Conditions: Solid Tumors
Keywords: lenvatinib E7080
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
This study will be conducted to assess the long-term safety of study drug(s) in participants who are enrolled in Eisai-sponsored lenvatinib studies.

Detailed description:
This is an open-label extension study to roll-over eligible participants from Eisai-sponsored lenvatinib studies. The participants may roll-over no sooner than the primary completion dates in their parent study or after all study data for the primary outcome measure have been collected for the parent study. The parent study is defined as the Eisai-sponsored lenvatinib clinical study in which the participant was receiving lenvatinib either as monotherapy or as combination therapy or was receiving any other comparator therapy. The participant can be enrolled in the current study for the purpose of long-term safety data collection if all the selection criteria for the current study are met. The intention is that the participant will not be without study drug during the transition from the parent study to the rollover study.

Arms:
arm 1: The roll-over eligible participants from Eisai-sponsored lenvatinib studies who received lenvatinib monotherapy or who crossed over from a comparator arm to receive lenvatinib monotherapy in their parent study will continue to receive lenvatinib monotherapy. arm 2: The roll-over eligible participants from Eisai-sponsored lenvatinib studies who received lenvatinib combination therapy or who crossed over from a comparator arm to receive lenvatinib combination therapy in their parent study will continue to receive lenvatinib combination therapy. arm 3: The roll-over eligible participants from Eisai-sponsored lenvatinib studies who received comparator treatment in their parent study will continue to receive comparator treatment, with exception of participants receiving placebo.

For China only: The roll-over eligible participants from Eisai-sponsored lenvatinib studies who received comparator treatment in their parent study will continue to receive sorafenib, with exception of participants receiving placebo.

Interventions: intervention 1: E7080 intervention 2: Comparator Drug intervention 3: Comparator Drug: Sorafenib
Intervention descriptions: intervention 1: Oral Administration. intervention 2: Per parent study. intervention 3: Per parent study.

Protocol document:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-G000-604
Study Protocol Title:
An open-label, multi-center, roll-over study to assess long term safety of 
lenvatinib monotherapy or lenvatinib combination regimen or comparator 
treatment arm to cancer patients in Eisai sponsored lenvatinib trials
Sponsor: 
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Eisai Ltd.
European Knowledge 
Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Eisai Co., Ltd.
4-6-10 Koishikawa
Bunkyo-Ku, 
Tokyo 112 8088
Japan
Investigational 
Product Name:
Lenvatinib (E7080) and additional investigational agents as per Eisai 
parent study if applicable
Indication:
Indication(s) for solid tumors as per Eisai parent study
Phase:
2 
Approval Date(s):
02 Aug 2017 
Original Protocol
25 Jan 2018 
Protocol Amendment 01
18 Oct 2018
Protocol Amendment 02
10 Mar 2021
Protocol Amendment 02 CHN-1
Local Protocol Amendment China Only
IND Number:
072010
EudraCT Number:
2017-003668-11
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
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
DATE
Highlights of Major Changes
Section/Change
10 Mar 2021
Amendment 02 CHN-1
Local Protocol Amendment China Only:
Section 9.4.1 Treatment(s) Administered: Text added to allow for the local
procurement of commercial comparator treatments as necessary.
Appendix 4: To add the standard of care that is recommended by sponsor. 
18 Oct 2018
Amendment 02: 
Title page: The IND number was added.
Synopsis (Study Design) and Section 9.1:  Clarity was added regarding the 
study design, process of ICF signing, and intention of non-interruption of 
treatment during a subject’s transitioning from the parent study to Study 
E7080-G000-604.
Section 9.1 (Figure 1): The figure was updated to clarify that the screening 
period for the study will overlap with the end of the parent study, and 
accordingly, subjects may remain on the parent study during the screening 
period.  Also, the footnote was updated to state that the Screening Period is 
“Approximately from Day 30 to Day 1).”
Section 9.4.1:  It was clarified that subjects must not be dispensed more 
than a 3-months (formerly, 2 months) supply of study drug(s) at any 
particular time during participation in this study.
Section 9.5.10:  Study discontinuation criteria were harmonized with the 
synopsis.
Synopsis (Inclusion Criteria):  The statement “Subjects must be rolled over 
within 30 days of termination from their parent study” was deleted to 
harmonize with inclusion criteria in the protocol, since this was left in the 
previous amendment in error.
The ICH definition was updated to match the current ICH definition on the 
title page, abbreviation list, Section 5.2, and investigator signature page.
25 Jan 2018
Amendment 01: 
The main reason for the protocol amendment is to align the safety data 
collection in the study with the FDA guidance for long-term safety data 
collection for oncology studies.

Accordingly, the protocol has been updated to define that only 
treatment emergent adverse events (TEAEs) and serious adverse events 
(SAEs) will be collected for all patients. 

It has been clarified that all safety related examinations (including vital 
signs, physical examination, electrocardiogram [ECG], 
echocardiogram [ECHO], multigated acquisition scan [MUGA], 
laboratory investigations should be performed as per local standard of 
care or as clinically indicated, and should be reported in the case report 
form (CRF) only if associated with an adverse event (AE/SAE) (ie, 
only the AE should be recorded in the CRF). Accordingly, all 


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DATE
Highlights of Major Changes
Section/Change
references to these procedures providing specific guidance on conduct 
of these procedures and statistical reporting in the study were deleted. 

Routine reporting of concomitant medications in the study CRF has 
been deleted. 
Other global updates were made to the protocol as follows:

The terminology “study” has been used throughout to replace “trial.”

AE has been updated throughout the protocol to TEAE.
Major revisions to individual sections are presented below:
The abbreviation list was updated.
The approximate number of sites and investigators initially planned for the 
study was updated from 100 sites and 100 investigators to 50 sites and 
50 investigators (Synopsis).
The primary objective was harmonized between the Synopsis and 
Section 8.1, and the term “Eisai-sponsored lenvatinib studies” was 
harmonized globally in the protocol.
The definition of “Parent study” was added in Section 9.1 and the 
Synopsis.
Figure 1 was updated in Section 9.1 to present all criteria for 
discontinuation.
It was emphasized that the subject will not be without study drug during 
transition from the parent study to the roll-over study.  Also, the timeline of 
30 days from termination in the parent study to enrollment in the roll-over 
study was deleted (Synopsis and Section 9.1).”
It was clarified in Section 9.1 and Synopsis that the SAE management and 
reporting requirements specific to study drugs will be as per the parent 
study protocol.  It was also clarified that ongoing adverse events (AEs) in 
the parent study will remain ongoing at the time of discontinuation in the 
parent study, and that the roll-over study will only capture new or 
worsening TEAEs occurring after signing the ICF for the roll-over study.
The number of subjects expected to initially roll over into the study was 
updated from 200 to 50 in Section 9.3 and Synopsis.
Inclusion criterion 2 “Demonstrate compliance with study drug(s), 
treatment visit schedules, requirements and restrictions listed in the consent 
form” in Section 9.3.1 and Synopsis was deleted, and the following
inclusion criterion was added “Must be able and willing to comply with the
current roll-over protocol requirements.”
All references to parent study protocols being included in the protocol 
appendices for E7080-G000-604 were deleted since the parent study 
protocols are not included in the protocol appendices for E7080-G000-604 
(Sections 9.1.1, 9.5.9.1, 9.5.9.2, and Synopsis).  


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DATE
Highlights of Major Changes
Section/Change
Added statement that the study drug(s) administered and dispensed (kit 
number) will be recorded in the CRF (Section 9.4.1 and Section 9.4.4, 
respectively).
Also, the following was added in Section 9.4.1: Subject must not be 
dispensed more than 2 months supply of study drug(s) at any particular 
time during participation in Study E7080-G000-604.
Recording in the study of all prior medications administered 30 days before 
first dose of study drug, any concomitant therapy until 30 days after the 
final dose of study drug, and any other diagnostic, therapeutic, or surgical 
procedures relating to malignancy was deleted, and it was clarified that if 
concomitant medication/therapy is administered for an AE, investigators 
will record that AE on the Adverse Event CRF (Section 9.4.2.4 [Prior and 
Concomitant Therapy] and Synopsis). 
The prohibited concomitant therapies and drugs in Section 9.4.2.6 and 
Synopsis were harmonized.  Also, it was clarified that palliative 
radiotherapy of painful pre-existing non-target bone metastases will be 
permitted without being considered progressive disease. This is in line with 
the current lenvatinib protocols.
The requirement for 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 was deleted since laboratory tests 
are not mandatory per protocol and will be performed as per local 
standards or only when clinically indicated [Section 9.4.4 (Drug Supplies 
and Accountability]).
Clarified in Section 9.4.1 and Section 9.2 that subjects rolling over to the 
study will continue receiving (in addition to lenvatinib or lenvatinib
combination regimen) any other comparator therapy (except placebo).  It 
was also added in Section 9.5.7.1 that, for this study, the study drugs 
include any other comparator therapy (except placebo) (in addition to 
lenvatinib or lenvatinib combination therapy). 
Study assessments:
Deleted recording of baseline characteristics, since only demography 
information will be recorded (Section 9.5.1).
Clarified that initial physical examination and any therapeutic area-specific 
assessments will be performed as per local standard of care or as clinically 
indicated (Section 9.5.2).
Clarified that tumor assessments will be performed as per local standard of 
care (Section 9.5.3).
Clarified that laboratory parameters, vital signs and physical examination 
should be performed as per local standard of care or as clinically indicated. 
Also, added that long term safety information will be collected at the time 
drug is dispensed to the subject (Section 9.5.7 and Synopsis).  


