequent 
TPC period
To explore biomarkers based on availability of serum and tissue samples


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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a single-arm, open-label, multicenter, phase 2 study to evaluate the safety and 
efficacy of subsequent systemic TPC (commercially available) following first-line lenvatinib 
treatment for uHCC.
Approximately 100 subjects with uHCC will be enrolled to receive first-line treatment with 
lenvatinib in 28-day treatment cycles.  Subjects with Child-Pugh A are eligible for this study.
Subjects will continue to receive lenvatinib treatment in continuous 28-day cycles until 
disease progression, development of unacceptable toxicity, subject request, withdrawal of 
consent, or study termination by the sponsor.  Upon subject’s completion of lenvatinib 
Off-Treatment Visit in first-line treatment of lenvatinib, subjects will be treated by commercially 
available, systemic TPC for uHCC in the subsequent TPC period.
The study will consist of Pretreatment Phase, Treatment Phase, and Post-Treatment Phase.
9.1.1
Pretreatment Phase
The pretreatment phase will last up to 21 days and will include Screening Period and a 
Baseline Visit/Period.
9.1.1.1
Screening Period
The Screening Period will last no longer than 21 days and will occur between Day –21 and 
Day –2.  The purpose of the Screening Period is to obtain informed consent and establish 
protocol eligibility and disease characteristics.  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.  Informed consent may be taken up to 4 weeks prior to Cycle 1 
Day 1.
The Screening Disposition case report form (CRF) must be completed to indicate whether the 
subject is eligible to enroll in the study and to provide reasons for screen failure, if 
applicable.
Subjects must be screened within 21 days prior to the first dose of study treatment. The 
results of all screening assessments and evaluations must be completed and reviewed by the 
investigator prior to the Baseline Visit.
9.1.1.2
Baseline Period/Visit
Baseline assessments can be performed on Day –1 or prior to the start of study treatment on 
Cycle 1 Day 1.  The purpose of the Baseline Visit is to confirm protocol eligibility and 


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disease characteristics, as specified in the inclusion/exclusion criteria (as detailed in 
Section 9.3.1 and Section 9.3.2).  
The screening assessment can serve as the baseline assessment, if performed within 72 hours 
before the first dose of study treatment.  If the screening physical examination is performed 
>7 days prior Cycle 1 Day 1, it must be repeated at the Baseline Visit.  Laboratory tests and a 
pregnancy test (for female subjects of childbearing potential) may be performed up to 72 
hours before the first dose of study treatment.
Subjects who complete the baseline assessment and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the treatment phase.  Results of baseline assessments 
must be obtained prior to the first dose of study treatment (Cycle 1 Day 1).
9.1.2
Treatment Phase
There will be 2 treatment periods in this study: Lenvatinib Treatment Period (Treatment 
Period 1) and the Subsequent TPC Treatment Period (Treatment Period 2).
9.1.2.1
Lenvatinib Treatment Period (Treatment Period 1)
Lenvatinib Treatment Period for each subject will begin with the administration of first dose 
of lenvatinib on Cycle 1 Day 1 and will consist of administration of lenvatinib in 28-day 
treatment cycles.  Treatment Period 1 will continue until completion of the lenvatinib 
Off-Treatment Visit that will occur within 30 days after the final administration of lenvatinib.  
Lenvatinib treatment cycles will be counted continuously regardless of dose interruptions.  
Subjects will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments (Table 3).  Subjects will continue to receive study treatment until 
disease progression, development of unacceptable toxicity, subject request, withdrawal of 
consent, or study termination by the sponsor.  
Subjects will be permitted to continue lenvatinib treatment beyond mRECIST defined 
disease progression as long as the treating investigator considers that there is clinical benefit 
and, the subject is tolerating study treatment.  The assessment of clinical benefit should take 
into account whether the subject is clinically deteriorating and unlikely to receive further 
benefit from continued treatment.  All decisions to continue treatment beyond initial 
progression must be discussed with the Eisai Medical Monitor.  Subjects will discontinue 
study treatment upon evidence of further progression and/or loss of clinical benefit, as judged 
by the investigator.
9.1.2.2
Subsequent Treatment Period (TPC Period, Treatment Period 2)
The subsequent TPC period will begin upon the completion of the lenvatinib Off-Treatment 
Visit in first-line treatment of lenvatinib.  Subjects will be treated with commercially 
available systemic TPC for uHCC. The first treatment of a single agent or combination of 
multiple drugs after lenvatinib treatment will be considered as the subsequent TPC. 
Locoregional therapies (ie, chemoembolization/radioembolization, etc) procedures will not 


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be considered as a second line treatment following lenvatinib. If the investigator deems a 
subject inappropriate for commercially available systemic TPC as the subsequent treatment 
following lenvatinib, subjects will be followed in the survival Follow-Up period.  All 
treatment following lenvatinib will be captured in the case report form. Data will be 
collected from the start of TPC, then at intervals as indicated in Schedule of 
Procedures/Assessments (Table 3). 
Subjects starting subsequent TPC ≥8 weeks after lenvatinib off-treatment visit may be 
considered after discussion with sponsor.
9.1.2.3
Follow-Up Period (Survival Follow-Up)
The Follow-Up Period will begin immediately after the final visit of the subsequent TPC 
period (Treatment Period 2).  Subjects will be followed every 12 weeks for survival and will 
continue as long as the study subject is alive or the subject withdraws consent.  If the 
investigator deems a subject inappropriate for commercially available subsequent systemic 
TPC, the subject will be followed for survival every 12 weeks after the lenvatinib 
Off-Treatment Visit of the Lenvatinib Treatment Period (Treatment Period 1).  Subjects’ 
survival status and all additional anticancer treatments received will be recorded.
The sponsor may decide to terminate survival follow-up of subjects after the completion of 
the primary analysis or when all subjects have discontinued study treatment.
9.2
Discussion of Study Design, Including Choice of Control Groups
This open-label, multicenter, phase 2 study will employ a single-arm design to evaluate the 
safety and efficacy of subsequent systemic TPC (commercially available) following first-line 
lenvatinib treatment of uHCC, and to gain more understanding of the safety and efficacy of 
other systemic anti-HCC therapy following lenvatinib treatment. 
9.3
Selection of Study Population
Approximately 100 subjects with uHCC are planned to be enrolled at approximately 20 to 
25 sites in the US and Canada.  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 uHCC with any of the following criteria:
a.
Histologically or cytologically confirmed diagnosis of HCC
b. Clinically confirmed diagnosis of HCC according to American Association for the 
Study of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology or with 
chronic hepatitis B or C infection criteria
2. At least one measurable target lesion regardless if hepatic or non-hepatic according to 


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mRECIST meeting the following criteria:
a. Hepatic lesion
• The lesion can be accurately measured in at least one dimension as ≥1.0 cm (viable 
tumor for typical; and longest diameter for atypical), and
• The lesion is suitable for repeat measurement, 
b. Nonhepatic lesion
• Lymph node lesion that measures at least one dimension as ≥1.5 cm in the short 
axis
• 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.
3. Subjects categorized on the Barcelona Clinic Liver Cancer (BCLC) staging system to 
Stage B (not applicable for transarterial chemoembolization [TACE]) or Stage C
4. Adequate bone marrow function, defined as:
•
Absolute neutrophil count (ANC) ≥1.5 × 109/L
•
Hemoglobin ≥8.5 g/dL
•
Platelet count ≥75 × 109/L
5. Adequate liver function, defined as:
•
Albumin ≥2.8 g/dL
•
Bilirubin ≤3.0 mg/dL
•
Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine 
aminotransferase (ALT) ≤5 × the upper limit of normal (ULN)
6. Adequate blood coagulation function, defined as international normalized ratio (INR) 
≤2.3
7. Adequate renal function defined as creatinine clearance >30 mL/min calculated per the 
Cockcroft and Gault formula
8. Adequate pancreatic function, defined as lipase ≤1.5 × ULN
9. Adequately controlled blood pressure (BP) with up to 3 antihypertensive agents, defined 
as BP ≤150/90 mmHg at Screening and no change in antihypertensive therapy within 
1 week prior to Cycle 1/Day 1
10. Child-Pugh A
11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1
12. Survival expectation of 12 weeks or longer before starting study drug
13. Males or females aged at least 18 years at the time of informed consent
14. Provide written informed consent
15. Willing and able to comply with all aspects of the protocol
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:


