Clinical trial NCT02657369
Conditions: Thyroid Carcinoma, Anaplastic
Keywords: Lenvatinib Thyroid Cancer, Anaplastic Lenvima E7080
Sponsor: Eisai Inc.
Start date: 2016-07-07; Completion date: 2018-09-26
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The primary purpose of the study is to evaluate objective response rate (\[ORR\]: complete response \[CR\] and partial response \[PR\]) by investigator review in participants with anaplastic thyroid cancer (ATC) treated with lenvatinib.

Detailed description:

Arms: arm 1: Participants will receive lenvatinib 24 milligrams (mg) (2 10-mg capsules and one 4-mg capsule) once daily by oral administration at approximately the same time each morning for up to approximately 24 months.
Interventions: intervention 1: Lenvatinib 24 mg
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol
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FINAL 24 May 2016
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-M000-213
Study Protocol 
Title:
An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib 
for the Treatment of Anaplastic Thyroid Cancer (ATC)
Sponsor: 
Eisai Inc.
100 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)
Indication:
Anaplastic Thyroid Cancer
Phase:
2
Approval Date:
V1.0
09 Nov 2015 (Original Protocol)
V2.0
12 Jan 2016 (Amendment 01)
V3.0
24 May 2016 (Amendment 02)
IND Number:
113656
EudraCT Number:
2015-001929-17 
GCP Statement:
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information that 
is not authorized in writing by the sponsor is strictly prohibited.  Such 
information may be used solely for the purpose of reviewing or 
performing this study.


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REVISION HISTORY
Revisions to Amendment 02 of the protocol (Version 3.0)
Date: 24 May 2016
Change
Rationale
Affected Protocol 
Sections
Global change to revise: 
LENVIMA™  to 
LENVIMA®
LENVIMA now has a registered 
trademark

Sections 7.1.2, 9.4.4, 
9.4.7.1, and 10
Investigational Product 
Name revised to:  Lenvatinib
(E7080)
Revised to be more consistent 
with naming convention used by 
Eisai.

Title Page

Protocol Signature 
Page

Investigator’s 
Signature Page
Frequency of scheduled 
tumor assessments decreased
from every 6 weeks ±1 week 
throughout the study to every 
6 weeks ±1 week for the first 
6 months, then every 8 weeks 
±1 week thereafter.
Feedback from Steering 
Committee members and other 
investigators suggests that every 6 
weeks tumor assessments are not 
necessary beyond 24 weeks of the 
study and the interval can be 
extended to every 8 weeks. Rapid 
progressors will be off the study 
by 24 weeks and endpoints will 
have already been collected.

Synopsis (Study 
Design, Efficacy 
Assessments)

Section 9.1.3

Section 9.3.3

Section 9.5.1.3.1

Table 4 (Schedule of 
Assessments, and 
footnotes “c” and 
“u”)
Inclusion Criterion for blood 
pressure revised.
In consideration of feedback from 
MHRA (letter dated 01 Mar 
2016) and to be consistent with 
the SmPC and Company Core 
Data Sheet for lenvatinib, blood 
pressure inclusion criteria is 
revised to ≤140/90 mmHg at 
screening

Synopsis (Inclusion 
Criterion #8)

Section 9.3.1 
(Inclusion Criterion 
#8)
Exclusion Criterion for prior
treatment with lenvatinib and 
any TKI is revised with an 
exception for radiation plus 
reduced dose TKI.
Feedback from Steering 
Committee members and other 
investigators suggests that 
enrollment will be enhanced if 
allow subjects previously treated 
with combination therapy and 
reduced dose TKI given for the 

Synopsis (Exclusion 
Criterion #3)

Section 9.3.2 
(Exclusion Criterion 
#3) 


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Revisions to Amendment 02 of the protocol (Version 3.0)
Date: 24 May 2016
Change
Rationale
Affected Protocol 
Sections
purpose of radiosensitization.
Change in Exclusion 
Criterion to indicate anti-
cancer treatment within 14 
days before the first dose of 
study drug.
Feedback from Steering 
Committee members and other 
investigators suggests that 21 day 
washout is not necessary and can 
be lowered to 14 days.

Synopsis (Exclusion 
Criterion #5)

Section 9.3.2 
(Exclusion Criterion 
#5) 
Change in Exclusion 
Criterion to:
a) more clearly define 
abstinence as one of the 
highly effective methods of 
contraception 
b) provide a new bullet to 
indicate exclusion of subjects 
who use oral hormonal 
contraceptives and do not 
agree to adding a barrier 
method. 
c) to clarify that sites outside 
of the EU will be permitted 
to use a double barrier 
method of contraception
In consideration of feedback from 
MHRA (letter dated 01 Mar 
2016), for trials of long duration, 
such as 213, the exclusion 
criterion wording with respect to 
the definition of abstinence needs 
to be revised.  Also, the exclusion 
criterion specifying that women 
using oral hormonal 
contraceptives must add a barrier 
method is now provided as a 
separate bullet for increased 
clarity.  Lastly, non-EU 
participants may use a double 
barrier method of contraception, 
as appropriate.

Synopsis (Exclusion 
Criterion #16)

Section 9.3.2 
(Exclusion Criterion 
#16) 
Management of
Hypertension section revised 
to clarify guidelines when 
blood pressure measurements  
SBP ≥140 up to <160 mmHg
or DBP ≥90 up to <100 
mmHg
In consideration of feedback from 
MHRA (letter dated 01 Mar 
2016) and to be consistent with 
the SmPC and Company Core 
Data Sheet for lenvatinib, 
management of hypertension is 
revised and clarified, as required. 

Synopsis 
(Management of 
Hypertension)

Section 9.4.1.1.1


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Revisions to Amendment 02 of the protocol (Version 3.0)
Date: 24 May 2016
Change
Rationale
Affected Protocol 
Sections
Multigated acquisition 
(MUGA) scan is offered as 
an alternative to 
echocardiograms for subjects 
who had prior anthracyclines.
In consideration of feedback 
provided by Steering Committee 
members, MUGA may be 
performed for certain subjects 
instead of echocardiograms to 
facilitate logistics.

Synopsis (Safety 
Analyses)

Section 9.5.1.5.7

Table 4 (Schedule of 
Assessments and 
footnote “o”)

Section 9.7.1.8

List of Abbreviations
Added text to provide 
guidelines for stopping and 
restarting lenvatinib if 
subject requires surgery 
during the study.
To provide investigators with 
specific instructions on how to 
adjust lenvatinib dosing under 
circumstances where elective 
surgery is required during the 
study.

Section 9.4.7
Lenvatinib drug-drug 
interactions text revised to 
clarify concomitant use of 
CYP3A, PgP and BCRP 
inhibitors, and CYP3A and 
PgP inducers. Additional 
references also provided.
Text revisions provided for 
greater clarity regarding use of 
lenvatinib without the need for 
dose adjustment when used with 
CYP3a, PgP and BCRP 
inhibitors, and CYP3A and PgP 
inducers. 

Section 9.4.7.1

Section 10
In Table 3, the laboratory 
tests, calcium and 
phosphorus, moved from 
“electrolytes” category to 
“other” category.
Calcium and phosphorus are not 
considered electrolytes

Table 3 (Clinical 
Laboratory Tests)
Revised criteria for obtaining 
repeat measurements for 
blood pressure elevations.
To remain consistent with  
revisions to text made in the
Management of Hypertension 
Section 9.4.1.1.1 (see above). 

Section 9.5.1.5.4

Table 4 (footnote 
“k”)
Frequency of pregnancy 
testing increased to Day 1 
visit of each cycle (Cycle 2 –
Additional pregnancy testing in 
included in response to MHRA 
letter (dated 01 Mar 2016), 

Section 9.5.1.5.7

Table 4 (Schedule of 
Assessments and 


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Revisions to Amendment 02 of the protocol (Version 3.0)
Date: 24 May 2016
Change
Rationale
Affected Protocol 
Sections
onwards).
requesting that pregnancy be 
performed once per cycle.
footnote “t”)
Telephone call on C1D8 to 
assess subjects for early 
toxicity replaced by clinic 
visit to obtain vitals. Original 
footnote “u” is deleted.
C1D8 visit now required due to 
mandatory requirement for blood 
pressure measurement in Europe
(per MHRA letter dated 01 Mar 
2016). 

Table 4 (Schedule of 
Assessments).
Added text requiring vital 
signs and urinalysis be 
performed at all unscheduled 
visits.
Due to lenvatinib toxicity 
resulting in hypertension and/or 
proteinuria, blood pressure and 
urinalysis are required at all 
unscheduled clinic visits.

Table 4 (Schedule of 
Assessments) 
footnotes “k” and “s”
Revisions to Amendment 01 of the protocol (Version 2.0)
Date: 12 Jan 2016
Change
Rationale
Affected Protocol 
Sections
Change in Exclusion Criteria 
with regard to description of 
highly effective methods of 
contraception that may be 
used by subjects 
This is a global study that will 
also use investigative sites in 
Europe.  Therefore, text is revised 
to conform with ex-US 
requirements and description for 
highly effective methods of 
contraception.

