Conditions: Thyroid Cancer
Keywords: Lenvatinib E7080 Iodine-131 Refractory Differentiated Thyroid Cancer Lenvima Phase 2 RR-DTC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 241
Healthy volunteers: no

Brief summary:
This is a multicenter, randomized, double-blind study being conducted as a postmarketing requirement to the US Food and Drug Administration (FDA) to evaluate whether there is a lower starting dosage of lenvatinib 24 mg once daily (QD) that provides comparable efficacy but has a better safety profile in participants with radioiodine-refractory differentiated thyroid cancer RR-DTC with radiographic evidence of disease progression within the prior 12 months.

Detailed description:
This study consists of 2 phases, the Prerandomization Phase and the Randomization Phase. The Prerandomization Phase will last no longer than 28 days and will include a Screening Period to establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease characteristics prior to randomization and treatment.

The Randomization Phase will consist of a Treatment Period and a Follow-up Period. It will begin at the time of randomization of the first participant and will consist of 28-day blinded study treatment cycles. The data cutoff for the primary analysis will occur at the end of the Randomization Phase, which is defined as when the last participant enrolled completes the Week 24 tumor assessments or discontinues study treatment if before Week 24.

Participants on treatment at the time of data cutoff for the primary analysis will remain on blinded investigational product until the primary analysis has been completed, after which they will transition to commercial lenvatinib outside the study. The last participant's last assessment (Off-treatment visit) will be the End of Study.

Participants will be randomly assigned to treatment with 1 of 2 blinded starting dosages of lenvatinib in a 1:1 ratio to receive lenvatinib 18 mg or 24 mg orally once daily (QD). Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, and 8 mg QD, or 18, 14, 10, 8, and 4 mg QD, respectively). Once the dose has been reduced, it may not be increased at a later date.

Arms:
arm 1: Participants will receive 24 mg once daily (QD) as the starting dose. Dose reductions will occur in succession based on the previous dose level (24, 20, 14, 10, or 8 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal. arm 2: Participants will receive 18mg QD as the starting dose. Dose reductions will occur in succession based on the previous dose level (18,14, 10, 8, or 4 mg QD). To maintain blinded treatment assignment, participants will be administered study drug in the form of two 10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 4 capsules) to be taken orally, at approximately the same time each morning and may be taken in a fasting state or following a meal.

Interventions: intervention 1: Lenvatinib intervention 2: Lenvatinib matching placebo
Intervention descriptions: intervention 1: Lenvatinib capsule. intervention 2: Lenvatinib matching placebo capsule.

Protocol document:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol Number:
E7080-G000-211
Study Protocol Title:
A Multicenter, Randomized, Double-Blind Phase 2 Trial 
of Lenvatinib (E7080) in Subjects With 131I-Refractory 
Differentiated Thyroid Cancer to Evaluate Whether an 
Oral Starting Dose of 18 mg Daily Will Provide 
Comparable Efficacy to a 24-mg Starting Dose, But Have 
a Better Safety Profile
Sponsor:  
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake, 
New Jersey 07677
USA
Eisai Ltd. 
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire 
AL10 9SN UK
Investigational Product 
Name:
Lenvatinib (E7080/LENVIMA®)
Indication:
131I-Refractory Differentiated Thyroid Cancer
Phase:
2
Approval Date(s):
Original Protocol:
23 Jul 2015
Amendment 01:
01 Dec 2015
Amendment 02:
31 May 2016
Amendment 03:
13 Feb 2017
Amendment 03.1:       14 Dec 2017
Amendment 04:          16 Feb 2018
Amendment 05:          21 May 2019
Amendment 06:          09 Jan 2020
IND Number:
IND 113656
NDA Number:
NDA 206947
EudraCT Number:
2014-005199-27
GCP Statement:
This study is to be performed in full compliance with 
International Council for Harmonisation of Technical 


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Requirements for Registration of Pharmaceuticals for 
Human Use (ICH) and all applicable local Good Clinical 
Practice (GCP) and regulations.  
All required study documentation will be archived as 
required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary 
information of Eisai (the sponsor).  Any viewing or 
disclosure of such information that is not authorized in 
writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of 
reviewing or performing this study.


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Highlights of Major Changes
Section/Change
23 Jul 2015
Original Protocol
01 Dec 2015
Amendment 01: 
Modified Inclusion Criterion 17 in the Synopsis and Section 9.3.1 to align with 
the Voluntary Harmonization Procedure (VHP) recommendations for highly 
effective contraception in clinical trials.
Added cautionary text to Section 9.4.5.1 regarding the use of lenvatinib with 
CYP3A4 substrates known to have a narrow therapeutic index to align with 
VHP recommendations.  
Added text to Section 9.5.1.2.3 for the exploratory endpoint of overall survival 
(OS) inadvertently omitted from the final protocol, per VHP recommendation.
31 May 2016
Amendment 02:
Updated Title Page to include Protocol Amendment 02 and to correct the 
sponsor address.
Increased the approximate number of study sites to up to 100 in the Synopsis, 
Section 6 and Section 9.3.
Corrected typographical error in Inclusion Criteria 6 in the Synopsis and 
Section 9.3.1.
Added Exclusion Criterion 14 in the Synopsis and Section 9.3.2 to exclude 
enrollment of subjects with bleeding or thrombotic disorders.
Added guidance for management of confirmed hypertension with systolic BP 
≥140 mmHg up to <160 mmHg or diastolic BP ≥90 mmHg up to <100 mmHg 
to the Synopsis and Section 9.4.2.1 as required by the French Health Authority.
Removed text in Section 5.3 to clarify that a separate Informed Consent Form is 
not required for pharmacokinetic assessments to be performed.
Corrected Table 6 as follows:
-
Added 3 hematology tests for consistency with footnote
-
Added footnote to clarify that ‘bands’ and ‘bicarbonate’ assessment 
will be optional if results cannot be obtained from the site’s local 
laboratory
-
Deleted collection of thyroid autoantibodies and the appropriate 
footnote
Clarified in Section 9.5.1.2.4 that bone scans will be performed using a 
technetium-based tracer.
Definition of concomitant medications in Section 9.7.1.5 revised to align with 
recording of concomitant medications for up to 28 days after the last dose of 
study drug.
Modified Table 7 (merged ‘screening’ and ‘baseline’ cells for bone scan) to 
indicate that the Prerandomization Phase bone scan to establish a baseline could 
be performed during screening or at baseline rather than just baseline.


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Highlights of Major Changes
Section/Change
Made the following changes to the appropriate footnotes in Table 7
-
Specified that screening electrolyte results must be reviewed and 
confirmed to be within normal limits prior to randomization.
-
Clarified that bone scans will be performed using a technetium-based 
tracer.
-
Corrected text to indicate that concomitant medications are to be 
captured for 28 days after the last dose of study drug.
-
Clarified that subjects will not be followed for PFS2 if their subsequent 
anticancer therapy is investigational and the information may not be 
provided to Eisai due to confidentiality.
-
Clarified the timing of sample collection for biomarker assessment.
-
Clarified that the blood sample used for pharmacogenomic analysis 
may be obtained at any visit that a blood sampling is scheduled to 
occur.
13 Feb 2017
Amendment 03:
Changed starting doses of lenvatinib from 24 mg, 20 mg, and 14 mg to 24 mg 
and 18 mg throughout.
Clarified throughout that this is now a 2-arm rather than a 3-arm study, with 
randomization in a 1:1 ratio rather than a 1:1:1 ratio.
Revised Figure 3 (Figure 1 in Amendment 03) according to new study design as 
follows:
-
Removed 20-mg dose group.
-
Changed 14-mg dose group to 18 mg
-
Changed randomization from 1:1:1 ratio to 1:1 ratio
Section 7.2 (Study Rationale) and Section 9.2 were revised and Section 7.3
(Rationale for Dose Selection) was rewritten describing the modified study 
design, and including Table 1 (Simulated Objective Response Rate [ORR] at 
24 Weeks) and Table 2 (Simulated Average Dose and Proportion of Subjects 
with at Least One/Two Dose Reduction During 24 Weeks).  This was done to 
make the wording of the protocol flow correctly to include the history of how 
the doses were selected for the initial study, and then to summarize the changes 
resulting from the new modeling and simulation, and subsequent discussions 
with FDA and agreement with EMA.
Section 7.2(Pharmacodynamics – Concentration-Effect Relationships) and 
subsections (7.2.1 and 7.2.2) were deleted as they were no longer relevant to the 
current study design.
Noted in the Synopsis, Section 9.5.1.5 Schedule of Procedures and Assessments 
(Table 7) and Section 9.1 that treatment assignment was unblinded for all 
subjects enrolled prior to Amendment 03, and that these subjects were 
transitioned to commercial product or an access program in their country.
Changed 6 months to 24 weeks throughout for ORR (ie, ORR6M changed to 
ORR24wk) for clarity that this is based on response at the Week 24 visit, rather 
than based on a 6 month calendar timeframe.


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Highlights of Major Changes
Section/Change
The secondary objective to evaluate the pharmacokinetic 
(PK)/pharmacodynamic relationship was revised to include that the modeling 
will use a mechanistically based approach, if possible, in response to EMA’s 
continued request to modify the PK and biomarker sampling, and to use a 
mechanistically based approach to modeling.
The description of the PK/pharmacodynamic analyses (Synopsis and 
Section 9.7.1.7.2) also was modified to reflect that the modeling will use a 
mechanistically based approach if possible.
The Number of Subjects section of the Synopsis and Section 9.3 (Selection of 
Study Population) was modified to describe the handling of the initial 
41 subjects randomized and subsequently unblinded and transitioned off the 
study, and the additional subjects who will be screened and randomized in the 
new design as of Protocol Amendment 03.
Section 9.4.2.2 (Management of Proteinuria) was revised to be consistent with 
clearer wording used in newer lenvatinib protocols.  Although the wording has 
changed, the actual management (including any dose modifications) has not 
changed from what was described in the initial wording.
Section 9.4.5 (Prior and Concomitant Therapy) and the Clinical Study Synopsis 
(Concomitant Drug/Therapy) were revised to provide lenvatinib treatment 
interruption instructions for subjects undergoing surgery while on study.
Section 9.4.5.2 (Prohibited Concomitant Therapies and Drugs) was modified to 
clarify what are and are not prohibited therapies and to clarify the disposition of 
subjects who do receive such therapies, to be consistent with current wording of 
newer lenvatinib protocols.  
In Section 9.5.1.4.4 (Vital Signs and Weight Measurements), text describing 
blood pressure measurement procedure was revised and clarified to be 
consistent with clearer wording in newer lenvatinib protocols.  Although the 
wording has changed, the actual procedure for measurement of blood pressure 
has not changed from what was described in the initial wording.
An optional visit at Cycle 1 Day 22 (C1D22) was added to the Schedule of 
Procedures and Assessments (Table 7) to allow for optional predose blood 
samples to be taken for PK and biomarker assessment.  Vital signs will also be 
measured, as well as the other assessments that occur throughout the study (eg, 
AEs).
The optional visit/phone call to check on subject’s blood pressure on C1D8 was
changed so that C1D8 is a mandatory clinic visit to assess vital signs and to 
draw predose blood samples for PK and biomarker assessments.  These 
assessments were added for the optional C1D22 visit, if the subject is willing to 
come to the clinic on that day.  Changes reflecting this were made in Section 
9.5.1.5 Schedule of Procedures and Assessments (Table 7), and in the 
corresponding text in Sections 9.5.1.3.1 (PK Assessments) and 9.5.1.4.4 (Vital 
Signs and Weight Measurements).
Removed reference to every-other-day dose administration in the Synopsis and 
Section 9.4.1, Table 3 (Study Treatments), and Table 4 (Study Treatment Dose 


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Highlights of Major Changes
Section/Change
Reduction and Interruption Instructions) since this is not a dosing option in the 
new study design.
Revised Statistical Methods section (Section 9.7 including subsections, and 
Synopsis), according to the new study design and dose groups.  Added 
statement to clarify that the efficacy results data from subjects randomized prior 
to implementation of Amendment 03 will be reported separately.
Major changes include the following:
-
Clarified the definition of PFS2 in Sections 9.5.1.2.2 and 9.7.1.1.2 (and 
Synopsis).
-
Section 9.7.1.6.1 (and Synopsis):
◦
Clarified that the analysis of the primary efficacy endpoint will be 
based on a noninferiority test on the odds ratio, with a 
noninferiority margin of 0.4.
◦
Removed text pertaining to analysis based on logistic regression.
◦
Removed text related to using the Cochran-Armitage trend test to 
assess statistically significant increasing trend in ORR6M across 
doses for statistical selection of the optimal dose.
-
Removed text pertaining to analysis of expected duration of response in 
Section 9.7.1.6.3 (and Synopsis).
-
In Section 9.7.1.7 (and Synopsis), clarified that analyses of PK and 
PK/pharmacodynamic data will include data from subjects treated prior 
to Amendment 03.
-
Removed text pertaining to analysis based on logistic regression and 
reporting of estimated odds ratios for treatment comparisons from 
Section 9.7.1.8.1 (Primary Safety Endpoint).
-
Section 9.7.1.8.4 (Laboratory Values) has been revised to reflect the 
use of CTCAE grading and grade shifts rather than the template 
language which mistakenly referred to the use of lab normal ranges 
(low, normal, high) for shift tables that is used in other therapeutic 
areas.
-
Revised sample size rationale in Section 9.7.2 (and Synopsis).  
Changed sample size from 210 (70 per arm) to 120 (60 per arm) 
accordingly throughout.
Appendix 5 (NYHA Cardiac Disease Classification) modified to clarify that this 
classification only applies to subjects with heart failure based on cardiac 
functional capacity.
Corrected the List of Abbreviations and Section 10 (Reference List).
14 Dec 2017
Amendment 03.1:
Amendment 03.1 was primarily created in response to VHP comments on the 
statistical methodology for demonstrating the noninferiority of the lenvatinib 
18 mg arm as compared to the 24 mg arm, and to implement corresponding 
changes in the sample size.


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Highlights of Major Changes
Section/Change
In addition, some modifications were made to the management of hypertension
and proteinuria based on feedback from investigators involved in the lenvatinib 
studies and also in order to harmonize with other ongoing studies for lenvatinib.
Other minor updates were made.
Main changes include the following:
-
Exclusion criterion #6 was updated in Section 9.3.2 (Exclusion Criteria)
and in the Synopsis to add examples of major surgeries to further 
clarify the type of surgeries that would require a time window of 
3 weeks prior to starting first dose of lenvatinib.
-
Exclusion criterion #9 stating conditions for significant cardiovascular 
impairment for exclusion were updated as follows: cardiac arrhythmias 
requiring medical treatment was updated to cardiac arrhythmias 
associated with hemodynamic instability; stroke was replaced with 
cerebral vascular accident.
-
Statistical assumptions in Section 9.7.1.6.1 (Primary Efficacy 
Analysis), Section 9.7.2 (Determination of Sample Size), and Synopsis 
were modified to enhance the robustness of the study design.  
Accordingly, the analysis of ORR24wk (24 mg vs 18 mg) based on a 
noninferiority margin of 0.4 on the odds ratio (OR) scale will be tested 
at a 1- sided alpha of 0.025 (previously 1-sided alpha of 0.05) and 
statistical power of 80%. It was also clarified that for the ORR, 95% 
confidence interval (CI) will be calculated (previously 90% CI). 
-
Corresponding to the changes in the statistical assumptions, the sample 
size was updated to 152 subjects with 76 subjects per arm (previously 
120 subjects with 60 subjects per arm) due to change in the precision 
for analysis to 1-sided alpha of 0.025 (Section 9.1 [Overall Study 
Design and Plan], Section 9.7.2 [Determination of Sample Size], 
Section 9.3 [Selection of Study Population] and Synopsis). The 
number of subjects required to be screened to obtain the revised sample 
size was updated from 156 to 180 subjects.  
-
It was clarified in Section 9.7.2 (Determination of Sample Size) and 
Synopsis that for the primary safety endpoint of TEAEs of CTCAE 
Grade 3 or higher, the revised sample size of 152 subjects will provide 
a precision for the observed differences between the arms with half 
widths of the 95% CI of about 15% (previously 17%).
-
Section 9.4.2.1 (Management of Hypertension), Section 9.5.1.4.4 (Vital 
Signs and Weight Measurements), Table 7 (Schedule of Procedures and 
Assessments – footnote “g” and “h”), and Synopsis:  Revised 
guidelines for management of hypertension as follows:
◦
Requirement of repeat blood pressure (BP) measurements has 
changed.  Repeat BP measurement now required only for subjects 
who have an elevated initial BP measurement as follows: systolic 
BP ≥140 mmHg or diastolic BP ≥90 mmHg.
◦
Definition of a BP assessment changed from 3 BP measurements to 
2 BP measurements taken at least 5 minutes apart.


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Highlights of Major Changes
Section/Change
◦
Time between BP assessments required for confirmation of 
hypertension changed from 2 BP assessments taken at least 1 hour 
apart to 2 BP assessments at least 30 minutes apart.
◦
Clarified that subjects with uncontrolled hypertension 
(BP ≥160 mmHg or diastolic ≥100 mmHg) must have their BP 
monitored on Day 15 (or more frequently if clinically indicated) for 
2 consecutive treatment cycles. Clarified that CTCAE grade is to 
be based solely on BP measurements.
-
Section 9.4.2.2 (Management of Proteinuria), Table 6 (Clinical 
Laboratory Tests) and Table 7 (Schedule of Procedures and 
Assessments – footnote “p”), and Synopsis: Revised guidelines for 
management of proteinuria as follows:
◦
Clarified that CTCAE grading for proteinuria will be based on a 
24-hour urine result.
◦
Section 9.4.2.2 (Management of Proteinuria) and Table 6 (Clinical 
Laboratory Tests):  Added the option to use an immediate spot 
urine protein-to-creatinine ratio (UPCR) test as an alternative to a 
24-hour urine protein test to quantify the 24-hour urine excretion if 
urine protein is ≥2+ (first occurrence or a subsequent increase in 
severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level, or at the new dose level when there has been a 
lenvatinib dose reduction).
◦
Specified that a 24-hour urine protein test is required if the UPCR 
result is ≥2.4.
◦
Clarified that subjects with proteinuria ≥2+ should be tested on 
Day 15 of each cycle (or more frequently as clinically indicated) 
until the results have been 1+ or negative for 2 consecutive
treatment cycles.
-
Section 9.1 and Synopsis:  Added text to clarify that subjects will 
receive study treatment until subject requests to discontinue or is lost to 
follow-up.
-
Typographical error in Section 9.7.2 (Determination of Sample Size) 
for the number of patients in placebo arm in Study 303 was corrected to 
N=131 (previously stated as N=161).
-
Section 9.5.1.2.4 and Synopsis: It was clarified that the Baseline tumor 
imaging scans will be sent to an imaging core laboratory for 
prospective eligibility confirmation and all postbaseline scans will be 
archived by the site and available for potential future review.
-
Added the abbreviation for UPCR to the abbreviation list.
-
Change in medical monitor from 
 to 
 is reflected on 
the signature page.
16 Feb 2018
Amendment 04:
PPD
PPD


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Highlights of Major Changes
Section/Change
Amendment 03.1 was written for regulatory purposes in response to VHP 
comments on Amendment 03, but was not released globally. Amendment 04 
formalizes these changes proposed in Amendment 03.1, and will be submitted 
to all regulatory authorities and sites.
21 May 2019
Amendment 05:
Amendment 05 was written to clarify that subjects will remain on blinded 
investigational product after the Randomization Phase ends (when last subject 
enrolled has completed the Week 24 tumor assessments or has discontinued
study treatment before Week 24) until the primary analysis has been completed.
-
Sections 5.1 (Institutional Review Boards/Independent Ethics 
Committees), 9.1 (Overall Study Design), 9.1.2 (Randomization Phase), 
and Synopsis
09 Jan 2020
Amendment 06:
Amendment 06 clarifies that the data cutoff for the primary analysis refers to the 
statistical end of the study for analysis purposes (end of the Randomization 
Phase) and that the End of Study refers to the last subject last visit after which 
all subjects will have completed their Off-treatment visits. It further makes clear 
that investigational product will be provided to ongoing subjects until they have 
had their Off-treatment visit to transition to commercial lenvatinib outside the 
study or an access program, and that subjects should follow the Schedule of 
Procedures and Assessments while taking investigational product. The
amendment also clarifies that at the End of Study, the Sponsor (or investigator 
where required) will ensure that all relevant IRBs/ECs and Competent 
Authorities are notified about the study completion per regulatory requirements 
in each country or region.
-
Sections 5.1 (Institutional Review Boards/Independent Ethics 
Committees), 9.1 (Overall Study Design and Plan), 9.1.2
(Randomization Phase), 9.7 (Statistical Methods), and Synopsis
It is also clarified that follow-up assessments will not be performed after the 
data cutoff for the primary analysis
-
Sections 9.3.3 (Removal of Subjects From Therapy or Assessment), 
9.5.1.2.4 (Tumor Assessments), 9.5.1.5 (Schedule of Procedures and 
Assessments, Table 7 footnotes t and v), and Synopsis
It is also clarified that estimated duration of each subject’s participation of 
18 months is the average.
-
Sections 9.1 (Overall Study Design and Plan) and Synopsis


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title:  
A Multicenter, Randomized, Double-Blind Phase 2 Trial of Lenvatinib (E7080) in Subjects With 
131I-Refractory Differentiated Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 mg
Daily Will Provide Comparable Efficacy to a 24-mg Starting Dose, But Have a Better Safety Profile
Investigators
To be determined.
Sites
Approximately 100 sites globally.
Study Period and Phase of Development
Approximately 60 months duration.
Phase 2
Objectives
Primary Objective

To determine whether a starting dose of lenvatinib 18 mg once daily (QD) will provide 
comparable efficacy (based on objective response rate [ORR] at 24 weeks [ORR24wk]) with an 
improved safety profile compared to 24 mg QD (based on treatment-emergent adverse events 
[TEAEs] of Grade 3 or higher in the first 24 weeks after randomization).
Secondary Objectives

To evaluate progression-free survival (PFS) in subjects treated with lenvatinib doses of 24 mg
and 18 mg QD.

To evaluate the PFS after next line of treatment (PFS2) in subjects treated with lenvatinib doses 
of 24 mg and 18 mg QD.

To evaluate the safety and tolerability of lenvatinib doses of 24 mg and 18 mg QD.

To evaluate the pharmacokinetic (PK)/pharmacodynamic relationship between exposure and 
biomarkers/efficacy/safety, using a mechanistically based approach, if possible.

To evaluate the impact of lenvatinib treatment on Health-Related Quality of Life (HRQoL) as 
measured by the instruments EQ-5D-3L and FACT-G.
Exploratory Objectives

To explore overall survival (OS) in subjects treated with lenvatinib doses of 24 mg and 18 mg
QD.

To explore thyroglobulin, thyroid-stimulating hormone (TSH), and other serum biomarkers as 
potential biomarkers for tumor response.

To explore DNA sequence variants in genes that may influence PK, safety, or pharmacodynamic 
data.
Study Design
This is a multicenter, randomized, double-blind study being conducted as a postmarketing 
commitment to the US Food and Drug Administration (FDA) and the European Medicines Agency 
(EMA) to evaluate whether there is a lower starting dosage of lenvatinib other than 24 mg QD that 


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provides comparable efficacy but has a better safety profile in subjects with radioiodine-refractory 
differentiated thyroid cancer (RR-DTC) with radiographic evidence of disease progression within the 
prior 12 months.
The initial study design was to compare starting daily doses of 24 mg, 20 mg and 14 mg lenvatinib. 
Based on discussions with FDA and EMA (see Sections 7.2 and 7.3), the study has been redesigned 
and the treatment assignments of all subjects randomized and treated in Study 211 prior to 
Amendment 03 were unblinded as of 26 Aug 2016.  Following unblinding, the subjects were treated 
with open-label lenvatinib study drug at the dose determined at the discretion of the investigator until 
they were transitioned to commercial lenvatinib drug product or an access program in their country.  
Adverse event (AE) data were collected for each of these subjects until they transitioned to lenvatinib 
treatment outside the study.
As per Amendment 03.1, eligible subjects will have measurable disease according to Response 
Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) and will be randomly assigned to 
treatment in a 1:1 ratio to receive lenvatinib 24 mg or 18 mg orally QD, with a total sample size of 
152 subjects (76 subjects per arm).  Treatment will be stratified at randomization by age (≤65 years or 
>65 years) and Eastern Cooperative Oncology Group (ECOG) performance status of 0 vs 1 or 2.  
Subjects will receive study treatment until disease progression, development of unacceptable toxicity, 
subject request to discontinue, withdrawal of consent, or lost to follow-up, until the End of Study, or 
until study termination by the sponsor.  After disease progression, subjects will be followed for PFS2 
and survival until the data cutoff for the primary analysis (ie, end of the Randomization Phase).
This study consists of 2 phases, the Prerandomization Phase and the Randomization Phase.
The Prerandomization Phase will last no longer than 28 days and will include a Screening Period to 
establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease 
characteristics prior to randomization and treatment.
The Randomization Phase will consist of a Treatment Period and a Follow-up Period.  It will begin 
at the time of randomization of the first subject and will consist of 28-day blinded study treatment 
cycles.  The data cutoff for the primary analysis will occur at the end of the Randomization Phase, 
which is defined as when the last subject enrolled completes the Week 24 tumor assessments or 
discontinues study treatment if before Week 24.
Subjects on treatment at the time of data cutoff for the primary analysis will remain on blinded 
investigational product until the primary analysis has been completed and will continue to receive 
investigational product until they complete the Off-treatment visit prior to their transition to 
commercial lenvatinib (if commercially available for that individual subject) or through an access 
program administered by the sponsor. While receiving investigational product, subjects should 
continue with the same assessments as noted in the Schedule of Assessments/Procedures. The last 
subject’s last assessment (Off-treatment visit) will be the End of Study.
Subjects will be randomly assigned to treatment with 1 of 2 blinded dosages of lenvatinib in a 1:1 
ratio. 

The Treatment Period for an individual subject will begin at the time of randomization and will 
end upon completion of the Off-treatment Visit, which will occur within 30 days after the final 
administration of study drug.  Serious adverse events (SAEs) must be captured for 28 days after 
the last dose of study drug.  Subjects will undergo safety and efficacy assessments as defined in 
the Schedule of Procedures/Assessments and will continue to receive study treatment until 
disease progression. 

The Follow-up Period will begin immediately after the Off-treatment Visit and will continue as 
long as the subject is alive, unless the subject withdraws consent, or until the data cutoff for 
primary analysis.  Subjects who discontinue study drug treatment prior to disease progression will 


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continue to be followed according to the Schedule of Procedures/Assessments until 
documentation of disease progression or initiation of another anticancer treatment.  Subjects will 
be followed every 12 weeks ± 1 week for survival, PFS2 and all anticancer treatments received 
(unless this information is not allowed to be provided due to confidentiality) will be recorded 
until the data cutoff for the primary analysis (ie, Follow-up ends at the end of the Randomization 
Phase). Subjects who were enrolled prior to implementation of Amendment 03 and who 
discontinued lenvatinib treatment due to progressive disease or due to an AE were followed for 
PFS2 and survival until the date that the last subject (who was enrolled prior to implementation of 
Amendment 03) transitioned to lenvatinib treatment outside the study (the data cutoff date for this 
group of 41 subjects).  
The average estimated duration of each subject’s participation in the study is 18 months.  After the
primary analysis is completed, subjects still receiving study treatment may continue taking lenvatinib 
available through their pharmacy (if commercially available for that individual subject) or through an 
access program administered by the sponsor.  After the study is unblinded, but before transitioning to 
commercial lenvatinib or an access program, subjects will continue to take study treatment until 
completing the Off-treatment visit. 
Number of Subjects
Prior to Amendment 03, approximately 300 subjects were planned to be screened to provide 
210 randomized subjects (70 per arm).  A total of 56 subjects were screened and 41 of these subjects 
were randomized and treated until study enrollment was temporarily halted. Efficacy and safety data 
for these initial 41 randomized subjects until they transitioned to lenvatinib treatment outside the 
study will be reported separately.
As of Amendment 03.1, an additional 180 subjects will be screened to provide 152 randomized 
subjects (76 per arm).
Inclusion Criteria
1.
Subjects must have histologically or cytologically confirmed diagnosis of one of the following 
differentiated thyroid cancer (DTC) subtypes:
a.
Papillary thyroid cancer (PTC)
◦
Follicular variant
◦
Variants (including but not limited to tall cell, columnar cell, cribriform-morular, solid, 
oxyphil, Warthin’s-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell 
variant of papillary carcinoma, poorly differentiated)
b.
Follicular thyroid cancer (FTC)
◦
Hürthle cell
◦
Clear cell
◦
Insular
2.
Measurable disease meeting the following criteria and confirmed by central radiographic review:
a.
At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm in the 
short-axis diameter for a lymph node that is serially measurable according to RECIST 1.1 
using computed tomography/magnetic resonance imaging (CT/MRI).  If there is only 1 target 
lesion and it is a non-lymph node, it should have a longest diameter of ≥1.5 cm.
b.
Lesions that have had external beam radiotherapy or locoregional therapies such as 
radiofrequency (RF) ablation must show evidence of progressive disease based on 
RECIST 1.1 to be deemed a target lesion.