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1. Imaging findings for HCC corresponding to any of the following:
a.
HCC with ≥50% liver occupation
b.
Clear invasion into the bile duct
c.
Portal vein invasion at the main portal branch (Vp4)
2. Subjects who have received any systemic chemotherapy, including sorafenib, regorafenib 
or other anti-vascular endothelial growth factor (VEGF) therapy, nivolumab, or any 
systemic investigational anticancer agents, including lenvatinib, for advanced/uHCC.  
Note:  Subjects who have received local hepatic injection chemotherapy (if not within 
28 days prior to the first dose of lenvatinib study treatment ) are eligible
3. Subjects who have received any anticancer therapy (including surgery, percutaneous 
ethanol injection, radio frequency ablation, transarterial [chemo] embolization, hepatic 
intra-arterial chemotherapy, biological, immunotherapy, hormonal, or radiotherapy) or 
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 lenvatinib study treatment.
4. Subjects who have not recovered from toxicities as a result of prior anticancer therapy
such as the local hepatic injection chemotherapy or any prior therapy for other cancer 
types.  Recovery is defined as <Grade 2 severity per Common Terminology Criteria for 
Adverse Events Version 4.03 (CTCAE v4.03), except alopecia and infertility
5. Significant cardiovascular impairment within 6 months of the first dose of study drug:  
history of congestive heart failure greater than New York Heart Association (NYHA) 
Class II, unstable angina, myocardial infarction or stroke, cardiac arrhythmia associated 
with hemodynamic instability, or a left ventricular ejection fraction (LVEF) below the 
institutional normal range as determined by multigated acquisition (MUGA) scan or 
echocardiogram
6. Prolongation of QTcF (QT interval corrected for heart rate using Fridericia’s correction) 
interval to >480 ms
7. Gastrointestinal malabsorption or any other condition that might affect the absorption of 
lenvatinib in the opinion of the investigator
8. Bleeding or thrombotic disorders or use of anticoagulants such as, warfarin or similar 
agents requiring therapeutic INR monitoring (Treatment with low molecular weight 
heparin is allowed)
9. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 
half teaspoon) within 28 days prior to the first dose of lenvatinib study treatment
10. Gastric or esophageal varices that require treatment
11. 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
12. Any history of, or current brain or subdural metastases
13. Subjects having >1+ proteinuria on urine dipstick testing will undergo 24-hour urine 
collection for quantitative assessment of proteinuria. Subjects with urine protein 
≥1 g/24 h will be ineligible.


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14. Arterial-portal venous shunt or arterial-venous shunt preventing proper diagnosis of 
tumor
15. Any medical or other condition that in the opinion of the investigator would preclude the 
subject’s participation in a clinical study
16. Known intolerance to lenvatinib or any of the excipients
17. Human immunodeficiency virus (HIV) positive or active infection requiring treatment 
(except for hepatitis virus)
18. Any history of drug or alcohol dependency or abuse within the prior 2 years
19. 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
20. Major surgery within 3 weeks prior to the first dose of lenvatinib study treatment or 
scheduled for surgery during the study
21. Subject has had a liver transplant
22. 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.
23. Females of childbearing potential who:

Within 28 days before study entry, did not use a highly effective method of 
contraception, which includes any of the following:
-
total abstinence (if it is their preferred and usual lifestyle)
-
an intrauterine device or intrauterine hormone-releasing system (IUS)
-
a contraceptive implant
-
an oral contraceptive (with additional barrier method) (Subject must be on a stable 
dose of the same oral contraceptive product for at least 28 days before dosing and 
throughout the study and for 28 days after study drug discontinuation.)
-
have a vasectomized partner with confirmed azoospermia.

Do not agree to use a highly effective method of contraception (as described above) 
throughout the entire study period and for 28 days after study drug discontinuation.
For sites outside of the 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 latex 
or synthetic condom plus diaphragm or cervical/vault cap with spermicide.
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 
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24. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential or 
practicing highly effective contraception throughout the study period and for 96 days 
after study drug discontinuation).  No sperm donation is allowed during the study period 
and for 96 days after study drug discontinuation.  
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.  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.
Follow-Up Period will begin immediately after the final visit in subsequent TPC period.  
Subjects will be followed every 12 weeks for survival and will continue as long as the study 
subject is alive unless the subject withdraws consent.  Subjects who do not take subsequent 
TPC will be followed for survival every 12 weeks after the lenvatinib Off-Treatment Visit of 
Lenvatinib Treatment Period.
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.
9.4
Treatments
9.4.1
Treatments Administered
9.4.1.1
Test Drug:  Lenvatinib
Lenvatinib capsules will be administered orally, QD in continuous 28-day cycles.  The 
starting dose of lenvatinib will be based on the subject’s baseline BW as follows:

BW ≥60 kg — Lenvatinib 12 mg (taken as three 4-mg capsules) QD.  

BW <60 kg — Lenvatinib 8 mg (taken as two 4-mg capsules) QD.  
Study medication should be taken at approximately the same time each day in a fasting state 
or following a meal.
If a dose is missed and cannot be taken within 12 hours, then that dose should be skipped and 
the next dose should be taken at the usual time of administration.
Lenvatinib treatment will continue until disease progression, development of unacceptable 
toxicity, subject requests to discontinue, withdrawal of consent, or termination of the study 


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by the sponsor.  The duration of lenvatinib treatment for each subject is estimated to be 6 to 
8 months.
If holidays or personal schedules make administration impossible on the scheduled days, then 
administration should be resumed as soon as possible.
9.4.1.1.1
DOSE REDUCTION AND INTERRUPTION OF LENVATINIB
Dose adjustments for management of intolerable toxicities will be made according to the 
guidelines provided in Table 1.
Table 1
Dose Modification and Treatment Discontinuation Guidelines for 
Management of Lenvatinib-Related Toxicity
Study Treatment Dose Reduction and Interruption Instructions
Dose reductions occur in succession based on the previous dose level (eg, 12, 8, and 4 mg/day, and 4 mg every 
other day for the subjects with initial BW ≥60 kg).  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.
Non-Hematologic Toxicities
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d or Grade 3e,d
First occurrence
Interrupt until resolved to Grade 0-1 
or baseline
One-level reduction
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
One-level reduction
Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
One-level reduction
Fourth occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-1 
or baseline
Discuss with sponsor
Grade 4g:  Discontinue Study Treatment
Hematologic Toxicities and Proteinuria
Treatment-Related Toxicitya
Management
Dose Adjustment
Grade 1 or Grade 2
Continue treatment
No change
Grade 3
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
One-level reduction
Third occurrence 
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Fourth occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Fifth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Discuss with sponsor
Grade 4
First occurrence
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Second occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
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Third occurrencef
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
One-level reduction
Fourth occurrence
(same toxicity or new toxicity)
Interrupt until resolved to Grade 0-2 
or baseline
Discuss with sponsor
Note:  Grading according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03.
AEs = adverse events, ALT = alanine aminotransferase, AST = aspartate aminotransferase, ULN = upper limit of normal
a:
An interruption of study treatment for more than 28 days (due to treatment-related toxicities) will require a discussion 
with the sponsor before treatment can be resumed.  During treatment interruption, repeat AEs assessment at least every 
7 days (until restarting administration).
b:
Initiate optimal medical management for nausea, vomiting, diarrhea and/or hypothyroidism prior to any study treatment, 
interruption, or dose reduction.
c:
Applicable only to Grade 2 toxicities judged by the subject and physician to be intolerable.
d:
For proteinuria, interrupt until Grade 0-2.
e:
Not applicable to abnormal clinical laboratory values that require no treatment (eg, sodium).  Manage ALT, AST, and 
gamma-glutamyltransferase values 10 × ULN or higher as Grade 3.  
f:
Please ignore this step for subjects who start at 8 mg once daily.
g:
Excluding laboratory abnormalities judged to be non-life-threatening, which should be managed as Grade 3.
9.4.1.1.2
MANAGEMENT OF HYPERTENSION
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 ≤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 Cycle 1/Day 1.  Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.  
Regular assessment of BP should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Hypertension will be graded using CTCAE v4.03, based on BP 
measurements only (and not on the number of antihypertensive medications).
Only one 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 (systolic BP ≥140 mmHg 
or diastolic BP ≥90 mmHg), the BP measurement should be repeated at least 5 minutes later.  
The mean value of these 2 measurements done at least 5 minutes apart is defined as one 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 mmHg or diastolic BP ≥90 mmHg), a 
confirmatory BP assessment should be obtained at least 30 minutes later by performing 
2 measurements at least 5 minutes apart (to yield a mean value).
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mmHg 
or diastolic BP ≥90 mmHg) is confirmed on 2 assessments at least 30 minutes apart.  One BP 
assessment is defined as the mean value of 2 measurements at least 5 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, 
monotherapy with one of the classes of antihypertensives should be started when systolic BP 
≥140 mmHg or diastolic BP ≥90 mmHg is first observed on 2 assessments at least 30 
minutes apart.  For those subjects already on antihypertensive medication, the dose of the 
current agent may be increased, if appropriate, or one or more agents of a different class of 


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antihypertensive should be added.  For subjects with hypertension and proteinuria, treatment 
with an angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist is 
preferred.
Study drug should be withheld in any instances 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 comorbidities).  Once the 
subject has been on same hypertensive medications for at least 48 hours and the BP is 
controlled, study drug should be resumed as described below.
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP 
monitored every 2 weeks (on Day 15 or more frequently as clinically indicated) until systolic 
BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment 
cycles.  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 2 consecutive treatment cycles.
The following guidelines should be followed for the management of systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg confirmed on repeat measurements after 30 minutes:
•
Continue study drug and institute antihypertensive therapy for subjects not already 
receiving antihypertensive medication.
•
For those subjects already on antihypertensive medication, the dose of the current agent 
may be increased, if appropriate, or one or more agents of a different class of 
antihypertensive should be added. 
•
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then study drug administration should be interrupted and 
restarted at a dose of 8 mg QD (one dose level reduction as specified in table above) 
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.
◦
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the 8 mg QD dose 
despite optimal management of hypertension with antihypertensive medications 
(either by dose increase or the addition of a different class of antihypertensive), then 
study drug administration should be interrupted and restarted at a dose of 4 mg QD 
(one dose level reduction as specified in the table above) only when systolic BP ≤150 
mmHg and diastolic BP ≤95mmHg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours. 
◦
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the 4 mg QD dose 
despite optimal management of hypertension with antihypertensive medications 
(either by dose increase or the addition of a different class of antihypertensive), then 
study drug administration should be interrupted and a restart of study medication 
should be discussed with the sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):