Synopsis (Exclusion 
Criterion #16, first 
bullet)

Section 9.3.2 
(Exclusion Criterion 
#16, first bullet)


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib for the Treatment of 
Anaplastic Thyroid Cancer (ATC)
Investigator(s)
Unknown
Sites
Approximately 20 centers in the United States (US), European Union (EU), and other regions, in 
collaboration with the International Thyroid Oncology Group (ITOG)
Study Period and Phase of Development
Approximately 24 months, which include 18 months of enrollment and 6 months of follow-up.
Phase 2
Objectives
Primary Objective

The primary objective of the study is to evaluate objective response rate ([ORR]: 
complete response [CR] and partial response [PR]) by investigator review in subjects with 
anaplastic thyroid cancer (ATC) treated with lenvatinib.
Secondary Objectives
The secondary objectives of the study are:

To evaluate 12-week progression-free survival (PFS)

To evaluate 6-month overall survival (OS) 

To evaluate median PFS and median OS

To evaluate safety and tolerability of lenvatinib in subjects with ATC
Exploratory Objectives

To explore clinical benefit rate ([CBR]: CR + PR + durable stable disease [SD]
≥23 weeks) 

To explore disease control rate ([DCR]: CR + PR + SD) 

To explore duration of response (DOR)

To identify and explore tumor and blood biomarkers that correlate with clinical 
outcomes, including efficacy
Study Design
This is an open-label, single arm, multicenter, Phase 2 study in subjects with ATC. 
A descriptive interim analysis, which requires the first 20 evaluable subjects, will be implemented 
in the study.  If the number of responders is 3 or less (ORR ≤15%), the enrollment will be halted 
and the safety and efficacy data will be further evaluated before making the decision of stopping 
the study permanently.  Otherwise, the enrollment will be continued to 57 evaluable subjects.  


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Since early stopping is not expected, to minimize the impact of interim analysis to clinical study 
operation, enrollment will not be halted after the first 20 evaluable subjects while waiting for the 
interim analysis results.  Therefore, there will be no enrollment gap for the interim analysis.
Subjects should have measurable disease according to Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1.
This study consists of 3 Phases: a Pretreatment Phase (Screening visit), a Treatment Phase 
(starting Cycle 1, Day 1), and a Posttreatment Phase (End of Treatment visit and survival 
follow-up).
The Pretreatment Phase will last no longer than 21 days and will include a Screening Period to 
establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease 
characteristics prior to treatment. 
The Treatment Phase will begin at the time of lenvatinib administration on Day 1 of Cycle 1 and 
end following the last dose of lenvatinib.  Subjects will be treated with lenvatinib dose of 24 mg 
once daily by oral administration.  Subjects will undergo safety and efficacy assessments.  
Subjects will discontinue treatment with lenvatinib at the time of disease progression, 
development of unacceptable toxicity, withdrawal of consent, or study termination by the sponsor. 
The Posttreatment Phase will start at the End of Treatment visit and will continue as long as the 
subject is alive or until the study subject withdraws consent.  Subjects who discontinue study 
treatment before disease progression will continue to undergo tumor assessment every 6 weeks 
±1 week for the first 24 weeks and every 8 weeks ±1 week thereafter, until documentation of 
disease progression or start of another anti-cancer therapy.  Follow-up assessment for survival 
will be performed every 12 weeks ±1 week.
Number of Subjects
Approximately 76 subjects will be enrolled in order to obtain 57 evaluable subjects.
Inclusion Criteria
1.
Males or females age ≥18 years at the time of informed consent form (ICF).
2.
Subjects must have histological diagnosis consistent of ATC. Cytologic diagnosis by fine 
needle aspiration alone is not sufficient.  Histologic diagnosis may be made by core needle 
biopsy, incisional biopsy, thyroidectomy, or other surgical biopsy.  Fresh tumor biopsies 
(re-biopsy) should be obtained whenever feasible. The central pathology review may take 
place prior to or after the subject starts treatment with lenvatinib. 
a.
Central review of pathology is required for study participation, but not required prior 
to enrollment or start of treatment in order to avoid delay. If the results of central 
pathology review are not available prior to the start of study treatment, the 
confirmation of diagnosis of ATC at the local laboratory is mandatory prior to 
scheduled start of treatment with lenvatinib. 
b.
If central pathology review indicates a diagnosis other than ATC, the subject may 
continue treatment with lenvatinib per standard of care, at the discretion of the 
treating investigator.  Subjects deemed to have another diagnosis (not ATC) will be 
taken off this study and replaced for the purpose of efficacy analyses.
c.
Differentiated thyroid carcinoma (DTC) with focus loci of ATC is allowed.  If a 
subject has pathology showing a small focus of ATC arising out of DTC and the 
measurable disease is not fully consistent with ATC, confirmation of ATC by biopsy 
is required.  
d.
An incidental focus of medullary thyroid cancer (MTC), DTC, and/or poorly 


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differentiated thyroid cancer in a subject with ATC is allowed.
e.
Histological diagnosis of ATC made through surgical resection is also acceptable.
3.
Prior neoadjuvant, adjuvant or palliative chemotherapy for ATC is allowed.
4.
Measurable disease based on investigator’s assessments meeting the following criteria:
a.
At least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or 
≥15 mm in the short-axis diameter for a lymph node which is serially measurable 
according to RECIST 1.1 using computerized tomography (CT) or magnetic 
resonance imaging (MRI).
b.
Lesions that have had external beam radiotherapy  or locoregional therapies such as 
radiofrequency  ablation must show evidence of subsequent progressive disease 
(substantial size increase of ≥20%) to be deemed a target lesion.
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 1 month prior to enrollment.
6.
All previous chemotherapy or radiation therapy-related toxicities, except dry mouth, 
dysphagia, esophagitis, mucositis, alopecia, and irreversible late sequelae of radiation therapy,
must have resolved to Grade 0 or 1 per Common Terminology Criteria for Adverse Events 
(CTCAE v 4.03), and all wounds from prior surgery must have adequately recovered.
7.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8.
Blood pressure (BP) ≤ 140/90 mmHg at screening with or without antihypertensive 
medications and no change in antihypertensive medications within 1 week prior to 
Cycle 1/Day 1.
9.
Adequate renal function as evidenced by calculated creatinine clearance ≥30 mL/min 
according to the Cockcroft and Gault formula.
10. Adequate bone marrow function:
a.
Absolute neutrophil count (ANC) ≥1.5 x 109/L and
b.
Hemoglobin ≥9.0 g/dL (can be corrected by growth factor or transfusion) and
c.
Platelet count ≥100 x 109/L
11. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤ 1.5
12. Adequate liver function:
a.
Bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia or Gilbert’s syndrome
b.
Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3 × ULN (≤5 × ULN if subject has liver metastases).  If 
ALP is > 3 × ULN (in the absence of liver metastases) or > 5 × ULN (in the presence 
of liver metastases) AND subjects are also known to have bone metastases, the 
liver-specific ALP must be separated from the total and used to assess the liver 
function instead of the total ALP.
13. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol.
Exclusion Criteria
1.
Differentiated thyroid cancer (DTC) or MTC.  However, ATC arising out of DTC is allowed, 


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as long as the measurable disease is clinically consistent with ATC ie, rapidly progressive 
and/or 18F fluorodeoxyglucose (FDG)-avid.
2.
Newly diagnosed patients who are considered appropriate candidates for comprehensive 
multimodality treatment (involving surgery and/or external beam radiotherapy or chemo 
radiotherapy).
3.
Prior treatment with lenvatinib or any tyrosine kinase inhibitor (except for combination 
therapy of radiation and reduced dose of TKI given for the purpose of radiosensitization).
4.
Major surgery within 2 weeks prior to the first dose of lenvatinib.
5.
Any anti-cancer treatment within 14 days or any investigational agent within 30 days before 
the first dose of study drug.
6.
Radiotherapy within 3 weeks prior to the first dose of lenvatinib.
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 hours will be ineligible.
8.
Significant cardiovascular impairment: History of (a) congestive heart failure greater than 
New York Heart Association (NYHA) Class II, (b) unstable angina, (c) myocardial infarction,
(d) stroke, or (e) cardiac arrhythmia associated with impairment within 6 months of the first 
dose of study drug.
9.
A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline 
prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval >500 msec). 
10. Active infection requiring systemic therapy.
11. Clinically significant hemoptysis or tumor bleeding within two weeks prior to first dose of 
lenvatinib
12. Radiographic evidence of major blood vessel invasion/infiltration.
13. Other active malignancy (except definitively treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within past 24 months.
14. Scheduled for major surgery during the study.
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic gonadotropin 
[hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).  A 
separate baseline assessment is required if a negative screening pregnancy test was obtained 
more than 72 hours before the first dose of study drug.
16. Females of childbearing potential who:

Do not agree to use a highly effective method of contraception (ie, total abstinence [if it 
is their preferred and usual lifestyle], an intrauterine device or intrauterine system, a 
contraceptive implant, an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) within 30 days before study entry and throughout the entire 
study period and for 30 days after study drug discontinuation.

Are currently totally abstinent (as their preferred and usual lifestyle), and who do not 
agree to be totally abstinent during the study period and for 30 days after study drug 
discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
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
Are using oral hormonal contraceptives and who do not agree to add a barrier method.