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3.
Subjects must show evidence of disease progression within 12 months (an additional month will 
be allowed to accommodate actual dates of performance of screening scans, ie, within 
≤13 months) prior to signing informed consent, according to RECIST 1.1 assessed and confirmed 
by central radiographic review of CT and/or MRI scans.
4.
Subjects must be 131I-refractory/resistant as defined by at least one of the following:
a.
One or more measurable lesions that do not demonstrate iodine uptake on any radioiodine 
scan.
b.
One or more measurable lesions that have progressed according to RECIST 1.1 within 
12 months (an additional month will be allowed to accommodate actual dates of performance 
of screening scans, ie, within ≤13 months) after 131I therapy, despite demonstration of 
radioiodine avidity at the time of that treatment by pre- or posttreatment scanning.  These 
subjects must not be eligible for possible curative surgery.
c.
Cumulative activity of 131I of >600 mCi or 22 gigabecquerels (GBq), with the last dose 
administered at least 6 months prior to study entry.
5.
Subjects with known brain metastases who have completed whole brain radiotherapy, stereotactic 
radiosurgery or complete surgical resection, will be eligible if they have remained clinically 
stable, asymptomatic, and off steroids for one month.
6.
Subjects must be receiving thyroxine suppression therapy and TSH should not be elevated (TSH 
should be ≤5.50 mcIU/mL).  When tolerated by the subject, thyroxine dose should be changed to 
achieve TSH suppression (TSH <0.50 mcIU/mL) and this dose may be changed concurrently 
upon starting study drug treatment.
7.
All chemotherapy- or radiation-related toxicities must have resolved to Grade <2 severity per 
Common Terminology Criteria for Adverse Events (CTCAE v4.03), except alopecia and
infertility. 
8.
Subjects must have an ECOG performance status of 0, 1 or 2.
9.
Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined 
as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week 
prior to Cycle 1/Day 1.
10. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft 
and Gault formula.
11. Adequate bone marrow function:
a.
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 × 103/μL)
b.
Platelets ≥100,000/mm3 (≥100 × 109/L)
c.
Hemoglobin ≥9.0 g/dL
12. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) 
≤1.5 (except for subjects on warfarin therapy where INR may be ≥2 and <3).
13. Adequate liver function:
a.
Bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated hyperbilirubinemia or 
Gilbert’s syndrome.
b.
Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) 
≤3 × ULN (≤5 × ULN if subject has liver metastases).  If alkaline phosphatase is >3 × ULN 
(in absence of liver metastases) or >5 × ULN (in presence of liver metastases) AND the 
subject also is known to have bone metastases, the liver-specific alkaline phosphatase must be 
separated from the total and used to assess the liver function instead of total alkaline 
phosphatase.
14. Males or females age ≥18 years at the time of informed consent.


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15. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative 
beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or 
equivalent units of ß-hCG. A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug.
16. All females will be considered to be of childbearing potential unless they are postmenopausal 
(amenorrheic for at least 12 consecutive months, in the appropriate age group and without other 
known or suspected cause) or have been sterilized surgically (ie, bilateral tubal ligation, total 
hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing). 
17. Females of childbearing potential should avoid becoming pregnant and use highly effective 
contraception while on treatment with lenvatinib and for at least 1 month after finishing 
treatment.  Females of childbearing potential must not have had unprotected sexual intercourse 
within 30 days before study entry and must agree to use a highly effective method of 
contraception (eg, total abstinence, an intrauterine device, a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire 
study period and for 30 days after study drug discontinuation.  Females who are using hormonal 
contraceptives must have been on a stable dose of the same hormonal contraceptive product for at 
least 4 weeks before dosing and must continue to use the same contraceptive during the study and 
for 30 days after study drug discontinuation.  Women using oral hormonal contraceptives should 
add a barrier method.
18. Subject must voluntarily agree to provide written informed consent.
19. Subject must be willing and able to comply with all aspects of the protocol.
Exclusion Criteria
1.
Anaplastic or medullary carcinoma of the thyroid.
2.
Diagnosed with meningeal carcinomatosis.
3.
Two or more prior VEGF/VEGFR-targeted therapies or any ongoing treatment for RR-DTC other 
than TSH-suppressive thyroid hormone therapy.
4.
Prior treatment with lenvatinib.
5.
Subjects who have received any anticancer treatment within 21 days or any investigational agent 
within 30 days (or 5 half-lives) prior to the first dose of study drug and should have recovered 
from any toxicity related to previous anticancer treatment.  This does not apply to the use of TSH-
suppressive thyroid hormone therapy.
6.
Major surgery (eg, laparotomy, thoracotomy or joint replacement) within 3 weeks prior to 
randomization or elective surgery scheduled to be performed during the study.
7.
Subjects having >1+ proteinuria on urine dipstick testing will undergo 24-hour urine collection 
for quantitative assessment of proteinuria.  Subjects with urine protein ≥1 g/24 h will be
ineligible.
8.
Gastrointestinal malabsorption or any other condition that in the opinion of the investigator might 
affect the absorption of study drug.
9.
Significant cardiovascular impairment:  history of congestive heart failure greater than New York 
Heart Association (NYHA) Class II, unstable angina, myocardial infarction or cerebral vascular 
accident within 6 months of the first dose of study drug, or cardiac arrhythmia associated with 
hemodynamic instability.
10. Prolongation of corrected QT interval (QTc) to >480 ms as demonstrated by a repeated 
electrocardiogram (ECG) or a clinically significant ECG abnormality, including a marked 
prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval >500 ms).


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11. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose 
of study drug.
12. Active infection (any infection requiring treatment).
13. Active malignancy (except for DTC or definitively treated melanoma in-situ, basal or squamous 
cell carcinoma of the skin, or carcinoma in situ of the cervix) within the past 24 months.
14. Bleeding or thrombotic disorders.
15. Known intolerance to study drug (or any of the excipients).
16. Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.
17. Females who are pregnant or breastfeeding.
Study Treatments
Study subjects, investigator site personnel, and the sponsor will be blinded to treatment assignment.  
Study subjects will be administered study drug in the form of two 10-mg capsules and two 4-mg 
capsules of lenvatinib or placebo provided in a blister package totaling a dose of 24, 20, 18, 14, 10, 8 
or 4 mg to be taken with water each morning.  Study drug should be taken at approximately the same 
time each morning.  Study drug may be taken in a fasting state or following a meal.
Study drug will be provided as follows for the 24-, 20-, 18-, 14-, 10-, 8-, and 4-mg doses:
Capsule Allocation
Total Dose (QD)
10 mg lenvatinib
10 mg placebo
4 mg lenvatinib
4 mg placebo
24 mg
2
0
1
1
20 mg
2
0
0
2
18 mg
1
1
2
0
14 mg
1
1
1
1
10 mg
1
1
0
2
8 mg
0
2
2
0
4 mg
0
2
1
1
Dose adjustments will be made according to the guidelines provided in the table below for 
management of intolerable toxicities.
Note:  Refer to the relevant sections below for management of hypertension, proteinuria, 
hepatotoxicity,  thromboembolic events, posterior reversible encephalopathy syndrome (PRES), and 
hypocalcemia.
Study Treatment Dose Reduction and Interruption Instructions
Subjects randomized prior to Amendment 03 received 1 of 3 starting doses of lenvatinib: 24 mg/day, 
20 mg/day, or 14 mg/day.  
As of Amendment 03, subjects will receive 1 of 2 starting doses of lenvatinib, 24 mg/day or 
18 mg/day.  Dose reductions will occur in succession based on the subject’s previous dose level (24, 
20, 14, 10, and 8 mg QD, or 18, 14, 10, 8, and 4 mg QD, respectively).  Any dose reduction beyond 3 
levels must be discussed with the sponsor.  Once the dose has been reduced, it may not be increased 
at a later date.  Drug blister packs with the appropriate dosage strength will be assigned by the 
interactive voice and web response system (IxRS) system according to the schema in the following 
table:


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MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling.  
Investigators should therefore ensure that subjects enrolled to receive treatment with lenvatinib have 
BP of ≤150/90 mmHg at the time of study entry and, if known to be hypertensive, have been on a 
stable dose of antihypertensive therapy for at least 1 week before Cycle 1/Day 1.  Early detection and 
effective management of hypertension are important to minimize the need for lenvatinib  dose 
interruptions and reductions.
Regular assessment of BP should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Hypertension will be graded using CTCAE v4.03, based on BP 
measurements only (and not on the number of antihypertensive medications).
If the subject’s initial BP measurement is elevated (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg), the BP measurement should be repeated at least 5 minutes later.  The mean value of 
2 measurements at least 5 minutes apart is defined as one BP assessment.  If the BP assessment (ie, 
the mean of the 2 BP measurements obtained at least 5 minutes apart) is elevated (systolic BP 
≥140 mmHg or diastolic BP ≥90 mmHg), a confirmatory BP assessment should be obtained at least 
30 minutes later by performing 2 measurements at least 5 minutes apart (to yield a mean value).
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop a 
hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mmHg, significant risk factors for cardiac disease, intracerebral 
Treatment-Related 
Toxicitya,b
including hepatic injury 
and thromboembolic 
events
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change (continue at Level 0)
Intolerable Grade 2c,d or Grade 3
First occurrence
Interrupt until 
resolved to Grade 0-1 
or baseline
Dose level -1 once a day (20 or 14 mg QD)
(1-level reduction from previous)
Second occurrence 
(same toxicity or new 
toxicity)
Interrupt until 
resolved to Grade 0-1 
or baseline
Dose level -2 once a day (14 or 10 mg QD)
(1-level reduction from previous)
Third occurrence (same 
toxicity or new toxicity)
Interrupt until 
resolved to Grade 0-1 
or baseline
Dose level -3 once a day (10 or 8 mg QD)
(1-level reduction from previous)
Fourth occurrence 
(same toxicity or new 
toxicity)
Interrupt until
resolved to Grade 0-1 
or baseline
Stop Treatment or discuss possible dose level -4 with 
sponsor (8 or 4 mg QD)
(1-level reduction from previous)
Grade 4e:  Discontinue Study Treatment
Note: For grading see Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Collect all CTCAE
grades of adverse events, decreasing and increasing grade.
QD = once daily.
a:
A delay of study treatment for more than 28 days (due to treatment-related toxicities) will require a discussion with 
the sponsor before treatment can be resumed.
b:
Initiate optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment, interruption, 
or dose reduction.
c:
Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d:
Obese subjects with weight loss do not need to return to baseline weight or Grade 1 weight loss to restart lenvatinib.  
There should be no weight loss for at least 1 week, and subjects should be started at the lower dose. Normal body 
mass index should be used as a reference for future dose reductions.
e:
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.


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hemorrhage, or other significant co-morbidities).  Once the subject has been on the same 
antihypertensive medications for at least 48 hours and the BP is controlled, lenvatinib should be 
resumed as described below
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on 
Day 15 (or more frequently as clinically indicated) until systolic BP has been ≤150 mmHg and 
diastolic BP has been ≤95 mmHg for 2 consecutive treatment cycles.  If a repeat event of systolic BP 
≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must resume the Day 15 evaluation until 
systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment 
cycles.
The following guidelines should be followed for the management of systolic BP ≥140 mmHg up to 
<160 mmHg or diastolic BP ≥90 mmHg up to <100 mmHg confirmed on repeat assessment after at 
least 30 minutes:

Continue lenvatinib and initiate antihypertensive therapy, if not already receiving.

Continue lenvatinib and increase the dose of the current antihypertensive therapy or initiate 
additional antihypertensive therapy.
The following guidelines should be followed for the management of systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg confirmed on repeat assessment after at least 30 minutes:

Continue study drug and institute antihypertensive therapy for subjects not already receiving this.

For those subjects already on antihypertensive medication, the dose of the current agent may be 
increased, if appropriate, or one or more agents of a different class of antihypertensive should be 
added.

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal antihypertensive 
therapy, then study drug administration should be interrupted and restarted at one dose level 
reduction only when systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg and the subject has 
been on a stable dose of antihypertensive medication for at least 48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first dose reduction 
despite optimal management of hypertension with antihypertensive medications (either by 
dose increase or the addition of a different class of antihypertensive), then study drug 
administration should be interrupted and restarted at an additional dose reduction only when 
systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg and the subject has been on a stable 
dose of antihypertensive medication for at least 48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose reduction 
despite optimal management of hypertension with antihypertensive medications (either by 
dose increase or the addition of a different class of antihypertensive), then study drug 
administration should be interrupted and restarted at a third dose reduction dose only when 
systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg and the subject has been on a stable 
dose of antihypertensive medication for at least 48 hours.
-
Additional dose reduction should be discussed with the sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):

Institute appropriate medical management

Discontinue study drug
MANAGEMENT OF PROTEINURIA
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria:


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1.
Grading of Proteinuria:
Grading according to CTCAE v4.03 will be based on the 24-hour urinary protein result.  
Management of lenvatinib administration will be based on the grade of proteinuria according to 
instructions contained in Table 4, “Study Treatment Dose Reduction and Interruption 
Instructions.”
2.
Detection and Confirmation
-
Perform urine dipstick testing per the Schedule of Assessments (Table 7).
-
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) or 
an immediate spot urine protein-to-creatinine ratio (UPCR) test is required in the following 
situations:
◦
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug
◦
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
◦
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is ≥2+
-
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when an immediate spot UPCR is ≥2.4
3.
Monitoring
-
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 of 
each cycle (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 2 consecutive treatment cycles.
MANAGEMENT OF HEPATOTOXICITY
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) 
should be monitored at baseline, every 2 weeks for the first 2 months and monthly thereafter, and as 
clinically indicated (see Schedule of Procedures and Assessments). If signs/symptoms indicating 
liver injury occur, instructions contained in “Study Treatment Dose Reduction and Interruption 
Instructions” should be followed.  Appropriate supportive care should be provided together with close 
monitoring.  If hepatic failure occurs, study drug must be discontinued.
MANAGEMENT OF THROMBOEMBOLIC EVENTS
Subjects should be advised to pay attention to symptoms suggestive of venous thromboembolic 
events which include acute onset of shortness of breath, dyspnea, chest pain, cough, hemoptysis, 
tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity swelling, and warmth to 
touch or tenderness. In case any of these symptoms appear, subjects should be instructed to report 
such symptoms promptly to the treating physician.  If a thromboembolic event is confirmed, 
instructions contained in “Study Treatment Dose Reduction and Interruption Instructions” should be 
followed.  Appropriate supportive care should be provided together with close monitoring.  If a 
subject experiences life-threatening (Grade 4) thromboembolic reactions, including pulmonary 
embolism, study drug must be discontinued.
MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY 
SYNDROME/REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME 
(PRES/RPLS)
In clinical studies with lenvatinib, events of PRES/RPLS were reported in <1% of lenvatinib-treated 
subjects.  PRES/RPLS is a neurological disorder that can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurological disturbances.  Mild to 
severe hypertension may be present.  An MRI is necessary to confirm the diagnosis of PRES/RPLS.  


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Appropriate measures should be taken to control BP.  In subjects with signs or symptoms of 
PRES/RPLS, “Study Treatment Dose Reduction and Interruption Instructions” should be followed.
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored monthly per the Schedule of Procedures and Assessments.  
Corrected serum calcium should be used to assess the grade of hypocalcemia per CTCAE v 4.03, 
using the following formula: 
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 × (40 - serum albumin [g/L]) 
The formula is not applicable when serum albumin concentration is normal (≥40 g/L); in such 
situations, the total (uncorrected) serum calcium should be used. 
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
Duration of Treatment
The duration of treatment for each subject is estimated to be:
Prerandomization Phase:  4 weeks
Randomization Phase: Depending upon when a subject is enrolled, their time on treatment may 
range from 6 months to 42 months.  Treatment will continue until disease progression, development 
of unacceptable toxicity, subject request to discontinue, withdrawal of consent, subject is lost to 
follow-up, sponsor termination of the study, or until the End of Study.  Subjects still on treatment 
will remain on blinded investigational product until the primary analysis is complete and will 
continue to receive investigational product until they complete the Off-treatment visit prior to their 
transition to commercial lenvatinib or an access program. While receiving investigational product, 
subjects should continue with the same assessments as noted in the Schedule of Assessments and 
Procedures.
Concomitant Drug/Therapy
Any treatment that is considered necessary for the subject’s health and that is not expected to interfere 
with the evaluation of thyroid cancer may be administered during the study.
Treatment of complications or AEs or therapy to ameliorate symptoms (including blood products, 
blood transfusions, fluid transfusions, antibiotics, antidiarrheal drugs, etc) may be administered at the 
discretion of the investigator unless it is expected to interfere with the evaluation of thyroid cancer.
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.
Any additional procedural or patient-specific particularities should be discussed by the investigator 
and the sponsor.
Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and anticoagulants are permissible but 
should be used with caution.
The following are prohibited:

Other investigational drugs

Other antitumor therapies (except for thyroid hormone suppressive therapy) such as 
chemotherapy, palliative radiotherapy, antitumor interventions (eg, surgical resection), or cancer 
immunotherapy


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Assessments
Efficacy Assessments
Tumor assessments will be performed according to RECIST 1.1.  Investigator-determined response 
assessments will be performed at each assessment time point and entered onto the case report form
(CRF).  Baselinetumor imaging scans will be sent to an imaging core laboratory designated by the 
sponsor for prospective eligibility confirmation. All postbaseline scans will be archived by the sites 
and available for potential future review.  Tumor assessments will be carried out following the 
guidelines provided by the imaging core laboratory.  Historical scans (within prior 12 months; an 
additional month will be allowed to accommodate actual dates of performance of screening scans, ie, 
within ≤13 months) that do not follow the guidelines completely may be used to demonstrate 
eligibility, as long as they meet minimum standards as separately defined by the imaging core 
laboratory. 
Tumor assessments (CT chest, and CT or MRI neck, abdomen, pelvis, and other known or suspected 
sites of disease) will be performed during the Prerandomization Phase and then every 8 weeks (within 
the 8th week) from the date of randomization during treatment cycles in the Randomization Phase.  A 
bone scan will be performed during the Prerandomization Phase to establish a baseline (a historical 
bone scan performed within 6 weeks before randomization is acceptable), every 24 weeks, and as 
clinically indicated.  Lesions identified on bone scans should be followed with cross-sectional 
imaging.  A brain scan will be performed at screening and as clinically indicated.  For subjects with a 
history of protocol-eligible treated brain metastases, a brain scan will be required at all tumor 
assessment time points (eg, every 8 weeks).  
Subjects discontinuing treatment without disease progression in the Randomization Phase will 
continue to undergo tumor assessments every 8 weeks until disease progression is documented or 
another anticancer therapy is initiated.
Pharmacokinetic Assessments
Sparse PK samples will be collected from all subjects and will be analyzed using the population 
approach.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Samples will be collected at protocol specified time points as indicated in the Schedule of Procedures 
and Assessments and may undergo enzyme-linked immunosorbent assay (ELISA), multiplex 
bead-based immunoassay and/or other appropriate analysis procedures to explore thyroglobulin, 
antithyroglobulin autoantibodies (anti-Tg), and other serum biomarkers (including VEGF, Ang-2, 
sTie-2, and FGF23).
A blood sample will be collected for potential pharmacogenomic analysis from all consented subjects 
except where prohibited by regional or local laws.  Variation in lenvatinib exposure or the occurrence 
of AEs observed in the study population may be evaluated by correlating single–nucleotide 
polymorphisms with PK, safety, or pharmacodynamic data. 
Safety Assessments
Safety assessments will consist of monitoring and recording of all AEs, including all CTCAE v4.03 
grades (for increasing severity), and SAEs; regular laboratory evaluations for hematology, blood 
chemistry, and urine values; periodic measurement of vital signs; ECGs; and the performance of 
physical examinations.  An echocardiogram or a multiple-gated acquisition (MUGA) scan including 
left ventricular ejection fraction (LVEF) will be performed at screening, and as clinically indicated.


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Progression of malignant disease should not be recorded as an AE in studies where it is included as an 
endpoint for underlying disease.  If the progression leads to an untoward medical occurrence 
(increased pain, pleural effusion, etc), then this medical occurrence should be the AE.  Disease 
progression is a study endpoint and is to be captured in the CRF per the guidelines for reporting 
disease progression.
Other Assessments
Health-Related Quality of Life (HRQoL) will be assessed at Baseline (prior to first dose of study 
drug), before performing tumor assessment scans every 8 weeks until Week 24, then every 16 weeks, 
and at the Off-treatment Visit.  Subjects will complete the EQ-5D-3L and FACT-G questionnaires.
The EQ-5D-3L generic QoL questionnaire comprises 5 dimensions: mobility, self-care, usual 
activities, pain or discomfort, and anxiety or depression.  Each dimension has 3 levels (1) no problem, 
(2) some problem, or (3) extreme problem.  Thus, the final scoring consists of 243 possible 
combinations or health states.  The utility value for each state is assigned based on a set of preference 
weights (tariffs) elicited from the general population.
The FACT-G QoL questionnaire is comprised of 4 domains: physical, social/family, emotional, and 
functional well-being.  Each domain is scored on a 5-point scale from 0 (not at all) to 4 (very much).  
Subscale scores are added to obtain a total score.
Bioanalytical Methods
Lenvatinib will be quantified by means of a validated liquid chromatography-mass spectrometry/ 
mass spectrometry (LC-MS/MS) method.
Statistical Methods
Study Endpoints
Primary Endpoints

Objective response rate (ORR) at 24 weeks (ORR24wk) as assessed by the investigator according 
to RECIST 1.1.  ORR24wk is defined as the proportion of subjects with a best overall response 
(BOR) of complete response (CR) or partial response (PR) at the Week 24 (after randomization) 
time point or earlier.

Rate of TEAEs with CTCAE grades of 3 or higher within 24 weeks after randomization (as of the 
Week 24 time point).
Secondary Endpoints

Progression-free survival, defined as the time from the date of randomization to the date of first 
documentation of disease progression or date of death, whichever occurs first.  Censoring rules 
for PFS will be defined in the statistical analysis plan (SAP) and will follow FDA guidance. 

PFS2, defined as the time from randomization to second objective disease progression (occurring 
during treatment with the next line of anticancer therapy), or death from any cause, whichever 
occurs first.  Censoring rules for PFS2 will be defined in the SAP.

Overall safety profile and tolerability.

Time to treatment discontinuation due to an AE.

Number of dose reductions.

Time to first dose reduction.

Plasma PK lenvatinib exposure parameters.

Interrelationships of lenvatinib exposure, changes in thyroglobulin and/or TSH, other exploratory 
serum biomarkers, and changes in tumor burden and PFS.


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
Relationship of lenvatinib exposure and changes in BP, and AEs of weight loss, fatigue, nausea, 
vomiting, diarrhea, and proteinuria CTCAE grades derived from urine protein measurements.

Impact of lenvatinib treatment on HRQoL as assessed using the validated instruments EQ-5D-3L 
and FACT-G.
Exploratory Endpoints

Duration of response, defined as the time from the initial achievement of a response to the date of 
first documentation of disease progression or the date of death, whichever occurs first.

Disease control rate (DCR), defined as the proportion of subjects who have BOR of CR, PR, or 
stable disease (SD).  BOR of SD must be achieved at least 7 weeks after randomization.

Clinical benefit rate (CBR), defined as the proportion of subjects who have BOR of CR, PR, or 
durable SD (duration of SD ≥23 weeks after randomization).

Duration of clinical benefit.

Overall survival (OS), measured from the date of randomization until date of death from any 
cause. In absence of confirmation of death, subjects will be censored either at the date that the 
subject was last known to be alive or the date of data cutoff, whichever comes earlier.

Associations between objective tumor response and serum thyroglobulin (accounting for anti-Tg), 
TSH, and other serum biomarkers (including VEGF, Ang-2, sTie-2, and FGF23).

Association between any observed DNA sequence variability and PK, pharmacodynamic, and 
clinical outcome measures including efficacy and safety-related endpoints.
Analysis Sets
Full Analysis Set will include all randomized subjects.  This will be the analysis set for all efficacy 
evaluations, which will be analyzed according to the treatment randomized, regardless of the 
treatment actually received.
Safety Analysis Set will include all subjects who were randomized and received at least one dose of 
study drug.  This will be the analysis set for all safety evaluations, which will be analyzed according 
to the treatment actually received.
Pharmacokinetic (PK) Analysis Set will include all subjects who received at least one dose of study 
drug and have evaluable lenvatinib plasma concentration data.
Pharmacodynamic Analysis Set will include all subjects who received at least one dose of study 
drug and have evaluable pharmacodynamic data.
Efficacy Analyses
All efficacy analyses will be performed on the Full Analysis Set.  For subjects who were randomized
to treatment before implementation of Amendment 03, efficacy results will not be included in the 
analyses for the final clinical study report (CSR), but will be reported separately.
Analyses of Primary Endpoint:
The analysis of ORR24wk will be based on a noninferiority test on the odds ratio (OR) and will be 
tested with a noninferiority margin of 0.4 on an OR scale (see Sample Size Rationale for the margin 
estimation) and a 1-sided alpha of 0.025.  The point estimate of ORR24wk for each treatment group 
(24 mg and 18 mg) will be summarized with corresponding 95% confidence interval (CI).  Treatment 
differences in ORR24w for the 24-mg and 18-mg dose groups will be estimated along with 95% CIs 
based on the normal approximation.  The OR of ORR24wk (18 mg vs 24 mg) along with the 95% CI 
will be calculated using the Cochran-Mantel-Haenszel (CMH) method stratified by ECOG PS (0 vs 1 
or 2) and age group (≤65 or >65 years).