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DATE
Highlights of Major Changes
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Clarified that only TEAEs will be collected in the study and definition of 
TEAE added (Section 9.5.7.1).
Specific guidance and details on conduct of laboratory tests (including the 
names of the laboratory parameters [formerly Table 2]), procedure for vital 
signs and weight measurements, conduct of physical examination, and 
ECG recording was deleted (Sections 9.5.7.5, 9.5.7.6, 9.5.7.7, and 9.5.7.8, 
respectively, and Synopsis) and it has been mentioned that these 
procedures and assessments should be performed per local standard of care 
or as clinically indicated.  It was also specified that for vital signs and 
ECG, only changes from screening vital signs or ECG findings that meet 
the definition of a TEAE will be recorded on the AE CRF (Section 9.5.7.6
and 9.5.7.8).
Table 3 (Schedule of Procedures and Assessments; Section 9.5.8.1) was 
deleted and replaced with the following statement: 
All assessments for efficacy and safety will be performed as per local 
standard of care or as clinically indicated
Reasons for discontinuation of the subjects from the study were 
harmonized between Section 9.1.1, Section 9.5.10, Figure 1 (Section 9.1) 
and Synopsis.  Additional criterion of pregnancy mentioned in Section 
9.5.10 was deleted (as it was added in error).
Reporting for TEAEs and SAEs throughout the protocol was harmonized 
in Sections 9.1, 9.5.7.1, and Synopsis as follows:
All TEAEs and SAEs, regardless of relationship to study drug or 
procedure, should be recorded beginning from the time the subject signs
the roll-over study informed consent form (ICF) for up to 28 days after the 
last dose of study drug(s) (or 5 × half-life of the study drug[s], whichever is 
longer).
Statistical analysis:
The study analysis set was updated from the “all treated population” to the 
“Safety Analysis Set” in Section 9.7 and the Synopsis, and the set was 
defined as the group of subjects who received at least 1 dose of study 
drug(s).
It was clarified that only demographic characteristics will be reported in the 
study and “other baseline characteristics” was deleted (Section 9.7.1.3).
Former Section 9.7.1.3 (Prior and Concomitant Therapy) was deleted since 
this data will not be collected in the study.
Section 9.7.1.6 (Safety Analyses) was modified to reflect that only TEAE 
and SAEs will be summarized.  Laboratory test results, physical 
examination findings, vital signs, and echocardiogram results were deleted 
as these assessments will not be summarized in the study report (also 
deleted from Section 9.7).  


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DATE
Highlights of Major Changes
Section/Change
Accordingly Section 9.7.1.9 (Laboratory Values), Section 9.7.1.10 (Vital 
signs), Section 9.7.1.11 (Electrocardiogram), and Section 9.7.1.12 (Other 
Safety Analyses) were deleted.
The definition of TEAE was updated in Section 9.7.1.8 as follows:
An AE that emerges during treatment in the roll-over study, having been 
absent before the time the subject signs the roll-over study ICF or

Re-emerges during treatment in the roll-over study, having been 
present before signing the ICF but stopped before signing the ICF, or 

Worsens in severity during treatment in the roll-over study relative to 
the pre-ICF state, when the AE is continuous.
It was added that for the TEAEs, the incidence, severity, duration and 
timing in relation to the start of study medication will be summarized.
Since the subjects are not required to adhere to a specific visit schedule, the 
following sentence was deleted from Section 9.5.10, “All subjects who 
discontinue the study are to complete the study’s early discontinuation 
procedures indicated in the Schedule of Procedures/Assessments found in
Table 3.”  Also, reasons for discontinuation were added.
Section 11.5 (Identification of Source Data): Recording of sampling date 
and time for drug concentration and sampling date and time for the clinical 
laboratory test in the CRF was deleted since these procedures will not be 
done in the study.
Appendix 3 – Updated Sponsor’s Grading for Laboratory Values Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03 for 
alkaline phosphatase and γ-glutamyl transpeptidase.
02 Aug 2017
Original Protocol


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7080
Name of Active Ingredient:  lenvatinib and additional investigational agents as per Eisai parent 
study if applicable
Study Protocol Title
An open-label, multi-center, roll-over study to assess long term safety of lenvatinib monotherapy or 
lenvatinib combination regimen or comparator treatment arm to cancer patients in Eisai sponsored 
lenvatinib trials
Investigators
Approximately 50 investigators worldwide are initially planned to participate in the roll-over study.  
It is anticipated that additional investigators may also participate in future.
Sites
Approximately 50 sites globally are initially planned to participate in the roll-over study. It is 
anticipated that additional sites may also participate in the future.
Study Period and Phase of Development

Study Period:  From the date the consent form for roll-over study is signed by first subject 
until 30 days following the last dose of study drug(s) by last subject

Phase:  2 (Extension Study)
Objectives
Primary Objective
The primary objective is to assess long-term safety of study drug(s) in subjects who are enrolled in 
Eisai-sponsored lenvatinib studies.
Secondary Objectives
None
Study Design
This is an open-label extension study to roll-over eligible subjects from Eisai sponsored lenvatinib
studies.  The subject can be enrolled in the roll-over study for the purpose of long-term safety data 
collection.  The subjects may roll-over no sooner than the primary completion dates in their parent 
study or after all study data for primary outcome measure were collected for the parent study.  The 
parent study is defined as the Eisai-sponsored lenvatinib clinical study in which the subject was 
receiving lenvatinib either as monotherapy or as combination therapy or was receiving any other 
comparator therapy.  The subjects willing to participate in the roll-over study have to sign the ICF for 
Study E7080-G000-604.  The “End of Treatment” assessments in the parent study are to be completed 
and reviewed by the investigator prior to enrollment of the subject into Study E7080-G000-604.  
Eligibility for the roll-over study is to be established based on meeting all inclusion and exclusion 
criteria for Study E7080-G000-604.  The intention is that the subject will not be without study drug 
during transition from the parent study to the roll-over study.  The subjects in Study E7080-G000-604
should receive the first dose of the study drug the following day after the last dose of the study drug in 
the parent study.  All treatment emergent adverse events (TEAEs) and serious adverse events (SAEs), 
regardless of relationship to study drug or procedure, should be recorded beginning from the time the 
subject signs the roll-over study ICF for up to 28 days after the last dose of study drug(s) (or 5 × half-
life of the study drug[s], whichever is longer).




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Safety assessments may consist of (but are not limited to) monitoring and recording TEAEs and
SAEs, using Common Terminology Criteria for Adverse Events (CTCAE) v. 4.03.
The other assessments including vital signs, physical examinations, ECG, and clinical laboratory 
assessments should be performed as per local standard of care and as per discretion of the 
investigator. For urgent safety issues, all appropriate medical care is to be administered to the subject 
and the appropriate study team member listed in the Investigator Study File should be contacted. All 
TEAEs and SAEs, regardless of relationship to study drug or procedure, should be recorded 
beginning from the time the subject signs the roll-over study ICF for up to 28 days after last dose of 
study drug(s) (or 5 × half-life of the study drug[s], whichever is longer).  Any exposure to study 
drug(s) through breastfeeding during the roll-over study or within 120 days of the last study drug(s), 
or 30 days following the last study drug(s) if the subject initiates a new anticancer therapy, whichever 
occurs first, must be reported. SAE management and reporting requirements specific to study drugs 
will be addressed as per instructions in the parent study protocol.
Number of Subjects
It is expected that approximately 50 subjects will be initially rolled over into the study.  It is 
anticipated that additional subjects may also roll over into the study in the future.
Inclusion Criteria
It is required for all subjects currently participating in other lenvatinib studies to meet the following 
eligibility criteria.  
1.
Provide signed written informed consent for the roll-over study
2.
Currently enrolled in an Eisai sponsored lenvatinib clinical study and still receiving at least one 
of the study drugs from that protocol 
3.
Currently deriving clinical benefit from at least one of the study drug(s) as determined by the 
investigator
4.
Must be able and willing to comply with the current roll-over protocol requirements 
5.
Continued ability to swallow and retain orally administered study drug(s)
6.
Does not have any clinically significant gastrointestinal abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach or bowels
7.
Women of childbearing potential and men with reproductive potential (if specified by the parent 
study) must be willing to continue to use highly effective methods of contraception  as per local 
practices of standard of care during the period of the study
8.
Women of childbearing potential must have a negative serum pregnancy test at the time of 
transition to the study and before continuing study drug(s)
Exclusion Criteria
1.
Permanent discontinuation of all study drug(s) in the parent study due to toxicity or disease 
progression and without clinical benefit
2.
Receiving any prohibited medication(s) as described in the parent study
3.
Any unresolved toxicity that meets the criteria for study drug(s) discontinuation or withdrawal 
criteria from the parent study at the time of transition to this study
4.
Uncontrolled diabetes, hypertension or other medical conditions at the time of transition to the 
roll-over study that may interfere with assessment of toxicity
5.
Pregnant or lactating female


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6.
Any serious and/or unstable pre-existing medical condition, psychiatric disorder or other 
conditions at the time of transition to the roll-over study that could interfere with subject's safety 
in the opinion of the investigator
Study Treatment
Eligible subjects from Eisai sponsored studies for lenvatinib will be rolled over to the appropriate 
cohort and continue receiving the study drug(s) as described in the above-mentioned sections.
Dose Modifications
Dose reduction and interruption to study drug(s), will be in accordance with the parent study
protocol.  If a subject is receiving more than one study drug, the investigator will decide the 
probability and causality of the event being related to one or both drugs.  The investigator will also 
decide if dose modification of one or both drugs is required.
Dose reductions will apply to individual subjects only.  Once the dose has been reduced, it cannot be 
increased at a later date unless the dose was mistakenly decreased; in this situation, the sponsor’s 
approval is required to increase the dose.
Details regarding the management of important identified risks associated with the use of study 
drug(s) will be in accordance with the parent study protocol.
Duration of Treatment
A subject will remain on study drug(s) until 1 or more of the following events occur(s):

Progressive disease (PD) (as confirmed by treating investigator)
Note:  Subjects will be permitted to continue study drug(s) beyond initial disease progression as 
long as investigator-assessed clinical benefit is observed after discussion and approval by the 
sponsor and if the subject is tolerating study drug(s).  Subjects will discontinue study drug(s) 
upon evidence of further progression and/or loss of clinical benefit as judged by the investigator

Unacceptable toxicity

Subject request

Withdrawal of consent

Termination of the study by sponsor

Use of non-permitted concomitant drug(s) 

Unacceptable non-compliance with the protocol

Lost to follow-up


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Concomitant Drug/Therapy
Any medication which is considered necessary for the subject’s welfare, and which is not expected to 
interfere with the evaluation of the investigational product, may be given at the discretion of the 
investigator.  
The concomitant therapies that are permitted and prohibited therapies that are not allowed during the 
study will be in accordance with the local prescribing information and/or investigator brochure for 
study drug(s).  
The following therapies are prohibited during the study: 

Concurrent other anticancer therapies such as chemotherapy, tyrosine-kinase inhibitor (TKIs), 
antitumor interventions (surgical resection, surgical de-bulking of tumors, etc.), or cancer 
immunotherapy 