(NOTE:  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]).
For sites outside of the EU, it is permissible that if a highly effective method of contraception 
is not appropriate or acceptable to the subject, then the subject must agree to use a medically 
acceptable method of contraception, ie, double barrier methods of contraception such as 
condom plus diaphragm or cervical/vault cap with spermicide.
17. Evidence of clinically significant disease (eg, cardiovascular, respiratory, gastrointestinal, 
renal disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments.
18. Known intolerance to the study drug or any of the excipients.
19. Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.
Study Treatment(s)
Test drug:  
Lenvatinib at a starting dose of 24 mg/day (two 10-mg capsules and one 4-mg capsule) is to be 
taken once a day (QD), recommended approximately at the same time each morning.  Dose 
adjustments will be made according to the guidelines provided in Synopsis Table 1 for 
management of intolerable toxicities.
Dose reductions occur in succession based on the previous dose level (24, 20, 14, and 10 mg/day).  
Any dose reduction below 10 mg/day must be discussed with the sponsor.  Once the dose has 
been reduced, it cannot be increased at a later date.
Table 1: Dose Reduction and Interruption Instructions for Lenvatinib-Related Toxicities
Treatment-Related 
Toxicitya,b
including hepatic injury and 
thromboembolic events
Management
Dose Adjustment
Grade 1 and tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c or Grade 3d, e
First occurrence
Interrupt until resolved to 
Grade 0-1 or baseline f
20 mg orally QD
(one-level reduction)
Second occurrence (same 
toxicity or new toxicity)
Interrupt until resolved to 
Grade 0-1 or baseline f
14 mg orally QD
(one-level reduction)
Third occurrence (same 
toxicity or new toxicity)
Interrupt until resolved to 
Grade 0-1 or baseline f
10 mg orally QD
(one-level reduction)
Fourth occurrence (same
toxicity or new toxicity)
Interrupt until resolved to 
Grade 0-1 or baseline f
Discuss with sponsor


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Management of Hypertension
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 
measurements after an hour:

Continue lenvatinib 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.
The following guidelines should be followed for the management of systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg confirmed on repeat measurements after an hour:

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at a dose of 20 mg once daily (or one dose level reduction) 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 20-mg once 
daily dose despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a dose of 14 mg once daily (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 14-mg once 
Grade 4g:  Discontinue Study Treatment
Note:  For grading, see Common Terminology Criteria for Adverse Events version 4.03.  
Collect all CTC grades of AEs, decreasing and increasing grade.
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:  Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and 
investigator.  If Grade 2 toxicity is determined to be intolerable, the dose of study drug will be 
reduced with or without dose interruption.  Interruption for Grade 3 toxicities is mandatory. 
d:  Obese subjects with weight loss requiring dose interruption and reduction do not need to 
return to baseline or Grade 1 weight loss to restart lenvatinib.  Based on the judgment of the 
investigator, subjects may be restarted at the lower dose of lenvatinib once the weight has been 
stable for at least 1 week.  Normal BMI should be used as the new baseline for future dose 
reductions.
e:  Not applicable to abnormal clinical laboratory values that are not clinically relevant based on 
the judgment of the investigator (eg, ALT, AST, γ-GTP values < 10 × ULN, and Na).
f: For hematology toxicities, restart treatment after toxicity resolves to Grade 2.
g: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage 
as Grade 3.


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daily dose despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted and restarted 
at a dose of 10 mg once daily (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
○
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 lenvatinib
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the Schedule of Visits and 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria:
Initial episode of proteinuria: if proteinuria ≥ 2+ is detected on urine dipstick testing, 
lenvatinib 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.  Grading according to 
the National Cancer Institute’s (NCI) CTCAE v4.03 will be based on the 24-hour urinary 
protein result.  Management of lenvatinib administration will be based on the grade of 
proteinuria according to the Study Treatment Dose Reduction and Interruption Instructions.
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 2 weeks 
(or more frequently as clinically indicated) until the results have been 1+ or negative for 
3 consecutive months.  Any subsequent increases in the level of proteinuria ≥2+ on urine 
dipstick testing must be confirmed with a 24-hour urinary protein test, which will be assessed 
and graded according to the Study Treatment Dose Reduction and Interruption Instructions.  
If a new event of proteinuria ≥2+ occurs, the subject must resume urine dipstick testing for 
evaluation of proteinuria every 2 weeks until results are 1+ or negative for 3 consecutive 
months.
Management of Hepatotoxicity
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted as 
clinically indicated.  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, lenvatinib 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, signs of deep vein thrombosis  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, lenvatinib must be 
discontinued.


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Management of Posterior Reversible Encephalopathy Syndrome 
In clinical studies with lenvatinib, events of posterior reversible encephalopathy syndrome 
(PRES) were reported in less than 1% of lenvatinib-treated subjects.  PRES is a neurological 
disorder, which can present with headache, seizure, lethargy, confusion, altered mental function, 
blindness, and other visual or neurological disturbances.  Mild to severe hypertension may be 
present.  MRI is necessary to confirm the diagnosis of PRES.  Appropriate measures should be 
taken to control BP.  In subjects with signs or symptoms of PRES, dose interruptions, dose 
adjustments, or discontinuation may be required as per instructions included in Synopsis Table 1.
Management of Hypocalcemia
Serum calcium should be monitored monthly per the Schedule of Visits and 
Procedures/Assessments.  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 6 months.
Concomitant Drug/Therapy
Subjects should not receive other antitumor therapies while on study.  If subjects receive 
additional antitumor therapies during the study, such as radiotherapy, other chemotherapy,  or 
immunotherapy, this will be judged to represent evidence of disease progression, and continuation 
of study medication should be discussed with the sponsor.  Following this discussion, if the joint 
decision is made to discontinue study treatment, then such subjects will complete all end of 
treatment assessments and continue to be followed for survival in the Follow-Up Period.
Assessments
Efficacy Assessments
The primary endpoint (ORR), secondary endpoints (12-week PFS, 6-month OS, median PFS and 
median OS), and exploratory endpoints (CBR, DCR, and DOR) will be evaluated by the 
investigator.  In addition, OS status will be assessed throughout the study.
Tumor assessments will be performed using RECIST 1.1.  Assessments are to be performed at the 
site by appropriately qualified personnel at each time point and results of the site interpretation are 
to be recorded on the appropriate case report forms (CRFs).  Historical standard of care scans that 
are performed with scanning parameters consistent with the requirements for this protocol within 
21 days prior to dosing are acceptable.  Tumor assessments (CT chest and CT/MRI of neck,
abdomen, pelvis, and other areas of known disease at screening plus any areas of newly suspected 
disease) should be performed at screening, every 6 weeks ±1 week for the first 24 weeks and 
every 8 weeks ±1 week thereafter, or sooner if clinically indicated, until documentation of disease 
progression.  A bone scan and brain scan will be performed within 21 days prior to Cycle 1 Day 1 
(C1D1), and continuing from C1D1 every 24 weeks ±1 week, or as clinically indicated.  If 
PET/CT is performed, a bone scan is not necessary. In addition, for subjects with a history of 
treated brain metastases, brain scans will be performed at tumor assessment time points, if 
clinically indicated. In subjects with CR based on body CT/MRI scans, a bone scan (or PET/CT, 
if performed at Screening) and brain scan assessment will be required at response confirmation.  
All objective responses must be confirmed at least 28 days following the initial achievement of 
the response.  Subjects going off lenvatinib treatment without disease progression in the 
Treatment Phase will continue to undergo tumor assessments according to the above schedule 
until disease progression is documented or another anticancer therapy is initiated.
All scans for tumor assessments performed during the study should be archived in accordance 


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with the standard local practice.  The scans must be accessible in the event of a sponsor request to 
submit them for central review.
Pharmacokinetic Assessments
Not applicable.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Tumor and blood biomarkers will be assessed to explore the correlation with clinical endpoints, 
including efficacy.
Safety Assessments
General safety will be assessed by the monitoring and recording of all adverse events (AEs) and 
serious adverse events (SAEs), regular monitoring of hematology and blood chemistry, regular 
measurement of vital signs, ECG, and the performance of physical examinations (PE) and other 
safety assessments in line with local regulations governing a study of this nature. 
Progression of ATC and signs and symptoms clearly related to the progression of ATC 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.
Anaplastic thyroid cancer can rapidly invade surrounding tissues, including trachea and carotid 
artery. In the case of life-threatening trachea fistula or carotid artery (or other major vessels) 
invasion or bleeding, the investigator should discuss the case with the Eisai Medical Monitor, in 
addition to discontinuing lenvatinib per Synopsis Table 1 for Grade 4 toxicity and treat the subject 
based on the institution’s standard practice.  Clinically significant tumor bleeding or bleeding due 
to major artery invasion will be considered as study-specific events and should always be 
considered as serious important medical events, which will be entered on the adverse event CRF 
and reported using the procedures for reporting SAEs, even if the study-specific event does not 
meet other serious criteria.
Bioanalytical Methods
Not applicable.
Statistical Methods
Study Endpoints
Primary Efficacy Endpoint

The primary efficacy endpoint is objective response rate (ORR) as determined by 
investigator review, using RECIST 1.1.  Objective response rate is the proportion of 
subjects who have best overall response (BOR) of CR or PR. 
Secondary Efficacy Endpoints  

Twelve-week PFS is the percentage of subjects in the analysis population who remain 
alive and progression-free at 12 weeks.

Six-month OS is defined as the percentage of subjects in the analysis population who are 
alive at 6 months.  It will be estimated using the Kaplan-Meier (KM) method.  