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The overall ORR will also be analyzed according to the same approach for ORR24wk as a sensitivity 
analysis.  
For the analysis of the primary safety endpoint, frequency (number and percentage) will be 
summarized for TEAEs with a CTCAE grade of 3 or higher by treatment (24 mg and 18 mg), and the 
difference in the frequency between the 2 treatment groups will also be presented with 95% CI.
Analysis of Secondary Endpoints:
Progression-free survival and PFS2 will be analyzed using stratified Cox regression including 
treatment as a factor and baseline ECOG PS and age group as strata.  The estimated hazard ratio (HR) 
will be reported for the treatment comparison between the 24-mg and 18- mg dose groups along with 
the corresponding 95% CIs.  The Kaplan-Meier (KM) product-limit estimates for each treatment 
group will be reported and plotted over time.
PFS2 is defined as the time from randomization to second objective disease progression (PD) or death 
from any cause, whichever occurs first.  Subjects who are alive and for whom a second objective PD
has not been observed will be censored at the last time they are known to be alive and without a 
second objective PD. Subjects who were enrolled prior to implementation of Amendment 03 and 
who discontinued lenvatinib treatment due to progressive disease or due to an AE were followed for 
PFS2 until the date that the last subject transitioned to lenvatinib treatment outside the study (the data 
cutoff date for this group of 41 subjects).  PFS2 data for these subjects will be included in a separate 
report.
Analysis of Exploratory Endpoints:
Duration of response will be summarized using descriptive statistics among responders for each 
treatment group.
The rates of durable SD, DCR (SD, CR, or PR), and CBR (CR, PR, and durable SD) and the 
corresponding 2-sided 95% CIs will be calculated by treatment group.  BOR of SD must be at least 
7 weeks following randomization.  Durable SD is SD at least 23 weeks after randomization.
Treatment differences (percentage-point difference) for 24 mg vs 18 will be summarized along with 
the corresponding 95% CIs.
To explore OS, the median survival time and the survival rates at 12, 18 and 24 months will be 
calculated using KM product-limit estimates for each treatment group and presented with 2-sided 
95% CIs.  The KM estimates of OS will be plotted over time. Subjects who were enrolled prior to 
implementation of Amendment 03 and who discontinued lenvatinib treatment due to progressive 
disease or due to an AE were followed for survival until the date that the last subject transitioned to 
lenvatinib treatment outside the study (the data cutoff date for this group of 41 subjects).  OS data for 
these subjects will be reported separately.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Pharmacokinetic Analyses
Plasma PK lenvatinib exposure parameters will be summarized by use of descriptive statistics and 
plotted as appropriate for each treatment group.
Plasma concentration data, including data from subjects randomized before Amendment 03, will be 
analyzed using a population PK approach to estimate population PK parameters.  The analyses will be 
detailed in a separate analysis plan.
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic/pharmacodynamic data from subjects randomized before Amendment 03 will be 
included in the models whenever possible.
Lenvatinib exposure parameters (AUC or concentration at the time of the event or cumulative AUC, 
as appropriate) derived from the population PK analysis will be related to biomarker, safety, and 
efficacy data and will be modeled using a mechanistically based approach, if possible.  For some 


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PK/pharmacodynamic analyses, data from this study will be pooled with data from the RR-DTC arm 
of the Phase 2 Study E7080-G000-201 (Study 201) and with data from the RR-DTC Phase 3 
Study E7080-G000-303 (Study 303).
For efficacy, a tumor growth inhibition model based on longitudinal tumor size measurements of 
target lesions will be included.  Lenvatinib exposure and measured biomarkers (including 
thyroglobulin [accounting for anti-Tg], TSH, VEGF, Ang-2, sTie-2, FGF23) will be explored as 
predictors or correlations with tumor burden changes in the tumor growth inhibition model.
Other analyses will include logistic regression analysis for ORR24wk, KM plots of PFS data stratified 
by lenvatinib exposure, and Cox-regression analysis.  For the Cox-regression analysis of PFS, 
adjustment will be made for each subject’s baseline characteristics or tumor-related features.  In 
addition to lenvatinib exposure, changes in biomarker concentrations (thyroglobulin and TSH) and/or 
tumor burden will be related to PFS.
For the exposure-response relationship of safety, the model-based analysis will include the following 
AEs: hypertension, proteinuria, weight loss, fatigue, nausea, vomiting and diarrhea.  For 
hypertension, BP data will be analyzed using an indirect-response model.  For proteinuria, urine 
dipstick and/or 24-hour urine data will be analyzed using a longitudinal categorical logistic regression 
analysis with Markov element.  For weight loss, fatigue, nausea, vomiting, and diarrhea, data will be 
analyzed using a longitudinal categorical logistic regression analysis.  For time to treatment 
discontinuation due to an AE and time to first dose reduction, KM plots stratified by lenvatinib 
exposure will be prepared.  
For the exposure-response relationship for biomarkers, thyroglobulin (accounting for anti-Tg), TSH, 
VEGF, Ang-2, sTie-2, and FGF23 data will be analyzed using a model-based approach.  Direct, 
indirect, and effect compartment models will be explored.
Population PK and PK/pharmacodynamic analyses will be detailed in a separate analysis plan.
Biomarker Analysis
The effect of lenvatinib treatment on serum thyroglobulin, TSH, and other exploratory serum 
biomarkers will be summarized by treatment group.  Associations between clinical outcomes and 
baseline biomarker levels, and/or change in levels from Baseline will be explored.  The analysis may 
be detailed in the biomarker analysis plan (BAP) and reported separately.
Safety Analyses
All safety analyses will be performed by treatment group.  The incidence of TEAEs, intolerable 
Grade 2 TEAEs that lead to dose interruption, dose reduction, or drug discontinuation, and SAEs will 
be summarized and rates will be descriptively summarized.
Time to treatment discontinuation due to an AE, number of dose reductions, and time to first dose 
reduction will be summarized.
Other Analyses
Laboratory test results, vital signs and their changes from baseline, and 12-lead ECG results, will be 
summarized using descriptive statistics.  Abnormal values will be flagged.  Prior and concomitant 
medications, medical / surgical history and subject demographics will be summarized and listed.
Descriptive statistics of the derived functional/symptom scales according to the scoring manual and 
global health status scores will be summarized at each time point by starting dose.  A separate 
prespecified HRQoL analysis following FDA and EMA patient-reported outcomes Guidelines will be 
performed and detailed in a separate SAP and a separate HRQoL report. 
Interim Analyses
No interim analysis is planned for this study.


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Sample Size Rationale
As of Amendment 03, the sample size determination is based on the required number of subjects to 
detect noninferiority of the primary efficacy endpoint ORR24wk, comparing the 18-mg arm to the
24-mg arm. Assuming a 70% retention of the effect of lenvatinib 24 mg versus placebo in Study 303, 
the noninferiority margin on the odds ratio (OR) scale is estimated to be 0.40 (ie, Ha: OR 
[18 mg/24 mg] >0.4).  A sample size of 152 subjects (76 per arm) will provide a statistical power of 
80% to declare noninferiority, assuming a 1-sided alpha of 0.025, an ORR24wk of 54.4% for lenvatinib 
24 mg, and a true OR of 1 with a noninferiority margin of 0.4. The sample size of 152 subjects will 
also provide a precision for the observed differences between the arms with half-widths of the 95% CI
of about 15%.


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................10
3
TABLE OF CONTENTS.............................................................................................26
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................31
5
ETHICS.......................................................................................................................34
5.1
Institutional Review Boards/Independent Ethics Committees.............................34
5.2
Ethical Conduct of the Study..............................................................................35
5.3
Subject Information and Informed Consent ........................................................35
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................36
7
INTRODUCTION AND STUDY RATIONALE.........................................................36
7.1
Clinical Experience With Lenvatinib in Thyroid Cancer.....................................36
7.2
Study Rationale..................................................................................................37
7.3
Rationale for Dose Selection..............................................................................38
8
STUDY OBJECTIVES................................................................................................39
8.1
Primary Objective ..............................................................................................39
8.2
Secondary Objectives.........................................................................................40
8.3
Exploratory Objectives.......................................................................................40
9
INVESTIGATIONAL PLAN ......................................................................................40
9.1
Overall Study Design and Plan...........................................................................40
9.1.1
Prerandomization Phase ...........................................................................43
9.1.1.1
Screening Period.............................................................................43
9.1.1.2
Baseline Period...............................................................................43
9.1.2
Randomization Phase ...............................................................................43
9.2
Discussion of Study Design, Including Choice of Control Groups......................44
9.3
Selection of Study Population ............................................................................44
9.3.1
Inclusion Criteria......................................................................................45
9.3.2
Exclusion Criteria.....................................................................................47
9.3.3
Removal of Subjects From Therapy or Assessment ..................................48
9.4
Treatments.........................................................................................................48
9.4.1
Treatments Administered..........................................................................48
9.4.2
Criteria for Interruption of Treatment, Dose Reduction and Resumption 
of Treatment.............................................................................................49
9.4.2.1
Management of Hypertension .........................................................50
9.4.2.2
Management of Proteinuria.............................................................52
9.4.2.3
Management of Hepatotoxicity.......................................................52
9.4.2.4
Management of Thromboembolic Events........................................53
9.4.2.5
Management of Posterior Reversible Encephalopathy Syndrome/ 
Reversible Posterior Leukoencephalopathy Syndrome ....................53


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9.4.2.6
Management of Hypocalcemia........................................................53
9.4.2.7
Chemical Name, Structural Formula of Lenvatinib .........................53
9.4.2.8
Comparator Drug............................................................................54
9.4.2.9
Labeling for Study Drug .................................................................54
9.4.2.10
Storage Conditions..........................................................................54
9.4.3
Method of Assigning Subjects to Treatment Groups.................................55
9.4.3.1
Selection of Doses in the Study.......................................................55
9.4.4
Blinding ...................................................................................................55
9.4.5
Prior and Concomitant Therapy................................................................56
9.4.5.1
Drug-Drug Interactions...................................................................57
9.4.5.2
Prohibited Concomitant Therapies and Drugs .................................57
9.4.6
Treatment Compliance .............................................................................57
9.4.7
Drug Supplies and Accountability ............................................................57
9.5
Study Assessments.............................................................................................59
9.5.1
Assessments .............................................................................................59
9.5.1.1
Demography and Baseline Assessments..........................................59
9.5.1.2
Efficacy Assessments......................................................................60
9.5.1.2.1
Primary Efficacy Assessment..........................................................60
9.5.1.2.2
Secondary Efficacy Assessments ....................................................60
9.5.1.2.3
Exploratory Efficacy Assessments ..................................................60
9.5.1.2.4
Tumor Assessments........................................................................60
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker.............................................................................61
9.5.1.3.1
Pharmacokinetic Assessments.........................................................61
9.5.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments.....................................................................................................62
9.5.1.4
Safety Assessments.........................................................................62
9.5.1.4.1
Adverse Events and Other Events of Interest...................................63
9.5.1.4.2
Serious Adverse Events and Other Events of Interest ......................65
9.5.1.4.3
Laboratory Measurements...............................................................66
9.5.1.4.4
Vital Signs and Weight Measurements............................................68
9.5.1.4.5
Physical Examinations....................................................................68
9.5.1.4.6
Electrocardiograms.........................................................................68
9.5.1.4.7
Echocardiograms ............................................................................69
9.5.1.4.8
Other Assessments..........................................................................69
9.5.1.5
Schedule of Procedures and Assessments........................................69
9.5.1.6
Description of Procedures/Assessments Schedule ...........................75
9.5.2
Appropriateness of Measurements............................................................75
9.5.3
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest .....................................................................................................75
9.5.3.1
Reporting of Serious Adverse Events..............................................75


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9.5.3.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................76
9.5.3.3
Reporting of Other Events of Interest..............................................76
9.5.3.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ................................................76
9.5.3.3.2
Reporting of Significant Laboratory Abnormality...........................77
9.5.3.3.3
Reporting of Study-Specific Events ................................................77
9.5.3.4
Expedited Reporting .......................................................................77
9.5.3.5
Breaking the Blind..........................................................................78
9.5.3.6
Regulatory Reporting of Adverse Events ........................................78
9.5.4
Discontinuation of Subjects......................................................................78
9.5.5
Abuse or Diversion of Study Drug............................................................79
9.5.6
Confirmation of Medical Care by Another Physician................................79
9.6
Data Quality Assurance......................................................................................79
9.6.1
Data Collection.........................................................................................79
9.6.2
Clinical Data Management .......................................................................79
9.7
Statistical Methods.............................................................................................79
9.7.1
Statistical and Analytical Plans.................................................................80
9.7.1.1
Study Endpoints..............................................................................80
9.7.1.1.1
Primary Endpoints ..........................................................................80
9.7.1.1.2
Secondary Endpoints ......................................................................80
9.7.1.1.3
Exploratory Endpoints ....................................................................81
9.7.1.2
Definitions of Analysis Sets............................................................81
9.7.1.3
Subject Disposition.........................................................................81
9.7.1.4
Demographic and Other Baseline Characteristics............................82
9.7.1.5
Prior and Concomitant Therapy ......................................................82
9.7.1.6
Efficacy Analyses...........................................................................82
9.7.1.6.1
Primary Efficacy Analysis ..............................................................82
9.7.1.6.2
Secondary Efficacy Analyses..........................................................83
9.7.1.6.3
Exploratory Efficacy Analyses........................................................83
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses..............................................................84
9.7.1.7.1
Pharmacokinetic Analyses ..............................................................84
9.7.1.7.2
Pharmacokinetic/Pharmacodynamic Analyses.................................84
9.7.1.7.3
Biomarker Analysis ........................................................................85
9.7.1.8
Safety Analyses ..............................................................................85
9.7.1.8.1
Primary Safety Endpoint.................................................................85
9.7.1.8.2
Extent of Exposure .........................................................................85
9.7.1.8.3
Adverse Events...............................................................................86
9.7.1.8.4
Laboratory Values ..........................................................................86
9.7.1.8.5
Vital Signs and Physical Examination Findings ..............................87


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9.7.1.8.6
Electrocardiograms.........................................................................87
9.7.1.8.7
Other Safety Analyses.....................................................................87
9.7.1.8.8
Health-Related Quality of Life Analyses.........................................87
9.7.2
Determination of Sample Size ..................................................................88
9.7.3
Interim Analysis.......................................................................................88
9.7.4
Other Statistical/Analytical Issues ............................................................88
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................88
10
REFERENCE LIST.....................................................................................................89
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......90
11.1
Changes to the Protocol......................................................................................90
11.2
Adherence to the Protocol..................................................................................90
11.3
Monitoring Procedures.......................................................................................90
11.4
Recording of Data..............................................................................................91
11.5
Identification of Source Data..............................................................................92
11.6
Retention of Records..........................................................................................92
11.7
Auditing Procedures and Inspection ...................................................................92
11.8
Handling of Study Drug .....................................................................................92
11.9
Publication of Results ........................................................................................93
11.10 Disclosure and Confidentiality ...........................................................................93
11.11 Discontinuation of Study....................................................................................93
11.12 Subject Insurance and Indemnity........................................................................94
12
APPENDICES.............................................................................................................95


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LIST OF IN-TEXT TABLES
Table 1
Simulated Objective Response Rate at 24 Weeks....................................38
Table 2
Simulated Average Dose and Proportion of Subjects with at Least 
One/Two Dose Reduction (DR) During 24 Weeks...................................................39
Table 3
Study Treatments....................................................................................49
Table 4
Study Treatment Dose Reduction and Interruption Instructions...............49
Table 5
Lenvatinib Pharmacokinetic Sampling Time Points................................61
Table 6
Clinical Laboratory Tests........................................................................67
Table 7
Schedule of Procedures and Assessments in E7080-G000-211 
Prerandomization and Randomization Phases (as of Protocol Amendment 03).........70
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E7080-G000-211 (as of Protocol 
Amendment 03).......................................................................................................42
LIST OF APPENDICES
Appendix 1
Thyroid Cancer Tumor-Node-Metastasis Staging System.......................96
Appendix 2
Response Evaluation Criteria in Solid Tumors 1.1..................................98
Appendix 3
Eastern Cooperative Oncology Group Performance Status......................99
Appendix 4
Cockcroft and Gault Formula ...............................................................100
Appendix 5
New York Heart Association Cardiac Disease Classification ................101
Appendix 6
Common Terminology Criteria for Adverse Events (v4.03)..................102
Appendix 7
Health-Related Quality of Life Questionnaire – EQ-5D-3L...................103
Appendix 8
Health-Related Quality of Life Questionnaire – FACT-G .....................106


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
131I
Radioiodine
AE(s)
adverse event(s)
AJCC
American Joint Committee on Cancer 
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
ANC
absolute neutrophil count
anti-Tg
antithyroglobulin autoantibodies
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
ASCO
American Society of Clinical Oncology
ATC
Anatomical Therapeutic Chemical
AUC
area under the concentration-time curve
β-hCG
beta-human chorionic gonadotropin
BAP
biomarker analysis plan
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
CBR
clinical benefit rate
CFR
Code of Federal Regulations
CI
confidence interval
CK/CPK
creatine phosphokinase 
CK-MB
a creatine kinase isoenzyme primarily found in cardiac muscle
CK-MM
a creatine kinase isoenzyme primarily found in skeletal muscle
CL/F
apparent clearance
CPMP
Committee for Proprietary Medicinal Products
CR
complete response
CRA
clinical research associate
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP/CYP3A4
cytochrome P450/cytochrome P450 3A4
DCR
disease control rate
DTC
differentiated thyroid cancer


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Abbreviation
Term
EC
European Communities
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
ECOG PS
ECOG performance status
EDoR
expected duration of response
EMA
European Medicines Agency
EU
European Union
FDA
Food and Drug Administration
FTC
follicular thyroid cancer
GCP
Good Clinical Practice
HR
hazard ratio
HRQoL
Health-Related Quality of Life
ICF
informed consent form
ICH
International Council for Harmonisation 
IEC
Independent Ethics Committee
IIR
independent imaging review
INR
international normalized ratio
IRB
Institutional Review Board
IxRS
interactive voice and web response system
KM
Kaplan-Meier
LNH
low/normal/high
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition
NaF PET
18F-sodium fluoride positron emission tomography
NCI
National Cancer Institute
NYHA
New York Heart Association
ORR24wk
objective response rate at 24 weeks
OR
odds ratio
ORR
objective response rate
OS
overall survival
PD
progressive disease


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Abbreviation
Term
PFS
progression-free survival
PI
principal investigator
PK
pharmacokinetic(s)
PPE
palmar-plantar erythrodysesthesia
PR
partial response
PRES
posterior reversible encephalopathy syndrome 
PTC
papillary thyroid cancer
pTNM
primary tumor-node-metastasis staging
QD
once daily
QTc
corrected QT interval (time from the start of the QRS complex to the end of the 
T wave corrected for heart rate)
RR-DTC
radioiodine-refractory differentiated thyroid cancer
RECIST
Response Evaluation Criteria in Solid Tumors
RPLS
reversible posterior leukoencephalopathy syndrome
RR
respiratory rate
RTK
receptor tyrosine kinase 
SAE(s)
serious adverse event(s)
SAP
statistical analysis plan
SD
stable disease
SOC
system organ class
SMQ
standardized MedDRA query
SUSARs
suspected unexpected serious adverse reactions 
T4
Thyroxine
TEAE(s)
treatment-emergent adverse event(s)
TEMAV
treatment-emergent markedly abnormal laboratory value
TNM
tumor-node-metastasis staging
TSH
thyroid stimulating hormone
ULN
upper limit of normal
UPCR
urine protein-to-creatinine ratio 
US
United States
VEGF
vascular endothelial growth factor 
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with 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 clinical 
research associates [CRAs], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) (or if regionally required, the head of the medical institution) with a copy to 
the sponsor before study start and the release of any study drug to the site by the sponsor or 
its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the heads of the medical 
institutions) 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.
The data cutoff for the primary analysis will occur at the end of the Randomization Phase, 
which is defined as the time the last subject enrolled completes the Week 24 tumor 
assessments or discontinues study treatment before Week 24.  Subjects will remain on
blinded investigational product until the primary analysis has been completed and, after study 
unblinding.  Subjects will continue to receive investigational product until they complete the 
Off-treatment visit prior to their transition to commercial lenvatinib or an access program.
The last subject last visit for the End of Study will be the date of the Off-treatment visit for 
the last subject. At the End of Study, the Sponsor (or investigator where required) will ensure 
that all relevant IRBs/ECs and Competent Authorities are notified about the study completion
per regulatory requirements in each country or region.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and Competent Authority within 15 calendar days, and a detailed written 
explanation of the reasons for the termination/halt should be given.


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5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki (2013)

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Pharmaceuticals for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any European Union (EU) country.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, 
to the Competent Authorities of all involved EU member states.
5.3
Subject Information and Informed Consent
As part of administering the ICF, the investigator must explain to each subject the nature of 
the study, its purpose, the procedures involved, the expected duration, the potential risks and 
benefits involved, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available to the subject, and the extent of maintaining confidentiality of the 
subject’s records.  Each subject must be informed that participation in the study is voluntary, 
that he/she may withdraw from the study at any time, and that withdrawal of consent will not 
affect his/her subsequent medical treatment or relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations. 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 
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The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 100 investigational sites globally.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor will be listed in the Investigator Study File provided to each site.
7
INTRODUCTION AND STUDY RATIONALE
Lenvatinib (E7080/LENVIMA®) is a receptor tyrosine kinase (RTK) inhibitor that inhibits 
the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 
(FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4).  Lenvatinib also inhibits other RTKs that 
have been implicated in pathogenic angiogenesis, tumor growth, and cancer progression in 
addition to their normal cellular functions, including fibroblast growth factor (FGF) receptors 
FGFR1, 2, 3, and 4; the platelet derived growth factor receptor alpha (PDGFRα), KIT, and 
RET (LENVIMA Package Insert).
Lenvatinib was approved for the treatment of patients with progressive, 
radioiodine-refractory differentiated thyroid cancer (RR-DTC) by the US Food and Drug 
Administration (FDA) on 13 Feb 2015, by the Pharmaceuticals and Medical Devices Agency 
(PMDA), Japan on 26 Mar 2015, and by the European Medicines Agency (EMA) on 
28 May 2015.  
The Committee for Medicinal Products for Human Use (CHMP) granted a positive opinion 
for LENVIMA (lenvatinib mesilate 4 mg and 10 mg capsules) on 26 Mar 2015 and the 
European Commission decision was adopted on 28 May 2015.  Lenvatinib is indicated for 
the treatment of adult patients with progressive, locally advanced or metastatic, differentiated 
(papillary/follicular/Hürthle cell) thyroid carcinoma, refractory to radioactive iodine.
This study is being conducted as a postmarketing commitment for the FDA and the EMA.
7.1
Clinical Experience With Lenvatinib in Thyroid Cancer
In Phase 3 study E7080-G000-303 (Study 303) in subjects with RR-DTC, lenvatinib 
treatment demonstrated a statistically significant and clinically meaningful benefit as 
measured by progression-free survival (PFS).  Based on Independent Imaging Review (IIR) 
assessments, lenvatinib prolonged median PFS by 14.7 months compared with placebo 
(18.3 months vs 3.6 months, respectively).  The difference in PFS between the lenvatinib and 
placebo arms was highly statistically significant (P<0.0001) using both stratified and 
unstratified log-rank tests.  The hazard ratio estimated from the stratified Cox proportional 
hazard model was 0.21 (99% confidence interval [CI]: 0.14, 0.31) in favor of lenvatinib.


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Lenvatinib treatment also resulted in a highly statistically significant effect on response rate 
(complete response [CR] + partial response [PR]) compared with placebo (64.8% vs 1.5%; 
P<0.0001).  Four subjects in the lenvatinib arm had a complete response, an atypical finding 
for an antiangiogenic agent.  The objective response rate (ORR) of the lenvatinib-treated 
subjects at 6 months was 57.5% (n=150). Thus, at 6 months, approximately 89% of the 
subjects who ultimately responded had already achieved a response.
Ad hoc analyses of Study 303 data indicated that lenvatinib induced a rapid onset of tumor 
shrinkage, with a large initial reduction (median reduction of 28% at 8 weeks after 
randomization) in the sum of the diameters of target lesions at the first tumor assessment, 
followed by continued reduction of 1.3% per month for the duration of treatment.  
Importantly, subjects who required a dose reduction from the 24 mg starting dose (median 
time to reduction was 3 months) due to toxicity had already achieved the majority of their 
tumor shrinkage prior to the first dose reduction (median time to first response was 
2 months). This appears to be a unique advantage of lenvatinib compared with other 
VEGF-targeted agents.
About 79% of subjects in Study 303 needed dose reductions from the starting dose of 24 mg 
because of treatment-emergent AEs (TEAEs), with the second and third most frequent doses 
administered being 14 mg and 20 mg, respectively. The most frequently reported TEAEs 
(≥30% of subjects, any grade) in the lenvatinib arm of the Safety Analysis Set were (in 
descending order of frequency) hypertension, diarrhea, decreased appetite, weight decreased, 
nausea, fatigue, headache, stomatitis, vomiting, proteinuria, palmar-plantar 
erythrodysesthesia (PPE) syndrome, and dysphonia. Hypertension and proteinuria were the 
TEAEs that led to dose reductions most frequently. Both these TEAEs are related to target 
engagement. 
In Study 303, PFS was significantly longer in lenvatinib-treated subjects who had a TEAE of 
hypertension during treatment compared with subjects who did not develop hypertension 
during treatment (18.8 vs 12.9 months, respectively; P=0.0085, unstratified log-rank test).  
The difference in overall survival (OS) between subjects with and without hypertension was 
also statistically significant (P=0.0003) using the unstratified log-rank test.  The development 
of hypertension was also predictive of the efficacy of lenvatinib for ORR and tumor 
shrinkage.  These data suggest that the TEAE of hypertension is a predictive biomarker of 
tumor response and target inhibition.  Refer to the Randomized Phase clinical study report 
(CSR) and the Open-Label Results CSR for complete study results.
7.2
Study Rationale
After reviewing the pre-NDA Briefing Book for lenvatinib in RR-DTC, FDA noted that 79% 
of the subjects randomized to receive lenvatinib in Study 303 were unable to tolerate the 
starting dose of 24 mg daily and required dose reduction, and expressed concern that an 
optimal dose of lenvatinib has not been established for the treatment of patients with 
progressive RR-DTC.  Clinical comments sent by the FDA on 25 Apr 2014 in response to the 
submitted Expanded Access Protocol, E7080-G000-398, again stated that the FDA was 
concerned that toxicity associated with the 24-mg/day dosing regimen used in Study 303 is 
increased.  They remarked that if lenvatinib is approved based on the review of Study 303, 


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the FDA will require that the safety and efficacy of lower lenvatinib doses be explored 
postmarketing.
This protocol was developed in response to the FDA’s request that Eisai conduct a study to 
test the hypothesis that a lower dose or alternative dosing regimen may result in comparable 
efficacy with less toxicity in patients with progressive RR-DTC.
Eisai agreed to conduct such a study using objective response rate at 24 weeks (ORR24wk) as 
the primary endpoint, since 57.5% of subjects had an objective response at 24 weeks and an 
ad-hoc analysis of Study 303 demonstrated that ORR predicted PFS and OS benefit.
This multicenter, randomized, double-blind, Phase 2 trial of lenvatinib (E7080) in subjects 
with RR-DTC was originally designed to evaluate whether an oral starting dose of 20 mg or 
14 mg daily would provide comparable efficacy to a 24-mg starting dose with an improved 
safety profile.  The study design and study endpoints were agreed upon by the FDA as 
specified in the NDA Approval Letter (13 Feb 2015). 
When the protocol was initially designed, the dose regimens were chosen based on available 
information that indicated that doses of 14 mg and above were projected to provide 
exposures that overlap with at least ~two-thirds of that of the 24 mg dose, and the 14, 20, and 
24 mg were the most common lenvatinib doses used in Study 303 in DTC.  
The revised study design of Protocol Amendment 03 is guided by results of new modeling 
and simulation data that indicate that the starting dose of 14 mg is considered highly unlikely 
to achieve efficacy comparable to the approved starting dose of 24 mg, whereas a starting 
dose of 20 mg is not sufficiently distinct from 24 mg to achieve improved safety.  Therefore, 
an 18-mg starting dose was selected as the comparator.  More information appears in 
Section 7.3.
7.3
Rationale for Dose Selection
Following additional discussions with the FDA on 26 Jul 2016, the lower starting doses of 
lenvatinib were changed from 14 mg and 20 mg to a single lower dose level, 18 mg.  This 
decision was based on the results of tumor-growth-inhibition (Emax) simulation studies
presented in Table 1 and Table 2.  The Emax model was created through a collaborative effort 
between Eisai and the FDA.  
Table 1
Simulated Objective Response Rate at 24 Weeks
Dosing Regimen
ORR (%)
24 weeks
24 mg without up-titration
50.0
18 mg without up-titration
41.5
14 mg with up-titration
41.7
20 mg without up-titration
43.5


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Table 1
Simulated Objective Response Rate at 24 Weeks
Dosing Regimen
ORR (%)
24 weeks
14 mg without up-titration
30.2
Dose levels in italics were those in the initial study design.
Table 2
Simulated Average Dose and Proportion of Subjects with at Least 
One/Two Dose Reduction (DR) During 24 Weeks
Dose Regimen
Subjects experienced at least 
1 DR (%)
Subjects Experienced at least 2 
DR (%)
24 weeks
24 mg without up-titration
68.5
33.8
18 mg without up-titration
57.3
20.8
14 mg with up-titration
65.4
23.8
20 mg without up-titration
63.5
23.1
14 mg without up-titration
48.1
11.9
Dose levels in italics were those in the initial study design.
The results of the simulations provided evidence contradicting the assumption of equipoise
between the 14-mg and 24-mg treatment arms.  The results suggest that while subjects
treated with the existing 14-mg dose regimen would likely experience less toxicity, the 
efficacy of this dose regimen could be compromised.  The FDA also observed that the 20-mg 
dose regimen would not provide sufficiently lower exposure to differentiate it from the 
24-mg dose. The FDA recommended the inclusion of either an 18-mg dose regimen without 
up-titration (for ease of administration) or a 14-mg dose with up-titration.  After internal 
discussion, Eisai decided that because of ease of administration, the 18-mg regimen should 
be used as the comparator.  Subsequently, the study design has been discussed and agreed 
with the EMA.
8
STUDY OBJECTIVES
8.1
Primary Objective

To determine whether a starting dose of lenvatinib 18 mg once daily (QD) will provide 
comparable efficacy (based on ORR24wk) with an improved safety profile compared to 24 
mg QD (based on treatment-emergent adverse events [TEAEs] of Grade 3 or higher in 
the first 24 weeks after randomization).