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•
Institute appropriate medical management
•
Discontinue study drug.
9.4.1.1.3
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 of Proteinuria
•
Grading of proteinuria according to CTCAE v4.03 will be based on the 24-hour urinary 
protein result.  Management of lenvatinib administration will be based on the grade of 
proteinuria according to the Dose Modification Guidelines (Table 1).
Detection and Confirmation
1. Perform urine dipstick testing per the Schedule of Assessments
2.
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 is required in the 
following situations:
a.
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug
b.
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
c.
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+
3.
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.
Monitoring
•
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.
9.4.1.1.4
MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (eg, ALT, AST, bilirubin levels) should be 
conducted as detailed in the Schedule of Assessments/Procedures (Table 3) and as clinically 
indicated.  Worsening liver function including hepatic encephalopathy should be closely 
monitored.  If signs occur indicating a decrease in liver function by 1 grade or more from 
baseline, the instructions contained in Table 1 should be followed.  Appropriate supportive 
care should be provided together with close monitoring.  If hepatic failure occurs, lenvatinib 
must be discontinued.


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9.4.1.1.5
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 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 1 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, lenvatinib must be discontinued.
9.4.1.1.6
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.  MRI is necessary to confirm the diagnosis of PRES.  Appropriate measures should 
be taken to control BP.  In subjects with signs or symptoms of PRES, dose interruptions, 
reductions, or discontinuation may be required per instructions included in Table 1.  Please 
refer to Section 7 of the Investigator's Brochure for further information on lenvatinib, 
including the full set of special warnings and precautions for use (Section 7.4.4).
9.4.1.2
Subsequent Treatment of Physician Choice (TPC)
The Subsequent Treatment Period (TPC period, Treatment Period 2) will begin upon the 
completion of lenvatinib Off-Treatment Visit in first-line treatment of lenvatinib.  Subjects 
will be treated by commercially available, systemic TPC for uHCC.  The first treatment of a 
single agent or combination of multiple drugs after lenvatinib treatment will be considered as 
the subsequent TPC. Locoregional therapies (ie, chemoembolization/radioembolization, etc.) 
will not be considered as a second line treatment following lenvatinib.  If the investigator 
deems a subject inappropriate for commercially available systemic TPC as the subsequent 
treatment following lenvatinib, subjects will be followed in the survival Follow-Up Period.
All treatment following lenvatinib will be captured in the case report form.  Data will be 
collected from the start of TPC, then at intervals as indicated in Schedule of 
Procedures/Assessments (Table 3). 
Subjects starting subsequent systemic TPC ≥8 weeks after lenvatinib off-treatment visit may 
be considered after discussion with sponsor.
For subjects who experience TPC-related toxicity, dose reduction and/or interruption will be 
in accordance with the prescribing information for each medication.  


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Subjects will continue to receive TPC treatment until disease progression, development of 
unacceptable toxicity, subject request, withdrawal of consent, or study termination by the 
sponsor. 
9.4.2
Identity of Investigational Product
The test drug (lenvatinib) in Treatment Period 1 will be supplied to the study sites by the
sponsor packaged as open-label #4-size hydroxypropyl methylcellulose 4-mg capsules 
(yellowish-red cap and body, containing 4 mg lenvatinib [anhydrous free base]) in labeled 
containers.
Commercially available treatment chosen by investigator (TPC) for subsequent treatment of 
uHCC will be supplied by the local pharmacy.
Labelling, packaging and storage of the commercially available TPC must be in accordance 
with local regulations and manufacturer’s instructions.
9.4.2.1
Chemical Name, Structural Formula of E7080 (Lenvatinib)

Test drug code:  E7080

Generic name:  Lenvatinib

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula:  C21H19CLN4O4•CH4O3S

Molecular weight:  522.96

Structural formula:  
9.4.2.2
Comparator Drug
Not applicable


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9.4.2.3
Labeling for Study Drug
Lenvatinib will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language for each of those 
countries.
Medications chosen by investigator for subsequent treatment will not be provided by the 
sponsor.
9.4.2.4
Storage Conditions
The sponsor will prepare the “Procedures for Handling Investigational Drug’’ which will be 
provided to the investigator, head of medical institution (as required by regional authority), 
or designated study drug manager before the investigational drug is delivered.  The 
investigational drug will be stored in accordance with the “Procedures for Handling 
Investigational Drug.”
Lenvatinib will be stored in accordance with the labeled storage conditions.  The expiry date 
for lenvatinib will be established based on the date that manufacturing/packing is completed 
or will be based on formulation testing, and will therefore be described in the “Procedures for 
Handling Investigational Drug.”
Study drug to be used in Period 2 will be stored as described in the locally approved product 
label or in the applicable Summary of Product Characteristics.
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 head of the medical institution) 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 be 
assigned to receive lenvatinib treatment in Treatment Period 1 followed by the TPC in 
Treatment Period 2.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
In Study 304, lenvatinib had an acceptable safety profile in HCC subjects when treatment 
was initiated at 8 mg or 12 mg QD (based on BW) and adjusted by a dose-reduction 
algorithm to manage toxicity (Study E7080-G000-304 Clinical Study Report, 2017).  Based 


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on these data, the starting dose of lenvatinib in this study will be based on baseline BW of the 
subjects:  12 mg QD for BW ≥60 kg and 8 mg QD for <60 kg.
9.4.5
Selection and Timing of Dose for Each Subject
Lenvatinib capsules are to be taken orally, QD in continuous 28-day cycles at approximately 
the same time each day in a fasting state or after a meal.
Administration of TPC should be in accordance with the approved prescribing information 
for the chosen treatment.
9.4.6
Blinding
The study will be open label.
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 28 days after last dose 
of lenvatinib treatment if subjects do not enter TPC period, or for 8 weeks after the start of 
TPC period, or up to 28 days after last dose of TPC if subject does not stay in the TPC period 
for the 8 weeks of safety monitoring.  All anticancer therapy will be recorded until time of 
death or termination of survival follow-up.  Additionally, all diagnostic, therapeutic, or 
surgical procedures relating to malignancy should be recorded.  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 the study medication 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) the study medication.
Aspirin, nonsteroidal anti-inflammatory drugs, and low-molecular-weight heparin 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 guidelines, but the 
subject should be carefully monitored for increases in red blood cell (RBC) counts.
9.4.7.1
Drug-Drug Interactions
The main metabolic pathways for lenvatinib in humans were identified as enzymatic 
(CYP3A and aldehyde oxidase) and non-enzymatic processes (lenvatinib – Global 
Investigator’s Brochure).
No dose adjustment of lenvatinib is recommended when coadministered with CYP3A, PgP, 
and breast cancer resistance protein (BCRP) inhibitors, and with CYP3A and PgP inducers 


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(lenvatinib – Global Investigator’s Brochure).  In a formal drug-drug interaction study, 
lenvatinib did not alter plasma concentrations of midazolam (a sensitive CYP3A and Pgp 
substrate).  Thus, lenvatinib is not expected to alter the metabolism of other co-administered 
drugs which are CYP3A4/Pgp substrates (lenvatinib – Global Investigator’s Brochure).
A population PK analysis also indicated that agents that raise gastric pH (eg, H2-blockers, 
proton pump inhibitors, antacids) do not have a significant effect on the absorption and 
bioavailability of lenvatinib (CPMS-E7080-007R-v1).  
Please refer to Flockhart DA, 2007 for the most current information regarding inhibitors and 
inducers of CYP3A4.
9.4.7.2
Prohibited Concomitant Therapies and Drugs
The following concomitant therapies will be prohibited from the time of informed consent
for this study until discontinuation from lenvatinib treatment:

Surgery or radiotherapy for the treatment of HCC. Palliative radiotherapy of up 
to 2 painful pre-existing nontarget bone metastases will be permitted without 
being considered progressive disease (PD).

Systemic therapy, hepatic intra-arterial chemotherapy, immunological therapy 
(eg, interferon, interferon-type drugs, etc), hormonal therapy, or local therapy of 
any kind (eg, percutaneous ethanol inject [PEI], radiofrequency ablation [RFA], 
TACE, etc) for the treatment of HCC. Subjects who are receiving antiviral 
therapy for hepatitis B virus will be allowed to continue to receive this therapy at 
the discretion of the investigator.

Other investigational drugs

Antiplatelet agents and anticoagulants that required INR monitoring, such as 
warfarin. (Treatments that do not require INR monitoring, such as low molecular 
weight heparin and certain factor X inhibitors are permitted.)
If subjects receive additional anticancer therapies, this will be judged to represent evidence of 
disease progression, and study medication will be discontinued.  These subjects should 
complete all off-treatment assessments and continue to be followed for survival in the 
Follow-Up Period.
Drugs that are not prohibited for concomitant use include drugs used to treat complications or 
AEs, or drugs used to ameliorate symptoms (including blood products, blood transfusions, 
fluid transfusions, antibiotics, steroids, antidiarrheal drugs, and tranquilizers, etc). These 
drugs and treatments can be concomitantly used, based on the judgment of the investigator or 
subinvestigator.