Radiotherapy except for palliative radiotherapy: palliative radiotherapy of painful pre-existing 
non-target bone metastases will be permitted without being considered progressive disease

Concurrent other investigational drugs
If subjects receive antitumor therapies listed above, or any additional antitumor therapies, this will be 
judged to represent evidence of disease progression, and study medication will be discontinued.  
Assessments
Efficacy Assessments
Only disease progression will be recorded in the study case report forms (CRFs).
Pharmacokinetic Assessments
Not applicable
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Not applicable
Safety Assessments
Safety assessments will consist of monitoring and recording all TEAEs and SAEs using Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03. Long term safety information will be 
collected at the time drug is dispensed to the subject.
Safety Reporting Requirements
All serious adverse events (SAEs) and all other events of interest as described in the parent study 
protocol must be captured in the CRFs and must be reported to sponsor’s safety representative (or 
sponsor’s dedicated local safety and pharmacovigilance contact personnel) and site’s ethics 
committee as per local regulatory requirements.  The safety reporting plan will be provided to 
participating sites outlining country specific requirements for safety reporting.
Bioanalytical Methods: 
Not applicable
Statistical Methods
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug(s).  The 
Safety Analysis Set will be used in all analyses of safety.  The following safety tables and listings 
will be available for review:


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
Extent of exposure, TEAEs, SAEs, TEAEs/SAEs related to study drug(s), TEAEs leading to 
discontinuation of study drug(s)/withdrawal, fatal TEAEs and deaths.  

Other TEAEs that the investigator deemed important to report and reasons for discontinuation of 
study drug(s).  
Interim Analyses
Not applicable
Sample Size Rationale
Not applicable


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TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
REVISION HISTORY ..........................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS............................................................................7
TABLE OF CONTENTS.............................................................................................13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................17
ETHICS.......................................................................................................................20
5.1
Institutional Review Boards/Independent Ethics Committees .............................20
5.2
Ethical Conduct of the Study..............................................................................20
5.3
Subject Information and Informed Consent ........................................................21
INVESTIGATORS AND STUDY PERSONNEL .......................................................22
INTRODUCTION.......................................................................................................22
STUDY OBJECTIVES................................................................................................24
8.1
Primary Objective ..............................................................................................24
8.2
Secondary Objective(s) ......................................................................................24
INVESTIGATIONAL PLAN ......................................................................................24
9.1
Overall Study Design and Plan...........................................................................24
9.1.1
Treatment Phase .......................................................................................26
9.2
Discussion of Study Design, Including Choice of Control Groups......................26
9.3
Selection of Study Population ............................................................................26
9.3.1
Inclusion Criteria......................................................................................26
9.3.2
Exclusion Criteria.....................................................................................27
9.3.3
Removal of Subjects From Therapy or Assessment ..................................27
9.4
Treatment(s).......................................................................................................28
9.4.1
Treatment(s) Administered .......................................................................28
9.4.1.1
Management of Toxicities...............................................................28
9.4.1.2
Chemical Name, Structural Formula of Lenvatinib..........................28
9.4.1.3
Chemical Name, Structural Formula of Study Drug in 
Combination Regimen other than Lenvatinib ..................................29
9.4.1.4
Prior and Concomitant Therapy.......................................................29
9.4.1.5
Drug-Drug Interactions...................................................................30
9.4.1.6
Prohibited Concomitant Therapies and Drugs .................................30
9.4.2
Treatment Compliance..............................................................................31
9.4.3
Drug Supplies and Accountability ............................................................31
9.5
Study Assessments.............................................................................................32
9.5.1
Demography.............................................................................................32
9.5.2
Medical History and Physical Examinations .............................................32
9.5.3
Efficacy Assessments ...............................................................................32


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9.5.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other  
Biomarker Assessments............................................................................33
9.5.5
Pharmacokinetic Assessments ..................................................................33
9.5.6
Pharmacodynamic, Pharmacogenomic, and Other Biomarker,  
Assessments .............................................................................................33
9.5.7
Safety Assessments ..................................................................................33
9.5.7.1
Adverse Events...............................................................................33
9.5.7.2
Assessing Severity of Adverse Events.............................................34
9.5.7.3
Assessing Relationship to Study Treatment(s).................................35
9.5.7.4
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................36
9.5.7.5
Laboratory Measurements...............................................................37
9.5.7.6
Vital Signs and Weight Measurements............................................37
9.5.7.7
Physical Examinations ....................................................................37
9.5.7.8
Electrocardiograms .........................................................................37
9.5.7.9
Other Assessments..........................................................................37
9.5.8
Schedule of Procedures/Assessments........................................................37
9.5.8.1
Schedule of Procedures/Assessments ..............................................37
9.5.9
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated  with Special Situations...........................................................38
9.5.9.1
Reporting of Serious Adverse Events..............................................38
9.5.9.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................38
9.5.9.3
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse,  Abuse, or Medication Error..............................39
9.5.9.4
Regulatory Reporting of Adverse Events.........................................40
9.5.10
Completion/Discontinuation of Subjects...................................................40
9.5.11
Abuse or Diversion of Study Drug............................................................40
9.5.12
Confirmation of Medical Care by Another Physician................................40
9.6
Data Quality Assurance......................................................................................41
9.6.1
Data Collection.........................................................................................41
9.6.2
Clinical Data Management .......................................................................41
9.7
Statistical Methods.............................................................................................41
9.7.1
Statistical and Analytical Plans.................................................................41
9.7.1.1
Definitions of Analysis Sets............................................................42
9.7.1.2
Subject Disposition.........................................................................42
9.7.1.3
Demographic Characteristics...........................................................42
9.7.1.4
Efficacy Analyses ...........................................................................42
Primary Efficacy Analysis....................................................................................42
9.7.1.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker  Analyses .............................................................42
Pharmacokinetic Analyses ...................................................................................42


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Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses................42
9.7.1.6
Safety Analyses ..............................................................................42
9.7.1.7
Extent of Exposure..........................................................................42
9.7.1.8
Adverse Events...............................................................................43
9.7.1.9
Other Analyses ...............................................................................43
9.7.2
Determination of Sample Size ..................................................................43
9.7.3
Interim Analysis .......................................................................................43
9.7.4
Other Statistical/Analytical Issues.............................................................43
9.7.5
Procedure for Revising the Statistical Analysis Plan .................................44
REFERENCE LIST.....................................................................................................45
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE  PROCEDURES)......47
11.1
Changes to the Protocol......................................................................................47
11.2
Adherence to the Protocol ..................................................................................47
11.3
Monitoring Procedures.......................................................................................47
11.4
Recording of Data..............................................................................................48
11.5
Identification of Source Data..............................................................................48
11.6
Retention of Records..........................................................................................49
11.7
Auditing Procedures and Inspection ...................................................................49
11.8
Handling of Study Drug .....................................................................................49
11.9
Publication of Results ........................................................................................50
11.10 Disclosure and Confidentiality ...........................................................................50
11.11 Discontinuation of Study....................................................................................50
11.12 Subject Insurance and Indemnity........................................................................51
LIST OF IN-TEXT TABLES
Table 1
Grading of adverse events as per Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03..............................................................35
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E7080-G000-604 .......................................25
Figure 2
Structural Formula of Lenvatinib Mesilate ......................................29
LIST OF APPENDICES
Appendix 1
Clinical Studies Evaluating Drug-Drug Interactions with 
Lenvatinib
52


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Appendix 2
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03
53
Appendix 3
Sponsor’s Grading for Laboratory Values Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.03.....................54
Appendix 4
For China only : Sponsor’s Recommended Standard of 
Care
56


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADL
activities of daily living
AE
adverse event
ALT
alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
BP
blood pressure
CA
competent authorities
CFR
Code of Federal Regulations
CI
confidence interval
CL/F
apparent clearance
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
Clinical Research Organization
CSR
clinical study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
curriculum vitae
DTC
differentiated thyroid cancer
EC
European Communities
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EU
European Union
FDA
Food and Drug Administration
g-CSF
granulocyte colony-stimulating factor
GCP
Good Clinical Practice
GGT
γ-glutamyl transpeptidase
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for  Pharmaceuticals for Human Use


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Abbreviation
Term
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IVRS/IWRS
interactive voice/web response system
LLN
lower limit of normal
LMWH
low-molecular-weight-heparin
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MHRA
Medicines and Healthcare Products Regulatory Agency
MUGA
multigated acquisition scan
NSAID
nonsteroidal anti-inflammatory drug
ORR
objective response rate
OS
overall survival
PD
progressive disease
PR
partial response
PFS
progression-free survival 
PI
principal investigator
PK
pharmacokinetic(s)
PRT
palliative radiotherapy
PSC
Protocol Steering Committee
PT
preferred term
RECIST
Response Evaluation Criteria in Solid Tumors
RR-DTC
radioiodine-refractory differentiated thyroid cancer
SAE
serious adverse event
SOC
system organ class
SOP
standard operating procedure
SUSARs
suspected unexpected serious adverse reactions
TEAEs
treatment-emergent adverse events
TKI
tyrosine kinase inhibitor
TTP
time to progression 
ULN
upper limit of normal


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Abbreviation
Term
US/USA
United States of America
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell (count)


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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 ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations.  Any protocol amendment or revision to the 
ICF will be resubmitted to the IRB/IEC for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in 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 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 
(CA) within 90 days.  The definition of the end of the study is the date of the data cutoff for 
the final analysis or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.
The sponsor should also provide the IRB/IEC with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki 2014


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
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

A waiver from the IRB(s)/IEC(s) will be obtained before study initiation for non-US 
studies conducted under an Investigational New Drug (IND) application.

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All SUSARs will be reported, 
as required, to the Competent Authorities of all involved EU member states.

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 
145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian/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 before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.