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8.2
Secondary Objectives

To evaluate PFS in subjects treated with lenvatinib doses of 24 mg and 18 mg QD.

To evaluate the PFS after next line of treatment (PFS2) in subjects treated with lenvatinib 
starting doses of 24 mg and 18 mg QD.

To evaluate the safety and tolerability of lenvatinib doses of 24 mg and 18 mg QD.

To evaluate the pharmacokinetic (PK)/pharmacodynamic relationship between exposure 
and biomarkers/efficacy/safety, using a mechanistically based approach, if possible.

To evaluate the impact of lenvatinib treatment on Health-Related Quality of Life 
(HRQoL) as measured by the instruments EQ-5D-3L and FACT-G.
8.3
Exploratory Objectives

To explore OS in subjects treated with lenvatinib doses of 24 mg and 18 mg QD.

To explore thyroglobulin, thyroid-stimulating hormone (TSH), and other serum 
biomarkers as potential biomarkers for tumor response.

To explore DNA sequence variants in genes that may influence PK, safety, or 
pharmacodynamic data.
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, double-blind study being conducted as a postmarketing 
commitment to the FDA and the EMA to evaluate whether there is a lower starting dosage of 
lenvatinib other than 24 mg QD that provides comparable efficacy but has a better safety 
profile in subjects with RR-DTC with radiographic evidence of disease progression within 
the prior 12 months.  
Eligible subjects will have measurable disease according to Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) and will be randomly assigned to treatment in a 
1:1 ratio to receive lenvatinib 24 mg or 18 mg orally QD with a total sample size of 
152 subjects (76 subjects per arm).  Treatment will be stratified at randomization by age 
(≤65 years or >65 years) and Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0 vs 1 or 2.  Subjects will receive study treatment until disease progression, 
development of unacceptable toxicity, subject requests to discontinue, withdrawal of consent, or 
lost to follow-up, until the end of the study, or until study termination by the sponsor.  After 
disease progression (PD), subjects will be followed for PFS2 and survival. Subjects who 
were enrolled prior to implementation of Amendment 03 and who discontinued lenvatinib 
treatment due to progressive disease or due to an AE were followed for PFS2 and survival 
until the date that the last subject transitioned to lenvatinib treatment outside the study (the 
data cutoff date for this group of 41 subjects).  


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This study consists of 2 phases, the Prerandomization Phase and the Randomization Phase.  
An overview of the study design is presented in Figure 1.  The average estimated duration of 
each subject’s participation is 18 months. The data cutoff for the primary analysis will occur 
when the last subject enrolled completes the Week 24 tumor assessments or discontinues 
study drug before Week 24. Therefore, the last subject enrolled will be on study for 24 
weeks.  Subjects on treatment at this time will remain on blinded investigational product until 
the primary analysis has been completed.  After the primary analysis is completed, subjects 
still receiving treatment will be able to continue taking lenvatinib through their pharmacy (if 
commercially available for that individual subject) or through an access program 
administered by the sponsor. Following study unblinding, subjects will continue to receive 
investigational product until they complete the Off-treatment visit prior to their transition to 
commercial lenvatinib or an access program. The last subject last visit for the End of Study
will be the date of the Off-treatment visit for the last subject. 
The treatment assignments of all subjects randomized and treated in Study 211 prior to 
Amendment 03 were unblinded as of 26 Aug 2016.  Following unblinding, these subjects 
were treated with open-label lenvatinib study drug at the dose determined at the discretion of 
the investigator until they were transitioned to commercial lenvatinib drug product or an 
access program in their country.  Adverse event data were collected for each of these subjects 
until they transitioned to lenvatinib treatment outside the study.


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PHASE
Prerandomization / Pretreatment
Randomization / Treatment
PERIOD
Screening
Baseline
Treatment
Off-treatment
Follow-Up
VISIT
1
2
3 to 18 etc
98
99
Lenvatinib 24 mg QD
PD
Survival
Randomization
(1:1 ratio)
and
PFS2
Lenvatinib 18 mg QD
PD
Day(s)
-28 to -2
-1
1 to 28 per cycle
Figure 1
Study Design for Study E7080-G000-211 (as of Protocol Amendment 03)
PD = progressive disease, PFS2 = progression-free survival after next line of anticancer treatment, QD = once daily.


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9.1.1
Prerandomization Phase
The Prerandomization Phase will last no longer than 28 days and will include a Screening 
Period to establish protocol eligibility and a Baseline Period to confirm eligibility and 
establish disease characteristics prior to randomization and treatment.  
9.1.1.1
Screening Period
Screening will occur between Day -28 and Day -2.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility according to the inclusion and 
exclusion criteria listed in Sections 9.3.1 and 9.3.2.  Informed consent will be obtained after 
the study has been fully explained to each subject and before the conduct of any screening 
procedures or assessments.  Procedures to be followed when obtaining informed consent are 
detailed in Section 5.3.  Subjects must have a histologically or cytologically confirmed 
diagnosis of papillary or follicular RR-DTC that meets the criteria for being 131I-refractory, 
and must have radiographic evidence of disease progression within the prior 12 months as 
defined in the inclusion criteria.  The Screening Disposition Case Report Form (CRF) page 
must be completed to indicate whether the subject is eligible to participate in the study and to 
provide reasons for screen failure, if applicable.
9.1.1.2
Baseline Period
The purpose of the Baseline Period is to establish disease characteristics prior to 
randomization to treatment, and to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria. Results of baseline assessments must be obtained and reviewed 
by the investigator prior to the first dose of study drug (Cycle 1 Day 1 [C1D1]) to confirm 
eligibility.  Baseline assessments may be performed on Day -1 or on C1D1 prior to treatment.
Subjects who continue to meet the criteria for inclusion/exclusion (Sections 9.3.1 and 9.3.2) 
will begin the Randomization/Treatment Phase.  
9.1.2
Randomization Phase
The Randomization Phase will consist of a Treatment Period and a Follow-up Period.  It 
will begin at the time of randomization of the first subject and will consist of 28-day blinded 
study treatment cycles.  The data cutoff for the primary analysis will occur at the end of the 
Randomization Phase, which is defined as when the last subject enrolled completes the Week
24 tumor assessments or discontinues study treatment before Week 24. Subjects on 
treatment at this time will remain on blinded investigational product until the primary 
analysis has been completed. After study unblinding, subjects will continue to receive 
investigational product until they complete the Off-treatment visit prior to their transition to 
commercial lenvatinib or an access program. The last subject last visit for the End of Study
will be the date of the Off-treatment visit for the last subject.
Subjects will be randomly assigned to treatment with 1 of 2 blinded dosages of lenvatinib in 
a 1:1 ratio. 


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The Treatment Period for an individual subject will begin at the time of randomization and 
will end upon completion of the Off-treatment Visit, which will occur within 30 days after 
the final administration of study drug.  Serious adverse events (SAEs) must be captured for 
28 days after the last dose of study drug.  Subjects will undergo safety and efficacy 
assessments as defined in the Schedule of Procedures and Assessments (Table 7) and will 
continue to receive study treatment until disease progression. The Follow-up Period will 
begin immediately after the Off-treatment Visit and will continue as long as the subject is 
alive unless the subject withdraws consent, or until the data cutoff for primary analysis.  
Subjects who discontinue study drug treatment prior to disease progression will continue to 
be followed according to the Schedule of Procedures and Assessments until documentation 
of disease progression or initiation of another anticancer treatment.  Subjects will be followed 
every 12 weeks ± 1 week for survival, PFS2 and all anticancer treatments received (unless 
this information is not allowed to be provided due to confidentiality) will be recorded until 
the data cutoff for primary analysis.  Subjects who were enrolled prior to implementation of 
Amendment 03 and who discontinued lenvatinib treatment due to progressive disease or due 
to an AE were followed for PFS2 and survival until the date that the last subject transitioned 
to lenvatinib treatment outside the study (the data cutoff date for this group of 41 subjects).  
9.2
Discussion of Study Design, Including Choice of Control Groups
The starting doses of 24 mg, 20 mg, and 14 mg were originally chosen because analysis of 
data from previous studies (Studies 201 and 303) showed that doses between 14 and 20 mg
provide exposures that overlap at least approximately two-thirds of that of the 24-mg dose.  
Subsequently, simulation models co-developed with the FDA showed that the median 
ORR24wk for the 14-mg dose without up-titration would likely be decreased by more than 
50% compared with the 24-mg dose and was, therefore, not acceptable from an efficacy 
standpoint.  Consequently, an alternative lower starting dose of 18 mg was selected.
Objective response rate at 24 weeks (ORR24wk) is the primary endpoint, since 57.5% of 
subjects had an objective response at 24 weeks and an ad-hoc analysis of Study 303 
demonstrated that ORR predicted PFS and OS benefit.
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg, 
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  Blinding to treatment 
will be used to reduce potential bias during data collection and evaluation of endpoints, 
particularly the safety endpoints.
9.3
Selection of Study Population
Prior to Amendment 03, approximately 300 subjects were planned to be screened to provide 
210 randomized subjects (70 per arm).  A total of 56 subjects were screened and of these,
41 subjects were randomized and treated. Efficacy and safety data for these 41 subjects 
enrolled from study start until they transitioned to lenvatinib treatment outside the study will 
be reported separately.


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As of Amendment 03.1, an additional 180 subjects will be screened to provide 
152 randomized subjects (76 per arm).  Subjects who meet all of the inclusion criteria and 
none of the exclusion criteria will be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Subjects must have histologically or cytologically confirmed diagnosis of one of the 
following differentiated thyroid cancer (DTC) subtypes:
a.
Papillary thyroid cancer (PTC)
◦
Follicular variant
◦
Variants (including but not limited to tall cell, columnar cell, cribriform-morular, 
solid, oxyphil, Warthin’s-like, trabecular, tumor with nodular fasciitis-like stroma, 
Hürthle cell variant of papillary carcinoma, poorly differentiated)
b.
Follicular thyroid cancer (FTC)
◦
Hürthle cell
◦
Clear cell
◦
Insular
2. Measurable disease meeting the following criteria and confirmed by central radiographic 
review:
a.
At least 1 lesion of ≥1.0 cm in the longest diameter for a non-lymph node or ≥1.5 cm 
in the short-axis diameter for a lymph node which is serially measurable according to 
RECIST 1.1 using computed tomography/magnetic resonance imaging (CT/MRI).  If 
there is only 1 target lesion and it is a non-lymph node, it should have a longest 
diameter of ≥1.5 cm.
b.
Lesions that have had external beam radiotherapy or locoregional therapies such as 
radiofrequency ablation must show evidence of progressive disease based on 
RECIST 1.1 to be deemed a target lesion.
3. Subjects must show evidence of disease progression within 12 months (an additional 
month will be allowed to accommodate actual dates of performance of screening scans, 
ie, within ≤13 months) prior to signing informed consent, according to RECIST 1.1 
assessed and confirmed by central radiographic review of CT and/or MRI scans.
4. Subjects must be 131I-refractory/resistant as defined by at least one of the following:
a.
One or more measurable lesions that do not demonstrate iodine uptake on any 
radioiodine scan.
b.
One or more measurable lesions that have progressed according to RECIST 1.1 
within 12 months (an additional month will be allowed to accommodate actual dates 
of performance of screening scans, ie, within ≤13 months) after 131I therapy, despite 
demonstration of radioiodine avidity at the time of that treatment by pre- or 
posttreatment scanning.  These subjects must not be eligible for possible curative 
surgery.


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c.
Cumulative activity of 131I of > 600 mCi or 22 gigabecquerels (GBq), with the last 
dose administered at least 6 months prior to study entry.
5. Subjects with known brain metastases who have completed whole brain radiotherapy, 
stereotactic radiosurgery or complete surgical resection, will be eligible if they have 
remained clinically stable, asymptomatic, and off steroids for one month.
6. Subjects must be receiving thyroxine suppression therapy and TSH should not be 
elevated (TSH should be ≤5.50 mcIU /mL).  When tolerated by the subject, thyroxine 
dose should be changed to achieve TSH suppression (TSH <0.50 mcIU/mL) and this 
dose may be changed concurrently upon starting study drug treatment.
7. All chemotherapy or radiation related toxicities must have resolved to Grade <2 severity 
per Common Terminology Criteria for Adverse Events (CTCAE v4.03), except alopecia
and infertility.  
8. Subjects must have an ECOG PS of 0, 1, or 2.
9. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive 
medications within 1 week prior to Cycle 1/Day 1.
10. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the 
Cockcroft and Gault formula.
11. Adequate bone marrow function:
a.
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 × 103/μL)
b.
Platelets ≥100,000/mm3 (≥100 × 109/L)
c.
Hemoglobin ≥9.0 g/dL
12. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5 (except for subjects on warfarin therapy where INR may be ≥2 and <3).
13. Adequate liver function:
a.
Bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia or Gilbert’s syndrome.
b. Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase 
(AST) ≤3 × ULN (≤5 × ULN if subject has liver metastases).  If alkaline phosphatase is 
>3 × ULN (in absence of liver metastases) or >5 × ULN (in presence of liver metastases) 
AND the subject also is known to have bone metastases, the liver-specific alkaline 
phosphatase must be separated from the total and used to assess the liver function instead 
of total alkaline phosphatase.
14. Males or females age ≥18 years at the time of informed consent.
15. Females must not be lactating or pregnant at Screening or Baseline (as documented by a 
negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 
25 IU/L or equivalent units of ß-hCG. A separate baseline assessment is required if a 
negative screening pregnancy test was obtained more than 72 hours before the first dose 
of study drug.
16. All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group and without other known or suspected cause) or have been sterilized surgically (ie,


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bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at 
least 1 month before dosing). 
17. Females of childbearing potential should avoid becoming pregnant and use highly 
effective contraception while on treatment with lenvatinib and for at least 1 month after 
finishing treatment.  Females of childbearing potential must not have had unprotected 
sexual intercourse within 30 days before study entry and must agree to use a highly 
effective method of contraception (eg, total abstinence, an intrauterine device, a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) throughout the entire study period and for 30 days after study 
drug discontinuation.  Females who are using hormonal contraceptives must have been 
on a stable dose of the same hormonal contraceptive product for at least 4 weeks before 
dosing and must continue to use the same contraceptive during the study and for 30 days 
after study drug discontinuation.  Women using oral hormonal contraceptives should add 
a barrier method.
18. Subject must voluntarily agree to provide written informed consent.
19. Subject must be willing and able to comply with all aspects of the protocol.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study.
1. Anaplastic or medullary carcinoma of the thyroid.
2. Diagnosed with meningeal carcinomatosis.
3. Two or more prior VEGF/VEGFR-targeted therapies or any ongoing treatment for 
RR-DTC other than TSH-suppressive thyroid hormone therapy.
4. Prior treatment with lenvatinib.
5. Subjects who have received any anticancer treatment within 21 days or any 
investigational agent within 30 days (or 5 half-lives) prior to the first dose of study drug
and should have recovered from any toxicity related to previous anticancer treatment.  
This does not apply to the use of TSH-suppressive thyroid hormone therapy.
6. Major surgery (eg, laparotomy, thoracotomy or joint replacement) within 3 weeks prior to 
randomization or elective surgery scheduled to be performed during the study.
7. Subjects having >1+ proteinuria on urine dipstick testing will undergo 24-hour urine 
collection for quantitative assessment of proteinuria.  Subjects with urine protein 
≥1 g/24 h will be ineligible.
8. Gastrointestinal malabsorption or any other condition that in the opinion of the 
investigator might affect the absorption of study drug.
9. Significant cardiovascular impairment:  history of congestive heart failure greater than 
New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction, or 
cerebral vascular accident within 6 months of the first dose of study drug, or cardiac 
arrhythmia associated with hemodynamic instability.
10. Prolongation of corrected QT interval (QTc) interval to >480 ms as demonstrated by a 
repeated electrocardiogram (ECG) or a clinically significant ECG abnormality, including 


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a marked prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval 
>500 ms).
11. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the 
first dose of study drug.
12. Active infection (any infection requiring treatment).
13. Active malignancy (except for DTC or definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix) within the past
24 months.
14. Bleeding or thrombotic disorders.
15. Known intolerance to study drug (or any of the excipients).
16. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study.
17. Females who are pregnant or breastfeeding.
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue study treatment or withdraw the subject from the study at 
any time for safety or administrative reasons.  The subject may decide to discontinue study 
treatment or withdraw from the study at any time for any reason.  The reason for 
discontinuation will be documented.  If a subject discontinues study treatment, the subject 
will enter the Follow-up Period and complete protocol-specified off-treatment visits, 
procedures, PFS2 and survival follow-up unless the subject withdraws consent.  The 
investigator should confirm whether a subject will withdraw from study treatment but agree 
to continue protocol-specified, off-treatment study visits, procedures, and PFS2 and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, the 
date will be documented in the source documents.  The Discontinuation From Treatment 
CRF page will be completed indicating the primary reason for discontinuation and all other 
reason(s) contributing to the subject’s discontinuation from treatment.  In addition, the date 
of last dose of study drug will be recorded on the Study Drug Dosing CRF page.
During the Follow-up Period, subjects who have discontinued study treatment without 
disease progression should continue to have tumor assessments performed every 8 weeks
until disease progression is documented, another anticancer therapy is initiated, or the data 
cutoff for primary analysis.
All subjects will be followed for survival until death, except where a subject withdraws 
consent or until the data cutoff for the primary analysis.
9.4
Treatments
9.4.1
Treatments Administered
Subjects randomized prior to Amendment 03 received 1 of the following 3 starting doses of 
lenvatinib: 24 mg/day, 20 mg/day, or 14 mg/day.  


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Beginning with Amendment 03, subjects will receive either 24 mg or 18 mg of lenvatinib
orally QD.  Study subjects, investigator site personnel, and the sponsor will be blinded to 
treatment assignment.  Study subjects will be administered study drug in the form of two 
10-mg capsules and two 4-mg capsules containing either lenvatinib or placebo (total of 
4 capsules) to be taken with water each morning.  Study drug is to be taken at approximately 
the same time each morning and may be taken in a fasting state or following a meal.  
Doses will be packaged in blister cards totaling 24, 20, 18, 14, 10, 8, or 4 mg, as shown in 
Table 3.
Table 3
Study Treatments
Capsule Allocation
Total Dose (QD)
10 mg Lenvatinib
10 mg Placebo
4 mg Lenvatinib
4 mg Placebo
24 mg
2
0
1
1
20 mg
2
0
0
2
18 mg
1
1
2
0
14 mg
1
1
1
1
10 mg
1
1
0
2
8 mg
0
2
2
0
4 mg
0
2
1
1
QD = once daily.
Each carton containing 2 blister cards will contain 16 doses (2 weeks plus 2 days allowing 
for a 2-day visit window).  The investigator will have discretion to dispense up to 2 cartons
simultaneously to a subject if it is appropriate for the subject to not return to clinic for 
28 days.
9.4.2
Criteria for Interruption of Treatment, Dose Reduction and Resumption of 
Treatment
Dose reduction and interruptions for subjects who experience toxicity will be made according 
to the guidelines provided in Table 4.  Dose reductions will occur in succession based on the 
subject’s previous dose level (24, 20, 14, 10, and 8 mg QD or 18, 14, 10, 8, and 4 mg QD, 
respectively).  Any dose reduction beyond 3 levels must be discussed with the sponsor.  Once 
the dose has been reduced, it may not be increased at a later date.  
Table 4
Study Treatment Dose Reduction and Interruption Instructions
Treatment-Related 
Toxicitya,b
including hepatic injury 
and thromboembolic 
events
Management
Dose Adjustment


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9.4.2.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling.
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mmHg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before Cycle 1/Day 1.  Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.
Regular assessment of BP should be conducted as detailed in Schedule of Procedures/ 
Assessments (Table 7).  Hypertension will be graded using CTCAE v4.03, based on BP 
measurements only (and not on the number of antihypertensive medications).
If the subject’s initial BP measurement is elevated (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg), the BP measurement should be repeated at least 5 minutes later.  The mean 
value of 2 measurements at least 5 minutes apart is defined as one BP assessment.  If the BP 
assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is 
elevated (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg), a confirmatory BP 
assessment should be obtained at least 30 minutes later by performing 2 measurements at 
least 5 minutes apart (to yield a mean value).
Grade 1 or Tolerable Grade 2
Continue treatment
No change (continue at Level 0)
Intolerable Grade 2c,d or Grade 3
First occurrence
Interrupt until resolved to 
Grade 0-1 or baseline
Dose level -1 once a day (20 or 14 mg QD)
(1-level reduction from previous)
Second occurrence 
(same toxicity or new 
toxicity)
Interrupt until resolved to 
Grade 0-1 or baseline
Dose level -2 once a day (14 or 10 mg QD)
(1-level reduction from previous)
Third occurrence (same 
toxicity or new 
toxicity)
Interrupt until resolved to 
Grade 0-1 or baseline
Dose level -3 once a day (10 or 8 mg QD)
(1-level reduction from previous)
Fourth occurrence 
(same toxicity or new 
toxicity)
Interrupt until resolved to 
Grade 0-1 or baseline
Stop Treatment or discuss possible dose level -4 with 
sponsor (8 or 4 mg QD)
(1-level reduction from previous)
Grade 4e:  Discontinue Study Treatment
Note:  For grading see Common Terminology Criteria for Adverse Events version 4.03.  Collect all grades of 
adverse events, decreasing and increasing grade.
QD = once daily.
a:  A delay of study treatment for more than 28 days (due to treatment-related toxicities) will require a 
discussion with the sponsor before treatment can be resumed.
b:  Initiate optimal medical management for nausea, vomiting, and/or diarrhea prior to any study treatment, 
interruption, or dose reduction.
c:  Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d:  Obese subjects with weight loss do not need to return to baseline weight or Grade 1 weight loss to restart 
lenvatinib.  There should be no weight loss for at least 1 week, and subjects should be started at the lower 
dose. Normal body mass index should be used as a reference for future dose reductions.
e:  Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.


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Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop 
a hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mmHg, significant risk factors for cardiac disease, 
intracerebral hemorrhage, or other significant co-morbidities).  Once the subject has been on 
the same antihypertensive medications for at least 48 hours and the BP is controlled, 
lenvatinib should be resumed as described below
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP 
monitored on Day 15 (or more frequently as clinically indicated) until systolic BP has been 
≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment cycles.  If a 
repeat event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must 
resume the Day 15 evaluation until systolic BP has been ≤150 mmHg and diastolic BP has 
been ≤95 mmHg for 2 consecutive treatment cycles.
The following guidelines should be followed for the management of systolic BP ≥140 mmHg 
up to <160 mmHg or diastolic BP ≥90 mmHg up to <100 mmHg confirmed on repeat 
assessment after at least 30 minutes:

Continue lenvatinib and initiate antihypertensive therapy, if not already receiving.

Continue lenvatinib and increase the dose of the current antihypertensive therapy or 
initiate additional antihypertensive therapy.
The following guidelines should be followed for the management of systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg confirmed on repeat assessment after at least 30 minutes:

Continue study drug and institute antihypertensive therapy for subjects not already 
receiving this.

For those subjects already on antihypertensive medication, the dose of the current agent 
may be increased, if appropriate, or one or more agents of a different class of 
antihypertensive should be added.

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then study drug administration should be interrupted and 
restarted at one dose level reduction only when systolic BP ≤150 mmHg and diastolic 
BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then study drug administration should be interrupted and restarted 
at an additional dose reduction only when systolic BP ≤150 mmHg and diastolic BP 
≤95 mmHg and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours. 
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then study drug administration should be interrupted and restarted 


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at a third dose reduction dose only when systolic BP ≤150 mmHg and diastolic BP 
≤95 mmHg and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours.
-
Additional dose reduction should be discussed with the sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):

Institute appropriate medical management

Discontinue study drug
9.4.2.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments (Table 7).  Guidelines for assessment and management of 
proteinuria:
1.
Grading of Proteinuria:
-
Grading according to CTCAE v4.03 will be based on the 24-hour urinary protein 
result.  Management of lenvatinib administration will be based on the grade of 
proteinuria according to instructions contained in Table 4,“Study Treatment Dose 
Reduction and Interruption Instructions”.
2. Detection and Confirmation
-
Perform urine dipstick testing per the Schedule of Procedures/ Assessments
(Table 7).
-
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) 
or an immediate spot urine protein-to-creatinine ratio (UPCR) test is required in the 
following situations:
◦
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study 
drug
◦
A subsequent increase in severity of urine dipstick proteinuria occurring on the 
same lenvatinib dose level
◦
When there has been a lenvatinib dose reduction and at the new dose level the 
urine protein dipstick result is ≥2+
-
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) 
to verify the grade of proteinuria is required when an immediate spot UPCR is ≥2.4.
3.
Monitoring
-
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on 
Day 15 of each cycle (or more frequently as clinically indicated) until the results have 
been 1+ or negative for 2 consecutive treatment cycles.
9.4.2.3
Management of Hepatotoxicity
Liver function tests (ALT, AST, bilirubin levels) should be monitored at baseline, every 
2 weeks for the first 2 months and monthly thereafter, and as clinically indicated (see 
Schedule of Procedures and Assessments [Table 7]). If signs/symptoms indicating liver 


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injury occur, instructions contained in Table 4, Study Treatment Dose Reduction and 
Interruption Instructions should be followed. Appropriate supportive care should be 
provided together with close monitoring. If hepatic failure occurs the study drug must be 
discontinued.
9.4.2.4
Management of Thromboembolic Events
Subjects should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, which include acute onset of shortness of breath, dyspnea, chest 
pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including 
lower-extremity swelling, and warmth to touch or tenderness. In case any of these symptoms 
appear, subjects should be instructed to report such symptoms promptly to the treating 
physician.  If a thromboembolic event is confirmed, instructions contained in Table 4, Study 
Treatment Dose Reduction and Interruption Instructions should be followed. Appropriate 
supportive care should be provided together with close monitoring. If a subject experiences 
life-threatening (Grade 4) thromboembolic reactions, including pulmonary embolism, the 
study drug must be discontinued.
9.4.2.5
Management of Posterior Reversible Encephalopathy Syndrome/ Reversible 
Posterior Leukoencephalopathy Syndrome
In clinical studies with lenvatinib, events of PRES/RPLS were reported in less than 1% of 
lenvatinib treated subjects.  PRES/RPLS is a neurological disorder that can present with 
headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or 
neurological disturbances.  Mild to severe hypertension may be present.  An MRI is 
necessary to confirm the diagnosis of PRES/RPLS.  Appropriate measures should be taken to 
control BP.  In subjects with signs or symptoms of PRES, dose interruptions, reductions, or 
discontinuation may be required per instructions included in Table 4.
9.4.2.6
Management of Hypocalcemia
Serum calcium should be monitored monthly per the Schedule of Procedures and 
Assessments (Table 7).  Corrected serum calcium should be used to assess the grade of 
hypocalcemia per CTCAE v 4.03, using the following formula: 
Corrected calcium (mmol/L) = measured total Ca (mmol/L) + 0.02 × (40-serum albumin 
[g/L]) 
The formula is not applicable when serum albumin concentration is normal (≥40 g/L); in 
such situations, the total (uncorrected) serum calcium should be used. 
Hypocalcemia should be treated per institutional guidelines (eg, using, as appropriate,
calcium, magnesium, and Vitamin D supplementation) until resolution.
9.4.2.7
Chemical Name, Structural Formula of Lenvatinib

Test drug code:  E7080

Generic name:  lenvatinib


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
Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-
6-carboxamide methanesulfonate

Molecular formula:  C21H19ClN4O4•CH3SO3H

Molecular weight: 522.96

Structural formula:
9.4.2.8
Comparator Drug
Not applicable.
9.4.2.9
Labeling for Study Drug
Lenvatinib and identical placebo will be labeled in accordance with text that is in full 
regulatory compliance with each participating country and is translated into the required 
language(s) for each of those countries.
The following information will be provided (but not limited to):

Name and address of the sponsor

Drug identifier

Lot number/batch number

Unique package number

Storage conditions, expiration date if necessary
9.4.2.10
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator (if regionally required, the head of 
the medical institution) or designee is responsible for ensuring that the temperature is 
monitored throughout the total duration of the trial and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.