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9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (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 head of the medical institution or the designated 
pharmacist) 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

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 FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the PI and all subinvestigators listed on 
Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s 
current medical license or medical registration number on the CV

A signed and dated clinical studies agreement

A copy of the regulatory authority approval for the country in which the study is 
being conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) 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 other than the parent, guardian, or authorized legal representative of a 
study subject.


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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, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 
drugs/study supplies that occurs at the site.  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 
(eg, FDA, MHRA).  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 head of the medical institution or the designated pharmacist) 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.  Approval for destruction to occur at the site must be 
provided by the sponsor in advance.  Upon completion of drug accountability and 
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 during Screening.  Demography 
information includes date of birth (or age), sex, race/ethnicity.
9.5.1.2
Baseline Assessments
Baseline assessments will be performed at Day -1 or at Cycle 1 Day 1 prior to treatment.  
The screening assessment can serve as the baseline assessment, if performed within 72 hours 
of the first dose of study treatment.  Assessments will include confirmation of subject 
eligibility with the inclusion and exclusion criteria, medical and surgical history, prior 
medications and procedures, pregnancy test (serum or urine) in women of childbearing 


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potential within 72 hours prior to the first dose of study treatment, blood coagulation test, 
ECOG PS (see Appendix 5), Child-Pugh score (see Appendix 4), vital signs and weight, 
clinical chemistry and hematology, and urine dipstick testing.
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
and Baseline Visits.  All medical and surgical history must be noted in the Medical History 
and Current Medical Conditions CRF.
Physical examinations (comprehensive or symptom directed) will be performed as designated 
in the Schedule of Assessments (Table 3).  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 complete neurological examination.  Documentation of 
the physical examination will be included in the source documentation at the site.  Significant 
findings at screening 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.
9.5.1.3
Efficacy Assessments
All efficacy endpoints, other than OS, will be based on the tumor response evaluation as 
determined by investigator assessment according to mRECIST (and including the 
RECIST 1.1 conventions for non-hepatic lesions).  Tumor assessments will be performed at 
the site by appropriately qualified personnel.  Treatment decisions will be based on tumor 
response assessments determined by the investigator.  
9.5.1.3.1
TUMOR ASSESSMENTS
Tumor assessments will be performed during the Screening/Baseline phase (standard of care 
scans performed up to 28 days before the first dose of study treatment are acceptable) and 
then every 8 weeks (±1 week), or sooner if clinically indicated, during the Lenvatinib 
Treatment Period until disease progression (Table 3). 
Subjects who discontinue lenvatinib treatment without disease progression should have 
tumor assessments performed (within 1 week of the lenvatinib Off-Treatment Visit) if more 
than 4 weeks have passed since the previous assessment and if the subject will not continue 
with follow-up scans. 
Subjects entering the subsequent TPC period should have TPC baseline tumor assessments 
performed unless the last tumor assessment performed in the Lenvatinib Treatment Period is 
less than 28 days before the subsequent treatment starts, in which case those scans may be 
used as the TPC period baseline.  A new tumor assessment baseline (selection of target and 
non-target lesions and calculation of a new baseline sum of diameters (SOD) must be 
established before beginning TPC. Subjects will continue tumor assessments during the 
subsequent TPC period every 8 weeks (±1 week), or until disease progression, subject death, 
withdrawal or loss to follow-up.


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Tumor assessments will utilize mRECIST based on Lencioni and Llovet (Appendix 2, 
Lencioni and Llovet, 2010).  Copies of all tumor imaging scans will be sent to an imaging 
core laboratory designated by the sponsor for potential future review.  All subjects are 
required to undergo chest, abdomen, and pelvis imaging at baseline and 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 precontrast, arterial and portal venous 
phase.
Screening 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 abdomen, pelvis, and other areas of known disease plus 
suspected disease should be performed within 28 days prior to treatment.
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should 
be performed within 28 days prior to treatment. During the Treatment 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, 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 every 8 weeks (during the 
eighth week; starting from the date of the first treatment of lenvatinib), 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 lenvatinib Off-Treatment 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 
lenvatinib Off-Treatment Visit).
If a subject discontinues from the study prior to the Week 8 scan, then a CT/MRI scan should 
be performed as close as possible to 8 weeks after treatment. If a subject discontinues prior 
to Week 8, the scans for tumor assessment should be performed as close as possible to 
Week 8 but before another anticancer therapy is initiated.
Target lesions in bone may not receive palliative radiotherapy. A maximum of 2 bone 
metastases that become painful and are being followed as bone non-target lesions on CT or 
MRI scans (using bone windows/sequences) may be treated with palliative radiotherapy. 
The lesion(s) should be considered as not evaluable (NE) for all subsequent time points,
unless they later progress unequivocally.
If a subject is unable to undergo a contrast CT due to allergy or renal insufficiency during 
follow-up, a chest CT without contrast, combined with MRI images of the remaining 
anatomy with gadolinium contrast, is preferred if tolerated by the subject. If it is determined 


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that neither CT nor MRI IV contrast can be tolerated by the subject during follow-up, a chest 
CT without contrast combined with high quality T1 and T2 weighted MRI images of the 
remaining anatomy should be provided. Importantly, such a modality switch will render the 
subsequent measurements of target lesions, especially typical hepatic target lesions, 
inadequate and the target lesion disease should be followed as NE or potentially progressing 
(if sufficient evidence is available).
The tumor assessment schedule should not be affected by interruptions in therapy, or any 
other events that might lead to imbalance between the treatment groups with regard to the 
timing of disease assessments.
CT and MRI scans should be of diagnostic quality acquired on spiral or multidetector CT 
with oral and IV contrast. Low dose noncontrast CT transmission scans from positron 
emission tomography (PET)/CT scanner are not acceptable. Spiral or multidetector CT
should be performed with a 5 mm contiguous slice reconstruction algorithm. If MRI scans 
are acquired, contiguous 5 mm slice thickness with minimal gap are also recommended. 
Ultrasound should not be used for radiographic assessment. A chest x-ray that clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of the 
CT/MRI scans.
Brain scans should be performed by MRI pre- and post-contrast enhancement or CT with 
contrast enhancement, with 5-mm contiguous slices recommended (maximum inter-slice gap 
of 1 mm on MRI).
In order to be eligible for this study, all subjects must have at least one measurable lesion 
visible on screening CT or MRI scans. To adequately determine lesion progression and 
response, the investigator will categorize the baseline disease burden on the screening image 
into typical, atypical, and nonhepatic target and nontarget lesions. Lesions previously treated 
with radiotherapy or surgical therapy should not be considered suitable as target lesions, 
unless they show radiographic evidence of disease progression. The investigator will follow 
each of the selected lesions at each subsequent imaging time point until radiological 
progression is determined. If a lesion that was not present at baseline is detected on a 
follow-up scan, it will be identified as a new lesion. At every time point, the investigator will 
determine the overall tumor response of a subject as CR, PR, stable disease (SD), NE, or PD, 
as appropriate (see Appendix 2 for further details).
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Not applicable.


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9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Pharmacodynamic Blood Biomarkers
Blood serum samples for pharmacodynamic and exploratory biomarkers analysis will be 
collected at the following time points: 
Treatment Period 1:  Before dosing (predose) lenvatinib on Cycle 1 Day 1, Cycle 1 Day 15, 
Day 1 of all subsequent cycles, and at the off-treatment assessment. 
Treatment Period 2:  Subjects entering the subsequent TPC period should have TPC baseline 
sample collected unless the lenvatinib Off-Treatment visit in the lenvatinib treatment period 
is ≤28 days before the subsequent treatment starts, in which case those samples may be used 
as the TPC period baseline.  Samples will then be collected at week 8 and week 16 
(±1 week).
A detailed biomarker analysis plan will be prepared separately. 
Pharmacogenetic Biomarker Assessments
Archived, fixed tumor tissue from the most recent surgery or biopsy will be collected (if 
available) from all enrolled subjects for potential assessment of mutations and other genetic 
alterations or genes and/or proteins that may be important in the development and 
progression of cancer as well as in response to study drug treatment for potential use in 
diagnostic development.  Appropriate technology/methodologies will be used based on the 
amount of tumor tissue available.  Note that in order to understand tumor-specific mutations, 
it may be necessary to compare the tumor genome with the germline genome.
A blood sample will be collected for potential genetic analysis from all enrolled subjects to 
evaluate whether genetic variation within a clinical study population correlates with response 
to the study treatment.  Furthermore, it is important to evaluate germline DNA variation 
across the genome in order to interpret tumor-specific DNA mutations.  
A blood plasma sample to isolate circulating cell-free nucleic acids will be collected at the 
following time points: 
Treatment Period 1:  Before dosing (predose) lenvatinib on Cycle 1 Day 1, Cycle 1 Day 15, 
Day 1 of all subsequent cycles, and at the off-treatment assessment. 
Treatment Period 2:  Subjects entering the subsequent TPC period should have TPC baseline 
sample collected unless the lenvatinib Off-Treatment visit in the lenvatinib treatment period 
is ≤28 days before the subsequent treatment starts, in which case those samples may be used 
as the TPC period baseline.  Samples will then be collected at week 8 and week 16 
(±1 week).
A detailed biomarker analysis plan will be prepared separately.