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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site. 
The subject 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.
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified physicians under the sponsorship of Eisai (the 
sponsor) at an unspecified number of treatment sites.
The name and contact information of the sponsor’s study team members and any Contract 
Research Organizations (CROs) used for this study are listed in the Physician Information 
Package provided to each site.
INTRODUCTION
Lenvatinib is an investigational tyrosine kinase inhibitor (TKI) agent and it has completed 
clinical registration studies for the treatment of radioiodine-refractory differentiated thyroid 
cancer (RR-DTC) and unresectable Hepatocellular Carcinoma. Moreover, a multicenter, 
open-label, randomized, Phase 3 trial is ongoing to compare the efficacy and safety of 
lenvatinib in combination with everolimus or pembrolizumab versus sunitinib alone in 
first-line treatment of subjects with advanced renal cell carcinoma (E7080-G000-307).  
Based on its efficacy and safety profile, lenvatinib was granted approval to treat patients with 
progressive, DTC whose disease progressed despite receiving radioactive iodine therapy
disease (Lenvima approval for DTC,13 Feb 2015).  Moreover, lenvatinib was approved for 
use in combination with everolimus (Afinitor®) in the treatment of advanced renal cell 
carcinoma following one prior antiangiogenic therapy (FDA Approved Drugs, 13 May 
2016). 
The activity of lenvatinib for treatment of patients with advanced, progressive DTC 
unresponsive to conventional radioiodine therapy has been initially established in a Phase 2 
trial E7080-G000-201, which enrolled 58 patients with RR-DTC (Cabanillas, et al., 2015)
and 59 patients with medullary thyroid cancer.  The primary efficacy endpoint of this study 
was the objective response rate (ORR) based on the assessments by the independent imaging 
review using modified Response Evaluation Criteria in Solid Tumors (RECIST).  In the RR-
DTC cohort, the ORR was 50%; 59% in patients with prior VEGF/VEGFR-targeted 
treatment and 46% in patients without prior vascular endothelial growth factor (VEGF)/
vascular endothelial growth factor receptor (VEGFR)-targeted therapy.  The median estimate 
of progression-free survival (PFS), at a minimum follow-up of 14 months, was 12.6 months.  
The 6-months PFS rate was 78% and the 12-months PFS rate was 55%.  The overall survival 


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(OS) rate was 86% at 12 months and was 78% at both 18 and 24 months.  The most 
frequently reported (>40% of all patients) treatment-emergent adverse events (TEAEs) were 
diarrhea, hypertension, proteinuria, fatigue, weight decreased, decreased appetite, nausea, 
headache, cough, and dysphonia.  In the DTC cohort, the most commonly reported Grade 3 
TEAEs (occurring in approximately 10% of patients) were hypertension, weight decrease, 
diarrhea, and proteinuria. 
The efficacy and safety of lenvatinib treatment has also been evaluated in the multicenter, 
randomized, double-blind, placebo-controlled Phase 3 trial E7080-G000-303 (SELECT trial) 
in patients with RR-DTC with documented disease progression within 13 months.  Patients 
were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and 
randomized 2:1 to lenvatinib or placebo arms (24 mg a day, 28-day cycle).  The primary 
endpoint was PFS assessed by Independent Radiologic Review; the secondary endpoints 
included ORR (ie, complete response [CR] + partial response [PR]), OS, and safety.  A total 
of 392 patients (63.0 years median age; 51.0% male) were randomized at over 100 sites in 
Europe, North and South America, and Asia.  Patients in the lenvatinib arm had a 
significantly prolonged PFS (hazard ratio = 0.21, 95% confidence interval [CI] = 0.14–0.31; 
P<0001) with a median PFS for the lenvatinib arm of 18.3 months (95% CI = 15.1–not 
evaluable) vs the placebo arm: 3.6 months (95% CI = 2.2–3.7).  The lenvatinib arm PFS 
benefit was observed in all predefined subgroups:  median lenvatinib arm PFS for patients 
with prior vs no prior VEGF-therapy was 15.1 months (n=66) and 18.7 months (n=195), 
respectively; rates (n) of CRs for the lenvatinib arm vs placebo arm were 1.5% (4) and 0, 
respectively; PRs for the lenvatinib arm vs the placebo arm were 63.2% (165) and 1.5% (2), 
respectively.  Median exposure durations for the lenvatinib arm vs the placebo arm were 13.8 
months and 3.9 months, respectively; median time to lenvatinib response was 2.0 months.  
Median OS has not been reached; deaths for the lenvatinib arm were 71 (27.2%) and for the 
placebo arm were 47 (35.9%).  The 5 most common lenvatinib treatment-related adverse 
events (AEs) (any grade) were hypertension (68%), diarrhea (59%), appetite decreased 
(50%), weight loss (46%), nausea (41%).  The most common Grade ≥3 lenvatinib treatment-
related AEs (≥5%) were hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea 
(8%), and appetite decreased (5%).  The lenvatinib dose was reduced in 78.5% of patients 
and lenvatinib was discontinued due to AEs in 14.2% of patients (Schlumberger, et al., 
2014). Based on the efficacy and safety information to date, patients with RR-DTC may 
benefit from lenvatinib treatment. 
In regards to efficacy and safety in RCC, the Phase 2 portion of Study E7080-G000-205
enrolled 153 patients with advanced or metastatic, clear- cell, RCC who had a history of 
receiving 1 prior VEGF agent. A total of 153 patients were randomized in a 1:1:1 ratio to 
receive treatment with lenvatinib plus everolimus, lenvatinib (24 mg once daily [QD]), or 
everolimus (10 mg QD). The safety profile for lenvatinib plus everolimus was consistent 
with the known toxic effects of each individual agent, with no unexpected TEAEs observed. 
The most common TEAEs of any grade in the lenvatinib plus everolimus arm were diarrhea 
and fatigue or asthenia. Grade 3 and 4 events occurred in fewer patients allocated single-
agent everolimus (25 [50%]) compared with those assigned lenvatinib alone (41 [79%]) or 
lenvatinib plus everolimus (36 [71%]).  The most common Grade 3 or 4 TEAEs in patients 
allocated lenvatinib plus everolimus was diarrhea (10 [20%]), in those assigned single-agent 


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lenvatinib it was proteinuria (10 [19%]), and in those assigned single- agent everolimus it 
was anemia (6 [12%]). Two deaths were deemed related to study drug,1 cerebral 
hemorrhage in the lenvatinib plus everolimus group and 1 myocardial infarction with single-
agent lenvatinib (Motzer, et al., 2015a).
In regards to efficacy and safety in unresectable HCC, lenvatinib has been evaluated in the 
Phase 3 study of “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” (E7080-G000-304). This was a
non-inferiority study of patients who had unresectable HCC with ≥ 1 measurable target 
lesion, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, Eastern Cooperative 
Oncology Group (ECOG) PS ≤ 1, and with no prior systemic therapy. Among 954 enrolled
patients, 478 patients received lenvatinib while 476 received sorafenib and were randomized 
1:1 to lenvatinib (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) or the comparator 
arm of sorafenib 400 mg twice daily. The efficacy of lenvatinib has been demonstrated to be 
non-inferior in terms of OS, and achieved statistically significant and clinically meaningful 
improvements in PFS, time to progression (TTP) and ORR by modified RECIST as first line 
therapy for unresectable hepatocellular carcinoma. The TEAEs were consistent with the 
known lenvatinib safety profile. Most common lenvatinib TEAEs were hypertension (42%), 
diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%)
(Cheng, et al., 2017). As there are patients who are continuing treatment from several 
ongoing clinical studies of different phases in the lenvatinib program at Eisai, the “roll-over” 
study will allow those patients to continue to receive their treatments of lenvatinib as 
monotherapy or in combination regimen provided that they are deriving clinical benefit.  
Long-term safety will be assessed in patients in this study.
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective is to assess long-term safety of study drug(s) in subjects who are 
enrolled in Eisai-sponsored lenvatinib studies.
8.2
Secondary Objective(s)
Not applicable.
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is an open-label extension study to roll-over eligible subjects from Eisai sponsored 
lenvatinib studies.  The subject can be enrolled in the roll-over study for the purpose of 
long-term safety data collection. The transition would occur after the completion and 
evaluation of the primary endpoint of the parent studies or after all study data for the primary 
outcome measure were evaluated for the parent study.  The parent study is defined as the 




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Cohort B: Subjects who received lenvatinib combination therapy or who crossed over from a 
comparator arm to receive lenvatinib combination therapy in their parent study will continue 
to receive lenvatinib combination therapy
Cohort C: Subjects who received comparator treatment in their parent study will continue to 
receive comparator treatment, with exception of subjects receiving placebo*
Discontinuation criteria: progression of disease, unacceptable toxicity, subject request, 
withdrawal of consent, termination of study by sponsor, use of non-permitted concomitant 
drugs, unacceptable non-compliance with the protocol, subject lost to follow-up.
Subjects will be permitted to continue study drug(s) beyond initial disease progression as 
long as the treating investigator considers that there is continued clinical benefit after 
discussing with the sponsor and if the subject is tolerating the study drug(s).
* Subjects who received placebo in their parent study and who were either not permitted to 
cross over or who opted not to cross over to active treatment will not be eligible to enroll in 
this study. 
9.1.1
Treatment Phase
During the Treatment Phase, subjects still on treatment will continue the same treatment they 
received upon discontinuation of the parent study. Subjects will remain on treatment in 
consecutive cycles as per the parent study protocol until disease progression, development of 
unacceptable toxicity, subject request, withdrawal of consent, discontinuation of Study 
E7080-G000-604 by the sponsor, use of non-permitted concomitant drugs, unacceptable 
non-compliance with the protocol, or if the subject is lost to follow-up. 
9.2
Discussion of Study Design, Including Choice of Control Groups
Subjects will enter the study at the same doses of study drug of lenvatinib or the combination 
regimen, or any other comparator therapy (except placebo), upon discontinuation of the 
parent study.  This is a roll-over open-label study with no control group. 
9.3
Selection of Study Population
It is expected that approximately 50 subjects will be initially rolled over to the study. It is 
anticipated that additional subjects may also roll over to the study in the future.  Subjects 
who meet all of the inclusion criteria and none of the exclusion criteria, with no evidence of 
progressive disease, and who have tolerated study drug(s) in their parent study without 
significant toxicities will be rolled over to this study. Subjects with evidence of disease 
progression but who continue to derive clinical benefit as determined by the investigator 
would require discussion with the sponsor on an individual case-by-case basis prior to 
enrollment in this study.
9.3.1
Inclusion Criteria
It is required for all subjects currently participating in other lenvatinib studies to meet the 
following eligibility criteria prior to entry in the study.
1. Provide signed written informed consent for the roll-over study


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2. Currently enrolled in an Eisai sponsored lenvatinib clinical study and still receiving at 
least one of the study drugs from that protocol
3. Currently deriving clinical benefit from at least one of the study drug(s) as determined by 
the investigator
4. Must be able and willing to comply with the current roll-over protocol requirements
5. Continued ability to swallow and retain orally administered study drug(s)
6. Does not have any clinically significant gastrointestinal abnormalities that may alter 
absorption such as malabsorption syndrome or major resection of the stomach or bowels
7. Women of childbearing potential and men with reproductive potential (if specified by the 
parent study) must be willing to continue to use highly effective methods of 
contraception control as per local practices of standard of care during the period of the 
study
8. Women of childbearing potential must have a negative serum pregnancy test at the time 
of transition to the study and before continuing study drug(s).
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Permanent discontinuation of study drug(s) in the parent study due to toxicity or disease 
progression and without clinical benefit
2. Receiving any prohibited medication(s) as described in the parent study
3. Have any unresolved toxicity that meets the criteria for study drug(s) discontinuation or 
withdrawal criteria from the parent study at the time of transition to this study
4. Uncontrolled diabetes, hypertension or other medical conditions at the time of transition 
to the roll-over study that may interfere with assessment of toxicity
5. Pregnant or lactating female
6. Any serious and/or unstable pre-existing medical condition, psychiatric disorder or other 
conditions at the time of transition to the roll-over study that could interfere with subject's 
safety in the opinion of the investigator
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject withdraws consent, the date 
will be documented in the CRF and source documents.