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9.4.3
Method of Assigning Subjects to Treatment Groups
Subjects will be randomized in a 1:1 ratio to receive lenvatinib 24 mg or 18 mg QD based on 
a computer-generated randomization scheme that will be reviewed and approved by an 
independent statistician.  Subjects will be stratified by age (≤65 years or >65 years) and 
ECOG PS of 0 versus 1 or 2.  
The randomization scheme and identification for each subject will be included in the final 
CSR for this study.  
Randomization will be performed centrally by an interactive voice and web response system 
(IxRS).  The IxRS or clinical supply vendor will generate the randomized blister card 
identification numbers.  At enrollment (and after successful completion of Visit 1), the 
investigator or designee will call/log into the IxRS to register the subject information.  At 
randomization (Visit 2), the IxRS will assign each subject a unique 6-digit randomization 
number.  To dispense every subsequent carton (or 2 cartons), the investigator or a designee 
will call/log into the IxRS to obtain dispensing instructions and register the subject’s visit and 
whether the same or a reduced dose should be dispensed.  
9.4.3.1
Selection of Doses in the Study
Two dosing regimens (24 mg and 18 mg) will be evaluated in this study beginning with 
Amendment 03. See Section 7.3 for information on dose selection and timing of dose for 
each subject.
Study drug capsules are to be taken orally once a day continuously at approximately the same 
time in the morning without regard to food intake from Cycle 1/Day 1 onward.  A cycle is 
considered 28 days. If a subject misses a dose, it may be taken within the 12 hours following 
the usual time of the morning dose.  If more than 12 hours have elapsed from the time of the 
usual daily dose, study drug should be taken the next day at the usual time in the morning.  In 
the event that a subject vomits after study drug administration, the subject should not take 
another dose until the next scheduled dose.
9.4.4
Blinding
Study subjects, investigator site personnel, and the sponsor will be blinded to treatment 
assignment.  Study treatments will be assigned according to the IxRS, an interactive voice 
and web response system described in Section 9.4.3.  The investigators will communicate 
with this system to assign the lenvatinib doses at randomization and at all visits where doses 
are dispensed throughout the study.  Randomization data will be kept strictly confidential, 
filed securely by an appropriate group with the sponsor or contract research organization 
(CRO) and accessible only to authorized persons (eg, Eisai Global Safety) until the time of 
unblinding, per standard operating procedure (SOP).
A master list of all treatments and the subject numbers associated with them will be 
maintained in a sealed envelope by the clinical supply vendor, the IxRS vendor, and the 
sponsor.  In the event that emergency conditions require knowledge of the study treatment 


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given, the blind may be broken via the code breaker facility within the IxRS.  Emergency 
procedures for revealing drug codes are given in Section 9.5.3.5.  If possible, before breaking 
the blind, the investigator should consult with the sponsor to ascertain the necessity of 
breaking the code.
If a subject is discontinued from the study for PD or toxicity and the treating physician is 
considering continuing treatment with lenvatinib, the PI may request the subject’s last 
dispensed dose level.  The PI will request this from the IxRS after entering confirmation that 
discontinuation is because of PD or toxicity.  This information will be provided by the PI to 
the treating medical professional.  This information should only be shared with others on the 
study treatment team on a need-to-know basis as required for patient care.
When the study is completed the PI may request the subject’s last dispensed dose level and 
provide to the treating physician.  
9.4.5
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 28 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 28 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with lenvatinib 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.
Any additional procedural or patient-specific particularities should be discussed by the 
investigator and the sponsor.
Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and anticoagulants 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, 


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institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell (RBC) counts.
If concomitant medication/therapy is administered for an AE, investigators will record that 
AE on the Adverse Events CRF.
9.4.5.1
Drug-Drug Interactions
Based on a population PK analysis, CYP3A4 inhibitors and inducers were found to have 
statistically significant but small effects on the apparent clearance (CL/F) of lenvatinib 
(CPMS-E7080-007R-v1).  CYP3A4 substrates known to have a narrow therapeutic index 
(eg, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids 
(ergotamine, dihydroergotamine) should be administered with caution in subjects receiving 
lenvatinib.
The population PK analysis also indicated that agents that raise gastric pH (eg, H2-blockers, 
proton pump inhibitors, antacids) do not have a significant effect on the absorption and 
bioavailability of lenvatinib (CPMS-E7080-007R-v1).
9.4.5.2
Prohibited Concomitant Therapies and Drugs
Any treatment that is considered necessary for the subject’s health and that is not expected to 
interfere with the evaluation of thyroid cancer may be administered during the study.
Subjects should not receive other antitumor therapies while on study.  If subjects receive 
additional antitumor therapies, such as chemotherapy, hormone therapy (except for thyroid 
hormone suppressive therapy and when given for uses other than thyroid cancer, eg, as an 
appetite stimulant), palliative or curative radiotherapy, or cancer immunotherapy, this will be 
judged to represent evidence of disease progression, and continuation of study drug and 
further participation in the study must be discussed and agreed upon with the sponsor.  If 
subjects discontinue, they should complete all off-treatment assessments and continue to be 
followed for survival in the Follow-up Period.
9.4.6
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study, including the 
follow-up period.  The CRAs will review treatment compliance during site visits and at the 
completion of the study.
9.4.7
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 the 
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
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572, where applicable

Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 
1572, where applicable

A signed and dated curriculum vitae  of the PI including a copy of the PI’s current 
medical license (required in the United States) or medical registration number on the 
curriculum vitae

A signed and dated clinical studies agreement
The investigator and the study staff (if regionally required, the head of the medical institution 
or the designated pharmacist) will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 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 Health 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 


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to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography and Baseline Assessments 
Subject demography and baseline characteristics will be collected during the 
Prerandomization Phase.  Demography information includes date of birth (or age), sex, and 
race/ethnicity (recorded in accordance with prevailing regulations). Baseline characteristics 
will include ECOG PS and NYHA cardiac disease classification (see Appendix 3 and 
Appendix 5, respectively).
Medical and surgical histories will be obtained during the Prerandomization Phase, along 
with a record of prior and concomitant medications.
Physical examinations (comprehensive or symptom-directed) will be performed as specified 
in the Schedule of Procedures and Assessments (Table 7).  A comprehensive physical 
examination will include evaluations of the head, eyes, ears, nose, throat, neck, chest 
(including heart and lungs), abdomen, limbs, skin, and a complete neurological examination.  
A urogenital examination will only be required in the presence of clinical symptoms related 
to this region.  Documentation of the physical examination will be included in the source 
documentation at the investigational site.  Significant findings prior to the start of study drug 
will be recorded on the Medical History and Current Medical Conditions CRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events CRF.
Subjects must have measurable disease according to RECIST 1.1 as defined in Inclusion 
Criterion no. 2 (Appendix 2).  Subjects must also fulfill the medical and physical 
characteristics identified in the inclusion criteria and not otherwise meet any of the exclusion 
criteria.


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9.5.1.2
Efficacy Assessments
9.5.1.2.1
PRIMARY EFFICACY ASSESSMENT
The primary efficacy endpoint is ORR24wk as assessed using RECIST 1.1.  ORR24wk is 
defined as the proportion of subjects with a best overall response (BOR) of CR or PR at the 
Week 24 time point or earlier.  
9.5.1.2.2
SECONDARY EFFICACY ASSESSMENTS
The secondary efficacy endpoint is PFS defined as the time from the date of randomization to 
the date of first documentation of disease progression, or date of death, whichever occurs 
first. PFS censoring rules will be defined in the statistical analysis plan (SAP).  
The date of the first subsequent objective disease progression on an anticancer therapy after 
objective progression on lenvatinib treatment will be collected (unless this information is not 
allowed to be provided due to confidentiality) and PFS2 will be calculated. 
PFS2 is defined as the time from randomization to second objective PD (occurring during 
treatment with next line of anticancer therapy) or death from any cause, whichever occurs 
first.  Censoring rules for PFS2 will be defined in the SAP.
9.5.1.2.3
EXPLORATORY EFFICACY ASSESSMENTS
Exploratory efficacy endpoints are duration of response, disease control rate (DCR), clinical 
benefit rate (CBR), OS, and duration of clinical benefit.  Duration of response is defined as 
the time from the initial achievement of a response to the date of first documentation of 
disease progression, or date of death, whichever occurs first.  Overall survival will be 
measured from the date of randomization until date of death from any cause.  
Disease control rate is defined as the proportion of subjects who have a BOR of CR, PR, or 
SD. A BOR of SD must be achieved at least 7 weeks after randomization.  Clinical benefit 
rate is defined as the proportion of subjects who have a BOR of CR, PR, or durable SD 
(duration of SD ≥23 weeks after randomization).  
9.5.1.2.4
TUMOR ASSESSMENTS
Tumor assessments will be performed using RECIST 1.1.  Investigator-determined response 
assessments will be performed at each assessment time point and entered onto the CRF.  
Baseline tumor imaging scans will be sent to an imaging core laboratory designated by the 
sponsor for prospective eligibility confirmation. All postbaseline scans will be archived by 
the sites and available for potential future review.  Tumor assessments will be carried out 
following the guidelines provided by the imaging core laboratory.  Historical scans (within 
prior 12 months) that do not follow the guidelines completely may be used to demonstrate 
eligibility, as long as they meet minimum standards as separately defined by the imaging 
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Tumor assessments (CT chest, and CT or MRI neck, abdomen, pelvis, and other known or 
suspected sites of disease) will be performed during the Prerandomization Phase and then 
every 8 weeks (within the 8th week) from the date of randomization during treatment cycles 
in the Randomization Phase.  The same imaging modality and image-acquisition protocol 
(including use or nonuse of contrast) should be used consistently across all time points.  
A bone scan (99m- technetium-based scintigraphy, whole-body bone MRI, or 18F-sodium 
fluoride positron emission tomography [NaF PET]) will be performed during the 
Prerandomization Phase to establish a baseline (a historical bone scan performed within 
6 weeks prior to randomization is acceptable), every 24 weeks, and as clinically indicated. 
Lesions identified on bone scans should be followed with cross-sectional imaging.  A brain 
scan will be performed at screening, and as clinically indicated.  For subjects with a history 
of protocol-eligible treated brain metastases, a brain scan will be required at all tumor 
assessment time points (eg, every 8 weeks). 
Subjects going off treatment without disease progression in the Randomization Phase will 
continue to undergo tumor assessments every 8 weeks until disease progression is
documented, another anticancer therapy is initiated, or the data cutoff for primary analysis.
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
9.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
Sparse PK samples will be collected from all subjects and will be analyzed using a
population approach.  Approximately 9 samples per subject will be obtained.  The actual time 
and date of PK blood collection as well as time of drug administration will be recorded on 
the appropriate page of the CRF.  
On Cycle 1/Day 1, subjects will be instructed not to take the Cycle 1/Day 8 dose of 
lenvatinib prior to arriving at the study site.  Similar instructions will be given to the subjects 
regarding the Cycle 1/Day 15, Cycle 1/Day 22 (if the subject will be coming to the study site 
for this visit), and Cycle 2/Day 1 doses. The Cycle 1/Day 8, Cycle 1/Day 15, Cycle 1/Day 22 
(optional) and Cycle 2/Day 1 doses of lenvatinib will be administered at the study site at 
approximately the same time of day as the Cycle 1/Day 1 dose was administered in order to 
accommodate PK sample collection timing.  The actual time of the last food intake will be 
recorded in the CRF before each predose sample.  Instructions for the collection, handling, 
and shipping procedures of PK samples will be provided in the Laboratory Manual.  Plasma 
concentrations of lenvatinib will be quantified by liquid chromatography/mass 
spectrometry/mass spectrometry (LC/MS/MS) methodology using a previously validated 
assay.
Table 5
Lenvatinib Pharmacokinetic Sampling Time Points
Time Point
Sample Number
Time (h)
Cycle 1/Day 1
1
0.5-4 h postdose
2
6-10 h postdose
Cycle 1/Day 8
3
Predose 
Cycle 1/Day 15a
4
Predose 
5
0.5-4 h postdose


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6
6-10 h postdose
Cycle 1/Day 22 (optional)b
7
Predose
Cycle 2/Day 1a
8
Predose 
9
2-12 h postdose
h = hour(s).
a
If dose interruption is necessary in these time points, only predose sample should be collected.
b. To be obtained in conjunction with biomarker sample if subject is willing to come to clinic for optional 
visit.
9.5.1.3.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS
Samples will be collected at protocol-specified time points as indicated in the Schedule of 
Procedures and Assessments (Table 7) and may undergo enzyme-linked immunosorbent 
assay (ELISA), multiplex bead based immunoassay and/or other appropriate analysis 
procedures to explore thyroglobulin, antithyroglobulin autoantibodies (anti-Tg), and other 
serum biomarkers (including VEGF, Ang-2, sTie-2, and FGF23).
A blood sample will be collected for potential pharmacogenomic analysis from all consented 
subjects except where prohibited by regional or local laws.  Variation in lenvatinib exposure 
or the occurrence of AEs observed in the study population may be evaluated by correlating 
single–nucleotide polymorphisms with PK, safety, or pharmacodynamic data.
Data obtained will be used for research purposes, to assist in developing safer and more 
effective treatments and will not be used to change the diagnosis of the subject or alter the 
therapy of the subject.  The DNA will not be used to determine or predict risks for diseases 
that an individual subject does not currently have.  Any sample or derivatives (DNA, RNA, 
and protein) may be stored for up to 15 years to assist in any scientific research questions 
related to lenvatinib and cancer.
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.
9.5.1.4
Safety Assessments
The rate of TEAEs with CTCAE grades of 3 or higher within 24 weeks after randomization 
(as of the Week 24 time point) is a primary study endpoint.  Determination of the overall 
safety profile and tolerability of lenvatinib, the time to treatment discontinuation due to an 
AE, number of dose reductions, and the time to first dose reduction are secondary study 
endpoints.  As part of the overall safety and tolerability assessment, the rate of TEAEs of 
Grade 2 that are intolerable and lead to dose reduction, dose interruption, or drug 
discontinuation will be determined (Section 7.2).
Safety assessments will consist of monitoring and recording all AEs, including all 
CTCAE v4.03 grades (for increasing severity), and SAEs; regular laboratory evaluation for 
hematology, blood chemistry, and urine values, periodic measurement of vital signs, ECGs; 
and the performance of physical examinations as detailed in Table 7. An ECG or multiple-
gated acquisition (MUGA) scan including left ventricular ejection fraction (LVEF) will be 
performed at screening and as clinically indicated.


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A pregnancy test will be administered to women of childbearing potential at the Screening
Visit, Baseline Visit, at the beginning of Cycles 2 and 3, and at the time the subject is 
off-study.
Progression of a subject’s thyroid cancer and signs and symptoms clearly related to disease 
progression should not be captured as an AE.  Disease progression is a study endpoint and 
should be captured in the CRF as per the guidelines for reporting disease progression.
9.5.1.4.1
ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal 
relationship with the medicinal product.  For this study, the study drug is lenvatinib 
administered at starting doses of 24 mg and 18 mg given QD.
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product

Any new disease or exacerbation of an existing disease. However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, whether prescribed in the 
protocol or not.
A laboratory result should be considered by the investigator to be an AE 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 an AE with regard to the subject’s medical profile

Increases in severity compared to baseline by 2 or more CTCAE grades (see Appendix 6
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 


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investigator to determine if it is of clinical significance and, if so, will be considered an 
AE.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF through the last visit.  Subjects who fail screening primarily due 
to AE(s) must have the AE(s) leading to screen failure reported on the Screening Disposition 
CRF.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 480 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Progression of malignant disease should not be recorded as an AE in studies where it is 
included as an endpoint for underlying disease.  If the progression leads to an untoward 
medical occurrence (increased pain, pleural effusion, etc), then this medical occurrence 
should be the AE.  Disease progression is a study endpoint and is to be captured in the case 
report form per the guidelines for reporting disease progression.
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  Subjects with onset of an AE or deterioration of a preexisting AE 
will be followed until resolution to baseline, start of a new anticancer treatment, or death.  
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 6).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  For Grade 2 AEs that lead to changes in study drug administration (dose held, dose 
reduced, or dosing discontinuation), the investigator will be required to confirm in the CRF 
that the AE is considered intolerable.
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
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
Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.4.2
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST
An SAE is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the AE as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  


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All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests will be performed locally.  All blood and urine samples will be 
collected and sent to the local laboratory on the day of collection unless otherwise instructed.  
Laboratory certification as available will be included in the final CSR for this study.
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of Cycle 1, and within 48 hours of 
Day 1 of all subsequent cycles.  Refer to Table 4 for the management of specific clinically 
significant laboratory abnormalities.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1 and the CRF Completion Guidelines).  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.  
Table 6 presents the clinical laboratory tests to be performed.


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Table 6
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, MCH, MCHC, MCV, platelets, RBC count, 
and WBC count with differential (bandsa, basophils, eosinophils, 
lymphocytes, monocytes, neutrophils), INRb
Chemistry
Screening Panel
Pregnancy test (serum or urine β-hCG)
Bicarbonatea, chloride, potassium, sodium, BUN or urea, creatinine, 
glucose, magnesium, phosphorus, calcium, albumin, total protein, 
alkaline phosphatase, ALT, AST, conjugated (direct) bilirubin, total 
bilirubin
LDH
TSH and free T4 levels
Baseline/Off-treatment Panel
Pregnancy test (serum or urine β-hCG)
Bicarbonatea, chloride, potassium, sodium, BUN or urea, creatinine, 
glucose, magnesium, phosphorus, calcium, albumin, total protein, 
alkaline phosphatase, ALT, AST, conjugated (direct) bilirubin, total 
bilirubin
Amylasec, lipase, CPKc
Total cholesterol, triglycerides
TSH
Treatment Panel
Pregnancy test (serum or urine β-hCG) 
Bicarbonatea, chloride, potassium, sodium, BUN or urea, creatinine, 
glucose, magnesium, phosphorus, calcium, albumin, total protein, 
alkaline phosphatase, ALT, AST, conjugated (direct) bilirubin, total 
bilirubin
Amylasec, lipase, CPKc
TSH
Urine Dipstick Testingd
glucose, hemoglobin (or blood), ketones, pH, proteine, specific gravity
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen,
CPK = creatine phosphokinase, β-hCG = beta-human chorionic gonadotropin, INR = International Normalized 
Ratio, LDH = lactate dehydrogenase, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular 
hemoglobin concentration, MCV = mean corpuscular volume, RBC = red blood cells, T4 = thyroxine,
TSH = thyroid stimulating hormone, UPCR = urine protein-to-creatinine ratio, WBC = white blood cells.
a:  optional if results cannot be obtained from the local laboratory.
b:  INR should only be performed as part of the screening assessment and when clinically indicated.
c:  Amylase isoenzymes (pancreatic and salivary type) and CPK isoenzymes (CK-MM and CK-MB) should be 
evaluated if amylase or CPK is greater than 3 x the upper limit of normal.
d:  If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory.
e:  If urine protein is ≥2+, then a 24-hour urine collection or an immediate spot UPCR test should be done to 
quantify the 24-hour urine protein excretion.
For laboratory abnormalities meeting the criteria of SAEs (see Section 9.5.1.4.2), the site 
must fax or email the SAE report including the laboratory report (as regionally required) to 
the sponsor using the SAE form (see Section 9.5.3.1).


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9.5.1.4.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital signs (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], respiratory rate 
[per minute], body temperature [in centigrade]), and weight (kg) will be measured 
periodically during the study.  Height will be measured at the Screening Visit only.  
Blood pressure, pulse, and respiratory rate will be measured after the subject has been resting 
for 5 minutes.  All BP measurements should be performed on the same arm, preferably by the 
same person. 
Only 1 BP measurement is needed for subjects with systolic BP <140 mmHg and diastolic 
BP <90 mmHg. If the subject’s initial BP measurement is elevated (systolic BP ≥140 mmHg 
or diastolic BP ≥90 mmHg), the BP measurement should be repeated at least 5 minutes later. 
The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP assessment. If 
the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart)  
is elevated (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg), a confirmatory 
assessment should be obtained at least 30 minutes later by performing 2 measurements (at 
least 5 minutes apart) to yield a mean value.  
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP 
monitored on Day 15 or more frequently, as clinically indicated) until systolic BP has been 
≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment cycles.
9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of Procedures and
Assessments (Table 7).  Documentation of the physical examination will be included in the 
source documentation at the site.  Only changes from screening physical examination 
findings that meet the definition of an AE will be recorded on the Adverse Events CRF.
9.5.1.4.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Procedures and 
Assessments (Table 7).  Complete, standardized, 12-lead ECG recordings that permit all 
12 leads to be displayed on a single page with an accompanying lead II rhythm strip below 
the customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a minimum of 
3 full complexes should be recorded from each lead simultaneously.  Subjects must be in the 
recumbent position for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
For ECG abnormalities meeting the criteria of an SAE (see Section 9.5.1.4.2), the site must 
fax or email the SAE report including the ECG report to the sponsor using the SAE form (see 
Section 9.5.3.1).


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9.5.1.4.7
ECHOCARDIOGRAMS
An echocardiogram or MUGA scan including LVEF will be performed at screening and as 
clinically indicated.  MUGA scans and echocardiograms should be performed locally in 
accordance with the institution’s standard practice.  MUGA scans are the preferred modality; 
however, whichever modality is used for an individual subject at the Baseline Visit should be 
repeated for all subsequent LVEF assessments for that subject.  LVEFs as assessed by the 
institution will be entered onto the CRF.  Investigator assessment will be based upon 
institutional reports.
9.5.1.4.8
OTHER ASSESSMENTS
Health-Related Quality of Life (HRQoL) will be assessed at Baseline (prior to first dose of 
study drug), before performing tumor assessment scans every 8 weeks until Week 24, then 
every 16 weeks, and at the Off-treatment Visit.  Subjects will complete the EQ-5D-3L
(Appendix 7) and FACT-G (Appendix 8) questionnaires.
The EQ-5D-3L generic QoL questionnaire comprises 5 dimensions: mobility, self-care, usual 
activities, pain or discomfort, and anxiety or depression.  Each dimension has 3 levels (1) no 
problem, (2) some problem, or (3) extreme problem.  Thus, the final scoring consists of 
243 possible combinations or health states.  The utility value for each state is assigned based 
on a set of preference weights (tariffs) elicited from the general population.
The FACT-G QoL questionnaire is comprised of 4 domains: physical, social/family, 
emotional, and functional well-being.  Each domain is scored on a 5-point scale from 0 (not 
at all) to 4 (very much).  Subscale scores are added to obtain a total score.
9.5.1.5
Schedule of Procedures and Assessments
Table 7 presents the schedule of procedures and assessments for the study.


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Table 7
Schedule of Procedures and Assessments in E7080-G000-211 Prerandomization and 
Randomization Phases (as of Protocol Amendment 03)
Phase
Prerandomization
Phase
Randomization Phase
All cycles are 28 days in duration
Period
Screena,b
Baselinea,b
Blinded Study Treatment Periodb
Off-Tx
Follow-Up
Visit
1
2
3
4
Optional
5
6
7, 9,
etc.
8, 10, 12, 
14, etc
99
Cycle 1
Cycle 2
Cycles 3 - Last
Day
-28 to -2
-1
1
8
15
22c
1
15
1
15
Procedures/Assessments
Informed consent
X
Medical/surgical history
X
X
Demographic data
X
ECOG PS/NYHA classificationd
X
X
X
X
pTNM staginge
X
Historic tumor assessmentsf
X
Inclusion/exclusion criteria
X
X
Randomization
X
Vital signsg
X
X
X
X
X
X
X
X
X
Xh
X
Physical examinationi
X
Xj
X
X
X
X
12-lead ECGk
X
X
X
X
Echocardiogram/MUGA scanl
X
As clinically indicated
Pregnancy testm
X
X
X
X
X
Clinical chemistry/hematologyn
X
X
X
X
X
X
X
Urine dipstick testingo
X
X
X
X
X
Xp
X
Study drug administration
Once daily
PK blood samplesq
X
X
X
X
X


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Table 7
Schedule of Procedures and Assessments in E7080-G000-211 Prerandomization and 
Randomization Phases (as of Protocol Amendment 03)
Phase
Prerandomization
Phase
Randomization Phase
All cycles are 28 days in duration
Period
Screena,b
Baselinea,b
Blinded Study Treatment Periodb
Off-Tx
Follow-Up
Visit
1
2
3
4
Optional
5
6
7, 9,
etc.
8, 10, 12, 
14, etc
99
Cycle 1
Cycle 2
Cycles 3 - Last
Day
-28 to -2
-1
1
8
15
22c
1
15
1
15
Procedures/Assessments
Tumor assessments (CT/MRI)r
X
Performed every 8 weeks (starting from date of randomization), or 
sooner if clinically indicated, until documentation of disease progression
X
Bone scans
X
Every 24 weeks, and as clinically indicated
Prior/Concomitant medicationst
Throughout
Only anticancer 
treatments 
recorded during 
the follow-up 
period
AEs/SAEsu
Throughout
Survival and PFS2v
—
X
HRQoL Questionnairesw
X
Performed every 8 weeks (until Week 24, then every 16 weeks)
X
Serum biomarkersx
X
X
X
X
X
X
Performed every 
8 weeks from Wk 8 
through Wk 24, then 
every 16 weeks
Blood sample for 
pharmacogenomic analysisy
X
NOTE:  Before implementation of Amendment 03, treatment assignments of all subjects randomized and treated prior to Amendment 03 were unblinded.  These 
subjects were treated with open-label lenvatinib provided through study supplies at the dose determined at the discretion of the investigator until they were
transitioned to commercial lenvatinib or an access program in their country.  Adverse event data were collected for each subject until transitioned to lenvatinib 


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treatment outside the study. PFS2 and survival data were collected for those subjects who discontinued study drug due to progressive disease or due to an adverse 
event until the last subject transitioned to lenvatinib treatment outside the study (data cutoff date for subjects treated prior to implementation of Amendment 03).
AE = adverse event, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BP = blood pressure, C1D1 = Cycle 1/Day 1, C1D8 = Cycle 1/Day 8, 
C1D15 = Cycle 1/Day 15, C1D22 = Cycle 1/Day 22, C2D1 = Cycle 2/Day 1, CT = computed tomography, ECG = electrocardiogram, ECOG PS = Eastern 
Cooperative Oncology Group performance status, HR = heart rate, MRI = magnetic resonance imaging, MUGA = multiple-gated acquisition, 
NaF PET = 18F-sodium fluoride positron emission tomography, NYHA = New York Heart Association, PK = pharmacokinetic, pTNM = primary 
tumor-node-metastasis staging, RECIST = Response Evaluation Criteria in Solid Tumors, RR = respiratory rate, SAEs = serious adverse events, Tx = treatment.
a.
The results of all screening assessments and evaluations must be completed and reviewed by the investigator prior to the Baseline Visit. Baseline 
assessments may be performed on Day -1 or on C1D1 prior to treatment. Informed consent may be obtained up to 4 weeks prior to randomization.
b.
Efforts should be made to conduct postbaseline study visits on the day scheduled (±1 day). Clinical laboratory assessments may be conducted any time 
within 72 hours prior to the scheduled visit, unless otherwise specified.
c.
Optional visit at Day 22 for vital signs measurements and blood samples for PK and biomarker analysis.
d.
ECOG PS assessment will be performed at the Screening and Baseline Visits, on C2D1, and on Day 1 of every subsequent cycle. NYHA assessment will 
only be performed at the Screening visit. ECOG PS assessments adapted from Oken, et al., 1982; NYHA assessments adapted from Criteria Committee of 
the New York Heart Association, 1994.
e.
pTNM staging, according to AJCC criteria (Greene, et al., 2002).
f.
Historic tumor assessments (CT/MRI images obtained up to 12 months before the Screening Visit/13 months before Randomization) that demonstrate 
progressive disease since the most recent anticancer treatment should be obtained and provided to the imaging core laboratory for confirmation of radiologic 
eligibility.
g.
Assessments will include vital signs (resting BP, HR, RR, body temperature, and weight). Height will be measured at the Screening visit only. Only one BP 
measurement is needed for subjects with systolic BP <140 mmHg and diastolic BP <90 mmHg. If the subject’s initial BP measurement is elevated (ie, 
systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg), the BP measurement should be repeated at least 5 minutes later. The mean value of 2 measurements at 
least 5 minutes apart is defined as 1 BP assessment.  If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is 
elevated (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg), a confirmatory BP assessment should be obtained at least 30 minutes later by performing 
2 measurements at least 5 minutes apart (to yield a mean value). Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP 
monitored on Day 15 or more frequently, as clinically indicated) until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 
2 consecutive treatment cycles .  If a new event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must resume the Day 15 
evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 2consecutive treatment cycles.
h.
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on Day 15 or more frequently as clinically indicated) until 
systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 2 consecutive treatment cycles. If a new event of systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg occurs, the subject must resume the Day 15 evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 
mmHg for 2 consecutive treatment cycles.
i.
A comprehensive physical examination (including a neurological examination) will be performed at the Screening or Baseline Visits, on Cycle 1/Day 15, on 
Day 1 of each subsequent cycle, and at the Off-treatment assessment. A symptom-directed physical examination will be performed on C1D1 and at any time 
during the study, as clinically indicated.
j.
Required if screening physical examination was performed >7 days prior to C1D1.
k.
Single 12-lead ECG. Subjects must be in the recumbent position for a period of 5 minutes prior to obtaining ECG.
l.
An echocardiogram or MUGA scan to assess left ventricular ejection fraction (LVEF) will be performed at Screening and as clinically indicated.