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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 study treatment, cancer and/or for potential diagnostic development.
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.
Biomarker correlative analyses may be performed to explore blood or tumor biomarkers that 
may be useful to predict subject’s response in a retrospective manner. The results of these 
studies are to gain further insight into the clinical mechanism of action for study drug but not 
foreseen to result in commercially valuable products.
This study will collect biomarker samples in all enrolled subjects who have consented for 
participation of the biomarker assessments.  Participation of any future exploratory research 
of leftover material will be optional.
9.5.1.5
Safety Assessments
Safety assessments consisted of monitoring and recording of all AEs, including all CTCAE 
v4.03 grades (for increasing severity), and serious adverse events (SAEs); regular laboratory 
evaluation for hematology, blood chemistry, and urine dipstick values; periodic measurement 
of ECOG PS, Child-Pugh score, vital signs, 12-lead electrocardiograms (ECGs), and 
echocardiograms or MUGA scans including LVEF; and the performance of physical 
examinations as detailed in Table 3.
Safety assessments will be performed at intervals as indicated in Schedule of 
Procedures/Assessments (Table 3) in both Treatment Periods. .
9.5.1.5.1
ADVERSE EVENTS
An 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.  
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 (HCC) should be captured under efficacy assessments as disease 
progression rather than as an AE.  If the disease progression leads to an untoward medical 
occurrence, then this medical occurrence should be recorded as an AE.


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
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 reported on the CRF. All AEs, regardless of 
relationship to study drug or procedure, should be recorded beginning from the time the 
subject signs the study ICF through the last visit and for 28 days after the last dose of 
lenvatinib treatment if subjects do not enter TPC period, or for 8 weeks after the start of TPC 
period.  SAE information should be collected for 8 weeks after the start of the TPC, or for at 
least 28 days after the last dose of lenvatinib/TPC if subjects do not continue into the TPC 
period or do not stay in the TPC period for the 8 weeks of safety monitoring.
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 QTcF 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.
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.  Investigators 
will report CTCAE grades for all AEs (for increasing 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


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
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
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
An 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. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; 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 reported 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.


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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
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed are summarized in Table 2.  All clinical laboratory 
tests during the study will be performed by local laboratories.  All hematology, blood 
chemistry (including pregnancy test, as applicable) are to be obtained prior to study drug 
administration and sent to the local laboratory on the day of collection, unless otherwise 
instructed.  Subjects should be in a seated or supine position during blood collection.  
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), INRa, PTa
Chemistry
Blood urea nitrogen (BUN), creatinine, aspartate aminotransferase, 
alanine aminotransferase, alkaline phosphatase, total bilirubin, 
lactate dehydrogenase, potassium, chloride, sodium, calcium total, 
cholesterol, total protein, albumin, total amylase, lipase, serum 
gamma glutamyl transpeptidase, C-reactive protein, ammonia.
Urinalysis/Urine Dipstick Testing
Glucose, hemoglobin (or blood), ketones, pH, protein, specific
gravity
Other
-Fetoprotein and thyroid-stimulation hormone
Pregnancy test (serum or urine β-hCG)
INR = International Normalized Ratio, PT = prothrombin time, RBC = red blood cell, WBC = white blood cell, 
a: INR and prothrombin time (PT) should only be performed as part of the screening assessment and when 
clinically indicated.
The Schedule of Procedures/Assessments (Table 3) shows the visits and time points at which 
blood for clinical laboratory tests and urine for urinalysis will be collected in the study (refer 
to the Laboratory Manual for a list of tests).  All hematology, blood chemistry (including 
pregnancy test, as applicable), and urinalysis samples are to be obtained prior to study drug 
administration and results reviewed prior to administration/dispensing of study drug at the 
beginning of each treatment cycle.


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Laboratory tests at baseline may be performed up to 72 hours prior to start of study 
treatment.  Hematology and clinical chemistry results will be reviewed within 48 hours after 
receiving quick estimation.  Assessments scheduled may be performed within 72 hours prior 
to the visit.  If subjects experience ≥Grade 3 hematologic or clinical chemistry toxicities, 
repeat laboratory tests and AE assessments at least every 7 days until improvement to 
<Grade 3. Refer to Table 1 for the management of clinically significant laboratory 
abnormalities.
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.
For laboratory abnormalities meeting the criteria of SAEs (Section 9.5.1.5.2), the site must 
send the SAE report including the laboratory report (as regionally required) to the SAE fax 
number or email provided in the Investigator File.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, BP [systolic and diastolic; mmHg], heart rate [beats per 
minute], respiratory rate [per minute], body temperature [in centigrade]) and BW (kg) will be 
obtained at the visits designated on the Schedule of Procedures/Assessments (Table 3) by a 
validated method.  Blood pressure and heart rate 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.  One BP assessment is defined as the mean value of 
2 measurements at least 5 minutes apart.  If the BP assessment is elevated (systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory BP assessment at least 30 minutes 
later should be obtained by performing 2 measurements (at least 5 minutes apart) to yield a 
mean value.
Starting dose of lenvatinib is determined based on measurement of BW at the Baseline Visit.  
Subsequent measurements of BW are not relevant for dose determination.
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  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.
9.5.1.5.6
ELECTROCARDIOGRAMS
A single resting 12-lead ECG will be performed as designated in the Schedule of 
Procedures/Assessments (Table 3).  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 


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minimum of 3 full complexes should be recorded from each lead simultaneously.  Subjects 
must be in the recumbent position 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.
For ECG abnormalities meeting criteria of an SAE (see Section 9.5.1.5.2), the site must fax 
or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.4.1).
9.5.1.5.7
OTHER SAFETY ASSESSMENTS
Echocardiograms or MUGA scans will be obtained as designated on the Schedule of
Procedures/Assessments (Table 3).  A MUGA scan (using technetium-99m-pertechnetate) or
an echocardiogram to assess LVEF will be performed during the Screening Visit and at the 
lenvatinib Off-Treatment Visit of the Lenvatinib Treatment Period (or sooner if clinically 
indicated).  MUGA scans and echocardiograms 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.  Investigator assessment 
will be based upon institutional reports.  
Pregnancy Test
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) at designated time points as specified in the Schedule of Procedures/Assessments 
(Table 3).
9.5.1.6
Other Assessments
Subjects perceived burden post lenvatinib treatment in the subsequent TPC period will be 
measured by completed PRO-CTCAE questionnaires. PRO-CTCAE data will be collected 
only at the lenvatinib Off-Treatment Visit in Treatment Period 1, and every 2 weeks for the 
first 4 weeks, and then at week 8 and week 16 (±1 week) in the TPC period. A TPC baseline 
assessment should be performed unless the lenvatinib Off-Treatment visit is completed 
within 7 days prior to the first TPC treatment.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 3 presents the schedule of procedures/assessments for the study.


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Table 3
Schedule of Procedures/Assessments in Study E7080-M001-222
Period Screeninga
Baselinea
Lenvatinib (Treatment Period 1) 
(All cycles are 28 days in duration)
TPC
(Treatment Period 2)
Survival 
FU
Visit
1
2
3
4
5
6
7
8, 9, etc
99
Day
-21 to -2
-1
Cycle 1b
Cycle 2c Cycle 3 – Lastc
Lenvatinib 
Off-Treatment 
Visit
TPC 
Baseline
Week 
2
Week 
4
Week 
8
Week 
16aa
Every 12 
weeks
1
8
15
1
15
1
15
Procedures/ 
Assessments
Informed consent
X
Inclusion/exclusion 
criteria
X
X
Demographic data
X
ECOG-PSd
X
X
X
X
X
Xd
X
X
X
NYHAd
X
BCLC staging
X
Medical/surgical history
X
X
Gastroenterological 
endoscopye
X
Virus tests (HIV Ab, 
HCV Ab, HBsAg)f
X
Phone contact or visitg
X
Vital signs and weighth,i
X
X
X
X
X
X
X
X
X
Xh
X
X
X
Physical examinationj
X
Xk
X
X
X
X
Xj
X
X
X
12-Lead ECGl
X
X
X
X
Xl
X
X
X
MUGA scan or 
echocardiogramm
X
X


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Period Screeninga
Baselinea
Lenvatinib (Treatment Period 1) 
(All cycles are 28 days in duration)
TPC
(Treatment Period 2)
Survival 
FU
Visit
1
2
3
4
5
6
7
8, 9, etc
99
Day
-21 to -2
-1
Cycle 1b
Cycle 2c Cycle 3 – Lastc
Lenvatinib 
Off-Treatment 
Visit
TPC 
Baseline
Week 
2
Week 
4
Week 
8
Week 
16aa
Every 12 
weeks
1
8
15
1
15
1
15
Procedures/ 
Assessments
Hematology and 
chemistryn
X
X
X
X
X
X
X
Xn
X
X
X
Urinalysiso,i
X
X
X
X
X
X
X
X
X i
X
X
X
Pregnancy testp
X
X
Child-Pugh scored
X
X
X
X
X
Xd
X
X
X
PRO-CTCAE 
questionnairesq
X
Xq
X
X
X
X
Blood coagulation test 
(PT/INR)
X
X
X
X
X
Special chemistriesr
X
X
X
X
X
X
Xr
X
X
Biomarker (whole 
blood) s
X
Biomarker
(serum/plasma) samples
X
X
X
X
X
Xs
X
X
Tumor assessments 
CT/MRIt
X
CT of the chest and CT or MRI of the 
abdomen, pelvis, and other areas of known 
disease at screening plus newly suspected 
disease will be performed every 8 weeks 
from the first dose of study treatment, or 
sooner if clinically indicated, until disease 
progression.  Triphasic CT/MRI of liver is 
X
Xt
X
Xt