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9.4
Treatment(s)
9.4.1
Treatment(s) Administered
Subjects enrolled from parent study will enter the roll-over study and will continue the study 
drug of lenvatinib, or combination regimen, or any other comparator therapy (except 
placebo) at the same doses upon discontinuation of the parent study. Study drug(s) 
administered will be recorded in the case report form (CRF). 
Subject must not be dispensed more than a 3-months supply of study drug(s) at any particular 
time during participation in Study E7080-G000-604.
For China Only:
Comparator Drug: Sorafenib
The subject(s) who receive the comparator in the parent study will be enrolled to Cohort C. 
In the event that comparator clinical supply is limited, the comparator treatment may be 
obtained commercially from local sources and reimbursed by the sponsor unless this is 
prohibited by specific country laws. Further instructions on acquisition procedures for 
commercial supply will be provided by the sponsor.
Criteria for Interruption of Treatment, Dose Reduction and Resumption
Dose reduction and interruptions for subjects who experience toxicity will be made according 
to the guidelines provided in the parent protocol.
9.4.1.1
Management of Toxicities
Management of toxicities including hypertension, proteinuria, hepatotoxicity, 
thromboembolic events, Posterior Reversible Encephalopathy Syndrome/ Reversible
Posterior Leukoencephalopathy Syndrome and hypocalcemia and any other adverse events 
will be according to the parent study.
9.4.1.2
Chemical Name, Structural Formula of Lenvatinib 

Test drug code: E7080

Generic name: lenvatinib, lenvatinib mesilate, lenvatinib mesylate

Chemical name: 4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula: C21H19ClN4O4•CH3SO3H

Molecular weight: 522.96

Structural formula: (see Figure 2)


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Figure 2
Structural Formula of Lenvatinib Mesilate
9.4.1.3
Chemical Name, Structural Formula of Study Drug in Combination Regimen 
other than Lenvatinib 
The following information if applicable will be provided in the corresponding parent study.
9.4.1.4
Prior and Concomitant Therapy
Any medication that is considered necessary for the subject’s health and that is not expected 
to interfere with the evaluation of or interact with lenvatinib or with the lenvatinib
combination regimen as per the parent study may be continued during the study.
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) lenvatinib.
If a subject is receiving treatment with lenvatinib and requires surgery during the study, the
stop time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding.

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and
then restart it at least 1 week after, once there is evidence of adequate healing and no risk
of bleeding.
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Granulocyte colony-stimulating 
factor (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.


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If concomitant medication/therapy is administered for an AE, investigators will record that 
AE on the Adverse Event CRF. 
9.4.1.5
Drug-Drug Interactions
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 enzymes 
(CYP P450) (Study No. XT063020) suggests a low risk of lenvatinib interference with the
PK of other drugs metabolized by CYP P450 enzymes which are co-administered in usual
clinic practice. Nonclinical studies identify CYP3A4 as the important CYP isozyme
responsible for human hepatic metabolism of lenvatinib. However, clinical studies
conducted showed that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp)
inhibitors or inducers is not of clinical concern. The main metabolic pathways for lenvatinib
in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic
processes (LENVIMA® Package Insert). Please refer to Appendix 1 and
http://medicine.iupui.edu/clinpharm/ddis/ for the most current information.
For subjects receiving everolimus, drugs or substances (including herbal supplements or
grapefruit juice) known to be potent inhibitors of CYP3A4/P-gp should not be used. Potent
inducers of CYP3A4/P-gp should not be used unless there is no alternative treatment
available. Moderate/ weak inhibitors or inducers or substrates of CYP3A4 and/or P-gp
should be used with caution.  Dose reduction of everolimus may be considered when
coadministering moderate CYP3A4 or P-gp inhibitors. For further information please refer 
to the prescribing information.  No formal pharmacokinetic drug interaction studies have 
been conducted with pembrolizumab. Pembrolizumab is a monoclonal antibody; 
pharmacokinetic interactions with lenvatinib (and vice-versa) are not expected.  Strong 
CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. 
CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection 
of an alternate concomitant medication with no or minimal enzyme inhibition or induction is 
recommended. A dose reduction for sunitinib to a minimum of 37.5 mg daily should be 
considered if sunitinib must be co-administered with a strong CYP3A4 inhibitor. A dose 
increase for sunitinib to a maximum of 87.5 mg daily should be considered if sunitinib must 
be co-administered with a CYP3A4 inducer.  If dose is increased, the patient should be 
monitored carefully for toxicity.  In regards, to lenvatinib combination regimen, please refer 
to drug-drug interactions section in the parent study.
9.4.1.6
Prohibited Concomitant Therapies and Drugs
The following therapies are prohibited during the study: 

Concurrent other anticancer therapies such as chemotherapy, tyrosine-kinase inhibitor 
(TKIs), antitumor interventions (surgical resection, surgical de-bulking of tumors, etc.), 
or cancer immunotherapy 

Radiotherapy except for palliative radiotherapy: palliative radiotherapy of painful 
pre-existing non-target bone metastases will be permitted without being considered 
progressive disease

Concurrent other investigational drugs


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If subjects receive antitumor therapies listed above, or any additional antitumor therapies, this 
will be judged to represent evidence of disease progression, and study medication will be 
discontinued.  
9.4.2
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.
9.4.3
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

An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable

Financial Disclosure form(s) for the principal investigator (PI) and all sub-investigators 
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
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 Good Clinical Practice (GCP) guidelines as well as local or regional 
requirements.
Study drug(s) dispensed (Kit #) will be recorded in the CRF.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs/study supplies will not be dispensed to any individual 
who is not enrolled in the study.  The site must maintain an accurate and timely record of the 


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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 drug 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, Medicines and Healthcare Products Regulatory Agency [MHRA]). As applicable, all 
unused study drugs and empty and partially empty blister packages 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.  
Destruction at the site will only occur under circumstances where regulation or supply type
prohibits the return of study drugs to the central or local depot(s). Approval for destruction
to occur at the site must be provided by the sponsor in advance. Upon completion of drug
accountability and 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
Demography
Subject demography information will be collected and recorded in the CRF.  Demography 
information includes age, sex, and race/ethnicity.
9.5.2
Medical History and Physical Examinations
Initial physical examination and any therapeutic area-specific assessments will be performed 
as per local standard of care or as clinically indicated.
9.5.3
Efficacy Assessments
Tumor assessments will be performed as per local standard of care .


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9.5.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments
Not applicable.
9.5.5
Pharmacokinetic Assessments
Not applicable.
9.5.6
Pharmacodynamic, Pharmacogenomic, and Other Biomarker,
Assessments
Not applicable.
9.5.7
Safety Assessments
Safety assessments will consist of monitoring and recording all TEAEs, including all 
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grades (for both 
increasing and decreasing severity), and SAEs. Long term safety information will be collected at 
the time drug is dispensed to the subject.
Monitoring of hematology, blood chemistry, and urine values; measurement of vital signs 
and performance of physical examinations should be performed per local standard of care or 
as clinically indicated 
9.5.7.1
Adverse Events
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drug(s) is/are 
lenvatinib, or lenvatinib combination regimen, or any other comparator therapy (except 
placebo) as per the parent study.
AEs collected in this study must be treatment-emergent adverse events (TEAE). This is 
defined as an AE that emerges during treatment in the roll-over study, having been absent 
before the time the subject signs the roll-over study ICF or

Re-emerges during treatment in the roll-over study, having been present before signing 
the ICF but stopped before signing the ICF, or 

Worsens in severity during treatment in the roll-over study relative to the pre-ICF state, 
when the AE is continuous.
The criteria for identifying TEAEs 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

Any new disease or exacerbation of an existing disease.


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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 a TEAE 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
A laboratory result should be considered by the investigator to be a TEAE if it:

Results in the withdrawal of study drug

Results in withholding of study drug pending some investigational outcome

Results in an intervention, based on medical evaluation (eg, potassium supplement for
hypokalemia

Results in any out-of-range laboratory value that in the investigator’s judgment fulfills 
the definitions of a TEAE with regard to the subject’s medical profile

Increases in severity compared to the pre-ICF state by 2 or more CTCAE grades (Table 1
and Appendix 2 for CTCAE v4.03), with the exception of lymphocytes, albumin, 
cholesterol, glucose, and phosphate. For these tests, any change of 2 or more grades will 
be evaluated by the investigator to determine if it is of clinical significance and, if so, will 
be considered a TEAE
All TEAEs and SAEs, regardless of relationship to study drug or procedure, should be 
recorded beginning from the time the subject signs the roll-over study ICF for up to 28 days 
after the last dose of study drug(s) (or 5 half-life of study drug[s], whichever is longer).  
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 a TEAE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute a 
TEAE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as a TEAE.  Any laboratory abnormality 
considered to constitute a TEAE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as a TEAE, should be considered a TEAE 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 a TEAE should be reported as such.
9.5.7.2
Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 Table 1. 
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing
severity).