Median PFS and median OS 
Exploratory Endpoints

CBR is the proportion of subjects who have BOR of CR or PR or durable SD. Stable 
disease must be achieved at ≥ 23 weeks after first lenvatinib administration to be 
considered durable SD. 

DCR is the proportion of subjects who have BOR of CR, PR, or SD. Stable disease must 


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be achieved at ≥ 5 weeks after the first lenvatinib administration to be considered BOR.

DOR is defined as the time from the date that the criteria are met for CR or PR 
(whichever is recorded first) to the date that PD is objectively documented or death, 
whichever occurs first.

Evaluate the association of tumor and blood biomarkers with clinical outcomes, including 
efficacy.
Analysis Sets
Full Analysis Set (FAS) will include all subjects who received at least one dose of lenvatinib.  
The FAS will be the population for the safety analysis.  Some selected efficacy endpoints will also 
be summarized in the FAS. 
Evaluable Analysis Set (EAS) will include FAS subjects with histological diagnosis of ATC that 
is confirmed by central pathology review.  The EAS will be the primary population for the 
efficacy analysis.
Efficacy Analyses
Primary efficacy analyses
In this population, ORR in the historical control is assumed to be approximately 10% based on 
recent trials.  The ORR in this trial is estimated as 27%, which is deemed a clinical meaningful 
improvement.  Hence, the null and alternative hypotheses are set as follows:
                                                     H0: ORR=10%
                                                     Ha: ORR ≥27%
A binomial exact test will be performed for hypothesis testing in the Evaluable Analysis Set.  If 
the obtained p-value is less than or equal to 0.025, it will be concluded that the single agent 
lenvatinib statistically significantly increases ORR compared with historical control.  Therefore, 
the superiority of single agent lenvatinib will be demonstrated.
Clopper Pearson 95% confidence interval (CI) of ORR will also be constructed to assess the 
precision of the rate estimate.
Secondary efficacy analyses
Progression-free survival (PFS) is defined as the time from the date of beginning of lenvatinib 
administration to the date of first documentation of disease progression or death, whichever 
occurs first. 
PFS censoring rule will follow FDA Guidance for Industry Clinical Trial Endpoints for the 
Approval of Cancer Drugs and Biologics (2007).
A 12-week PFS of ≥70% in single agent lenvatinib and 50% in the historical control 
(corresponding to a median PFS improvement of approximately 3 months assuming exponential 
distribution) are assumed in the hypothesis testing: 
                                                     H0: 12-week PFS=50%
                                                     Ha: 12-week PFS ≥70%
Kaplan-Meier method will be used to estimate 12-week PFS, along with the corresponding 95% 
CI constructed using Greenwood’s formula.  The CI approach will be used to demonstrate the 
superiority of 12-week PFS in the single agent lenvatinib over historical control.  If the lower 
bound is above 50%, it will be concluded that the single agent lenvatinib statistically significantly 
increases 12-week PFS compared with historical control.


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OS is defined as the time from the date of beginning of lenvatinib administration until date of 
death from any cause.  Six-month OS is assumed to be approximately 44% in the historical 
control (corresponding to a median OS of approximately 5 months assuming an exponential 
distribution).  Six-month OS and its 95% CI will be calculated using the same methods as 
described in the 12-week PFS analyses.  If the lower bound of 95% CI for 6-month OS is above 
44%, it will be concluded that the single agent lenvatinib statistically significantly increases 
6-month OS compared with historical control.
Median PFS and median OS will be estimated using the KM method.  Their 2-sided 95% CIs will 
be constructed with a generalized Brookmeyer and Crowley method.  Kaplan-Meier estimates of 
PFS and OS will be plotted over time.
Secondary efficacy endpoints will be analyzed sequentially, as listed above.
Exploratory efficacy analyses
Clinical benefit rate (CBR), DCR, and DOR will be analyzed using the statistical methods as 
described above.
Tumor and blood biomarkers will be analyzed to assess the correlation with clinical endpoints, 
including efficacy.
Formal analyses
A formal analysis will be carried out approximately 6 months following the enrollment of the last
subject.  The timing of the formal analysis is chosen such that the secondary endpoints, 12-week 
PFS and 6-month OS will be adequately described.  The primary population for efficacy analysis 
is EAS.  Efficacy and safety analysis will also be performed in FAS.
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Exploratory analyses of tumor and blood biomarkers will be performed to assess the correlation 
with clinical endpoints, including efficacy.  The analysis plan will be described in a separate 
report.
Safety Analyses
Safety, using the FAS, will be assessed by monitoring and recording of all AEs including all 
CTCAE v4.03 grades (both increasing and decreasing severity), regular monitoring of hematology 
and clinical chemistry, urinalysis, regular measurement of vital signs, 12-lead ECGs, 
echocardiogram or multigated acquisition (MUGA) scan results (only for subjects who had prior 
anthracyclines) including left ventricular ejection fraction and performance of PEs. 
Adverse events and other clinical safety data will be summarized descriptively in the FAS.  The 
incidence of treatment-emergent adverse events (TEAEs), SAEs, drug-related AEs and AEs 
leading to discontinuation will be summarized in tabulation.  Hematology, serum chemistry, vital 
sign variables and ECG will be summarized descriptively for observed values, by grade, and by 
change from Baseline by cycle.  All AEs and lab parameters will be listed.
Interim Analyses
One interim analysis will be performed after the first 20 evaluable subjects complete at least 2
tumor assessments or discontinue treatment due to any reason.  The trial will be halted if the 
number of responders is 3 or less (ORR ≤15%).  Since type I error calculation for the primary 
efficacy analysis does not factor in this descriptive interim analysis, the interim decision will not 
affect the overall type I error in the formal primary analysis. Further action regarding enrollment 
will be taken after evaluating other efficacy and safety outcomes in the treated subjects.  The 
probabilities of not passing interim threshold are 0.87, 0.41, and 0.17 when underlying true ORR 
are 10%, 20%, and 27%, respectively.


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The study team will define the datasets for the interim analysis.  The study team will assess the 
impact of any issues such as unsolved data queries, missing data or data entry delays on the 
interim results.  The study statistician will perform the interim analysis, which includes 
calculating ORR per protocol.
Sample Size Rationale
The sample size calculation was based on the assumed ORR of 27% in the trial as compared to 
10% in the historical control.  Using a binomial exact test, the power is 0.932 with 57 evaluable 
subjects to demonstrate statistical significance at a 1-sided alpha of 0.025.  To evaluate the power 
in the secondary endpoint 12-week PFS, an exponential distribution assuming 12-week PFS being
70% was used to simulate PFS data.  Censoring times were generated such that the average 
number of observed PFS events was approximately 45 in the 57 evaluable subjects.  In the 5,000 
simulation runs, the lower bound of 95% CI for PFS at 12 weeks was greater than 50% (historical 
control), 87.7% of the time.  Hence, the power is 0.877 in demonstrating statistical superiority of 
the 12-week PFS in single agent lenvatinib.  Similarly, approximately 35 observed OS events in 
57 evaluable subjects yield a power of approximately 0.857 in demonstrating a statistically 
significant increase in 6-month OS over historical control.  Assuming ATC confirmation rate is 
75% in the enrolled subjects, approximately 76 subjects will need to be enrolled.  Subjects 
deemed to have another diagnosis (not ATC) will be replaced for the purpose of efficacy analyses.


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3
TABLE OF CONTENTS
1
TITLE PAGE.....................................................................................................................1
REVISION HISTORY...............................................................................................................2
2
CLINICAL PROTOCOL SYNOPSIS...............................................................................6
3
TABLE OF CONTENTS.................................................................................................18
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................23
5
ETHICS............................................................................................................................26
5.1
Institutional Review Boards/Independent Ethics Committees ..............................26
5.2
Ethical Conduct of the Study.................................................................................26
5.3
Subject Information and Informed Consent...........................................................27
6
INVESTIGATORS AND STUDY PERSONNEL..........................................................28
7
INTRODUCTION ...........................................................................................................28
7.1
Indication ...............................................................................................................28
7.1.1
Current Therapeutic Options........................................................................28
7.1.2
E7080/Lenvatinib.........................................................................................29
7.1.2.1
Mechanism of Action...........................................................................29
7.1.2.2
Clinical Experience With Lenvatinib in Radioiodine-Refractory 
Differentiated Thyroid Cancer.............................................................30
7.2
Study Rationale......................................................................................................31
8
STUDY OBJECTIVES....................................................................................................31
8.1
Primary Objective..................................................................................................31
8.2
Secondary Objectives.............................................................................................31
8.3
Exploratory Objectives ..........................................................................................32
9
INVESTIGATIONAL PLAN..........................................................................................32
9.1
Overall Study Design and Plan..............................................................................32
9.1.1
Pretreatment Phase.......................................................................................32
9.1.1.1
Screening Period..................................................................................32
9.1.1.2
Baseline Period ....................................................................................33
9.1.2
Treatment Phase...........................................................................................33
9.1.3
Posttreatment Phase .....................................................................................33
9.2
Discussion of Study Design, Including Choice of Control Groups.......................33
9.3
Selection of Study Population................................................................................34
9.3.1
Inclusion Criteria .........................................................................................34
9.3.2
Exclusion Criteria ........................................................................................35
9.3.3
Removal of Subjects From Therapy or Assessment....................................37
9.4
Treatment ...............................................................................................................38