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Period Screeninga
Baselinea
Lenvatinib (Treatment Period 1) 
(All cycles are 28 days in duration)
TPC
(Treatment Period 2)
Survival 
FU
Visit
1
2
3
4
5
6
7
8, 9, etc
99
Day
-21 to -2
-1
Cycle 1b
Cycle 2c Cycle 3 – Lastc
Lenvatinib 
Off-Treatment 
Visit
TPC 
Baseline
Week 
2
Week 
4
Week 
8
Week 
16aa
Every 12 
weeks
1
8
15
1
15
1
15
Procedures/ 
Assessments
mandatory at screening and all subsequent 
time points.
Brain scanu
X
Brain scans will be performed if clinically indicated.
Archive tumor block or 
slidesv
X
Survivalw
Throughout
X
Study treatment
QD for lenvatinib
TPCx
Prior/Concomitant 
medicationy
Throughout
AEs/SAEsz
Throughout
AE = adverse event, BCLC = Barcelona Clinic Liver Cancer, CT = computed tomography, ECG = electrocardiogram, ECOG PS = Eastern Cooperative 
Oncology Group Performance Status, FU = Follow up, HBsAg = Hepatitis B surface antigen, HBV = hepatitis B virus, HCV Ab= hepatitis C virus 
antibody, HIV Ab = human immunodeficiency virus antibody, INR = international normalized ratio, MRI = magnetic resonance imaging, NYHA = New 
York Heart Association, MUGA = multigated acquisition, PRO-CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for 
Adverse Events, PT = prothrombin time, SAE = serious adverse event, TPC = treatment of physician choice.
a:
Subjects must be screened within 21 days prior to the first dose of study treatment.  The screening assessment can serve as the baseline assessment, if 
performed within 72 hours before the first dose of study treatment.  The baseline assessments can be performed on C1D1, prior to the first dose of study 
treatment. Informed consent may be taken up to 4 weeks prior to C1D1.
b:
Efforts should be made to conduct study visits on the day scheduled (± 1 day).  Clinical laboratory assessments may be conducted anytime within 72 hours 
prior to the scheduled visit, unless otherwise specified in the Schedule of Procedures/Assessments.


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c:
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 the Schedule of Visits and Procedures.
d:
See protocol appendices for ECOG assessments, NYHA Cardiac Disease Classification, and Child-Pugh assessments. NYHA cardiac disease classification 
should be only performed at Screening if needed.  For ECOG and Child-Pugh assessments, a TPC baseline assessment should be performed unless the 
lenvatinib Off-Treatment visit is completed ≤7 days prior to the first TPC treatment.
e:
Gastroenterological endoscopy at screening is necessary only if more than 3 months have passed since the previous assessment.  Gastroenterological 
endoscopy must have been performed within 3 months prior to receiving first dose of the study treatment.
f:
Subjects who are receiving antiviral therapy for hepatitis B virus (HBV) may continue to receive this therapy at the discretion of the investigator.
g:
Telephone contact on or visit on C1D8 to assess subjects for development of early toxicity.  An unscheduled visit will occur prior to C1D15 if deemed 
necessary by the investigator.
h:
Assessments will include vital signs (resting BP, heart rate, respiratory rate, and body temperature), and weight measured at Screening, Baseline, Day 1 and 
Day 15 of every cycle, lenvatinib Off-Treatment visit in Treatment Period 1, and at week 2, week 4, and week 8 (±1 week) in TPC period. A TPC baseline 
assessment should be performed unless the lenvatinib Off-Treatment visit is completed ≤7 days prior to the first TPC treatment. One BP assessment is 
defined as the mean value of 2 measurements at least 5 minutes apart.  If the BP assessment is elevated (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg), a confirmatory BP assessment at least 30 minutes later should be obtained by performing 2 measurements (at least 5 minutes apart) to yield a 
mean value.  Starting dose is determined based on measurement of body weight at the Baseline Visit.  Subsequent measurements of body weight not 
relevant for dose determination.  See dose adjustment table for management of hypertensive subjects.
i:
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored every 2 weeks (on Day 15) or more frequently as 
clinically indicated until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment cycles.  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 2 consecutive treatment cycles.  
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 2 weeks (on 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 15 urine 
dipstick testing for evaluation of proteinuria until results are 1+ or negative for 2 consecutive treatment cycles.  
Note:  During Cycle 3 and subsequent cycles in Treatment Period 1, subjects will return to the clinic for the Day 15 visit only if BP monitoring or urine 
dipstick testing is required as specified above.  The Day 15 visit is mandatory in Cycles 1 and 2. In TPC period, a baseline urine dipstick testing should be 
performed unless the lenvatinib Off-Treatment visit is completed ≤7 days prior to the first TPC treatment, and then the testing should be done at week 2, 
week 4, and week 8 (±1 week) .
j:
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 lenvatinib Off-Treatment Visit in Treatment Period 1 and at week 2, week 4, and week 8 (±1 week) in TPC period. A 
TPC baseline assessment should be performed unless the lenvatinib Off-Treatment visit is completed ≤7 days prior to the first TPC treatment. A symptom-
directed physical examination will be performed on C1D1 and at any time during the study as clinically indicated.  Height will be measured at the 
Screening Visit only.
k:
Required if screening physical examination is performed >7 days prior to C1D1.


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l:
Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG. ECG will be performed at week 2, week 4, 
and week 8 (±1 week) in TPC period. A TPC baseline assessment should be performed unless the lenvatinib Off-Treatment visit is completed ≤7 days prior 
to the first TPC treatment.
m:
MUGA or echocardiogram during screening and at lenvatinib Off-Treatment Visit or sooner if clinically indicated.  Assessment should utilize the same 
methodology (MUGA or echocardiogram).
n:
Clinical laboratory tests (hematology and clinical chemistry) will be performed at local laboratory.  Laboratory tests at Baseline may be performed up to 
72 hours prior to first dose of lenvatinib treatment.  Review hematology clinical chemistry results within 48 hours after receiving quick estimation.  
Assessments scheduled may be performed within 72 hours prior to the visit.  If ≥Grade 3 hematologic or clinical chemistry toxicities, repeat laboratory 
test and AE assessment at least every 7 days (until improvement to <Grade 3). Clinical laboratory tests will be performed at week 2, week 4, and week 8
(±1 week) in TPC period. A TPC baseline assessment should be performed unless the lenvatinib Off-Treatment visit is completed ≤7 days prior to the first 
TPC treatment.
o:
For subjects with proteinuria ≥2+ (see the dose adjustment table for management of proteinuria).
p:
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).  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.
q:
PRO-CTCAE data will be collected at the following time points: lenvatinib Off-Treatment Visit during Treatment Period 1, every 2 weeks for the first 
4 weeks, and then at week 8 and week 16 (±1 week) in Treatment Period 2. A TPC baseline assessment should be performed unless the lenvatinib 
Off-Treatment visit is completed ≤7 days prior to the first TPC treatment.
r:
-Fetoprotein (AFP) and thyroid-stimulation hormone (TSH) will be measured at screening visit, Baseline, on C1D15, C2D1, C3D1, and every 2 cycles 
thereafter (C5D1, C7D1, C9D1, etc) in Treatment Period 1, and week 8 and week 16 (±1 week) in TPC period. A TPC baseline assessment should be 
performed unless the lenvatinib Off-Treatment visit is completed ≤7 days prior to the first TPC treatment.
s:
Collection of blood sample to obtain serum and plasma to be used for biomarker studies.  Samples will be obtained on C1D1 (predose), predose on C1D15, 
Day 1 of and all subsequent cycles, and the lenvatinib Off-Treatment Visit in Treatment Period 1, and at week 8 and week 16 (±1 week) in Treatment 
Period 2 (TPC period). A TPC baseline assessment should be performed unless the lenvatinib Off-Treatment visit in Treatment Period 1 is ≤28 days before 
the first TPC treatment.  A whole blood sample for genetic analysis will be obtained at baseline. If sampling is not performed predose, sampling may occur 
at any subsequent visit in which other blood sampling is scheduled to occur.  
t:
Screening Period:  Tumor assessments using triphasic liver CT/MRI (optimized for precontrast, 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 first dose of study treatment.
Treatment Period:  Tumor assessments using triphasic liver CT/MRI (optimized for precontrast, 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 or newly suspected disease should 
be performed every 8 weeks (during the 8th week) (±1 week) 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.  
Tumor assessments will be performed during the Screening/Baseline Phase (standard of care scans performed up to 28 days before the first dose of study 
treatment are acceptable) and then every 8 weeks, or sooner if clinically indicated, during lenvatinib treatment phase until disease progression. Subjects 