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Table 1
Grading of adverse events as per Common Terminology Criteria 
for Adverse Events (CTCAE) Version 4.03
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 bed-ridden
For further details regarding MedDRA, refer to the MedDRA website at: http://www.meddra.org/. 
CTCAE v4.03 is available online at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html
9.5.7.3
Assessing Relationship to Study Treatment(s)
Items to be considered when assessing the relationship of a TEAE to the study treatment(s)
are:

Temporal relationship of the onset of the event to the initiation of the study treatment(s)

The course of the event, especially the effect of discontinuation of study treatment(s) or 
reintroduction of study treatment(s), as applicable

Whether the event is known to be associated with the study treatment(s) or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of non-study, treatment(s)-related factors that are known to be associated 
with the occurrence of the event
Classification of Causality
The relationship of each TEAE to the study drug(s) will be recorded on the CRF in response 
to the following question:
Is there a reasonable possibility that the study drug(s) caused the AE?


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Yes (related)
A causal relationship between the study drug(s) and the TEAE is a 
reasonable possibility.
No (not related) A causal relationship between the study drug(s) and the TEAE is not a 
reasonable possibility.
9.5.7.4
Serious Adverse Events and Events Associated with Special Situations
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug(s) through breastfeeding; TEAEs 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 TEAEs 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.
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(s) or insertion of access for 
administration of study drug(s)

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry.


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9.5.7.5
Laboratory Measurements
Clinical laboratory tests including hematology, chemistry, and urinalysis should be 
performed per local standard of care or as clinically indicated.
A laboratory abnormality may meet the criteria to qualify as a TEAE as described in this 
protocol (see Section 9.5.7.1 and the CRF Completion Guidelines).  In these instances, the 
TEAE corresponding to the laboratory abnormality will be recorded on the Adverse Event 
CRF.
9.5.7.6
Vital Signs and Weight Measurements
Vital signs measurements (will be performed as per local standard of care or as clinically 
indicated. Only changes from screening vital signs findings that meet the definition of a 
TEAE will be recorded on the Adverse Events CRF. 
9.5.7.7
Physical Examinations
Physical examinations will be performed as per local standard of care or as clinically 
indicated. Only changes from screening physical examination findings that meet the 
definition of a TEAE will be recorded on the Adverse Events CRF.
9.5.7.8
Electrocardiograms
Complete, standardized, 12-lead ECG recordings (if required) will be performed as per local 
standard of care. 
Only changes from screening ECG findings that meet the definition of a TEAE will be 
recorded on the Adverse Events CRF.
9.5.7.9
Other Assessments
Not applicable.
9.5.8
Schedule of Procedures/Assessments
9.5.8.1
Schedule of Procedures/Assessments
All assessments for efficacy and safety will be performed as per local standard of care or as 
clinically indicated.  


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9.5.9
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.9.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from when the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected as indicated in 
the parent protocol. 
Regardless of treatment arm, all SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
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.
9.5.9.2
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 study treatment, or any 
exposure to study drug through breastfeeding during study treatment(s) or within 30 days of 
last study treatment, must be reported as indicated by the parent study. For subjects 
receiving treatment with lenvatinib combination regimen, any pregnancy in which the 
estimated date of conception is either before the last visit or within the timeline (as indicated 
in the parent study protocol ) of the last study treatment or 30 days following last study 


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treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported. Regardless of the treatment arm, if an adverse outcome of a pregnancy is suspected 
to be related to study drug exposure, this should be reported regardless of the length of time 
that has passed since the exposure to study treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.9.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 24 hours from the date the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study. 
9.5.9.3
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 TEAEs 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 TEAEs 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 9.5.9.1) even if the TEAEs do not meet serious criteria.  
Abuse is always to be captured as a TEAE.  If the TEAE 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.


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9.5.9.4
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.10
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.
Subjects who discontinue early from the study will be discontinued for 1 or more of these 
primary reasons: unacceptable toxicity, subject lost to follow-up, subject request, 
progression of disease (as confirmed by the clinical judgment of the investigator and/or 
radiological assessment), withdrawal of consent, study terminated by sponsor, use of 
non-permitted concomitant drug(s), or unacceptable non-compliance with the protocol.  
Subjects will be permitted to continue study drug(s) beyond an initial disease progression as 
long as an investigator-assessed clinical benefit is observed after discussion and approval by 
the sponsor and if the subject is tolerating the study drug(s).  Subjects will discontinue the 
study drug(s) upon evidence of further progression and/or the loss of clinical benefit as 
judged by the investigator.
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.  
Study disposition information will be collected on the Subject Disposition CRF.
9.5.11
Abuse or Diversion of Study Drug
Not applicable
9.5.12
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 


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physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
The Safety Analysis Set is the group of subjects who received at least 1 dose of study 
drug(s). The Safety Analysis Set will be used in all analyses of safety. The following safety 
tables and listing will be available for review:
Extent of exposure, TEAEs, serious AEs (SAEs), TEAEs/SAEs related to study drug(s), 
TEAEs leading to discontinuation of study drug(s)/withdrawal, fatal TEAEs and deaths, and 
other TEAEs that the investigator deemed important to report and reasons for discontinuation 
of study drug(s).
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.


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9.7.1.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study 
drug(s).
9.7.1.2
Subject Disposition
The number of subjects enrolled, treated, and prematurely discontinued from study treatment 
will be summarized.  The reason for study drug discontinued will be summarized according 
to the categories in the CRF. 
9.7.1.3
Demographic Characteristics
Demographic characteristics for the safety analysis set will be summarized using descriptive 
statistics. 
9.7.1.4
Efficacy Analyses
PRIMARY EFFICACY ANALYSIS
Not applicable.
9.7.1.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
Not applicable.
PHARMACOKINETIC ANALYSES
Not applicable.
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Not applicable.
9.7.1.6
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set. All safety analyses will be
summarized separately by treatment group. TEAEs and SAEs will be summarized using 
descriptive statistics.  Time to treatment discontinuation due to a TEAE, number of dose 
reductions, and time to first dose reduction will be summarized.
9.7.1.7
Extent of Exposure
The number of days on treatment, quantity of study drug administered, and the number of 
subjects requiring treatment interruption, and treatment discontinuation due to TEAEs will be 
summarized.


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9.7.1.8
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the most recent MedDRA lower level term 
(LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database.
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment in the roll-over study, having been absent before the time the subject signs the 
roll-over study ICF or

Re-emerges during treatment in the roll-over study, having been present before signing 
the ICF but stopped before signing the ICF, or 

Worsens in severity during treatment in the roll-over study relative to the pre-ICF state, 
when the AE is continuous.
All TEAEs will be presented in subject data listings.
An overview table, including the incidence of and the number of subjects with TEAEs,
SAEs, deaths, and those TEAEs that led to study drug discontinuation, or dose interruption 
will be provided.  The number (percentage) of subjects with TEAEs will also be summarized 
by relationship to study drug (Yes [related] and No [not related]).  The number (percentage) 
of subjects with TEAEs will also be summarized by relationship to study drug (Yes [related] 
and No [not related]).
For the TEAEs, the incidence, severity, duration and timing in relation to the start of study 
medication will be summarized. 
9.7.1.9
Other Analyses
Not applicable.
9.7.2
Determination of Sample Size
Not applicable for this study.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable


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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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REFERENCE LIST
Cheng AL, Finn RS, Qin S, Han KH, 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). J Clin Oncol. 2017;35(suppl):abstr 4001.
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.
E7080-G000-307. Summary available from:
https://clinicaltrials.gov/ct2/show/NCT02811861?cond=lenvatinib++renal+cell&phase=2&ra
nk=1
FDA Approved Drugs. Lenvatinib in combination with everolimus [approval for advanced 
RCC]. 13 May 2016. Available from:
https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm501070.htm
Lenvima approval for DTC. 13 Feb 2015. Available from:
https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm434288.htm.  Accessed 
on 2 Aug 2017.
Lenvima (lenvatinib) package insert. Woodcliff Lake (NJ): Eisai, Inc. Available from: 2016:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s004lbl.pdf. 2015: 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf. 
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, 
everolimus, and the combination in patients with metastatic renal cell carcinoma: a
randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015[a];16(15):1473-82.
National Cancer Institute (NCI), Cancer Therapy Evaluation Program. Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 [published 28 May 2009 
(v4.03: 14 Jun 2010)].  Available from: http://evs.nci.nih.gov/ftp1/CTCAE/About.html.
(Accessed 07 Jun 2017).
Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. A phase 3, 
multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 
131I-refractory differentiated thyroid cancer (SELECT). ASCO Annual Meeting. Abstract 
LBA6008. Presented June 2, 2014.
Cabanillas ME, Schlumberger M, Jarzab B, Martins RG, Pacini F, Robinson B, et al. A phase 
II trial of lenvatinib (E7080) in advanced, progressive, radioiodine-refractory, differentiated 
thyroid cancer: a clinical outcomes and biomarker assessment. Cancer. 2015;121(16):2749-
56.


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Shumaker R, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effect of rifampicin on the 
pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014;34(9):651-9.
Shumaker R, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effects of ketoconazole on 
the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharm Drug Dev. 
2015;4(2):155-60.


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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 (or appropriate 
study team member) and the IRB/IEC for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits. Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to,
the following:

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, computed tomography 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 correction 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 dose reduction).

Discontinuation information.

Comments and other information on AEs (eg, severity, relationship to study drug,
outcome).


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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572 ICFs, and IRB/IEC correspondence). The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
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(s) will be supplied to the principal investigator (or a designated pharmacist) 
by the sponsor, or when there is agreement between the PI and sponsor, the site can source 
study drug if it is commercially available in the country and be reimbursed by the sponsor.  
Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored 
according to the conditions specified on the drug labels.  The investigator (or a designated 
pharmacist) must maintain an accurate record of the shipment and dispensing of the study 
drug in a drug accountability ledger, a copy of which must be given to the sponsor at the end 
of the study.  An accurate record of the date and amount of study drug dispensed to each 
subject must be available for inspection at any time.  The CRA will visit the site and review 
these documents along with all other study conduct documents at appropriate intervals once 
study drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or, when approval is given by the sponsor, will destroy supplies and 
containers at the site.


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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 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.