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m. A serum or urine pregnancy test will be performed at the Screening Visit, at the Baseline Visit (or within 72 hours prior to the first dose of study drug), at 
Day 1 of every cycle (starting with Cycle 2), and at the off-treatment assessment in women of childbearing potential (ie, premenopausal and perimenopausal 
women who have been amenorrheic for less than 12 months).
n.
The screening electrolyte results must be reviewed and confirmed to be within the normal (or reference) range prior to randomization of the subject.  Clinical 
chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 and within 48 hours after dispensing study drug for all 
subsequent cycles. Scheduled assessments may be performed within 72 hours prior to the visit. If there is Grade ≥3 hematologic or clinical chemistry 
toxicity, repeat the specific laboratory test and AE assessment at least every 3 days (until improvement to Grade <3).
On Cycle 1 Day 15 and Cycle 2 Day 15, only liver function tests (albumin, total protein, alkaline phosphatase, ALT, AST, conjugated (direct) bilirubin, total 
bilirubin) will be performed.
o.
For subjects with a history of proteinuria >2+, urine dipstick testing should be performed every 2 weeks. If proteinuria ≥2+ is detected on urine dipstick 
testing, study drug will be continued and a 24-hour urine collection for total protein will be obtained as soon as possible within 72 hours to verify the grade 
of proteinuria.
p.
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 of each cycle (or more frequently as clinically indicated) until the 
results have been 1+ or negative for 2 consecutive treatment cycles. Urine dipstick testing should be performed preferably at the investigational site (but 
may be performed locally by the primary care physician or a local laboratory if the subject does not have to come for a visit to the site).  If a new event of 
proteinuria ≥2+ occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 
2 consecutive treatment cycles.  For subjects with a history of dipstick proteinuria ≥2+, see Section 9.4.2.2 for management of proteinuria.
q.
Blood samples will be drawn for PK assessment of study drug at 0.5-4 hours and 6-10 hours postdose on C1D1; predose on C1D8; predose, 0.5-4 hours, and 
6-10 hours postdose on C1D15; predose (optional) on C1D22, and predose and 2-12 hours postdose on C2D1.
r.
Screening: Screening tumor assessments using CT of the brain, neck, chest, abdomen and pelvis, and other areas of known or suspected disease should be 
performed within 28 days prior to C1D1. Detailed image acquisition guidelines will be provided by the imaging core laboratory. Scans that were performed 
within this window but before informed consent may be used if they were acquired consistent with the guidelines provided by the imaging core laboratory. 
Randomization Phase: Tumor assessments of the neck, chest, abdomen, pelvis and other areas of known disease at screening or newly suspected disease 
should be performed every 8 weeks (during the eighth week, starting from the date of randomization), or sooner, if clinically indicated until progressive 
disease. Subjects with protocol-eligible treated brain metastases must also have brain CT/MRI performed at tumor assessment time points. For other 
subjects, brain scans should be performed as clinically indicated. The same methodology (CT or MRI) and scan acquisition techniques should be used as for 
the screening assessments. Tumor assessment at the Off-treatment Visit is only necessary for subjects who discontinue study drug without disease 
progression if more than 4 weeks have passed since the previous assessment (window for these assessments is within 1 week of the Off-treatment Visit). 
If a subject discontinues from study treatment without disease progression, tumor assessments should continue to be performed every 8 weeks until 
documentation of disease progression or beginning a new anticancer treatment.
s.
A bone scan (99m-technetium-based scintigraphy, whole body bone MRI, or 18F-NaF PET) to assess bone metastases will be performed within 6 weeks prior 
to randomization (historical scans are acceptable) to establish a baseline, and then every 24 weeks (within the 24th week) from randomization, or sooner if 
clinically indicated.
t.
Concomitant medications will be recorded from the Screening Visit through 28 days after the last dose of study drug. All anticancer therapy will be 
recorded until time of death or the data cutoff for primary analysis.
u.
Adverse events and SAEs will be recorded from the signing of Informed Consent until 28 days after the last dose of study drug. SAEs, irrespective of 
relationship to study drug, must be reported as soon as possible but not later than 1 business day after their occurrence. Signs/symptoms related to disease 


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progression should not be reported as AEs. During treatment interruption due to AEs, repeat AE assessments should be performed at least every 7 days 
(until restarting study drug administration).
v.
Subjects who discontinue treatment before the data cutoff for the primary analysis will be followed for survival and post-lenvatinib disease progression 
(PFS2 collected until the data cutoff for the primary analysis; unless this information is not allowed to be provided due to confidentiality) every 12 weeks 
(±1 week) after the Off-treatment Visit. If a clinic visit is not feasible, follow-up information may be obtained via telephone or email.
w.
Health-Related Quality of Life (HRQoL) will be assessed at Baseline (prior to first dose of study drug), before performing tumor assessment scans every 
8 weeks until Week 24, then every 16 weeks, and at the Off-treatment Visit.  Subjects will complete the EQ-5D-3L and FACT-G questionnaires.
x.
Thyroglobulin, antithyroglobulin autoantibodies (anti-Tg), and other exploratory serum biomarkers (including VEGF, Ang-2, sTie-2, and FGF23) will be 
assessed at Baseline (see footnote a), at 0.5-4 hours and 6-10 hours postdose on C1D1, predose on C1D8, predose on C1D15, predose on C1D22 (optional), 
predose on C2D1, and predose every 8 weeks from Week 8 through Week 24, then every 16 weeks thereafter.  
y.
Collection of whole blood to obtain genomic DNA will be obtained at Baseline except where prohibited by regional or local laws.  If sampling is not 
performed predose, sampling may occur at any subsequent visit in which other blood sampling is scheduled to occur.  


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9.5.1.6
Description of Procedures/Assessments Schedule
Refer to Table 7 for a description and timing of each procedure and assessment in the 
Prerandomization and Randomization Phase.
9.5.2
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of RR-DTC.  
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, radiologic studies, and assessment of AEs, are standard 
evaluations to ensure subject safety.
9.5.3
Reporting of Serious Adverse Events, Pregnancy, and Other Events of 
Interest
9.5.3.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form and sent by facsimile as soon as possible 
but no later than 24 hours from the date the investigator becomes aware of the event.
Deaths and life-threatening events should be reported immediately by telephone.  The 
immediate report should be followed up within 24 hours by emailing or faxing the completed 
SAE form.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for up to 28 days after the subject’s last dose.  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 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.


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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 CRO 
monitor and filed in the sponsor’s Trial Master File.
9.5.3.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 30 days of last study treatment, must be reported.
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.3.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.3.3
Reporting of Other Events of Interest
9.5.3.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose.
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol.
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects


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Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.3.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.3.3.2
REPORTING OF SIGNIFICANT LABORATORY ABNORMALITY
Any significant treatment-emergent laboratory abnormality observed during the clinical 
study should be entered on the Adverse Event CRF and reported using the procedures 
detailed in Reporting of Serious Adverse Events (Section 9.5.3.1), even if the laboratory 
abnormality does not meet serious criteria.  If the significant laboratory abnormality 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.
A laboratory result should be considered a treatment-emergent significant abnormality if the 
result:

Is within normal limits at baseline and has increased in severity to meet CTCAE (v4.03) 
criteria for laboratory values of Grade 3 or above (Appendix 6)

Is outside normal limits at baseline and increases in severity to CTCAE (v4.03) Grade 4 
or above.  These abnormalities are automatically considered to be serious, with the 
exception of expected and reproducible hematologic abnormalities.

Is otherwise considered by the investigator to meet serious criteria as defined in 
Section 9.5.1.4.2
Significant laboratory abnormalities should not be listed as separate AEs or SAEs if they are 
considered to be part of the clinical syndrome that is being reported as an AE or SAE.
9.5.3.3.3
REPORTING OF STUDY-SPECIFIC EVENTS
Not applicable.
9.5.3.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.


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9.5.3.5
Breaking the Blind
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above.  Any broken 
code will be clearly justified and documented.  The medical monitor must be notified 
immediately of the blind break.
9.5.3.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
SUSARs will be reported, as required, to the competent authorities of all involved EU 
member states.
9.5.4
Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  Subjects who choose 
to discontinue study drug prior to disease progression will be followed in the poststudy 
treatment follow-up period and continue to undergo regularly scheduled disease assessment 
until documentation of disease progression or initiation of alternative anticancer treatment.  
All subjects who discontinue study drug will be followed for PFS2 and OS, and all 
postprogression cancer treatments administered will be recorded.  Subjects may at any time 
withdraw consent for further study participation.  No further data will be collected on 
subjects once consent has been withdrawn.  All subjects who discontinue the study are to 
complete the study’s early discontinuation procedures indicated in the Schedule of 
Procedures and Assessments (Table 7).  
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for one of these primary 
reasons: AE(s), lost to follow-up, subject choice, progressive disease, or administrative/other.  
In addition to the primary reason, the subject may indicate one or more secondary reason(s)
for discontinuation.  Study disposition information will be collected on the Subject 
Disposition CRF.
A subject removed from the study for any reason may not be replaced.


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9.5.5
Abuse or Diversion of Study Drug
Not applicable.
9.5.6
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.  
9.6.1
Data Collection
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.
9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed (based on the data cutoff for the primary analysis) and the database is locked and 
released for unblinding.  Statistical analyses will be performed using SAS software or other 


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validated statistical software as required.  Details of the statistical analyses will be included 
in a separate SAP.
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock and 
treatment unblinding.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINTS

ORR24wk as assessed by the investigator using RECIST 1.1. ORR24wk is defined as the 
proportion of subjects with BOR of CR or PR at the Week 24 time point or earlier.

Rate of TEAEs with CTCAE grades of 3 or higher within 24 weeks after randomization 
(as of the Week 24 time point).
9.7.1.1.2
SECONDARY ENDPOINTS

PFS, defined as the time from the date of randomization to the date of first 
documentation of disease progression, or date of death, whichever occurs first. 
Censoring rules for PFS will be defined in the SAP and will follow FDA guidance. 

PFS2, defined as the time from randomization to second objective disease progression 
(occurring during treatment with next line of anticancer therapy), or death from any 
cause, whichever occurs first.  Censoring rules for PFS2 will be defined in the SAP.

Overall safety profile and tolerability.

Time to treatment discontinuation due to an AE.

Number of dose reductions.

Time to first dose reduction.

Plasma PK lenvatinib exposure parameters.

Interrelationships of lenvatinib exposure, changes in thyroglobulin, TSH, or other 
exploratory serum biomarkers, and changes in tumor burden and PFS.

Relationship of lenvatinib exposure and changes in BP, and AEs of weight loss, fatigue, 
nausea, vomiting, diarrhea, and proteinuria CTCAE grades derived from urine protein 
measurements.

Impact of lenvatinib treatment on HRQoL as assessed using the validated instruments 
EQ-5D-3L and FACT-G.


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9.7.1.1.3
EXPLORATORY ENDPOINTS 

Duration of response, defined as the time from the initial achievement of a response to 
the date of first documentation of disease progression, or the date of death, whichever 
occurs first.

DCR, defined as the proportion of subjects who have BOR of CR, PR, or SD. BOR of 
SD must be achieved at least 7 weeks after randomization.

CBR, defined as the proportion of subjects who have BOR of CR, PR, or durable SD 
(duration of SD ≥23 weeks after randomization).

Duration of clinical benefit.

OS, measured from the date of randomization until date of death from any cause.  In 
absence of confirmation of death, subjects will be censored either at the date that the 
subject was last known to be alive or the date of data cutoff, whichever comes earlier.

Associations between objective tumor response and serum thyroglobulin (accounting for 
anti-Tg), TSH, and other serum biomarkers (including VEGF, Ang-2, sTie-2, and 
FGF23).

Association between any observed DNA sequence variability and PK, 
pharmacodynamic, and clinical outcome measures including efficacy and safety-related 
endpoints.
9.7.1.2
Definitions of Analysis Sets
Full Analysis Set will include all randomized subjects. This will be the analysis set for all 
efficacy evaluations which will be analyzed according to the treatment randomized, 
regardless of the treatment actually received.
Safety Analysis Set will include all subjects who were randomized and received at least one 
dose of study drug. This will be the analysis set for all safety evaluations which will be 
analyzed according to the treatment actually received.
Pharmacokinetic (PK) Analysis Set will include all subjects who received at least one dose 
of study drug and have evaluable lenvatinib plasma concentration data.
Pharmacodynamic Analysis Set will include all subjects who received at least one dose of 
study drug and have evaluable pharmacodynamic data.
9.7.1.3
Subject Disposition
All subjects who were screened for the study will be accounted for and reported in the study 
results.  The reasons for screen failures will be described and documented by subject and 
summarized by total number of subjects with screen failures.  If deemed relevant, the reasons 
for excluding subjects will be evaluated to determine if these reasons could help clarify the 
appropriate subject population for eventual drug use.  The number of subjects treated and the 


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outcome of the treatment as well as treatment discontinuations and reasons for 
discontinuation will be reported.  
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized and listed.  For 
continuous demographic/baseline variables including age, weight, and vital signs, results will 
be summarized and presented as N, mean, standard deviation, median, and minimum and 
maximum values.  For categorical variables such as race/ethnicity, the number and 
percentage of subjects will be used.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded on the CRF will be coded using the World 
Health Organization (WHO) Drug Dictionary. Prior medications will be defined as 
medications that started prior to the first dose of study drug, some of the prior medications 
may continue after the initiation of the study drug. Concomitant medications will be defined 
as medications that (i) started before the first dose of study drug and were continuing at the 
time of the first dose of study drug, or (ii) started on or after the date of the first dose of study 
drug up to 28 days following the last dose in randomization phase. Medications that cannot 
be determined to be prior/concomitant/posttreatment due to missing or incomplete dates will 
be regarded as concomitant.
Prior medications will be summarized by anatomical class (Anatomical Therapeutic 
Chemical [ATC] Level 1), pharmacological class (ATC Level 3), and World Health 
Organization (WHO, Geneva, Switzerland) generic drug name by frequency counts and 
percentages. The same summary will be provided for concomitant medications except
thyroxine suppression therapy and hypertensive therapy. Concomitant thyroxine suppression 
therapy and hypertensive therapy will be summarized separately. In addition, there also will 
be a separate summary for the concomitant medications of P-glycoprotein inhibitors and/or 
inducers. Data listings will be provided for all prior and concomitant medications, for all 
concomitant thyroid suppression therapy, for all concomitant hypertensive therapy, and for 
all concomitant P-glycoprotein inhibitors and/or inducers.  
9.7.1.6
Efficacy Analyses
All efficacy analyses will be performed on the Full Analysis Set.  For subjects who were 
randomized before implementation of Amendment 03, efficacy results will not be included in 
the analyses, but will be included in a separate report.
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
The analysis of ORR24wk will be based on a noninferiority test on the odds ratio (OR) and 
will be tested with a noninferiority margin of 0.4 on an OR scale (see Section 9.7.2, 
Determination of Sample Size, for the margin estimation) and a 1-sided alpha of 0.025.  The 
point estimate of ORR24w for each treatment group will be summarized with the 
corresponding 95% confidence interval (CI).  Treatment differences in ORR24wk for the 
24-mg and 18-mg dose groups will be estimated along with 95% CIs based on the normal 


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approximation.  The OR of ORR24wk (18 mg vs 24 mg) along with the 95% CI will be 
calculated using the Cochran-Mantel-Haenszel (CMH) method stratified by ECOG PS (0 vs 
1 or 2) and age group (≤65 or >65 years).
Overall ORR will also be analyzed according to the same approach for ORR24wk as a 
sensitivity analysis.  
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
The stratified log-rank test using ECOG PS and age group as strata will be used to compare 
differences in PFS and PFS2 as assessed by investigator between the 24-mg and 18-mg 
treatment groups. The hazard ratio (HR) for the corresponding treatment comparisons will 
be estimated by the stratified Cox regression including treatment as a factor and baseline 
ECOG PS and age group as strata. The estimated HR will be reported for the treatment 
comparison between 24 mg vs 18 mg, along with the corresponding (2-sided) 95% CI. The 
Kaplan-Meier (KM) product-limit estimates for each treatment group will be reported and 
plotted over time.
PFS2 is defined as the time from randomization to second objective disease progression, or 
death from any cause, whichever occurs first.  Subjects who are alive and for whom a second 
objective disease progression has not been observed will be censored at the last time they are 
known to be alive and without a second objective disease progression. Subjects who were 
enrolled prior to implementation of Amendment 03 and who discontinued lenvatinib 
treatment due to progressive disease or due to an AE were followed for PFS2 until the date 
that the last subject transitioned to lenvatinib treatment outside the study (the data cutoff date 
for this group of 41 subjects).  PFS2 data for these subjects will be included in a separate 
report.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
Duration of response will be defined as the time from the date of first documented response 
until date of documented progression or death in the absence of disease progression, the end 
of response should coincide with the date of progression or death from any cause used for the 
PFS endpoint.  The time of the initial response will be defined as the latest of the dates 
contributing towards the first visit response of PR or CR. If a subject does not progress 
following a response, then their duration of response will use the PFS censoring time.
Duration of response will be summarized using KM product-limit estimates for each 
treatment group and presented with 2-sided 95% CIs.  The rates of durable SD, DCR (SD, 
CR, or PR), and CBR (CR, PR, or durable SD) and the corresponding 2-sided 95% CIs will 
be calculated by treatment group.  BOR of SD must be at least 7 weeks following 
randomization. Durable SD is SD at least 23 weeks after randomization. Treatment 
differences (percentage-point difference) for 24 mg vs 18 mg will be summarized along with 
the corresponding 95% CIs based on the normal approximation.
To explore OS, the median survival time and the survival rates at 12, 18, and 24 months will 
be calculated using KM product-limit estimates for each treatment group and presented with 


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2-sided 95% CIs.  The KM estimates of OS will be plotted over time. Subjects who were 
enrolled prior to implementation of Amendment 03 and who discontinued lenvatinib 
treatment due to progressive disease or due to an AE were followed for survival until the date 
that the last subject transitioned to lenvatinib treatment outside the study (the data cutoff date 
for this group of 41 subjects).  OS data for these subjects will be included in a separate 
report.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
All PK analyses will be performed on the PK Analysis Set.
Lenvatinib plasma concentration data, including data from subjects randomized before 
implementation of Amendment 03, will be summarized using descriptive statistics and 
plotted as appropriate for each treatment group.
In addition lenvatinib plasma concentration data will be analyzed using a population PK 
approach to estimate population PK parameters.  The analyses will be detailed in a separate 
analysis plan and reported separately from the CSR.
9.7.1.7.2
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Pharmacokinetic/pharmacodynamic data from subjects randomized before implementation of 
Amendment 03 will be included in the models.
Lenvatinib exposure parameters (AUC or concentration at the time of the event or 
cumulative AUC, as appropriate) derived from the population PK analysis will be related to 
biomarker, safety, and efficacy data and will be modeled using a mechanistically based 
approach, if possible.  For some PK/pharmacodynamic analyses, data from this study will be 
pooled with data from the RR-DTC arm of the Phase 2 Study E7080-G000-201 (Study 201) 
and with data from the RR-DTC Phase 3 Study E7080-G000-303 (Study 303).
For efficacy, a tumor growth inhibition model based on longitudinal tumor size 
measurements of target lesions will be included.  The plan is to explore both lenvatinib 
exposure and/or measured biomarkers (including thyroglobulin [accounting for anti-Tg], 
TSH, VEGF, Ang-2, sTie-2, FGF23) as predictors and/or correlations with tumor burden 
changes in the tumor growth inhibition model.
Other analyses will include logistic regression analysis for ORR24wk, KM plots of PFS data 
stratified by lenvatinib exposure, and Cox-regression analysis.  For the Cox-regression 
analysis of PFS, adjustment will be made for a subject’s baseline characteristics or 
tumor-related features.  In addition to lenvatinib exposure, changes in biomarker 
concentrations (thyroglobulin and TSH) and/or tumor burden will be related to PFS.
For the exposure-response relationship of safety, the model-based analysis will include the 
following AEs: hypertension, proteinuria, weight loss, fatigue, nausea, vomiting and 


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diarrhea.  For hypertension, BP data will be analyzed using an indirect-response model.  For 
proteinuria, urine dipstick and/or 24-hour urine data will be analyzed using a longitudinal 
categorical logistic regression analysis with Markov element.  For weight loss, fatigue, 
nausea, vomiting, and diarrhea, data will be analyzed using a longitudinal categorical logistic 
regression analysis.  For time to treatment discontinuation due to an AE and time to first dose 
reduction, KM plots stratified by lenvatinib exposure will be prepared.  
For the exposure-response relationship for biomarkers, thyroglobulin (accounting for 
anti-Tg), TSH, VEGF, Ang-2, sTie-2, and FGF23 data will be analyzed using a model-based 
approach.  Direct, indirect, and effect compartment models will be explored.
Population PK and PK/pharmacodynamic analyses will be detailed in a separate analysis plan
and reported separately from the CSR.
9.7.1.7.3
BIOMARKER ANALYSIS
The effect of lenvatinib treatment on serum thyroglobulin, TSH, and other exploratory serum 
biomarkers will be summarized by treatment group.  In addition, association between clinical 
outcomes and baseline biomarker levels, and/or change in levels from baseline will be 
explored. The analyses may be detailed in the BAP and reported separately.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  All safety analyses will be 
summarized separately by treatment group.  Adverse events and SAEs, laboratory test 
results, physical examination findings, vital signs, and echocardiogram results (including 
LVEF), and their changes from Baseline will be summarized using descriptive statistics.  
Abnormal values will be flagged. Safety data from subjects randomized before 
Amendment 03 will be reported in a separate report, and will also be included in the final 
CSR for this study.
Time to treatment discontinuation due to an AE, number of dose reductions, and time to first 
dose reduction will be summarized.
9.7.1.8.1
PRIMARY SAFETY ENDPOINT
For the analysis of the primary safety endpoint, the frequency (number and percentage) of 
TEAEs with CTCAE grade of 3 or higher will be summarized by treatment group (24 mg and 
18 mg); the difference in the frequency between the 2 treatment groups will be presented 
with 95% CI.
9.7.1.8.2
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to AEs will be summarized.


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9.7.1.8.3
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 16.1 or higher) lower 
level term closest to the verbatim term.  The linked MedDRA preferred term and primary 
system organ class (SOC) are also captured in the database.
TEAEs will be defined as AEs that emerge during treatment, having been absent 
pretreatment (at baseline) or those that:

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
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, dose modification, or 
dose interruption will be provided.
The incidence of TEAEs will be summarized by SOC, preferred term, CTCAE grade, and 
relatedness to study drug.  All summaries will be performed by treatment group.  Although a 
MedDRA term may be reported more than once for a subject, that subject will be counted 
only one time in the incidence count for that MedDRA term with the highest CTCAE grade 
(in the summary by CTCAE grade) or with the closest relationship to study treatment (in the 
summary by relatedness to study treatment).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
In addition, the overall proportion of subjects with TEAEs of CTCAE Grade 3 or higher and 
the overall proportion of subjects with intolerable CTCAE Grade 2 TEAEs that result in dose 
modification will be analyzed using the same approach for the primary safety endpoint, as 
sensitivity analyses.
9.7.1.8.4
LABORATORY VALUES
Laboratory test results, vital signs and their changes from baseline, and 12-lead ECG results, 
will be summarized using descriptive statistics.  Abnormal values will be flagged.  
Laboratory results will be summarized using Système International units, as appropriate.  For 
all quantitative parameters listed in Section 9.5.1.4.3, the actual value and the change from 
baseline to each postbaseline visit and to the end of treatment (defined as the last 
on-treatment value) will be summarized by visit and treatment arm using descriptive 
statistics.  Qualitative parameters listed in Section 9.5.1.4.3 will be summarized using 


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frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results.  
Laboratory parameters will be categorized according to CTCAE v4.0 grades and shifts from 
baseline CTCAE grades to maximum and the last postbaseline grades will be assessed. The 
CTCAE Grade 3 and 4 test results will be summarized. 
9.7.1.8.5
VITAL SIGNS AND PHYSICAL EXAMINATION FINDINGS
Changes from baseline in vital signs parameters (resting BP, pulse, RR and body 
temperature, weight) and height will be summarized.  See the Schedule of Procedures and 
Assessments in Table 7.
9.7.1.8.6
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit, by starting dose, and by dose at the assessment time. Shift tables will present changes 
from baseline in ECG interpretation (categorized as normal; abnormal, not clinically 
significant; and abnormal, clinically significant) by visit. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Bazett and QTc Fridericia during the treatment period will be summarized.  
Clinically abnormal ECG results in QTc Bazett and QTc Fridericia will be categorized as 
follows:
Absolute QTc interval prolongation:

QTc interval >450 ms

QTc interval >480 ms

QTc interval >500 ms
Change from baseline in QTc interval:

QTC interval increases from baseline >30 ms

QTC interval increases from baseline >60 ms
9.7.1.8.7
OTHER SAFETY ANALYSES
MUGA scans and echocardiograms will be assessed locally.  Descriptive summary statistics 
for LVEF changes from baseline will be calculated and summarized.
9.7.1.8.8
HEALTH-RELATED QUALITY OF LIFE ANALYSES
Descriptive statistics of the derived functional/symptom scales according to the scoring 
manual and global health status scores will be summarized at each time point by starting 
dose.  A separate prespecified HRQoL analysis following FDA and EMA patient-reported 


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outcomes Guidelines will be performed and detailed in a separate SAP and a separate 
HRQoL report.
9.7.2
Determination of Sample Size
Sample size determination is based on the number of subjects required to detect 
noninferiority of the primary efficacy endpoint, ORR24wk, comparing the 18-mg arm to the 
24-mg arm.  Based on the data from Study 303, the ORR24wk for the lenvatinib 24-mg arm 
was 54.4% (142 responders, N=261) and 0.8 % for the placebo arm (1 responder, N=131) 
and the lower 95% CI of the OR for lenvatinib 24 mg vs placebo was 21.4.  Assuming a 70% 
retention of the effect of lenvatinib 24 mg versus placebo, the noninferiority margin on the 
OR scale is estimated to be 0.40 (ie, Ha: OR [18 mg/24 mg] >0.4).
A sample size of 152 subjects (76 per arm) will provide a statistical power of 80% to declare 
noninferiority, assuming a 1-sided alpha of 0.025, an ORR24wk of 54.4% for lenvatinib 24 mg 
and a true OR of 1, with a noninferiority margin of 0.4.
For the primary safety endpoint, based on the data from Study 303, where 70.5% of subjects 
in the lenvatinib 24-mg arm had a TEAE of CTCAE Grade 3 or higher during the first 
24 weeks, the sample size of 152 subjects will provide a precision for the observed 
differences between the arms with half widths of the 95% CI of about 15%.
9.7.3
Interim Analysis
No interim analysis is planned for this study.
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the CSR.