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9.4.1
Treatment Administered ..............................................................................38
9.4.1.1
Criteria for Interruption of Treatment, Dose Reduction and 
Resumption of Treatment ....................................................................38
9.4.1.1.1
Management of Hypertension........................................................39
9.4.1.1.2
Management of Proteinuria............................................................40
9.4.1.1.3
Management of Hepatotoxicity......................................................41
9.4.1.1.4
Management of Thromboembolic Events......................................41
9.4.1.1.5
Management of Posterior Reversible Encephalopathy 
Syndrome.......................................................................................41
9.4.1.1.6
Management of Hypocalcemia ......................................................41
9.4.2
Identity of Investigational Product...............................................................42
9.4.2.1
Chemical Name, Structural Formula of E7080....................................42
9.4.2.2
Comparator Drug .................................................................................42
9.4.2.3
Labeling for Study Drug......................................................................42
9.4.2.4
Storage Conditions...............................................................................43
9.4.3
Method of Assigning Subjects to Treatment Groups...................................43
9.4.4
Selection of Doses in the Study...................................................................43
9.4.5
Selection and Timing of Dose for Each Subject..........................................43
9.4.6
Blinding........................................................................................................43
9.4.7
Prior and Concomitant Therapy...................................................................43
9.4.7.1
Drug-Drug Interactions........................................................................44
9.4.7.2
Prohibited Concomitant Therapies and Drugs.....................................45
9.4.8
Treatment Compliance.................................................................................45
9.4.9
Drug Supplies and Accountability...............................................................45
9.5
Study Assessments.................................................................................................47
9.5.1
Assessments.................................................................................................47
9.5.1.1
Demography.........................................................................................47
9.5.1.2
Medical History and Physical Examinations.......................................47
9.5.1.3
Efficacy Assessments...........................................................................47
9.5.1.3.1
Tumor Assessments .......................................................................47
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments.............................................................49
9.5.1.4.1
Pharmacokinetic Assessments .......................................................49
9.5.1.4.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments...................................................................................49
9.5.1.5
Safety Assessments..............................................................................50
9.5.1.5.1
Adverse Events and Events Associated with Special Situations ...50


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9.5.1.5.2
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................52
9.5.1.5.3
Laboratory Measurements .............................................................53
9.5.1.5.4
Vital Signs and Weight Measurements..........................................54
9.5.1.5.5
Physical Examinations...................................................................54
9.5.1.5.6
Electrocardiograms ........................................................................55
9.5.1.5.7
Other Safety Assessments..............................................................55
9.5.2
Schedule of Procedures/Assessments ..........................................................55
9.5.2.1
Schedule of Procedures/Assessments ..................................................55
9.5.2.2
Description of Procedures/Assessments Schedule...............................60
9.5.3
Appropriateness of Measurements...............................................................60
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations..............................................................60
9.5.4.1
Reporting of Serious Adverse Events..................................................60
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................61
9.5.4.3
Reporting of Events Associated with Special Situations.....................61
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................61
9.5.4.3.2
Reporting of Study-Specific Events...............................................62
9.5.4.4
Expedited Reporting ............................................................................62
9.5.4.5
Breaking the Blind...............................................................................62
9.5.4.6
Regulatory Reporting of Adverse Events ............................................62
9.5.5
Completion/Discontinuation of Subjects.....................................................62
9.5.6
Abuse or Diversion of Study Drug ..............................................................63
9.5.7
Confirmation of Medical Care by Another Physician .................................63
9.6
Data Quality Assurance .........................................................................................63
9.6.1
Data Collection ............................................................................................63
9.6.2
Clinical Data Management ..........................................................................64
9.7
Statistical Methods.................................................................................................64
9.7.1
Statistical and Analytical Plans....................................................................64
9.7.1.1
Study Endpoints...................................................................................64
9.7.1.1.1
Primary Endpoint...........................................................................64
9.7.1.1.2
Secondary Endpoints .....................................................................64
9.7.1.1.3
Exploratory Endpoints ...................................................................65
9.7.1.2
Definitions of Analysis Sets.................................................................65
9.7.1.3
Subject Disposition..............................................................................65


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9.7.1.4
Demographic and Other Baseline Characteristics ...............................65
9.7.1.5
Prior and Concomitant Therapy...........................................................66
9.7.1.6
Efficacy Analyses ................................................................................66
9.7.1.6.1
Primary Efficacy Analysis.............................................................66
9.7.1.6.2
Secondary Efficacy Analyses ........................................................66
9.7.1.6.3
Exploratory Efficacy Analyses ......................................................67
9.7.1.6.4
Formal Analyses ............................................................................68
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses...................................................................68
9.7.1.7.1
Pharmacokinetic Analyses.............................................................68
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses.........................................................................................68
9.7.1.8
Safety Analyses....................................................................................68
9.7.1.8.1
Extent of Exposure.........................................................................68
9.7.1.8.2
Adverse Events ..............................................................................69
9.7.1.8.3
Laboratory Values..........................................................................69
9.7.1.8.4
Vital Signs......................................................................................69
9.7.1.8.5
Electrocardiograms ........................................................................70
9.7.1.8.6
Other Safety Analyses....................................................................70
9.7.1.9
Other Analyses.....................................................................................70
9.7.2
Determination of Sample Size .....................................................................70
9.7.3
Interim Analysis...........................................................................................70
9.7.4
Other Statistical/Analytical Issues ...............................................................71
9.7.5
Procedure for Revising the Statistical Analysis Plan...................................71
10
REFERENCE LIST .........................................................................................................72
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......74
11.1
Changes to the Protocol .........................................................................................74
11.2
Adherence to the Protocol......................................................................................74
11.3
Monitoring Procedures...........................................................................................74
11.4
Recording of Data..................................................................................................75
11.5
Identification of Source Data.................................................................................75
11.6
Retention of Records..............................................................................................76
11.7
Auditing Procedures and Inspection......................................................................76
11.8
Handling of Study Drug.........................................................................................76
11.9
Publication of Results ............................................................................................77
11.10 Disclosure and Confidentiality ..............................................................................77
11.11 Discontinuation of Study .......................................................................................77


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11.12 Subject Insurance and Indemnity...........................................................................78
12
APPENDICES .................................................................................................................79
LIST OF IN-TEXT TABLES
Table 1 
Treatment Administered ............................................................................38
Table 2
Dose Reduction and Interruption Instructions for Lenvatinib-Related 
Toxicities....................................................................................................39
Table 3
Clinical Laboratory Tests...........................................................................53
Table 4
Schedule of Visits and Procedures/Assessments in E7080-M000-213 
Pretreatment and Treatment Phases...........................................................56
LIST OF IN-TEXT FIGURES
None.
LIST OF APPENDICES
Appendix 1
Anaplastic Thyroid Cancer Tumor-Node-Metastasis  Staging System......80
Appendix 2
Overview of RECIST v1.1 for Evaluation of Tumors Response...............81
Appendix 3
Eastern Cooperative Oncology GroupPerformance Status .......................87
Appendix 4
Cockcroft and Gault Formula ....................................................................88
Appendix 5
New York Heart Association Cardiac Disease Classification ...................89
Appendix 6
Common Terminology Criteria for AdverseEvents (v4.03) .....................90
Appendix 7
Sponsor’s Grading for Laboratory Values .................................................91


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
anaplastic thyroid cancer
ß-hCG
beta-human chorionic gonadotropin
BOR
best overall response
BP
blood pressure
C1D1
Cycle 1 Day 1
CBR
clinical benefit rate
CI
confidence interval
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSR
clinical study report
CT
computerized tomography
CTCAE 
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DOR
duration of response
DTC
differentiated thyroid cancer
EAS
evaluable analysis set
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EMA
European Medicines Agency
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
FDG
18F fluorodeoxyglucose


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Abbreviation
Term
FGF
fibroblast growth factor
GCP
Good Clinical Practice
hCG
human chorionic gonadotropin
ICF
Informed consent form
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board
ITOG
International Thyroid Oncology Group
KM
Kaplan-Meier
MedDRA®
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTC
medullary thyroid cancer
MUGA
multigated acquisition
NaF
18F-sodium fluoride
NCI
National Cancer Institute
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PE
physical examinations
PET
positron emission tomography
PFS
progression-free survival
PI
principal investigator
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PT
preferred term
QD
once a day
RBC
red blood cell count
RECIST
Response Evaluation Criteria in Solid Tumors
RR-DTC
radioiodine-refractory differentiated thyroid cancer
RTK
receptor tyrosine kinase
SAE
serious adverse events
SAP
statistical analysis plan


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Abbreviation
Term
SD
stable disease
SmPC
Summary of Product Characteristics
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
TTP
time to progression
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice [GCP]), Section 3, and any local regulations i.e., Code of Federal Regulations, Title 
21 CFR Part 56.  Any protocol amendment or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval, except for changes involving only logistical or 
administrative aspects of the study (eg, change in clinical research 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) (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 (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 (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 definition for end of the study, as required by certain regulatory agencies, is the time of 
data cutoff for the formal analysis or the time of last subject/last treatment, whichever occurs 
later.  
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 Conference on Harmonisation of Pharmaceuticals for Human Use


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
Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding 
clinical studies, including Part 50 and Part 56 concerning informed subject consent and 
IRB regulations and applicable sections of US 21 CFR Part 312