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who discontinue lenvatinib treatment without disease progression should have tumor assessments performed (within one week of the lenvatinib Off-
Treatment Visit) if more than 4 weeks have passed since the previous assessment and if the subject will not continue with follow-up scans. 
Subjects entering subsequent treatment period (TPC period) should have TPC period baseline tumor assessments performed unless the last tumor 
assessment performed in lenvatinib treatment period is less than 28 days before the subsequent treatment starts, in which case those scans may be used as 
the TPC period baseline. A new tumor assessment baseline (selection of target and non-target lesions and calculation of a new baseline sum of diameters 
(SOD) must be established before beginning TPC. Subjects will continue tumor assessments during subsequent TPC every 8 weeks (±1 week) or until 
disease progression, subject death, withdrawal or loss to follow-up.  Detailed image acquisition guidelines will be provided by the imaging core 
laboratory.
u:
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should be performed within 28 days prior to the first dose of study 
treatment.  During the study drug treatment period, 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.
v:
An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review may be collected at 
screening or at any time during the study, unless no such material is available.
w:
Subjects who do not take subsequent TPC will be followed for survival every 12 weeks after the Off-Treatment visit. Otherwise, subjects will be followed 
for survival every 12 weeks after the final Visit in the subsequent TPC period.  If a clinic visit is not feasible, follow up information may be obtained via 
telephone or email. Subjects’ survival status and all additional anticancer treatments received will be recorded.
x:
Treatment dose and schedule on Prescribing Information of commercially available TPC should be followed.
y:
Concomitant meds will be recorded for 28 days after last dose of lenvatinib treatment if subjects do not enter TPC period, or for 8 weeks after the start of 
TPC period or up to 28 days after last dose of TPC if subject does not stay in the TPC period for the 8 weeks of safety monitoring.  All anticancer therapy will be 
recorded until time of death or termination of survival follow-up. Prior medication information before screening should be collected at the screening period.
z:
SAEs irrespective of relationship to study treatment must be reported as soon as possible but not later than 1 business day.  AEs will be recorded for 
28 days after last dose of lenvatinib treatment if subjects do not enter TPC period, or for 8 weeks after the start of TPC period.  During treatment 
interruption due to AEs, repeat AE assessment at least every 7 days (until restarting administration).  SAE information should be collected for 8 weeks after 
the start of the TPC, or for at least 28 days after the last dose of lenvatinib/TPC if subjects do not continue into the TPC period or do not stay in the TPC 
period for the 8 weeks of safety monitoring.
aa: After week 16, only tumor assessment and TPC dose information will be collected until the end of TPC (disease progression, development of unacceptable 
toxicity, subject request, withdrawal of consent, or study termination by the sponsor).


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9.5.2.2
Description of Procedures/Assessments Schedule
Please refer to the Schedule of Procedures/Assessments (Table 3).
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in HCC studies.
Tumor assessments by the investigator will be done using mRECIST criteria (as opposed to 
RECIST 1.1) as it more appropriately reflects changes in intrahepatic lesions by measuring 
only the viable portions of the lesions.  Other differences between mRECIST and 
RECIST 1.1 include requiring interval growth for new atypical hepatic lesions before 
considering them as unequivocal and requiring cytologic evidence of malignancy to consider 
ascites/effusions as malignant given that underlying cirrhosis is common in HCC subjects 
(Lencioni and Llovet, 2010).
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, ECGs/echocardiograms, 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 1 business day from the date the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, should be collected for 8 weeks 
after the start of the TPC, or for at least 28 days after the last dose of lenvatinib/TPC if 
subjects do not continue into the TPC period or do not stay in the TPC period for the 8 weeks 
of safety monitoring.  All SAEs must be followed to resolution or, if resolution is unlikely, to 
stabilization.  Any SAE judged by the investigator to be related to lenvatinib treatment or any 
protocol-required procedure should be reported to the sponsor regardless of the length of 
time that has passed since study completion.
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 24 hours by emailing or faxing the 
completed SAE form.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
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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 1 business day 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.
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.
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 a female subject (or partner of a male subject) in which the estimated date 
of conception is either before the last visit or within 30 days of last dose of study treatment, 
or any exposure to study drug through breastfeeding during study treatment or within 30 days 
of last dose of study treatment, 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 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 1 business day 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 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 


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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: 
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.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators and regulatory authorities of reportable events, in 
compliance with applicable 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.


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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 3).
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: AE(s), lost to follow-up, subject choice, progression of disease, withdrawal of 
consent, pregnancy, study terminated by sponsor, or other.  In addition to the primary reason, 
the subject may indicate 1 or more secondary reason(s) for discontinuation.  Study 
disposition information will be collected on the Subject Disposition CRF.
9.5.6
Abuse or Diversion of Study Drug
Not applicable
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
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.


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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 study is 
completed and the database is locked and released.  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).
9.7.1
Statistical and Analytical Plans
The statistical analyses of 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 ENDPOINT
The primary endpoint is the safety and tolerability of subsequent systemic TPC following the 
first-line lenvatinib treatment in uHCC subjects, and will be analyzed by summarizing the 
incidence of treatment-emergent adverse events (TEAEs) and SAEs.  
9.7.1.1.2
SECONDARY ENDPOINTS
•
Overall survival (OS), measured from the date of first dose of study treatment until date of 
death from any cause.  Subjects who are lost to follow-up will be censored at the last date 
the subject was known to be alive, and subjects who remain alive will be censored at the 
time of data cutoff.

Progression-free survival (PFS), defined as the time from the date of first dose of 
first-line lenvatinib treatment to the date of first documentation of disease progression, or 
date of death, during the subsequent systemic TPC, whichever occurs first.  
•
Time to progression (TTP), defined as the time from the date of first dose of first-line 
lenvatinib treatment to the date of first documentation of disease progression during
subsequent systemic TPC.
9.7.1.1.3
EXPLORATORY ENDPOINT
Patient-reported outcome (PRO) results from a well-defined PRO instrument (PRO-CTCAE) 
will be determined by scores in the subsequent TPC period.


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9.7.1.2
Definitions of Analysis Sets
The Safety Analysis Set (Full Analysis Set) is the group of subjects who received at least 
1 dose of study drug.  This will be the analysis set for all safety and efficacy evaluations.
The Pharmacodynamic Analysis Set is all the subjects who have received at least 1 dose of 
lenvatinib and had sufficient pharmacodynamic data to derive at least 1 pharmacodynamic 
measurement and with documented dosing history.
9.7.1.3
Subject Disposition
The number (percentage) of subjects who completed the study treatment/study and 
discontinued from the study treatment/study and reasons for discontinuation will be provided.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Full Analysis Set will be summarized
using descriptive statistics.  Continuous demographic and baseline variables include age, 
BW, and height; categorical variables include sex, age group, BW group, race, region, 
macroscopic portal vein invasion and/or extra hepatic spread, ECOG-PS, NYHA cardiac 
disease classification, BCLC staging, and Child-Pugh score.  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms (verbatim terms) for medications recorded in the CRF will be coded to 
an 11-digit code using the World Health Organization Drug Dictionary (WHO DD).  The 
number (percentage) of subjects who took prior and concomitant medications will be 
summarized, using Anatomical Therapeutic Chemical (ATC) class and WHO DD preferred 
term.  Prior 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 28 days after last dose of 
lenvatinib treatment if subjects do not enter TPC period, or for 8 weeks after the start of TPC 
period or up to 28 days after last dose of TPC if subject does not stay in the TPC period for 
the 8 weeks of safety monitoring.  All medications will be presented in subject data listings.  
All anticancer therapy will be recorded until time of death or termination of survival follow-
up.
9.7.1.6
Efficacy Analyses
Efficacy analyses will be performed based on the Safety Analysis Set.  
OS
The median OS and the cumulative probability of OS at selected time points will be 
calculated and presented with 2-sided 95% CIs.  The selected time points will depend on the 


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OS times that are observed during the study and will be specified in the SAP.  Kaplan-Meier 
(KM) estimates of OS will be plotted over time.
PFS
Median PFS time and the cumulative probability of PFS at selected time points will be 
calculated, and presented with corresponding 2-sided 95% CIs.  The selected time points will 
depend on the PFS times that are observed during the study and will be specified in the SAP.  
KM estimates of PFS will be plotted over time.
TTP
TTP (based on the tumor response evaluation as determined by investigator assessment 
according to mRECIST) will be evaluated using same procedure as used for PFS.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Not applicable
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The effect of study treatment on soluble, tissue, genetic and/or other relevant biomarkers will 
be summarized using descriptive statistics using the Pharmacodynamic Analysis Set and 
correlated with clinical outcomes-related endpoints for safety and/or efficacy as appropriate.  
Details will be included in a separate analysis plan.
9.7.1.8
Safety Analyses
All safety analyses based on Safety Analysis Set will be performed for each treatment period.  
Safety data will be summarized on an “as treated” basis.  The incidence of TEAEs and SAEs 
will be summarized.  Laboratory test results, vital signs and their changes from baseline, and 
12-lead ECG and echocardiogram results including LVEF, will be summarized using 
descriptive statistics.  Abnormal values will be flagged.
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 due to AEs will be summarized.
Additionally, the following data will be summarized: percentage of subjects that receive 
TPC, average dose intensity and relative dose intensity of lenvatinib treatment and TPC, and 
feasibility rate (defined as the percentages of subjects completing the first 2, 4, and 6 cycles 
of lenvatinib treatment without requiring dose reduction due to AE).