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10 REFERENCE LIST
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. 
The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Disease of the Heart and Great Vessels. 9th ed. 1994: 253-256.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).  
Eur J Cancer. 2009;45(2):228-47. 
Available from:  http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733.
Greene FL, Page DL, Fleming ID, et al, eds. AJCC Cancer Staging Handbook: TNM 
Classification of Malignant Tumors, 6th ed. New York: Springer-Verlag, 2002.
Lenvima Package Insert.  Eisai Inc.  Available from: http://www.lenvima.com
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.
1982:5(6):649-655.


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES)
11.1
Changes to the Protocol
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (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, CT scans, magnetic resonance images, radioactive images, 
ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function tests) regardless of 
how these images are stored, including microfiche and photographic negatives

Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and serve 
as their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the 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.


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11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items, the data recorded directly on the CRF are to be considered source data.

Study drug compliance (eg, the reason for dose reduction).

Discontinuation information.

Sampling date and time for drug concentration.

Sampling date and time for the clinical laboratory test.

Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome).
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug will be supplied to the PI (or a designated pharmacist) by the sponsor.  Drug 
supplies must be kept in an appropriate secure area (eg, locked cabinet) and stored according 
to the conditions specified on the drug labels.  The investigator (or a designated pharmacist) 
must maintain an accurate record of the shipment and dispensing 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 


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


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


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12 APPENDICES


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Appendix 1
Thyroid Cancer Tumor-Node-Metastasis Staging System
The TNM (tumor-node-metastasis) Staging System is the most widely used system for cancer 
staging in the world.  Created by the American Joint Committee on Cancer (AJCC), a 
distinguished group of experts from national healthcare organizations and major cancer 
centers around the country, the system defines cancer stage by describing:
Primary Tumora
Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor 2 cm or less in greatest dimension limited to the thyroid
T2
Tumor more than 2 cm but not more than 4 cm in greatest dimension limited to the 
thyroid
T3
Tumor more than 4 cm limited to the thyroid or any tumor with minimal extrathyroid 
extension (eg, extension to sternothyroid muscle or perithyroid soft tissues)
T4a
Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft 
tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve
T4b
Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
Regional Nodesb
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
N1a
Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph 
nodes)
N1b
Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal 
lymph nodes
Distant Metastasis
Mx
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis


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Papillary or Follicular Carcinoma
Stage Groupc
T Stage
N Stage
M Stage
Under 45 Years
I
Any T
Any N
M0
II
Any T
Any N
M1
45 Years and Older
I
T1
N0
M0
II
T2
N0
M0
III
T3
N0
M0
T1
N1a
M0
T2
N1a
M0
T3
N1a
M0
IVA
T4a
N0
M0
T4a
N1a
M0
T1
N1b
M0
T1
N1b
M0
T2
N1b
M0
T3
N1b
M0
T4a
N1b
M0
IVB
T4b
Any N
M0
IVC
Any T
Any N
M1
a.
All categories may be subdivided: (a) solitary tumor, (b) multifocal tumor (the largest determines the 
classification).
b.
Regional nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.
c.
Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic 
(undifferentiated) carcinoma.


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Appendix 2
Response Evaluation Criteria in Solid Tumors 1.1
Tumor response assessments in this clinical trial will use Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) based on the 2009 article by Eisenhauer, et al entitled, New 
Response Evaluation Criteria in Solid Tumors:  revised RECIST guideline (version 1.1).
The sole modification to RECIST 1.1 to be implemented in this study is that chest x-rays 
may not be used to follow disease; only CT scans may be used to follow chest disease.  As 
required by RECIST 1.1, the protocol states that the minimum duration of SD is 7 weeks 
following the date of first dose of study drug.
The Eisenhauer article, published in the European Journal of Cancer, is available online at:  
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733.


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


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Appendix 4
Cockcroft and Gault Formula
Male
(140 - age) × weight (kg)
= XX mL/min 
Serum creatinine (mg/dL) × 72
Female
(140 - age) × weight (kg) × 0.85
= XX mL/min
Serum creatinine (mg/dL) × 72
Adapted from Cockcroft DW, et al.  Nephron.  1976;16(1):31-41.
For serum creatinine measured in μmol/L:
Male
(140 - age) × weight (kg) × 1.23
= XX mL/min
Creatinine (µmol/L)
Female
(140 - age) × weight (kg) × 1.23 × 0.85
= XX mL/min
Creatinine (µmol/L)


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Appendix 5
New York Heart Association Cardiac Disease 
Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for heart failure patients 
based on cardiac functional capacity.  Based on NYHA definitions, heart failure subjects are 
to be classified as follows:
Class
NYHA Status
Class I
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II
Subjects with slight, mild limitation of activity; they are comfortable at
rest or with mild exertion.
Class III
Subjects with marked limitation of activity; they are comfortable only at 
rest.
Class IV
Subjects who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest.
NYHA = New York Heart Association.
Adapted from The Criteria Committee of the New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th ed. 1994:253-6.


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Appendix 6
Common Terminology Criteria for Adverse Events (v4.03)
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE)
v4.0 [published 28 May 2009 (v4.03:  14 June 2010)] provides descriptive terminology to be 
used for adverse event reporting in clinical trials.  A brief definition is provided to clarify the 
meaning of each AE term.  To increase the accuracy of AE reporting, all adverse event terms 
in CTCAE version 4.0 have been correlated with single-concept, Medical Dictionary for 
Regulatory Activities (MedDRA®) terms.
CTCAE v4.0 grading refers to the severity of the AE.  CTCAE grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Grade
CTCAE Status
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2
Moderate: minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL).a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b
4
Life-threatening consequences: urgent intervention indicated.
5
Death related to adverse event.
CTCAE = Common Terminology Criteria for Adverse Events.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.0.  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 25 Jun 2015).
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 (Accessed 25 Jun 2015).


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Appendix 7
Health-Related Quality of Life Questionnaire – EQ-5D-3L
By placing a checkmark in one box in each group below, please indicate which 
statements best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or 
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain / Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety / Depression


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I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



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To help people say how good or bad a health state is, we 
have drawn a scale (rather like a thermometer) on which 
the best state you can imagine is marked 100 and the 
worst state you can imagine is marked 0.
We would like you to indicate on this scale how good or 
bad your own health is today, in your opinion. Please do 
this by drawing a line from the box below to whichever 
point on the scale indicates how good or bad your health 
state is today.
Your own health 
state today
9
0
8
0
7
0
6
0
5
0
4
0
3
0
2
0
1
0
100
0
Best imaginable 
health state


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Appendix 8
Health-Related Quality of Life Questionnaire – FACT-G
FACT-G Version 4
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to the 
past 7 days.
PHYSICAL WELL-BEING
Not 
at all
A little 
bit
Some-what
Quite
a bit
Very 
much
GP1
I have a lack of 
energy
..................................................................
0
1
2
3
4
GP2
I have 
nausea
..................................................................
0
1
2
3
4
GP3
Because of my physical condition, I have 
trouble meeting the needs of my 
family
..................................................................
0
1
2
3
4
GP4
I have 
pain
..................................................................
0
1
2
3
4
GP5
I am bothered by side effects of 
treatment
..................................................................
0
1
2
3
4
GP6
I feel 
ill
..................................................................
0
1
2
3
4
GP7
I am forced to spend time in 
bed
0
1
2
3
4
SOCIAL/FAMILY WELL-BEING
Not 
at all
A little 
bit
Some-what
Quite 
a bit
Very 
much
GS1
I feel close to my 
friends
..................................................................
0
1
2
3
4
GS2
I get emotional support from my 
family
..................................................................
0
1
2
3
4
Worst imaginable 
health state


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Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days.
EMOTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-what
Quite 
a bit
Very 
much
GE1
I feel 
sad
..................................................................
0
1
2
3
4
GE2
I am satisfied with how I am coping with 
my 
illness
..................................................................
0
1
2
3
4
GE3
I am losing hope in the fight against my 
illness
..................................................................
0
1
2
3
4
GE4
I feel 
nervous
..................................................................
0
1
2
3
4
GS3
I get support from my 
friends
..................................................................
0
1
2
3
4
GS4
My family has accepted my 
illness
..................................................................
0
1
2
3
4
GS5
I am satisfied with family communication 
about my 
illness
..................................................................
0
1
2
3
4
GS6
I feel close to my partner (or the person 
who is my main 
support)
..................................................................
0
1
2
3
4
Q1
Regardless of your current level of sexual 
activity, please answer the following 
question. If you prefer not to answer it, 
please mark this box            and go to the 
next section.
GS7
I am satisfied with my sex 
life
0
1
2
3
4


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GE5
I worry about 
dying
..................................................................
0
1
2
3
4
GE6
I worry that my condition will get 
0
1
2
3
4
FUNCTIONAL WELL-BEING
Not 
at all
A little 
bit
Some-what
Quite
a bit
Very 
much
GF1
I am able to work (include work at 
home)
..................................................................
0
1
2
3
4
GF2
My work (include work at home) is 
fulfilling
..................................................................
0
1
2
3
4
GF3
I am able to enjoy 
life
..................................................................
0
1
2
3
4
GF4
I have accepted my 
illness
..................................................................
0
1
2
3
4
GF5
I am sleeping 
well
..................................................................
0
1
2
3
4
GF6
I am enjoying the things I usually do for 
fun
..................................................................
0
1
2
3
4
GF7
I am content with the quality of my life 
right 
0
1
2
3
4


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-G000-211
Study Protocol Title:
A Multicenter, Randomized, Double-Blind Phase 2 Trial of 
Lenvatinib (E7080) in Subjects With 131I-Refractory 
Differentiated Thyroid Cancer to Evaluate Whether an Oral 
Starting Dose of 20 mg or 14 mg Daily Will Provide 
Comparable Efficacy to a 24-mg Starting Dose, But Have a 
Better Safety Profile
Investigational Product 
Name:
Lenvatinib (E7080/LENVIMA®)
IND Number:
IND 113656
EudraCT Number:
2014-005199-27
SIGNATURES
Authors:
e
Date
Clinical Pharmacologist
Executive Dir
 Translational 
O
c.
Date
Sharon Xie, PhD
Primary Statistician
Manager, Biostatistics
Oncology Business Group, Eisai Inc.
Date
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-211
Study Protocol Title:
A Multicenter, Randomized, Double-Blind Phase 2 Trial of 
Lenvatinib (E7080) in Subjects With 131I-Refractory 
Differentiated Thyroid Cancer to Evaluate Whether an Oral 
Starting Dose of 18 mg Daily Will Provide Comparable 
Efficacy to a 24-mg Starting Dose, But Have a Better Safety 
Profile
Investigational Product
Name:
Lenvatinib (E7080/LENVIMA®)
IND Number:
IND 113656
EudraCT Number:
2014-005199-27
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7080-G000-211 (2-Arm Design)
Study Protocol 
Title:
A Multicenter, Randomized, Double-Blind Phase 2 Trial of 
Lenvatinib (E7080) in Subjects With 131I-Refractory Differentiated 
Thyroid Cancer to Evaluate Whether an Oral Starting Dose of 18 mg 
Daily Will Provide Comparable Efficacy to a 24-mg Starting Dose, 
But Have a Better Safety Profile
Date:
20 March 2020
Version:
Final Version 1.0


Statistical Analysis Plan
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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...............................................................................................2
LIST OF IN-TEXT TABLES ..........................................................................................4
LIST OF IN-TEXT FIGURES.........................................................................................4
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................5
3
INTRODUCTION.........................................................................................................8
3.1
Study Objectives..................................................................................................8
3.1.1
Primary Objective ......................................................................................8
3.1.2
Secondary Objectives .................................................................................9
3.1.3
Exploratory Objectives...............................................................................9
3.2
Overall Study Design and Plan.............................................................................9
4
DETERMINATION OF SAMPLE SIZE.....................................................................10
5
STATISTICAL METHODS........................................................................................11
5.1
Study Endpoints.................................................................................................11
5.1.1
Primary Endpoints....................................................................................11
5.1.2
Secondary Endpoints................................................................................11
5.1.3
Exploratory Endpoints..............................................................................12
5.2
Study Subjects ...................................................................................................12
5.2.1
Definitions of Analysis Sets......................................................................12
5.2.2
Subject Disposition...................................................................................13
5.2.3
Protocol Deviations ..................................................................................14
5.2.4
Demographic and Other Baseline Characteristics......................................14
5.2.5
Prior and Concomitant Therapy................................................................14
5.2.5.1
Previous Therapies..........................................................................15
5.2.6
Treatment Compliance .............................................................................15
5.3
Data Analysis General Considerations................................................................15
5.3.1
Pooling of Centers....................................................................................15
5.3.2
Adjustments for Covariates ......................................................................15
5.3.3
Multiple Comparisons/Multiplicity...........................................................15
5.3.4
Examination of Subgroups........................................................................15
5.3.5
Handling of Missing Data, Dropouts, and Outliers....................................15
5.3.6
Other Considerations................................................................................16
5.4
Efficacy Analyses ..............................................................................................16
5.4.1
Primary Efficacy Analyses .......................................................................16
5.4.2
Secondary Efficacy Analyses ...................................................................16
5.4.3
Other Efficacy Analyses...........................................................................17


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5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...........................................................................................17
5.5.1
Pharmacokinetic Analyses........................................................................17
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses....17
5.6
Safety Analyses..................................................................................................18
5.6.1
Extent of Exposure...................................................................................18
5.6.2
Adverse Events.........................................................................................18
5.6.3
Laboratory Values ....................................................................................20
5.6.4
Vital Signs................................................................................................21
5.6.5
Electrocardiograms...................................................................................21
5.6.6
Other Safety Analyses ..............................................................................22
5.7
Other Analyses...................................................................................................22
5.8
Exploratory Analyses.........................................................................................22
6
INTERIM ANALYSES...............................................................................................22
7
CHANGES IN THE PLANNED ANALYSES ............................................................22
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................22
8.1
Baseline .............................................................................................................22
8.2
Study Day..........................................................................................................23
8.3
Conversion Rules for Day to Month to Year.......................................................23
8.4
Censoring Rules.................................................................................................23
8.5
Missing Date Handling ......................................................................................25
8.5.1
Adverse Event with Missing Dates ...........................................................25
8.5.2
Medication with Date Missing or Partially Missing ..................................25
8.6
Unscheduled Visits ............................................................................................25
9
PROGRAMMING SPECIFICATIONS .......................................................................25
10
STATISTICAL SOFTWARE......................................................................................25
11
MOCK TABLES, LISTINGS, AND GRAPHS............................................................25
12
REFERENCES............................................................................................................26
13
APPENDICES.............................................................................................................27
13.1
Clinically Significant TEAEs.............................................................................27
13.2
Thyroid Cancer Tumor-Node-Metastasis Staging System...................................28
13.3
Response Evaluation Criteria in Solid Tumors 1.1..............................................30
13.4
Eastern Cooperative Oncology Group Performance Status .................................31
13.5
New York Heart Association Cardiac Disease Classification..............................32
13.6
Common Terminology Criteria for Adverse Events (v4.03)................................33


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LIST OF IN-TEXT TABLES
Table 1
Analysis Sets..........................................................................................13
Table 2
Clinical Laboratory Tests........................................................................20
Table 3
Blood Pressure Grading per CTCAE Version 4.03..................................21
Table 4
Censoring Rules for Progression-Free Survival.......................................24
LIST OF IN-TEXT FIGURES
Figure 1
Study Design for Study E7080-G000-211 (as of Protocol 
Amendment 05)......................................................................................10


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
131I
Radioiodine
β-hCG
beta-human chorionic gonadotropin
AE
adverse event
AJCC
American Joint Committee on Cancer
ALT
alanine aminotransferase
anti-Tg
antithyroglobulin autoantibodies
AST
aspartate aminotransferase
ATC
anatomical therapeutic class
BMI
body mass index
BOR
best overall response
BP
blood pressure
BUN
blood urea nitrogen
CBR
clincial benefit rate
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
CR
complete response
CRF
case report form
CSE
clincially significant treatment-emergent adverse event
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CS
clinically significant
DCR
disease control rate
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
FDA
US Food and Drug Administration
HRQoL
Health-Related Quality of Life


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Abbreviation
Term
INR
International Normalized Ratio
KM
Kaplan-Meier
LDH
lactate dehydrogenase
LLT
lower level term
LVEF
left ventricular ejection fraction
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MUGA
multiple-gated acquisition
NCS
not clinically significant
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PD
progression disease
PFS
progression-free survival
PFS2
progression-free survival after next line of treatment
PK
pharmacokinetic
PR
partial response
PS
performance status
PT
preferred term
pTNM 
primary tumor-node-metastasis staging
Q1
1st Quartile
Q3
3rd Quartile
QD
once daily
RBC
red blood cells
RECIST 1.1
Response Evaluation Criteria in Solid Tumors Version 1.1
RR-DTC
radioiodine-refractory differentiated thyroid cancer
RR
respiratory rate


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Abbreviation
Term
SAE
treatment-emergent serious adverse event
SAP
statistical analysis plan
SD
stable disease
SI
Système International
SOC
system organ class
T4
thyroxine
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
Tg
thyroglobulin
TSH
thyroid-stimulating hormone
UPCR
urine protein-to-creatinine ratio
VEGF
vascular endothelial growth factor
WBC
white blood cells
WHO DD
World Health Organization Drug Dictionary


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3
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 results for Eisai Protocol E7080-
G000-211, A Multicenter, Randomized, Double-Blind Phase 2 Trial of Lenvatinib (E7080) in 
Subjects With Radioiodine-Refractory Differentiated Thyroid Cancer (RR-DTC) to Evaluate 
Whether an Oral Starting Dose of 18 mg Daily Will Provide Comparable Efficacy to a 24-mg 
Starting Dose, But Have a Better Safety Profile. This SAP focuses on the primary analysis 
planned and specified in Protocol Amendment 05 (dated as 21 May 2019). This SAP will be 
finalized and approved before database lock.
This study was initially designed as a 3-arm trial to evaluate whether an oral lenvatinib starting 
dose of 20 mg or 14 mg daily will provide comparable efficacy to a 24-mg lenvatinib starting 
dose, but have a better safety profile in subjects with 131I-refractory differentiated thyroid 
cancer (DTC). Results of new modeling and simulation tests became available, indicating that 
the planned alternate starting doses might not be the appropriate doses to evaluate the study 
hypothesis. Agreement was then reached with the FDA and EMEA to redesign the study to a 
2-arm design, with 1 proposed alternate dose.
As of Protocol Amendment 03, the study design was changed to a 2-arm design to evaluate 
whether an oral lenvatinib starting dose of 18 mg daily will provide comparable efficacy to a 
24-mg lenvatinib starting dose, but have a better safety profile. Consequentially, the sample 
size was changed to 152 subjects, with 76 subjects per arm.  
There will be 2 separate Clinical Study Reports (CSRs): one for the 3-arm design with 41 
randomized subjects and one for the 2-arm design with 152 randomized subjects. The purpose 
of this SAP is to describe the procedures and the statistical methods that will be used to analyze 
and report results for Eisai Protocol E7080-G000-211, 2-arm design. This SAP does not cover 
the analyses of pharmacokinetic (PK)/pharmacodynamics, biomarkers, and HRQoL. The 
analyses of PK/pharmacodynamics data from both parts will be analyzed and reported 
separately. The Health-Related Quality of Life (HRQoL) will also be reported separately.
However, results for both analyses will be briefly summarized in the CSR for the 2-arm design. 
3.1
Study Objectives
3.1.1
Primary Objective
To determine whether a starting dose of lenvatinib 18 mg once daily (QD) will provide 
comparable efficacy (based on objective response rate [ORR] at 24 weeks [ORR24wk]) with an 
improved safety profile compared to 24 mg QD (based on treatment-emergent adverse events 
[TEAEs] of Grade 3 or higher in the first 24 weeks after randomization).


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3.1.2
Secondary Objectives
•
To evaluate progression-free survival (PFS) in subjects treated with lenvatinib doses of 24 
mg and 18 mg QD
•
To evaluate the PFS after next line of treatment (PFS2) in subjects treated with lenvatinib 
doses of 24 mg and 18 mg QD.
•
To evaluate the safety and tolerability of lenvatinib doses of 24 mg and 18 mg QD.
•
To 
evaluate 
the 
PK/pharmacodynamic 
relationship 
between 
exposure 
and 
biomarkers/efficacy/safety, using a mechanistically based approach, if possible.
•
To evaluate the impact of lenvatinib treatment on HRQoL as measured by the instruments 
EQ-5D-3L and FACT-G.
3.1.3
Exploratory Objectives
•
To explore overall survival (OS) in subjects treated with lenvatinib doses of 24 mg and 18 
mg QD.
•
To explore thyroglobulin, thyroid-stimulating hormone (TSH), and other serum 
biomarkers as potential biomarkers for tumor response.
•
To explore DNA sequence variants in genes that might influence PK, safety, or 
pharmacodynamics data.
3.2
Overall Study Design and Plan
This was a multicenter, randomized, double-blind study being conducted as a postmarketing 
commitment to the US Food and Drug Administration (FDA) and the European Medicines 
Agency (EMA) to evaluate whether there was a lower starting dosage of lenvatinib other than 
24 mg QD that could provide comparable efficacy but have a better safety profile in subjects 
with RR-DTC with radiographic evidence of disease progression (PD) within the prior 12 
months.
Eligible subjects should have measurable disease according to Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) and evidence of PD within 13 months before signing 
informed consent (both assessed by independent radiologic review) and were randomly 
assigned to treatment in a 1:1 ratio to receive lenvatinib 24 mg or 18 mg orally QD. The total 
sample size is 152 subjects (76 subjects per arm). Randomization was stratified by age 
(≤65 years or >65 years) and Eastern Cooperative Oncology Group (ECOG) performance 
status (PS) of 0 vs 1 or 2. Study ended when the last subject enrolled completed the Week 24 
tumor assessments or discontinued study drug before Week 24. Subjects received study 
treatment until disease progression, development of unacceptable toxicity, subject requested
to discontinue, withdrew consent or was lost to follow-up, end of the study, or until study 
termination by the sponsor. After PD was observed, subjects were followed for PFS2 and 
survival.


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This study consisted of 2 phases: the Prerandomization/Pretreatment Phase and the 
Randomization/Treatment Phase (see Figure 1). The Schedules of Procedures and Assessments
for both study phases are explained in Table 7 of Protocol Amendment 05. Per protocol, tumor 
assessments were performed during the Prerandomization Phase and then every 8 weeks 
(within the 8th week) from the date of randomization during treatment cycles in the 
Randomization Phase.  Subjects who discontinued treatment without PD in the Randomization 
Phase continued to undergo tumor assessments every 8 weeks until PD was documented or 
another anticancer therapy was initiated. Subjects were then followed every 12 weeks (±1 
week) for survival, PFS2 and all subsequent anticancer treatments received (unless this 
information was not allowed to be provided due to confidentiality) had been recorded until the 
End of Study.
Figure 1. Study Design for Study E7080-G000-211 (as of Protocol Amendment 05)
PD = progressive disease, PFS2 = progression-free survival after next line of anticancer treatment, 
QD = once daily.
4
DETERMINATION OF SAMPLE SIZE
Sample size determination was based on the number of subjects required to detect 
noninferiority of the primary efficacy endpoint, ORR24wk, comparing the 18 mg arm to the 24 
mg arm.  Based on the data from Study 303, the ORR24wk for the lenvatinib 24 mg arm was 
54.4% (142 responders, N=261) and 0.8 % for the placebo arm (1 responder, N=131) and the 
lower 95% CI of the Odds Ratio for lenvatinib 24 mg vs placebo was 21.4.  Assuming a 70% 
retention of the effect of lenvatinib 24 mg versus placebo, the noninferiority margin on the 
Odds Ratio scale was estimated to be 0.40 (i.e, Ha: Odds Ratio [18 mg/24 mg] >0.4).
A sample size of 152 subjects (76 per arm) would provide a statistical power of 80% to declare 
noninferiority, assuming a 1-sided alpha of 0.025, an ORR24wk of 54.4% for lenvatinib 24 mg 
and a true Odds Ratio of 1, with a noninferiority margin of 0.4.


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For the primary safety endpoint, based on data from Study 303, where 70.5% of subjects in the 
lenvatinib 24 mg arm had a TEAE of Common Terminology Criteria for Adverse Events
(CTCAE) Grade 3 or higher during the first 24 weeks, the sample size of 152 subjects provides
a precision for the observed differences between the arms with half-widths of the 95% CI of 
about 15%.
5
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation, median, 1st quartile (Q1), 3rd quartile (Q3), and minimum and maximum values and 
will be specified in the outputs.  Categorical variables will be summarized as the number 
(percentage) of subjects.
Unless otherwise specified, summary reporting will be presented by lenvatinib starting dose
(24 mg, 18 mg) and overall treatment; the analysis set to be used is explained in Table1 (Section 
5.2.1).
5.1
Study Endpoints
All study planned analysis endpoints are explained in this section. Per protocol, tumor 
assessment related endpoints will be defined based on investigator review per RECIST 1.1. 
The tumor assessment schedules are described in Table 7 of Protocol Amendment 05.
5.1.1
Primary Endpoints

ORR24wk as assessed by the investigator using RECIST 1.1. ORR24wk is defined as the 
proportion of subjects with best overall response (BOR) of complete response (CR) or 
partial response (PR) at the Week 24 time point or earlier. The BOR for each subject will 
be determined based on RECIST 1.1 without a requirement for response confirmation.

Rate of TEAEs with CTCAE grades of 3 or higher within 24 weeks after randomization 
(as of the Week 24 time point).
5.1.2
Secondary Endpoints

PFS, defined as the time from the date of randomization to the date of first documentation 
of disease progression, or date of death, whichever occurs first  

PFS2, defined as the time from randomization to second objective disease progression 
(occurring during treatment with next line of anticancer therapy), or death from any cause, 
whichever occurs first  

Overall safety profile and tolerability

Time to treatment discontinuation due to an adverse event (AE)

Number of dose reductions


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
Time to first dose reduction

*Plasma PK lenvatinib exposure parameters

*Interrelationships of lenvatinib exposure, changes in thyroglobulin, TSH, or other 
exploratory serum biomarkers, and changes in tumor burden and PFS

*Relationship of lenvatinib exposure and changes in blood pressure (BP), and AEs of 
weight loss, fatigue, nausea, vomiting, diarrhea, and proteinuria CTCAE grades derived 
from urine protein measurements

*Impact of lenvatinib treatment on HRQoL as assessed using the validated instruments 
EQ-5D-3L and FACT-G
* Will be provided in separate reports.
5.1.3
Exploratory Endpoints

Duration of response, defined as the time from the initial achievement of a response (CR 
or PR) to the date of first documentation of disease progression, or the date of death, 
whichever occurs first

Disease control rate (DCR), defined as the proportion of subjects who have BOR of CR, 
PR, or stable disease (SD). BOR of SD must be achieved at least 7 weeks after 
randomization

Clinical benefit rate (CBR), defined as the proportion of subjects who have BOR of CR,
PR, or durable SD (duration of SD ≥23 weeks after randomization)

OS, measured from the date of randomization until date of death from any cause

*Associations between objective tumor response and serum thyroglobulin (accounting for 
anti-Tg), TSH, and other serum biomarkers (including VEGF, Ang-2, sTie-2, and FGF23)

*Association 
between 
any 
observed 
DNA 
sequence 
variability 
and 
PK, 
pharmacodynamic, and clinical outcome measures including efficacy and safety-related 
endpoints
* Will be provided in a separate report.
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
Full Analysis Set will include all randomized subjects.  This will be the analysis set for all 
efficacy evaluations, which will be analyzed according to the treatment randomized, regardless 
of the treatment actually received.