European GCP 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 document, the investigator must explain to each subject or 
guardian/legally authorized representative the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, any potential 
discomfort, potential alternative procedure(s) or course(s) of treatment available to the 
subject, and the extent of maintaining confidentiality of the subject’s records.  Each subject 
must be informed that participation in the study is voluntary, that he/she may withdraw from 
the study at any time, and that withdrawal of consent will not affect his/her subsequent 
medical treatment or relationship with the treating physician.
This ICF should be given by means of a standard written statement, written in nontechnical 
language.  The subject or the subject’s legally acceptable representative should understand 
the statement before signing and dating it and will be given a copy of the signed document.  
If a subject is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire ICF discussion.  After the ICF and any 
other written information to be provided to subjects is read and explained to the subject or the 
subject’s legally acceptable representative, and after the subject or the subject’s legally 
acceptable representative has orally consented to the subject’s participation in the study and, 
if capable of doing so, has signed and personally dated the ICF, the witness should sign and 
personally date the consent form.  The subject will be asked to sign an ICF at the Screening 
Visit before any study-specific procedures are performed.  No subject can enter the study 
before his/her ICF 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 
according to local procedures at the site.  For biomarker assessments, subjects will be asked 
to either sign a separate ICF or provide consent within the main ICF (see Section 9.5.1.4.2).  
Subjects may also be asked to either sign a separate ICF or provide consent within the main 
ICF to allow the sponsor to request scans of their tumor assessments for central review.
The subject or the subject’s legally authorized representative should be informed in a timely
manner if new information becomes available that may be relevant to the subject’s 


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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 20 investigational sites in the US, EU, and other regions, in 
collaboration with the International Thyroid Oncology Group (ITOG).
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organization (CRO) are listed in the Regulatory 
Binder provided to each site.
7
INTRODUCTION
7.1
Indication
This is an open-label, single-arm, multicenter Phase 2 study to evaluate the efficacy and 
safety of lenvatinib in subjects with anaplastic thyroid cancer (ATC).
7.1.1
Current Therapeutic Options
ATC is one of the most aggressive solid tumors affecting humans.  It represents only 
1% - 2% of all thyroid cancers, but it is responsible for up to 40% annual mortality related to 
thyroid cancer.  ATC is primarily a disease of the elderly with the peak incidence in sixth and 
sevenths decades of life.  The incidence of ATC in the United States has held steady during a 
period between 1975 and 2009 (SEER database) and it is estimated at 1 to 2 cases per million 
population per year (Davies and Welch, 2014).  The incidence varies geographically with 
higher incidence reported in areas with endemic goiter.  ATC is 3 times more common in 
females than males. 
The diagnosis of ATC is usually suspected on clinical examination and confirmed by core 
biopsy.  ATC is usually advanced at diagnosis and often surgically unresectable.  Distant 
metastases are found in approximately 50% of patients at diagnosis with 25% developing 
new metastases during the rapid course of the disease.  The most common sites of metastases 
are lungs (80%), bone (6-16%), and brain (5-13%).  Because of the aggressive nature of the 
disease, all patients with ATC are classified by the American Joint Committee on Cancer as 
having stage IV disease, regardless of the tumor size or the presence of lymph node or distant 
metastases. 
Prognosis for ATC is very poor with a median survival of 3 to 5 months following diagnosis, 
with only 10% -15% patients alive at 2 years.  The most important prognostics factors are 
age, gender, presence of distant metastases, and local extent of the disease.  Younger
(< 65 years old), female patients with small size ATC (less than 5 cm or intra-thyroidal) and 
no distant metastases at diagnosis, have a better prognosis. 


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Treatment of patients diagnosed with ATC is difficult and not standardized due to 
aggressiveness, rarity and resistance of this disease to chemotherapy.  The treatment options 
include surgery, radiotherapy, and chemotherapy.  These treatment modalities must be 
combined to control local and metastatic disease.  Preventing tumor penetration of 
surrounding tissues and compression of vital neck structures is an important palliative 
endpoint. 
Complete resection of ATC has been identified as a positive prognostic factor.  However, 
ATC usually cannot be resected completely because it is very invasive and a surgery must 
not compromise the functional anatomy of the neck structures.  Following partial resection of 
ATC, the adjuvant radiotherapy is used to improve locoregional control.  External 
radiotherapy up to 65 Gy, may slow progress of the disease but rarely controls it.
Single or combination agents treating ATC have shown limited efficacy, due in large part to 
toxicity, mostly in elderly patients who are the most affected by ATC.  Doxorubicin is the 
most frequently used chemotherapy treatment for ATC.  In a randomized study of Eastern 
Cooperative Oncology Group, a monotherapy with doxorubicin was not able to achieve 20% 
response rate, however the combination of doxorubicin with cisplatin was more effective 
than doxorubicin alone and produced a higher (26% versus 17%) response rate 
(Shimaoka et al, 1985).  More recently, a study of docetaxel as first-line chemotherapy in 
7 patients with advanced ATC reported median time to progression (TTP) of 1.5 months and 
median overall survival (OS) of 3.25 months (Kawada et al, 2010).  Similar results in a Phase 
2 clinical trial of sorafenib in 20 ATC patients reported median TTP of 1.9 months and 
median OS of 3.9 months (Savvides et al, 2013).  A recent study of carboplatin and paclitaxel 
combination reported median progression-free survival (PFS) and OS of 3.1 months and 
4.0 months, respectively, in 25 ATC patients (Sosa et al, 2014).  
7.1.2
E7080/Lenvatinib
Lenvatinib (LENVIMA®) is a kinase inhibitor that was approved by the US Food and Drug 
Administration (FDA) on 13 Feb 2015 by the European Medicines Agency (EMA) on 
28 May 2015, and indicated for the treatment of patients with locally recurrent or metastatic, 
progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)
(LENVIMA® US package insert/EU SmPC).  
7.1.2.1
Mechanism of Action
Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that inhibits the kinase activity of 
vascular endothelial growth factor (VEGF) receptors VEGFR1, VEGFR2, and VEGFR3.  
Lenvatinib also inhibits other RTKs that have been implicated in pathogenesis, 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, c-kit receptor CD117, and rearranged during transfection protein.  
Through its inhibition of angiogenesis, lenvatinib has demonstrated antitumor activity and 
manageable toxicity for the treatment of radioiodine-refractory differentiated thyroid cancer


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(RR-DTC) in a randomized Phase 3 study (n=392) (Schlumberger et al, 2014), which is 
described below.  
7.1.2.2
Clinical Experience With Lenvatinib in Radioiodine-Refractory Differentiated 
Thyroid Cancer
In Phase 3 study E7080-G000-303 (Study 303) (Schlumberger et al, 2014), in subjects with 
RR-DTC, lenvatinib treatment demonstrated a statistically significant and clinically 
meaningful benefit as measured by PFS.  Based on Independent Imaging Review
assessments, lenvatinib prolonged median PFS by 14.7 months compared with placebo
(18.3 months versus 3.6 months, respectively).  The difference in PFS between the lenvatinib
and placebo arms was highly statistically significant (P<0.0001) using both stratifiedand
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.
Lenvatinib treatment also resulted in a highly statistically significant effect on response rate 
(complete response [CR] + partial response [PR]) compared with placebo (64.8% versus 
1.5%; P<0.001).  Four subjects in the lenvatinib arm had a CR, an atypical finding for an 
antiangiogenic agent.  The objective response rate (ORR) of thelenvatinib-treated subjects at 
6 months was 57.5% (n=150).  Thus, at 6 months, approximately 89% ofthe subjects who 
ultimately responded had already achieved a response.
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 reportedTEAEs
(≥30% of subjects, any grade) in the lenvatinib arm of the Safety Analysis Set were (in
descending order of frequency) hypertension, fatigue, diarrhea, arthralgia/myalgia, decreased 
appetite, weight decreased, nausea, stomatitis, headache, vomiting, proteinuria, palmar-
plantar erythrodysesthesia syndrome, abdominal pain, and dysphonia.  Hypertension and 
proteinuria were the TEAEs that led to dose reductions most frequently.  
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 versus 12.9 months, respectively; P=0.0085, unstratified log-rank
test).
The difference in OS between subjects with and without hypertension was also statistically 
significant (P=0.0003) using the unstratified log-rank test.  Thedevelopment 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.  