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9.7.1.8.2
ADVERSE EVENTS
Adverse Events will be graded using CTCAE v4.03.  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 TEAE is defined as an AE that emerges during treatment, 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.
TEAE will be defined and summarized for each treatment period separately.
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 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 TEAEs will also be summarized by relationship to 
study drug (probably related, possibly related, and not related).
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-emergent 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 
or leading to study drug dose changes will be summarized by MedDRA SOC and PT.  A 
subject data listing of all AEs leading to discontinuation from study drug or leading to study 
drug dose changes 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, the actual value and the change from baseline to each 
postbaseline visit will be summarized by visit using descriptive statistics.  Qualitative 
parameters will be summarized using frequencies (number and percentage of subjects).


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Percentages will be based on the number of subjects with both nonmissing baseline and at 
least 1 postbaseline results.
Laboratory parameters will be categorized according to CTCAE v4.03 grades, and shift 
tables from baseline CTCAE grades to the maximum/worst and final postbaseline grades will 
be provided.  
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, heart rate, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit.  Change from baseline to each postbaseline visit and to end of treatment in ECG 
findings will be summarized by visit.  
9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive statistics and changes from baseline for LVEF assessed on echocardiogram or 
MUGA scans will be presented.
9.7.1.9
Other Analyses
PRO-CTCAE questionnaire results will be summarized descriptively.
9.7.2
Determination of Sample Size
With the sample size of 100 subjects, assuming that more than 50% subjects will go on to 
receive TPC, and that the rate of TEAE with CTCAE Grade ≥3 is 75%, the half width of 
95% CI for the rate of TEAE with CTCAE Grade ≥3 will be no more than 12%. 
Table 4 provides the 95% CI estimates for the rate of TEAEs with CTCAE Grade ≥3, when 
the percentages of subjects receiving TPC range from 100% to 50%.
Table 4
Half width of 95% CI estimates for Rate of TEAE with CTCAE 
Grade≥3 for Subjects Receiving TPC (Range from 100% to 50%)
Percentage of subjects receiving TPC
The half width of 95% CI for the rate of 
TEAE with CTCAE Grade ≥3
100%
8.5%
90%
8.9%
80%
9.5%
70%
10.1%
60%
11%


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50%
12%
CI = confidence interval, CTCAE = Common Terminology Criteria for Adverse Events, TEAE = treatment 
emergent adverse events, TPC = treatment of physician choice
9.7.3
Interim Analysis
No interim analysis is planned for this study.
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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10 REFERENCE LIST
Bruix J, Qin S, Merle P, Granito A, Huang YH, Bodoky G, et al. Regorafenib for patients 
with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a 
randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389:56–66.
Cheng A, Finn R, Qin S, Han K, Ikeda K, Piscaglia F, et al. Phase III trial of lenvatinib 
(LEN) vs sorafenib (SOR) in first-line treatment of patients (pts) with unresectable 
hepatocellular carcinoma (uHCC). ASCO Annual Meeting, Chicago IL, June, 2017.
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in 
patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-
comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017; 389:2492–502.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47.
FDA grants accelerated approval to nivolumab for HCC previously treated with sorafenib.  
Available from:  
https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm577166.htm
Gosalia AJ, Martin P, Jones P, et al. Advances and future directions in the treatment of 
hepatocellular carcinoma. Gastroenterol Hepatol. 2017;13(7):398–410. 
Ikeda K, Kudo M, Kawazoe S, Osaki Y, Ikeda M, Okusaka T, et al. Phase 2 study of 
lenvatinib in patients with advanced hepatocellular carcinoma. J Gastroenterol. 2017;52:512–
9.
Ikeda M, Okusaka T, Mitsunaga S, Ueno H, Tamai T, Suzuki T, et al. Safety and 
pharmacokinetics of lenvatinib in patients with advanced hepatocellular carcinoma. Clin 
Cancer Res. 2016;22:1385–94.
Lencioni R., Llovet J. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis. 2010;30:52–60.
LENVIMA® Package Insert: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf
Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J, et al. SHARP Investigators 
Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 
2008;359(4):378–390.
Marrero JA, Kudo M, Venook AP, Ye SL, Bronowicki JP, Chen XP, et al. Observational 
registry of sorafenib use in clinical practice across Child-Pugh subgroups: The GIDEON 
study. J Hepatol. 2016;65(6):1140–1147.


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Study E7080-G000-304 (Clinical Study Report). A Multicenter, Randomized, Open-Label, 
Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib (E7080) Versus Sorafenib in 
First-Line Treatment of Subjects With Unresectable Hepatocellular Carcinoma. May, 2017.
CTCAE Reference
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.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’s medical monitor 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 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 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 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 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:

Clinic, office, or hospital charts


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
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 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 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.
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 drug will be supplied to the PI (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, returns and destruction 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.
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 


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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 
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 


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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 study 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 one 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 
(regardless of modality/scanner type and slice thickness/reconstruction interval). 
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 


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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, malignant pleural effusions, malignant ascites, and malignant porta 
hepatis lymph nodes (≥2.0 cm in short axis).  Nontarget lesions will be assessed qualitatively, 
and the possible assessments are CR, NonCR/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 

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. 


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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 = NonCR/Non-PD, PD = progressive disease, PR = partial 
response, SD = stable disease.


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Appendix 3
Barcelona Clinic Liver Cancer (BCLC) Staging System
BCLC = Barcelona Clinic Liver Cancer, CLT = cadaveric liver transplantation, HCC = hepatocellular 
carcinoma, LDLT= living donor liver transplantation, OS = overall survival, PEI = percutaneous ethanol inject, 
RF = radiofrequency ablation, TACE = transarterial chemoembolization.
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. 


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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, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. 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 Jun 
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.meddramsso.com


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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 enzyme responsible for 
human hepatic 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.  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.  A single dose of lenvatinib 
was coadministered 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. 
Please refer to http://medicine.iupui.edu/clinpharm/ddis/ for the most current information 
regarding co-administration of lenvatinib and CYP3A4 substrates, inhibitors, and inducers.   


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Appendix 9
Pharmacogenomic and Biomarker Research
Subjects enrolled in this clinical study will have samples collected for pharmacogenomic and 
biomarker analysis. The aim of the analysis is 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 noncoding regulatory regions. The research 
may include the investigation of polymorphisms in genes that are likely to influence the 
study drug PK or therapeutic response. Similarly, biomarker discovery and validation may be 
performed to identify blood or tumor biomarkers that may be useful to predict subject 
response to lenvatinib and the subsequent treatment.
Collection of the samples for pharmacogenomic and biomarker analysis will be bound by the 
sample principles and processes outlined in the main study protocol. Sample collection for 
pharmacogenomic and biomarker analysis is required per the study protocol unless the 
collection and use of the samples is prohibited by specific country laws or the subject 
declines participation.
SAMPLE COLLECTION AND HANDLING
The samples will be collected according to the schedule of Procedures/Assessments. If, for 
operational or medical reasons, the blood sample for pharmacogenomic analysis 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, including DNA/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 by the sponsor. 
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 [CSR] to the appropriate regulatory agencies). At the 
end of the storage period, samples will be destroyed. Samples may be stored longer if a 
Health 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.


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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 ICH15 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 if they can still be 
identified (not anonymized). Once samples have been anonymized, it will not be possible to 
identify which samples have come from a particular individual. Therefore, it will not be 
possible to destroy subject samples after anonymization. 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. Samples that are processed for analysis 
(DNA/RNA extracted) may be double-coded. Double-coding involves removing the initial 
code 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 
identification (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) as long 
as the initial tube does not carry any personal identifiers or the random code assigned by the 
central laboratory or biorepository. 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.”
Sample anonymization may occur by destruction of the “key.” Once the “key” is destroyed, it 
will not be possible to trace the pharmacogenomics assay results back to an individual. 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 anonymized 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 IRBs 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 anonymized 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 planned analysis, it will not be possible to return individual 
data to subjects participating in the pharmacogenomic and biomarker analysis.


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-M001-222
Study Protocol Title:
A Single-Arm, Multicenter, Phase 2 Trial to Evaluate Safety and 
Efficacy of Treatment of Physician Choice (TPC) Following 
First-Line Treatment of Lenvatinib in Subjects With 
Unresectable Hepatocellular Carcinoma (uHCC)
Investigational Product 
Name:
LENVIMA® (E7080/Lenvatinib)
IND Number:
115650
SIGNATURES
Authors:
Date
Oncology Business Group, Eisai Inc.
Date
Oncology Business Group, Eisai Inc.
Date
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-M001-222
Study Protocol Title:
A Single-Arm, Multicenter, Phase 2 Trial to Evaluate Safety 
and Efficacy of Treatment of Physician Choice (TPC) 
Following First-Line Treatment of Lenvatinib in Subjects With 
Unresectable Hepatocellular Carcinoma (uHCC)
Investigational Product
Name:
LENVIMA® (E7080/Lenvatinib)
IND Number:
115650
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 on 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.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date