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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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Appendix 1
Clinical Studies Evaluating Drug-Drug Interactions with
Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme
responsible for metabolism of lenvatinib. Clinical studies were conducted to test these
findings.  Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly 
(15% to19%) increases systemic exposure to lenvatinib (Shumaker, et al., 2015). Since no 
change was observed in half-life, tmax, or lag time (tlag), the slight increase in systemic 
exposure is probably related to a decrease in first pass metabolism. However, since the 
magnitude of change is small, co-administration of lenvatinib with CYP3A4/P-gp inhibitors 
is not of clinical concern.  The influence of P-gp inhibition on lenvatinib PK has been 
investigated. P-gp inhibition was accomplished by co-administering a single dose of rifampin 
with a single dose of lenvatinib.  Preliminary results suggest P-gp inhibition increases 
systemic exposure to lenvatinib 26% to 32%. Thus, co-administration of lenvatinib with 
P-gp inhibitors only causes a small increase in lenvatinib exposure.  
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been
investigated. Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK
was accomplished by administering rifampin QD for 21 days (Shumaker, et al., 2014). A
single dose of lenvatinib was co-administered with the 15th dose of rifampin. Based on
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib
exposure as mean Cmax increased about 8% while AUC decreased about 7%. 
Coadministration of lenvatinib with CYP3A4/P-gp inducers is not of clinical concern. The 
main metabolic pathways for lenvatinib in humans were identified as enzymatic (CYP3A and 
aldehyde oxidase) and non-enzymatic processes (Lenvima® Package Insert).


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Appendix 2
Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03
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 studies. 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.
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:
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 NCI, Cancer Therapy Evaluation Program. CTCAE v4.03
For further details regarding MedDRA, refer to the MedDRA website at:  http://www meddra.org


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Appendix 3
Sponsor’s Grading for Laboratory Values Common 
Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE MARROW
Hemoglobin  
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L 
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening 
consequences; urgent 
intervention indicated
Leukocytes (total WBC)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes 
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils 
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 – 50,000/mm3
<50.0 – 25.0109/L
<50,000 – 25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/LABORATORY
Albumin, serum- low 
(hypoalbuminemia) 
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening 
consequences; urgent 
intervention indicated
Alkaline phosphatase 
>ULN – 2.5ULN
>2.5 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin (hyperbilirubinemia)
>ULN – 1.5ULN 
>1.5 – 3.0ULN
>3.0 – 10.0ULN 
>10.0ULN
Calcium, serum-low (hypocalcemia) 
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high (hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high 
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL
>10.34 – 12.92 mmol/L 
>500 mg/dL
>12.92 mmol/L 
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN
GGT (γ-glutamyl transpeptidase) 
>ULN – 2.5ULN
>2.5 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high (hyperglycemia)
Fasting glucose value:
>ULN – 160 mg/dL
>ULN – 8.9 mmol/L 
Fasting glucose value:
>160 – 250 mg/dL
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL;
>13.9 – 27.8 mmol/L;
hospitalization indicated
>500 mg/dL;
>27.8 mmol/L;
life-threatening 
consequences 
Glucose, serum-low (hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L


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Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
life-threatening 
consequences; seizures
Phosphate, serum-low 
(hypophosphatemia) 
<LLN – 2.5 mg/dL
<LLN – 0.8 mmol/L
<2.5 – 2.0 mg/dL
<0.8 – 0.6 mmol/L
<2.0 – 1.0 mg/dL
<0.6 – 0.3 mmol/L
<1.0 mg/dL
<0.3 mmol/L
life-threatening 
consequences
Potassium, serum-high 
(hyperkalemia)
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization indicated
>7.0 mmol/L
life-threatening 
consequences
Potassium, serum-low (hypokalemia) 
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L; 
symptomatic; 
intervention indicated
<3.0 – 2.5 mmol/L
hospitalization indicated
<2.5 mmol/L
life-threatening 
consequences
Sodium, serum-high (hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization indicated
>160 mmol/L
life-threatening 
consequences
Sodium, serum-low (hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening 
consequences
Triglyceride, serum-high 
(hypertriglyceridemia) 
150 – 300 mg/dL
1.71 – 3.42 mmol/L
>300 – 500 mg/dL
>3.42 – 5.7 mmol/L 
>500 – 1000 mg/dL
>5.7 – 11.4 mmol/L
>1000 mg/dL
>11.4 mmol/L
life-threatening 
consequences 
Uric acid, serum-high (hyperuricemia)
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
N/A
>ULN – 10 mg/dL  
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL
>0.59 mmol/L 
life-threatening 
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal, WBC = 
white blood cell.
Based on Common Terminology Criteria for Adverse events (CTCAE) Version 4.0.  Published: May 28, 2009 (v4.03: June 14, 2010).


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Appendix 4
For China only : Sponsor’s Recommended Standard of 
Care
CCI




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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-604
Study Protocol Title:
An open-label, multi-center, roll-over study to assess long term safety 
of lenvatinib monotherapy or lenvatinib combination regimen or 
comparator treatment arm to cancer patients in Eisai sponsored 
lenvatinib trials
Investigational Product
Name:
Lenvatinib (E7080) and additional investigational agents as per 
Eisai parent study if applicable
IND Number:
Not Applicable
EudraCT Number:
2017-003668-11
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
As regionally required
President of Japan/Asia 
Clinical Research Product 
Creation Unit
Signature
Date

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7080-G000-604
Study Protocol 
Title:
An open-label, multi-center, roll-over study to assess long term 
safety of lenvatinib monotherapy or lenvatinib combination regimen 
or comparator treatment arm to cancer patients in Eisai sponsored 
lenvatinib trials
Date:
28 Feb 2024
Version:
Version 2.0


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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................2
2
VERSION HISTORY....................................................................................................4
3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................5
4
INTRODUCTION.........................................................................................................6
4.1
Study Objectives..................................................................................................6
4.1.1
Primary Objective ......................................................................................6
4.2
Overall Study Design and Plan.............................................................................6
5
DETERMINATION OF SAMPLE SIZE.......................................................................7
6
STATISTICAL METHODS..........................................................................................8
6.1
Study Assessments...............................................................................................8
6.1.1
Demographics ............................................................................................8
6.1.2
Medical History and Physical Examinations ...............................................8
6.1.3
Efficacy Assessments .................................................................................8
6.1.4
Safety Assessments ....................................................................................8
6.2
Study Subjects .....................................................................................................8
6.2.1
Definitions of Analysis Sets........................................................................8
6.2.2
Subject Disposition.....................................................................................9
6.2.3
Protocol Deviations ....................................................................................9
6.2.4
Demographic and Other Baseline Characteristics........................................9
6.2.5
Prior and Concomitant Therapy..................................................................9
6.3
Data Analysis General Considerations..................................................................9
6.4
Efficacy Analyses ................................................................................................9
6.5
Safety Analyses....................................................................................................9
6.5.1
Extent of Exposure.....................................................................................9
6.5.2
Adverse Events...........................................................................................9
6.5.3
Laboratory Values ....................................................................................11
6.5.4
Vital Signs................................................................................................11
6.5.5
Physical Examinations..............................................................................11
6.5.6
Electrocardiograms...................................................................................11
6.6
Other Analyses...................................................................................................11
6.7
Exploratory Analyses.........................................................................................12
7
INTERIM ANALYSES...............................................................................................12
8
CHANGES IN THE PLANNED ANALYSES ............................................................12
9
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................12
10
PROGRAMMING SPECIFICATIONS .......................................................................12
11
STATISTICAL SOFTWARE......................................................................................12


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12
MOCK TABLES, LISTINGS, AND GRAPHS............................................................12
13
REFERENCES............................................................................................................12
14
APPENDICES.............................................................................................................13


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2
VERSION HISTORY
Version
Description
Date
1.0
Initial version
05 Jun 2019
2.0
•
Revised the scope of the statistical analysis plan to reflect 
the decision by the team to prepare only 1 clinical study 
report which would present all analyses by region 
(China, Rest of World).
•
Clarified that adverse events are considered treatment 
emergent in this rollover study if they occurred on or 
after the first dose date of study drug and on or before 
28 days after the last dose date of study drug.
•
Reduced the number of TLGs to only present major 
adverse event categories, eg, TEAEs, treatment-related 
TEAEs, SAEs, AEs CTCAE Grade ≥3, AEs leading to 
discontinuation.
28 Feb 2024


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3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADaM
Analysis Data Model
AE
adverse event
CTCAE
Common Terminology Criteria for Adverse Events
eCRF
electronic case report form
ICF
informed consent form
MedDRA
Medical Dictionary for Regulatory Activities
PT
preferred term
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
WHO
World Health Organization


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4
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report the results for Eisai Protocol 
E7080-G000-604. This is a long term, open-label extension study to roll over eligible 
subjects from Eisai-sponsored lenvatinib studies.  This study was conducted in China and 
several other countries including Australia, Belgium, Germany, Italy, Netherlands, Poland, 
Romania, South Korea, Thailand, and the United States; summaries will be prepared by 
region (China vs Rest of World) and across all subjects.
4.1
Study Objectives
4.1.1
Primary Objective
The primary objective is to assess the long-term safety of study drug(s) in subjects who were
enrolled in Eisai-sponsored lenvatinib studies.
4.2
Overall Study Design and Plan
This is an open-label extension study to roll over eligible subjects from Eisai-sponsored
lenvatinib studies. Subjects are enrolled in the rollover study for the purpose of long-term 
safety data collection. The transition from the parent study to the extension study would 
occur after the completion and evaluation of the primary endpoint of the parent studies or 
after all study data for the primary outcome measure were evaluated for the parent study. 
The parent study is defined as the Eisai-sponsored lenvatinib clinical study in which the 
subject was receiving lenvatinib either as monotherapy or as combination therapy, or was
receiving any other comparator therapy.
The subjects willing to participate in the rollover study have to sign the informed consent 
form (ICF) for Study E7080-G000-604. The “End-of-Treatment” assessments in the parent 
study are to be completed and reviewed by the investigator prior to subject enrollment into 
Study E7080-G000-604. The eligibility for the rollover study is to be established based on 
meeting all inclusion and exclusion criteria described in Section 9.3 of the protocol. The 
intention is that the subject will not be without study drug during the transition from the 
parent study to the rollover study. The subjects in Study E7080-G000-604 should receive the 
first dose of the study drug the following day after the last dose of the study drug in the 
parent study. All treatment-emergent adverse events (TEAEs) and serious adverse events 
(SAEs), regardless of relationship to study drug or procedure, should be recorded beginning 
from the time the subject signs the rollover study ICF for up to 28 days after the last dose of 
study drug(s) (or 5 × half-life of study drug[s], whichever is longer). SAE management and
reporting requirements specific to study drugs will be addressed as per the instructions in the
parent study protocol. Ongoing AEs in the parent study will remain ongoing at the time of
discontinuation in the parent study, and the rollover study will capture only new or
worsening TEAEs occurring after signing the rollover study ICF.
Screening period:


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From approximately Day -30 to Day -1, subjects may remain on the parent study.
Subjects will be enrolled into the study under the following cohort definitions.
Cohort A: Subjects who received lenvatinib monotherapy or who crossed over from a
comparator arm to receive lenvatinib monotherapy in their parent study will continue to
receive lenvatinib monotherapy.
Cohort B: Subjects who received lenvatinib combination therapy or who crossed over from a 
comparator arm to receive lenvatinib combination therapy in their parent study will continue 
to receive lenvatinib combination therapy.
Cohort C: Subjects who received comparator treatment in their parent study will continue to 
receive comparator treatment, with the exception of subjects receiving placebo. Subjects 
who received placebo in their parent study and who were either not permitted to cross over or 
who opted not to cross over to active treatment will not be eligible to enroll in this study.
Treatment Phase: 
During the Treatment Phase, subjects still on treatment will continue the same treatment they
received upon discontinuation of the parent study. Subjects will remain on treatment in
consecutive cycles as per the parent study protocol until disease progression, development of
unacceptable toxicity, subject request, withdrawal of consent, discontinuation of Study
E7080-G000-604 by the sponsor, use of non-permitted concomitant drugs, unacceptable
noncompliance with the protocol, or if the subject is lost to follow-up.
This is a rollover open-label study with no control group.  Subjects will enter the study at the 
same doses of study drug of lenvatinib or the combination regimen, or any other comparator 
therapy (except placebo), upon discontinuation of the parent study.
Discontinuation criteria are as follows: progression of disease, unacceptable toxicity, subject 
request, withdrawal of consent, termination of study by sponsor, use of non-permitted 
concomitant drugs, unacceptable non-compliance with the protocol, subject lost to follow-up.
Subjects will be permitted to continue study drug(s) beyond initial disease progression as
long as the treating investigator considers that there is continued clinical benefit after
discussing with the sponsor and if the subject is tolerating the study drug(s).
5
DETERMINATION OF SAMPLE SIZE
This is a rollover open-label safety study; no formal sample size calculations were 
performed. It is expected that approximately 50 subjects will be initially rolled over to the 
study. It is anticipated that additional subjects may also roll over to the study in the future. 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria, with no 
evidence of progressive disease, and who have tolerated study drug(s) in their parent study 
without significant toxicities will be rolled over to this study. Subjects with evidence of 
disease progression but who continue to derive clinical benefit, as determined by the 


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investigator, would require discussion with the sponsor on an individual case-by-case basis 
prior to enrollment in this study.
6
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, Q1, Q3, minimum and maximum.  Categorical variables will be 
summarized as number (percentage) of subjects.
6.1
Study Assessments
6.1.1
Demographics
Subject demographic information will be collected and recorded in the electronic case report 
form (eCRF).  Demographic information includes age, sex, and race/ethnicity.
6.1.2
Medical History and Physical Examinations
Initial physical examination and any therapeutic area-specific assessments will be performed
as per local standard of care or as clinically indicated.  Results of these examinations will not 
be recorded in the eCRF and will not be summarized.
6.1.3
Efficacy Assessments
Tumor assessments will be performed as per local standard of care.  Results of these 
assessments will not be recorded in the eCRF and will not be summarized.
6.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all TEAEs, including all
Common Terminology Criteria for Adverse Events (CTCAE) v4.03 grades (for both
increasing and decreasing severity), and SAEs. Long-term safety information will be 
collected at the time study drug is dispensed to the subject.
Monitoring of laboratory measurements, vital signs, and performance of electrocardiograms 
or physical examinations will be done per local standard of care or as clinically indicated.
6.2
Study Subjects
6.2.1
Definitions of Analysis Sets
The Safety Analysis Set is the group of subjects who received at least 1 dose of study 
drug(s).


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6.2.2
Subject Disposition
The number of subjects enrolled, treated, and prematurely discontinued from study treatment
will be summarized. The reason for study drug discontinuation will be summarized 
according to the categories in the eCRF.
6.2.3
Protocol Deviations
Not applicable.
6.2.4
Demographic and Other Baseline Characteristics
Demographic characteristics (age, sex, race, ethnicity) for the Safety Analysis Set will be 
summarized using descriptive statistics.
6.2.5
Prior and Concomitant Therapy
Concomitant medications are not collected in the eCRF. If the subject takes a concomitant 
medication in response to an AE, the AE will be recorded in the Adverse Events eCRF.
6.3
Data Analysis General Considerations
Descriptive statistics for continuous variables will include the number of subjects, mean, 
standard deviation (SD), median, Q1, Q3, and range (minimum, maximum).
Categorical 
variables will be summarized by reporting the number and percentage of subjects. In most 
cases, the denominator for calculating percentages will be the number of subjects in the column 
header.  Whenever a different subset is used to define the denominator, a footnote will be 
provided to describe the set of subjects to be used as the denominator.  The reporting number 
of decimal places will be provided in the table shells.
6.4
Efficacy Analyses
Not Applicable
6.5
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.
6.5.1
Extent of Exposure
The length of time on treatment (months), and the quantity of study drug administered [dose 
intensity (mg/day)] will be summarized.
6.5.2
Adverse Events
The adverse event (AE) verbatim descriptions (investigator terms from the eCRF) will be 
classified into standardized medical terminology using the Medical Dictionary for Regulatory 


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Activities (MedDRA). The linked MedDRA preferred term (PT) and primary system organ 
class (SOC) are also captured in the database.
AEs collected in this study must be treatment-emergent adverse events (TEAE).  This is 
defined as an AE that emerges during treatment in the rollover study, having been absent 
before the time the subject signs the rollover study ICF or
•
Re-emerges during treatment in the rollover study, having been present before signing the 
ICF but stopped before signing the ICF, or
•
Worsens in severity during treatment in the rollover study relative to the pre-ICF state,
when the AE is continuous.
Only those AEs that are treatment emergent will be included in summary tables.  TEAEs are 
those occurring on or after the first dose date of study drug and on or before 28 days after the 
last dose of study drug. All TEAEs will be presented in subject data listings.
An overview table, including the number and percentage of subjects with TEAEs, SAEs, 
deaths, and those with TEAEs that led to study drug discontinuation, interruption, or dose 
reduction will be provided. The number (percentage) of subjects with TEAEs will be 
summarized by SOC and PT, by relationship to study drug (Yes [related] and No [not 
related]), and by CTCAE toxicity grade as follows:
•
Overview of TEAEs
•
TEAEs by SOC and PT
•
TEAEs by decreasing frequency of PT
•
TEAEs with CTCAE Grade ≥3 by decreasing incidence of PT
•
Treatment-emergent serious AEs by decreasing incidence of PT
•
Overview of treatment-related TEAEs
•
Treatment-related TEAEs by SOC and PT
•
Treatment-related TEAEs by decreasing frequency of PT
•
Treatment-related TEAEs with CTCAE Grade ≥3 by decreasing incidence of PT
•
Treatment-related treatment–emergent serious AEs by decreasing incidence of PT 
•
Fatal TEAEs by decreasing incidence of PT
•
TEAEs leading to treatment discontinuation of lenvatinib
The following listings will be provided for the subjects in the Safety Analysis Set:
•
Demographics


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•
Disposition
•
Lenvatinib dosing
•
All AEs
•
All SAEs
•
Adverse events with CTCAE Grade 3 or above
•
All AEs leading to study drug discontinuation
•
All fatal AEs
6.5.3
Laboratory Values
Clinical laboratory tests including hematology, chemistry, and urinalysis will be performed 
per local standard of care or as clinically indicated. Laboratory values will not be collected 
in the eCRF, but any laboratory abnormalities that meet the definition of a TEAE (see 
protocol section 9.5.7.1) will be recorded on the Adverse Events eCRF. These will be 
summarized as TEAEs along with all other TEAEs.
6.5.4
Vital Signs
Vital signs measurements will be performed as per local standard of care or as clinically
indicated. Only changes from screening vital signs findings that meet the definition of a TEAE 
will be recorded on the Adverse Events eCRF.  These will be summarized as TEAEs along 
with all other TEAEs.
6.5.5
Physical Examinations
Physical examinations will be performed as per local standard of care or as clinically
indicated. Only changes from screening physical examination findings that meet the
definition of a TEAE will be recorded on the Adverse Events eCRF.  These will be 
summarized as TEAEs along with all other TEAEs.
6.5.6
Electrocardiograms
Complete, standardized, 12-lead ECG recordings (if required) will be performed as per local
standard of care. Only changes from screening ECG findings that meet the definition of a 
TEAE (see protocol section 9.5.7.1) will be recorded on the Adverse Events eCRF.  These 
will be summarized as TEAEs along with all other TEAEs.
6.6
Other Analyses
Not Applicable


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6.7
Exploratory Analyses
Not Applicable
7
INTERIM ANALYSES
No interim analyses are planned for this study.
8
CHANGES IN THE PLANNED ANALYSES
No changes to planned analyses are expected.
9
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
Statistical programming and analyses will be performed using SAS® (SAS institute, Inc., 
Cary, NC, USA), Version 9.4 or higher.
In general, missing or partial dates for adverse events will be imputed in order to assign 
treatment emergent status.  The details on data handling will be provided in Analysis Data 
Model (ADaM) Specification Documents.
10 PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
11 STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS v 9.4 or later. Statistical summaries will 
be prepared by Eisai or its designee.
12 MOCK TABLES, LISTINGS, AND GRAPHS
The study table, listing and graph (TLG) shells will be provided in a separate document, which 
will show the content and format of all tables, listings, and graphs in detail.
13 REFERENCES
Not applicable


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14 APPENDICES
Not Applicable