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Safety Analysis Set will include all subjects randomized and received at least one dose of 
study drug.  This will be the analysis set for all safety evaluations, which will be analyzed 
according to the treatment actually received.
Pharmacokinetic (PK) Analysis Set will include all subjects who received at least one dose 
of study drug and who have evaluable lenvatinib plasma concentration data.
The parameters analyzed for each analysis set are listed in Table 1.
Table 1
Analysis Sets
Analysis Sets
Analyses to be performed
Enrolled 
Subjects
Full
Analysis Set
Safety 
Analysis Set
PK
Analysis Set
Protocol Deviations
●
Disposition
●
Demography & Baseline 
Characteristics
●
Disease History
●
Prior & Concomitant 
Medications
●
Progression-Free Survival
●
Progression-Free Survival 2
●
Overall Survival
●
Tumor Response
●
Drug Exposure
●
Adverse Events
●
Deaths
●
●
Laboratory Tests
●
Vital Signs
●
Electrocardiograms (ECGs)
●
Echocardiography
●
Pharmacokinetics
●
Clinical Biomarkers
●
5.2.2
Subject Disposition
The number of subjects enrolled and the number (percentage) of subjects who were screen 
failures and the primary reason for screen failure will be summarized based on data from the 
Case Report Form (CRF) of Screening Disposition. 
The number of subjects screened, randomized, treated, and with major protocol deviations 
will be counted by site. Subject disposition on study treatment (treatment ongoing at data 
cutoff date, treatment discontinued, and the primary reason for discontinuation) will be 


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summarized. Study status at data cutoff and reason for withdrawal from the study will also 
be summarized using data from survival follow-up. 
5.2.3
Protocol Deviations
Major protocol deviation criteria will be established and all subjects with potential major 
protocol deviations will be identified and reviewed in a blinded manner prior to database 
lock. Major protocol deviations will be summarized by each category and will be listed.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized. Continuous 
demographic and baseline variables include age, body weight and height, body mass index
(BMI), categorical variables include sex, age group (≤65, >65), race, ethnicity, region, body 
weight group (<60 kg, ≥60 kg), ECOG (0, 1, 2), New York Heart Association (NYHA)
classification, and baseline TSH (≤0.5, >0.5 to 2.0, >2.0 to 5.5 μIU/mL).
DISEASE HISTORY
Disease history and characteristics at study entry will be summarized based on data recorded 
on the CRFs, including thyroid cancer pTNM staging at diagnosis, DTC subtype diagnosis, 
stage group at diagnosis, time since diagnosis (original and metastatic), and prior therapy 
(anticancer medications, radiotherapy, previous radioiodine therapy). In addition, locally 
advanced or metastatic DTC will be characterized using the location of both target and 
nontarget lesions at screening, and summarized. The number of metastatic sites per subject 
will also be included in the summary table. 
MEDICAL HISTORY
Subjects with any previous medical condition and current medical condition, as recorded on 
the CRF, will be summarized by system organ class (SOC) and preferred term (PT). The 
Medical Dictionary for Regulatory Activities (MedDRA) version 23.0 will be used.
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) Version 
(WHODDMAR20B3). Prior medications will be defined as medications that started before 
the first dose of study drug. Concomitant medications will be defined as medications that (1) 
started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or (2) started on or after the date of the first dose of study drug up to 28 days after 
the subject’s last dose. Medications that cannot be determined to be 
prior/concomitant/posttreatment because of missing or incomplete dates will be regarded as 
concomitant. 


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The number (percentage) of subjects who took prior medications will be summarized by 
anatomical class (Anatomical Therapeutic Chemical [ATC] Level 1), pharmacological class 
(ATC Level 3), and World Health Organization Drug Name (preferred term). The same 
summary will be repeated for concomitant medications except for thyroxine suppression 
therapy and antihypertensive therapy. Concomitant thyroxine suppression therapy and 
antihypertensive therapy will be summarized separately. In addition, there will be a separate 
summary for P-glycoprotein inhibitors and/or inducers taken as concomitant medications.  
5.2.5.1
Previous Therapies
Previous chemotherapy, VEGF-targeted therapy, radiotherapy, radioiodine therapy, and 
antithyroid cancer surgery will be summarized, and listings will be provided for previous 
anticancer medications, radioiodine therapy, and radiotherapy.
Prior database lock, previous chemotherapy and previous VEGF-targeted therapy will be 
identified by the clinical and coding team based on data from the Previous Anticancer 
Medications CRF page. Similarly, previous antithyroid cancer surgery will be identified 
from the Medical History CRF page.  
5.2.6
Treatment Compliance
Treatment compliance will be summarized by the number (percentage) of subjects with any 
drug interruption not due to investigator request. In addition, the percentage of days that 
study drug was interrupted not due to investigator request will be calculated.
5.3
Data Analysis General Considerations
5.3.1
Pooling of Centers 
This is a multicenter study. Subjects from all centers will be pooled for all analyses.
5.3.2
Adjustments for Covariates
Not applicable.
5.3.3
Multiple Comparisons/Multiplicity
Not applicable. 
5.3.4
Examination of Subgroups
No subgroup analyses are planned for this study.
5.3.5
Handling of Missing Data, Dropouts, and Outliers
Rules for handling full/partial missing dates, and the censoring rules for PFS, PFS2, and OS
are explained in Section 8.4. The handling of missing data in the analyses of ORR, CBR and 


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DCR is explained in Sections 5.4. Any potential outlier values will be investigated and will 
be analyzed in the locked database as originally reported.
5.3.6
Other Considerations
No other consideration.
5.4
Efficacy Analyses
5.4.1
Primary Efficacy Analyses
The noninferiority analysis of ORR24wk between lenvatinib starting doses of 24 mg and 
18 mg will be performed at the 1-sided alpha of 0.025, based on the calculated odds ratio of 
ORR24wk response (18 mg vs 24 mg ) along with its 95% confidence interval (CI) using the 
Cochran-Mantel-Haenszel (CMH) method, stratified by the randomization stratification 
factors. The test will be performed per the 95% CI using the noninferiority margin of 0.4.
Noninferiority will be declared if the lower limit of the 95% CI for the odds ratio is greater 
than 0.4. 
The point estimate of ORR24w for each group will be summarized with the corresponding 95% 
CI using asymptotic normal approximation. Treatment difference (18 mg minus 24 mg) will 
also be estimated with its 95% CI using asymptotic normal approximation. 
SENSITIVITY ANALYSIS
A sensitivity analysis will be performed for overall ORR using the same methods as used for 
ORR24wk.
5.4.2
Secondary Efficacy Analyses
•
The following analyses will be performed on PFS, and censoring rules are detailed in 
Section 8.4:
-
The difference in PFS between lenvatinib starting dose of 24 mg and 18 mg using 
stratified log-rank test with the randomization stratification factors, tested at an alpha 
level of 0.05 
-
The estimate of the hazard ratio calculated from Cox proportional hazard model on PFS 
with lenvatinib starting dose as the independent variable and stratified by the 
randomization stratification factors with a 2-sided 95% CI
-
Kaplan-Meier (KM) estimated quartiles of PFS and their 95% CIs (using the 
generalized Brookmeyer and Crowley method) per lenvatinib starting dose
-
KM estimated PFS rates at 6, 12, 18 and 24 months and their 95% CIs (using 
Greenwood log-log formula) per lenvatinib starting dose
-
KM plot of estimated PFS over time 


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•
The analyses of PFS will be repeated for PFS2, and the censoring rule is detailed in 
Section 8.4
5.4.3
Other Efficacy Analyses
Duration of response (months), defined as the time from the initial achievement of a response
(CR or PR) to the date of first documentation of PD or the date of death, whichever occurs 
first. It will be summarized for subjects with BOR of CR or PR. 
For both endpoints, the censoring rules are the same as those for PFS censoring, when 
applicable. KM estimated quartiles and their 95% CIs per lenvatinib starting dose, using the 
generalized Brookmeyer and Crowley method, will be provided. 
DCR and CBR will be evaluated using the same method as that used for ORRwk24.
OS will be evaluated using the same method as that used for PFS, and censoring rule is detailed 
in Section 8.4.
In addition, waterfall plots will be presented by lenvatinib starting dose for the percentage 
changes from Baseline to postbaseline nadir value in the sum of diameters of target lesions. 
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
5.5.1
Pharmacokinetic Analyses
Individual listings with a summary of plasma concentrations of lenvatinib and a figure 
containing lenvatinib plasma concentrations versus PK sampling time will be provided by 
subject and lenvatinib starting dose (18 vs 24 mg) for subjects in the Pharmacokinetic Analysis 
Set. Other PK analyses will be described in a separate SAP for PK/PD/Biomarkers.
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Summary of TSH, thyroglobulin (Tg), anti-Tg antibodies and other serum biomarkers 
(including VEGF, Ang-2, sTie-2, FGF23) will be provided by visit using Safety Analysis Set.
Listings and Box and Whisker plots of serum pharmacodynamic results over time and the 
figure for the percentage change from Baseline for serum pharmacodynamic results over time 
will be provided.
Other pharmacodynamic and biomarker analyses will be described in a separate SAP for 
PK/PD/Biomarker.


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5.6
Safety Analyses
All safety analyses will be performed on the Safety Analysis Set.  Safety data, presented by 
the starting lenvatinib dose of 24 mg or 18 mg and overall will be summarized on an “as 
treated” basis using descriptive statistics (i.e., n, mean, standard deviation, median, 
minimum, and maximum values for continuous variables; n [%] for categorical variables). 
Safety variables include TEAEs, TEAEs with CTCAE Grade ≥3, intolerable TEAEs of 
CTCAE Grade 2 (based on data collected in CRF), treatment-related TEAEs, treatment-
emergent serious adverse events (SAEs), clinical laboratory parameters, vital signs, 12-lead 
ECG results, ECOG PS scores, and left ventricular ejection fraction (LVEF). Abnormal 
values will be flagged.
Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.
5.6.1
Extent of Exposure
Treatment period consisted of 28-day blinded study treatment cycles (i.e., 1 to 28 days per 
cycle) (Section 3.2). Per protocol, subjects received 1 of the 2 starting doses, lenvatinib 24 
mg/day or lenvatinib 18 mg/day.  Dose reductions would occur in succession based on the 
subject’s previous dose level (24, 20, 14, 10, and 8 mg QD, or 18, 14, 10, 8, and 4 mg QD, 
respectively).
The following analyses will be performed:
•
Duration of Treatment (months): (last dose date – first dose date + 1) / (365.25/12)
•
Number of Subject-months: sum of treatment time (in months) for all subjects (including 
dose interruption).
•
Total dose (mg) taken per subject
•
Dose intensity (mg/day) per subject (i.e., total dose/treatment duration), relative dose 
intensity (%) per subject (i.e., percentage of dose intensity relative to the planned dose at 
Baseline)
•
Dose modification (reduction, interruption), frequency of dose modification
•
Treatment discontinuation due to AE (from treatment disposition page)
•
Time to first dose reduction (weeks), time to treatment discontinuation due to AE (weeks). 
Both will be analyzed using KM method (same as for PFS, see Section 5.4.1) and estimated
quartiles and the 95% CI will be presented.
5.6.2
Adverse Events
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the MedDRA.  Adverse events will be coded to 
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MedDRA PT and primary SOC will also be captured in the database. The CTCAE grading 
(version 4.03) will be included in the database.
A TEAE is defined as an AE that emerged during treatment (from time of first dose up to 28 
days following the last dose of study drug), having been absent pretreatment (Baseline) or 
•
Reemerged during treatment, having been present pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsened in severity during treatment relative to the pretreatment state, when the AE was 
continuous
Only TEAEs will be summarized. A subject will be counted only once within each category 
(i.e., SOC, PT, worst grade, or other specific category to be summarized in table) even if the 
subject experienced more than 1 TEAE within the category. All AEs, treatment-emergent or 
otherwise, will be presented in subject data listings.
For the analysis of the primary safety endpoint of rate of TEAEs with CTCAE Grade ≥3
within 24 weeks after randomization (as of the Week 24 time point), the number (percentage) 
of subjects with TEAEs of CTCAE Grade ≥3 as of Week 24 will be reported; the difference 
in frequency between the treatments (18 mg minus 24 mg) will be presented with 95% CI, 
using asymptotic normal approximation. In addition, the number (percentage) of subjects 
with TEAEs with CTCAE Grade >=3 as of the Week 24 will be summarized by SOC and 
PT. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC, PT and worst CTCAE grade. The number (percentage) of subjects with TEAEs will 
also be summarized by PT and worst CTCAE grade.
The number (percentage) of subjects with treatment-related TEAEs, TEAEs leading to 
treatment discontinuation, TEAEs leading to dose reduction/interruption, will be summarized 
by SOC, PT and worst CTCAE grade. All SAEs, treatment-related SAEs, fatal TEAEs, and 
nonfatal SAEs will be summarized by SOC and PT. Treatment-related TEAEs include those 
events considered by the investigator to be related to study treatment or TEAEs with a 
missing causality on the CRF. 
In addition, summaries of clinically significant TEAEs (CSEs) (i.e., subject incidence, time 
to first onset of Grade 3 or 4) will be provided.  Appendix 13.2 includes the list of CSEs.  
These CSEs include those AEs known to be of concern with lenvatinib or of VEGF-targeted 
agents in general.
TEAEs, SAEs, treatment-related TEAEs, treatment-related SAEs, CSEs will also be 
summarized by PT in decreasing frequency.
The number (percentage) of subjects with all deaths and deaths on treatment or within 30 days 
of last lenvatinib dose will be summarized.


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Subject data listings for (1) all AEs, (2) AEs of CTCAE Grade 2 (intolerable) or above, 
(3) serious adverse events, (4) fatal AEs, (5) all deaths, (6) AEs leading to treatment 
discontinuation, and (7) AEs leading to dose reduction or interruption will be provided.
5.6.3
Laboratory Values
Clinical laboratory test parameters, per category, are listed in Table 2. The results will be 
standardized using System International (SI) units and categorized according to CTCAE
grade (v4.03) (see protocol Appendix 13.8). 
Table 2
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, MCH, MCHC, MCV, platelets, RBC count, and 
WBC count with differential (bandsa, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), INRb
Chemistry
Bicarbonatea, chloride, potassium, sodium, BUN or urea, creatinine, glucose, 
magnesium, phosphorus, calcium, albumin, total protein, alkaline 
phosphatase, ALT, AST, conjugated (direct) bilirubin, total bilirubin, TSH, 
Amylasec, lipase, CPKc, LDHf, 
Total cholesterol, triglycerides, free T4 levelsf
Urine Dipstick Testingd
glucose, hemoglobin (or blood), ketones, pH, proteine, specific gravity
ALT = alanine aminotransferase, AST = aspartate aminotransferase, BUN = blood urea nitrogen, 
CPK = creatine phosphokinase, β-hCG = beta-human chorionic gonadotropin, INR = International Normalized 
Ratio, LDH = lactate dehydrogenase, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular 
hemoglobin concentration, MCV = mean corpuscular volume, RBC = red blood cells, T4 = thyroxine, 
TSH = thyroid stimulating hormone, UPCR = urine protein-to-creatinine ratio, WBC = white blood cells. 
a: Optional if results cannot be obtained from the local laboratory.
b: INR should only be performed as part of the screening assessment and when clinically indicated.
c: Amylase isoenzymes (pancreatic and salivary type) and CPK isoenzymes (CK-MM and CK-MB) should be 
evaluated if amylase or CPK is greater than 3 × the upper limit of normal.
d: If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory.
e: If urine protein is ≥2+, then a 24-hour urine collection or an immediate spot UPCR test should be done to 
quantify the 24-hour urine protein excretion.
f: For screening only.
Each parameter will be summarized or plotted by visit (with at least 10% of subjects) for
actual value observed and change from Baseline. For thyroid stimulating hormone (TSH), 
the lowest postbaseline values will be summarized per category (≤0.5; >0.5–2.0; >2.0–5.5; 
>5.5 mIU/L). 
Shift tables from Baseline to worst postbaseline CTCAE grade will be provided for 
hematology, chemistry, dipstick, and 24-hour urine collection. Grade 3 or 4 treatment-
emergent laboratory results for hematology and chemistry will also be summarized.


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5.6.4
Vital Signs
Each parameter of vital signs assessments (diastolic and systolic BP, pulse rate, respiratory 
rate, temperature) and body weight will be summarized/plotted by visit (only those having 
results for ≥10% of subjects) for the actual value observed and its change from Baseline.  
Hypertension, based on diastolic and systolic BP measurements, will also be summarized as
shift from Baseline to worst postbaseline grade (see Table 3 for CTCAE grading).
Table 3
Blood Pressure Grading per CTCAE Version 4.03
5.6.5
Electrocardiograms
Each parameter of ECG assessments (heart rate, QT interval, QTcB interval, QTcF interval, 
RR interval) will be summarized by visit based on actual value observed and its change from 
Baseline. 
ECG findings (normal; abnormal, not clinically significant [NCS]; abnormal, clinically 
significant [CS]) will also be summarized as shift from Baseline to the worst value during the 
treatment period. In addition, the number (percentage) of subjects with at least 1 
postbaseline abnormal ECG result in QTc, using both Bazett’s (QTcB) and Fridericia’s 
(QTcF) correction formulas, during the treatment period will be summarized. Clinically 
abnormal ECG results in QTcB and QTcF will be categorized as follows:
•
Absolute QTc interval prolongation:
-
≤450 ms
-
>450 ms - ≤480 ms  
-
>480 ms - ≤500 ms  
-
>500 ms
•
Increase from Baseline in QTc interval:
-
≤30 ms
-
>30 ms - ≤60
-
>60 ms 


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5.6.6
Other Safety Analyses
Shift tables for ECOG PS from Baseline to worst postbaseline score (0 to 4) will be 
presented.
Descriptive statistics for LVEF as assessed by either echocardiogram or MUGA and changes
from Baseline will be summarized. 
5.7
Other Analyses
Health-related Quality of Life will be described in a separate SAP. 
5.8
Exploratory Analyses
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriately titled and labeled as exploratory and will be clearly 
distinguished from planned analyses when results are reported in the Clinical Study Report.
6
INTERIM ANALYSES
No interim analysis is planned for this study.
7
CHANGES IN THE PLANNED ANALYSES
This SAP focuses on the analyses for the 2-arm design of the study. 
The Safety Analysis Set will be used for the summary table of biomarker parameters, while 
the Pharmacodynamic Analysis Set will be defined in a separate SAP for PK/PD analyses. 
The exploratory endpoint of Duration of Clinical Benefit will not be analyzed in this study as 
it is not a widely used and well-defined endpoint; furthermore, it was not included in the RR-
DTC Phase 3 study, E7080-G000-303. 
Clinically abnormal ECG results based on QTcB and QTcF will be summarized the same 
way as done in Study E7080-G000-303. The categories are slightly different than the ones 
stated in the study protocol.  
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
Baseline
Baseline is defined as the nonmissing value most recently collected prior to the first dose of
study drug. 


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8.2
Study Day
Study Day is defined as the day counting from the first lenvatinib dose date as follows:
•
For a date on or after the first dosing date, Study Day= event date – first dose date of 
study drug +1
•
For a date prior to the first dosing date, Study Day= event date – first dose date of study 
drug
8.3
Conversion Rules for Day to Month to Year
1 month = 30.4375 days; 1 year = 365.25 days. 
8.4
Censoring Rules
The censoring rules for PFS are explained in Table 4, based upon investigator’s tumor 
assessments and the FDA Guidance for Industry, Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2007).  
For PFS2, if a subject did not have PD (solely based on the investigator-provided information 
on the Survival Status eCRF) after starting a new anticancer treatment, or did not die during 
the study, the subject will be censored on the date last known to be alive.
For OS, in the absence of confirmation of death, subjects will be censored either at the date
last known to be alive or the date of data cutoff, whichever is earlier.


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Table 4
Censoring Rules for Progression-Free Survival
No.
Situation
Date of Progression or Censoring
Outcome
1
No baseline or postbaseline tumor 
assessments
Date of randomization
Censored
2
Progression documented between 
scheduled visits
Date of first radiologic PD assessment 
Progressed
3
No progression at the time of data cutoff 
Date of last adequate radiologic 
assessment prior to or on date of data 
cutoff
Censored
4
New anticancer treatment started
Date of last adequate radiologic 
assessment prior to or on date of new 
anticancer treatment
Censored
5
Death before first PD assessment
Date of death
Progressed
6
Death between adequate assessment visits*
Date of death
Progressed
7
Death or progression after more than one
missed visit** or after 28 days from the last 
dose of study treatment
Date of last adequate radiologic 
assessment before missed tumor 
assessments
Censored
8
Treatment discontinuation for reasons other 
than PD
Date of last radiologic assessment before 
treatment discontinuation
Censored
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease.
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined 
by investigators. 
** More than 1 missed visits is defined as having either 1 of the following 2 durations being longer than 18 
weeks - 1 day, which is 125 days ( = ((8+1) × 2 × 7) – 1) for subjects on the every-8-week tumor assessment 
schedule in this study:
a. Duration between 2 consecutive tumor assessments
b. Duration between the last adequate tumor assessment and death or PD
The priority of the censoring rules is as follows:
1. If the subject had PD or death, the following sequence will be applied:

If a subject did not have a baseline tumor assessment (No. 1), the subject will be censored on the date 
of randomization.  However, if the subject died within 125 days (18 weeks – 1 day) after 
randomization and did not receive new anticancer treatment, the date of death will be the PFS event 
date (not censored).

If a subject had new anticancer treatment before PD or death (No. 4), the subject will be censored on the 
date of the last tumor assessment prior to or on the start date of new anticancer treatment.

If PD is reported after the drug discontinuation visit, the subject will be censored at the date of last 
radiologic assessment before drug discontinuation except when PD occurred at the same visit as drug 
discontinuation (No. 8). If PD occurred within 4 weeks of drug discontinuation, it will be considered 
PD at the drug discontinuation visit and counted as a PFS event.

If a subject missed more than 1 assessment before PD or death (No. 7), the subject will be censored on 
the date of the last tumor assessment before PD or death.  Note that if a subject is censored by both 
this criterion and the anticancer treatment criteria, the earliest censoring date will be used.

Otherwise, if a subject had an event (No. 2, No. 5 or No. 6), the earliest event date will be used.
2. If a subject did not have PD or death, the censoring date will be the earliest censoring date if the subject met 
multiple censoring criteria (No. 1, No. 3, No. 4, or No. 7).


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8.5
Missing Date Handling
Missing data will not be imputed unless otherwise stated in the SAP or in the footnote of an 
output. Missing data will not be included in any analysis unless otherwise specified. When 
relevant, the number of subjects with missing data will be presented.
8.5.1
Adverse Event with Missing Dates
If the missing start and/or end dates of the AE do not indicate that the AE started prior to the 
start of study drug or after the 28th day after the last dose of study drug, it will be classified 
conservatively as a TEAE (Section 5.6.2). This data handling is only for the determination of 
TEAEs; no imputation will be performed to AE start/end dates in datasets and listings.
8.5.2
Medication with Date Missing or Partially Missing
See Section 5.2.5 for the missing date handling in determination of prior and concomitant
medications. 
8.6
Unscheduled Visits
Data from unscheduled visits (e.g., vital signs or laboratory tests) will be excluded from the 
by-visit summary but will contribute to the worst value in required summary tables. Listings 
will include all visits, both scheduled and unscheduled.
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications will be provided in a 
separate document (analysis datasets specification).
10 STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS version 9.3 or higher.
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study tables, listings, and graphs (TLG) shells will be provided in a separate document, 
which will show the content and format of all tables, listings, and graphs in detail.


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12 REFERENCES
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute, Washington, DC, USA, June 14, 2010.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1).  Eur J 
Cancer. 2009;45:228-47.


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13 APPENDICES
13.1
Clinically Significant TEAEs
The following are the Clinically Significant AE groups considered in analyses:
1. Arterial Thromboembolic Events
2. Cardiac Dysfunction
3. Fistula Formation
4. GI Perforation
5. Hemorrhage
6. Hepatotoxicity
7. Hypertension
8. Hypocalcemia
9. Hypothyroidism
10. Palmar Plantar Erythrodysesthesia Syndrome
11. Posterior Reversible Encephalopathy Syndrome
12. Proteinuria
13. QT Prolongation
14. Renal Events


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13.2
Thyroid Cancer Tumor-Node-Metastasis Staging System
The TNM (tumor-node-metastasis) Staging System is the most widely used system for cancer 
staging in the world.  Created by the American Joint Committee on Cancer (AJCC), a 
distinguished group of experts from national healthcare organizations and major cancer 
centers around the country, the system defines cancer stage by describing:
Primary Tumora
Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor 2 cm or less in greatest dimension limited to the thyroid
T2
Tumor more than 2 cm but not more than 4 cm in greatest dimension limited to the thyroid
T3
Tumor more than 4 cm limited to the thyroid or any tumor with minimal extrathyroid 
extension (eg, extension to sternothyroid muscle or perithyroid soft tissues)
T4a
Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, 
larynx, trachea, esophagus, or recurrent laryngeal nerve
T4b
Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels
Regional Nodesb
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
N1a
Metastasis to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)
N1b
Metastasis to unilateral, bilateral, or contralateral cervical or superior mediastinal lymph 
nodes
Distant Metastasis
Mx
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis


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Papillary or Follicular Carcinoma
Stage Groupc
T Stage
N Stage
M Stage
Under 45 Years
I
Any T
Any N
M0
II
Any T
Any N
M1
45 Years and Older
I
T1
N0
M0
II
T2
N0
M0
III
T3
N0
M0
T1
N1a
M0
T2
N1a
M0
T3
N1a
M0
IVA
T4a
N0
M0
T4a
N1a
M0
T1
N1b
M0
T1
N1b
M0
T2
N1b
M0
T3
N1b
M0
T4a
N1b
M0
IVB
T4b
Any N
M0
IVC
Any T
Any N
M1
a.
All categories may be subdivided: (a) solitary tumor, (b) multifocal tumor (the largest determines the 
classification).
b.
Regional nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.
c.
Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic 
(undifferentiated) carcinoma.


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13.3
Response Evaluation Criteria in Solid Tumors 1.1
Tumor response assessments in this clinical trial will use Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) based on the 2009 article by Eisenhauer, et al. entitled, New 
Response Evaluation Criteria in Solid Tumors:  revised RECIST guideline (version 1.1).
The sole modification to RECIST 1.1 to be implemented in this study is that chest x-rays 
may not be used to follow disease; only CT scans may be used to follow chest disease.  As 
required by RECIST 1.1, the protocol states that the minimum duration of SD is 7 weeks 
following the date of first dose of study drug.
The Eisenhauer article, published in the European Journal of Cancer, is available online at:  
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733.


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13.4
Eastern Cooperative Oncology Group Performance Status
Scale
ECOG Performance Status
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light house work, office work).
2
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  
Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or 
chair.
5
Dead.
ECOG = Eastern Cooperative Oncology Group.
Adapted from Oken MM, et al. Am J Clin Oncol. 1982;5:649-55.


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13.5
New York Heart Association Cardiac Disease Classification
The NYHA cardiac disease classification provides a functional and therapeutic classification 
for the prescription of physical activity for patients with heart failure, based on cardiac 
functional capacity.  Based on NYHA definitions, subjects with heart failure are to be 
classified as follows:
Class
NYHA Status
Class I
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II
Subjects with slight, mild limitation of activity; they are comfortable at rest 
or with mild exertion.
Class III
Subjects with marked limitation of activity; they are comfortable only at 
rest.
Class IV
Subjects who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest.
NYHA = New York Heart Association.
Adapted from The Criteria Committee of the New York Heart Association.  Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels.  9th ed. 1994:253-6.


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13.6
Common Terminology Criteria for Adverse Events (v4.03)
The NCI’s Common Terminology Criteria for Adverse Events (CTCAE) v4.0 [published 28 
May 2009 (v4.03:  14 June 2010)] provides descriptive terminology to be used for adverse 
event reporting in clinical trials.  A brief definition is provided to clarify the meaning of each 
AE term.  To increase the accuracy of AE reporting, all AE terms in CTCAE version 4.0 
have been correlated with single-concept, Medical Dictionary for Regulatory Activities 
(MedDRA®) terms.
CTCAE v4.0 grading refers to the severity of the AE.  CTCAE grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on the general guideline for 
activities of daily living:
Grade
CTCAE Status
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2
Moderate: minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL.a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b
4
Life-threatening consequences: urgent intervention indicated.
5
Death related to adverse event.
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.0.  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 25 Jun 2015).
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
(Accessed 25 Jun 2015).


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SIGNATURE PAGE
Author:  
Date
Approval:
Date
Date
PPD
PPD
PPD