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7.2
Study Rationale
The current therapeutic treatment options for ATC, which is often advanced and metastatic at 
diagnosis, are limited.  Partial resection followed by adjuvant radiotherapy is only partially 
effective and does not improve survival of patients with ATC.  The current monotherapy 
drug treatments are not able to achieve a 20% response rate.  As such, new treatment options 
are greatly needed.
An interim analysis of an ongoing Japanese Phase 2 study (E7080-J081-208) in 43 subjects, 
including 23 RR-DTC, 9 medullary thyroid cancer (MTC), and 11 ATC, showed a consistent 
safety profile with that of previous lenvatinib studies and encouraging efficacy results in the 
small ATC cohort.  The safety profile of lenvatinib was comparable to previous clinical 
studies of lenvatinib with manageable toxicity with dose reduction and interruption. The 
most frequently reported treatment related TEAE for the study subject population (RR-DTC, 
MTC, and ATC) was hypertension, followed by palmar-plantar erythrodysaesthesia 
syndrome, fatigue, decreased appetite, proteinuria, stomatitis, and diarrhea.  Among 11 ATC 
subjects, lenvatinib demonstrated promising anti-tumor activity with 27% ORR, 64% stable 
disease, 7.4 months median PFS and 10.6 months median OS (Takahashi et al, 2014). 
Based on the results obtained in E7080-J081-208, lenvatinib is a promising treatment for 
ATC demonstrating higher response rate than any drug monotherapy investigated to date.  
The encouraging activity and manageable toxicity of lenvatinib reported in 11 ATC subjects 
warrants further evaluation in a larger population of ATC subjects in the proposed Phase 2 
study.
8
STUDY OBJECTIVES
8.1
Primary Objective

The primary objective of the study is to evaluate ORR (CR and PR) by investigator 
review in subjects with ATC treated with lenvatinib.
8.2
Secondary Objectives
The secondary objectives of the study are:

To evaluate 12-week PFS

To evaluate 6-month OS 

To evaluate median PFS and median OS

To evaluate safety and tolerability of lenvatinib in subjects with ATC


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8.3
Exploratory Objectives

To explore clinical benefit rate ([CBR]: CR + PR + durable stable disease 
[SD ≥23 weeks]) 

To explore disease control rate ([DCR]: CR + PR + SD) 

To explore duration of response (DOR) 

To identify and explore tumor and blood biomarkers that correlate with clinical 
outcomes, including efficacy
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is an open-label, single arm, multicenter, Phase 2 study in subjects with ATC. 
A descriptive interim analysis, which requires the first 20 evaluable subjects, will be 
implemented in the study.  If the number of responders is 3 or less  (ORR ≤15%), the 
enrollment will be halted and the safety and efficacy data will be further evaluated before 
making the decision of stopping the study permanently.  Otherwise, the enrollment will be 
continued to 57 evaluable subjects.  Since early stopping is not expected, to minimize the 
impact of interim analysis to clinical study operation, enrollment will not be halted after the 
first 20 evaluable subjects while waiting for the interim analysis results.  Therefore, there will 
be no enrollment gap for the interim analysis.
Subjects should have measurable disease according to RECIST 1.1.
This study consists of 3 Phases: a Pretreatment Phase (Screening and Baseline visits), a 
Treatment Phase (starting Cycle 1 Day 1 [C1D1]), and a Posttreatment Phase (End of 
Treatment visit and survival follow-up).
9.1.1
Pretreatment Phase
The Pretreatment Phase will last no longer than 21 days and will include a Screening Period 
to establish protocol eligibility and a Baseline Period to confirm eligibility and establish 
disease characteristics prior to treatment.
9.1.1.1
Screening Period
Screening will occur between Day –21 and Day –2.  The purpose of the Screening Period is 
to obtain ICF and to establish protocol eligibility.  Informed consent will be obtained after 
the study has been fully explained to each subject and before the conduct of any screening 
procedures or assessments.  Procedures to be followed when obtaining ICF are detailed in 
Section 5.3.


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Subjects must have a histologically confirmed diagnosis of ATC.
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 starting 
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 (C1D1) to confirm eligibility.  Baseline assessments will be 
performed on Day -1 prior to treatment on C1D1.
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase.
9.1.2
Treatment Phase
The Treatment Phase will begin at the time of lenvatinib administration on C1D1 and end 
following the last dose of lenvatinib. Subjects will be treated with lenvatinib dose of 24 mg 
(2 capsules of 10 mg each and 1 capsule of 4 mg) once daily by oral administration.  Subjects 
will undergo safety and efficacy assessments. Subjects will discontinue treatment with 
lenvatinib at the time of disease progression (radiological or clinical), development of 
unacceptable toxicity (AE), lost to follow-up, withdrawal of consent, subject choice, 
pregnancy, or study termination by the sponsor.
9.1.3
Posttreatment Phase
The Posttreatment Phase will start at the End of Treatment visit and will continue as long as 
the subject is alive or until the study subject withdraws consent or is lost to follow-up.  
Subjects who discontinue study treatment before disease progression will continue to 
undergo tumor assessment every 6 weeks ±1 week for the first 24 weeks and every 8 weeks 
±1 week thereafter, until documentation of disease progression or start of another anti-cancer 
therapy.  Follow-up assessment for survival will be performed every 12 weeks ±1 week.
9.2
Discussion of Study Design, Including Choice of Control Groups
This multicenter, single arm, Phase 2 trial is designed to assess the efficacy and safety of 
lenvatinib in subjects with ATC, which is a rare aggressive disease with no established 
standard chemotherapy.  Lenvatinib has established activity in RR-DTC and, more recently, 
an interim analysis of an ongoing Phase 2 study has also shown promising anti-tumor effects 
in a small cohort of ATC patients.  
The current study is designed primarily to provide additional efficacy and safety data for 
single-agent lenvatinib in a larger cohort of ATC subjects.  Efficacy endpoints (eg, ORR,


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PFS, and OS) in lenvatinib-treated subjects will be compared to those from the historical 
controls based on published studies.  The efficacy and safety parameters being evaluated are 
commonly used in oncology trials. 
9.3
Selection of Study Population
Approximately 76 subjects will be enrolled at approximately 20 centers in the US, EU, and 
other regions, in collaboration with ITOG.  Subjects who do not meet all of the inclusion 
criteria or who meet any of the exclusion criteria will not be eligible to receive study drug.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Males or females age ≥18 years at the time of ICF.
2. Subjects must have histological diagnosis consistent of ATC.  Cytologic diagnosis by 
fine needle aspiration alone is not sufficient.  Histologic diagnosis may be made by 
core needle biopsy, incisional biopsy, thyroidectomy, or other surgical biopsy.  Fresh 
tumor biopsies (re-biopsy) should be obtained, whenever feasible.  The central 
pathology review may take place prior to or after the subject starts treatment with 
lenvatinib. 
a.
Central review of pathology is required for study participation, but not required 
prior to enrollment or start of treatment in order to avoid delay.  If the results of 
central pathology review are not available prior to the start of study treatment, 
the confirmation of diagnosis of ATC at the local laboratory is mandatory prior 
to scheduled start of treatment with lenvatinib. 
b. If central pathology review indicates a diagnosis other than ATC, the subject 
may continue treatment with lenvatinib per standard of care,  at the discretion of 
the treating investigator.  Subjects deemed to have another diagnosis (not ATC) 
will be taken off this study and replaced for the purpose of efficacy analyses.
c.
DTC with focus loci of ATC is allowed.  If a subject has pathology showing a 
small focus of ATC arising out of DTC and the measurable disease is not fully 
consistent with ATC, confirmation of ATC by biopsy is required. 
d. An incidental focus of MTC, DTC, and/or poorly differentiated thyroid cancer in 
a subject with ATC is allowed.
e.
Histological diagnosis of ATC made through surgical resection is also 
acceptable.
3. Prior neoadjuvant, adjuvant or palliative chemotherapy for ATC is allowed.
4. Measurable disease based on investigator’s assessments meeting the following 
criteria:
a.
At least 1 lesion of ≥ 10 mm in the longest diameter for a non-lymph node or 
≥15 mm in the short-axis diameter for a lymph node which is serially 


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measurable according to RECIST 1.1 using computerized tomography (CT) or 
magnetic resonance imaging (MRI).  
b.
Lesions that have had external beam radiotherapy or locoregional therapies such
as radiofrequency  ablation must show evidence of subsequent progressive 
disease (substantial size increase of ≥20%) to be deemed a target lesion.
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 1 month prior to 
enrollment.
6. All previous chemotherapy or radiation therapy-related toxicities, except dry mouth, 
dysphagia, esophagitis, mucositis, alopecia, and irreversible late sequelae of radiation 
therapy, must have resolved to Grade 0 or 1 per Common Terminology Criteria for 
Adverse Events (CTCAE v 4.03), and all wounds from prior surgery must have 
adequately recovered.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
8. Blood pressure (BP) ≤ 140/90 mmHg at screening with or without antihypertensive 
medications and no change in antihypertensive medications within 1 week prior to 
C1D1.
9. Adequate renal function as evidenced by calculated creatinine clearance ≥30 mL/min 
according to the Cockcroft and Gault formula (Appendix 4).
10. Adequate bone marrow function:
a.
Absolute neutrophil count (ANC) ≥1.5 x 109/L and
b.
Hemoglobin ≥9.0 g/dL (can be corrected by growth factor or transfusion) and
c.
Platelet count ≥100 x 109/L 
11. Adequate blood coagulation function as evidenced by an International Normalized 
Ratio (INR) ≤ 1.5
12. Adequate liver function:
a.
Bilirubin ≤1.5 × upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia or Gilbert’s syndrome
b.
Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3 × ULN (≤5 × ULN if subject has liver metastases).  
If ALP is > 3 × ULN (in the absence of liver metastases) or > 5 × ULN (in the 
presence of liver metastases) AND subjects are also known to have bone 
metastases, the liver-specific ALP must be separated from the total and used to 
assess the liver function instead of the total ALP.
13. Voluntary agreement to provide written ICF and the willingness and ability to comply 
with all aspects of the protocol.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:


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1. DTC or MTC.  However, ATC arising out of DTC is allowed, as long as the 
measurable disease is clinically consistent with ATC ie, rapidly progressive and/or 
18F fluorodeoxyglucose (FDG)-avid.
2. Newly diagnosed patients who are considered appropriate candidates for 
comprehensive multimodality treatment (involving surgery and/or external beam 
radiotherapy or chemo radiotherapy).
3. Prior treatment with lenvatinib or any tyrosine kinase inhibitor (except for 
combination therapy of radiation and reduced dose of TKI given for the purpose of 
radiosensitization).
4. Major surgery within 2 weeks prior to the first dose of lenvatinib.
5. Any anti-cancer treatment within 14 days or any investigational agent within 30 days 
before the first dose of study drug.
6. Radiotherapy within 3 weeks prior to the first dose of lenvatinib.
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 hours will be ineligible.
8. Significant cardiovascular impairment: History of (a) congestive heart failure greater 
than New York Heart Association (NYHA) Class II, (b) unstable angina, 
(c) myocardial infarction, (d) stroke, or (e) cardiac arrhythmia associated with 
impairment within 6 months of the first dose of study drug.
9. A clinically significant electrocardiogram (ECG) abnormality, including a marked 
baseline prolonged QT/QTc interval (eg, a repeated demonstration of a QTc interval 
>500 msec). 
10. Active infection requiring systemic therapy.
11. Clinically significant hemoptysis or tumor bleeding within two weeks prior to first 
dose of lenvatinib.
12. Radiographic evidence of major blood vessel invasion/infiltration.
13. Other active malignancy (except definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) 
within past 24 months.
14. Scheduled for major surgery during the study.
15. Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [ß-hCG] (or human chorionic 
gonadotropin [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units 
of ß-hCG [or hCG]).  A separate baseline assessment is required if a negative 
screening pregnancy test was obtained more than 72 hours before the first dose of 
study drug.
16. Females of childbearing potential who:

Do not agree to use a highly effective method of contraception (ie, total 
abstinence [if it is their preferred and usual lifestyle], an intrauterine device or 
intrauterine system, a contraceptive implant, an oral contraceptive, or have a 


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vasectomized partner with confirmed azoospermia) within 30 days before study 
entry and throughout the entire study period and for 30 days after study drug 
discontinuation.

Are currently totally abstinent (as their preferred and usual lifestyle), and do not 
agree to be totally abstinent during the study period and for 30 days after study 
drug discontinuation.

Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do 
not agree to use the same contraceptive during the study and for 30 days after 
study drug discontinuation.  

Are using oral hormonal contraceptives and who do not agree to add a barrier 
method.

(NOTE:  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]).
For sites outside of the EU, it is permissible that if a highly effective method of 
contraception is not appropriate or acceptable to the subject, then the subject must 
agree to use a medically acceptable method of contraception, ie, double barrier 
methods of contraception such as condom plus diaphragm or cervical/vault cap with 
spermicide.
17. Evidence of clinically significant disease (eg, cardiovascular, respiratory, 
gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect 
the subject’s safety or interfere with the study assessments.
18. Known intolerance to the study drug or any of the excipients.
19. Any medical or other condition that in the opinion of the investigator(s) would 
preclude the subject’s participation in a clinical study.
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete protocol-specified off-
treatment visits, procedures, and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, the 
date will be documented in the source documents.  The Subject Disposition CRF page will be 
completed indicating the primary reason for discontinuation and all other reason(s) 


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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, in subjects who have discontinued study treatment without 
documented disease progression (radiological or clinical), every effort should be made to 
continue monitoring their disease status by radiologic imaging every 6 weeks ±1 week for the 
first 24 weeks and every 8 weeks ±1 week thereafter from the date of the last assessment 
until (1) the start of new anticancer treatment, (2) disease progression (3) death, or (4) the 
end of the study, whichever occurs first.
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to halt survival follow-up after completion of the primary 
study analysis.
9.4
Treatment
9.4.1
Treatment Administered
Subjects will take lenvatinib as described in Table 1.  Study subjects will be instructed to 
take study drug in the form of two 10-mg capsules and one 4-mg capsule containing 
lenvatinib (total of 3 capsules) with water each morning.  Study drug is to be taken at 
approximately the same time each morning, with or without food. 
Table 1
Treatment Administered
Drug Name
Strength
Oral Dose Form
Number Dispensed and Frequency
Lenvatinib
24 mg
Capsule
Two 10 mg capsules and one 4-mg capsule to be 
taken QD
QD = once a day
9.4.1.1
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 2.
Dose reductions will occur in succession based on the previous dose level (24, 20, 14, and 
10 mg/day).  Any dose reduction below 10 mg/day must be discussed with the sponsor.  
Once the dose has been reduced, it cannot be increased at a later date.


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Table 2
Dose Reduction and Interruption Instructions for Lenvatinib-
Related Toxicities
Treatment-Related Toxicitya,b
including hepatic injury and 
thromboembolic events
Management
Dose Adjustment
Grade 1 and tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c or Grade 3d, e
First occurrence
Interrupt until resolved to Grade 0-1 or 
baseline f
20 mg orally QD
(one-level reduction)
Second occurrence (same toxicity or 
new toxicity)
Interrupt until resolved to Grade 0-1 or 
baseline f
14 mg orally QD
(one-level reduction)
Third occurrence (same toxicity or 
new toxicity)
Interrupt until resolved to Grade 0-1 or 
baseline f
10 mg orally QD
(one-level reduction)
Fourth occurrence (same toxicity or 
new toxicity)
Interrupt until resolved to Grade 0-1 or 
baseline f
Discuss with sponsor
Grade 4g:  Discontinue Study Treatment
QD = once a day
Note:  For grading, see Common Terminology Criteria for Adverse Events version 4.03.  Collect all CTC 
grades of AEs, decreasing and increasing grade.
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:  Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and investigator.  If 
Grade 2 toxicity is determined to be intolerable, the dose of study drug will be reduced with or without dose 
interruption. Interruption for Grade 3 toxicities is mandatory. 
d:  Obese subjects with weight loss requiring dose interruption and reduction do not need to return to baseline 
or Grade 1 weight loss to restart lenvatinib.  Based on the judgment of the investigator, subjects may be 
restarted at the lower dose of lenvatinib once the weight has been stable for at least 1 week.  Normal BMI 
should be used as the new baseline for future dose reductions.
e:  Not applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment 
of the investigator (eg, ALT, AST, γ-GTP values < 10 × ULN, and Na).
f: For hematology toxicities, restart treatment after toxicity resolves to Grade 2.
g: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
9.4.1.1.1
MANAGEMENT OF HYPERTENSION
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 measurements after an hour:

Continue lenvatinib 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.


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The following guidelines should be followed for the management of systolic BP ≥ 160 
mmHg or diastolic BP ≥ 100 mmHg confirmed on repeat measurements after an hour :

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at a dose of 20 mg once daily (or one dose level reduction) 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 20-mg 
once daily dose despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different 
class of antihypertensive), then lenvatinib administration should be interrupted 
and restarted at a dose of 14 mg once daily (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 14-mg 
once daily dose despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different 
class of antihypertensive), then lenvatinib administration should be interrupted 
and restarted at a dose of 10 mg once daily (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.
○
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 lenvatinib
9.4.1.1.2
MANAGEMENT OF PROTEINURIA
Regular assessment of proteinuria should be conducted as detailed in the Schedule of Visits 
and Procedures/Assessments (Table 4).  Guidelines for assessment and management of 
proteinuria:
Initial episode of proteinuria: if proteinuria ≥ 2+ is detected on urine dipstick testing, 
lenvatinib 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.  Grading 
according to the National Cancer Institute’s (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE, v4.03) will be based on the 24-hour urinary protein result.  
Management of lenvatinib administration will be based on the grade of proteinuria 
according to the Study Treatment Dose Reduction and Interruption Instructions.
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed every 
2 weeks (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 3 consecutive months.  Any subsequent increases in the level of proteinuria 
≥2+ on urine dipstick testing must be confirmed with a 24-hour urinary protein test, 


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which will be assessed and graded according to the Study Treatment Dose Reduction and 
Interruption Instructions.  If a new event of proteinuria ≥2+ occurs, the subject must 
resume urine dipstick testing for evaluation of proteinuria every 2 weeks until results are 
1+ or negative for 3 consecutive months.
9.4.1.1.3
MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted 
as clinically indicated.  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, lenvatinib must be discontinued.
9.4.1.1.4
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, signs of deep vein thrombosis  
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, lenvatinib must 
be discontinued.
9.4.1.1.5
MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME  
In clinical studies with lenvatinib, events of posterior reversible encephalopathy syndrome 
(PRES) were reported in less than 1% of lenvatinib-treated subjects.  PRES is a neurological 
disorder, which can present with headache, seizure, lethargy, confusion, altered mental 
function, blindness, and other visual or neurological disturbances.  Mild to severe 
hypertension may be present.  MRI is necessary to confirm the diagnosis of PRES.  
Appropriate measures should be taken to control BP. In subjects with signs or symptoms of 
PRES, dose interruptions, dose adjustments, or discontinuation may be required as per 
instructions included in Table 2.
9.4.1.1.6
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored monthly per the Schedule of Visits and 
Procedures/Assessments (Table 4). Hypocalcemia should be treated per institutional 
guidelines (eg, using appropriate calcium, magnesium, and Vitamin D supplementation) until 
resolution.


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9.4.2
Identity of Investigational Product
9.4.2.1
Chemical Name, Structural Formula of E7080

Test drug code:  E7080

Generic name:  lenvatinib

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula:  C21H19ClN4O4•CH3SO3H

Molecular weight: 522.96

Structural formula:
9.4.2.2
Comparator Drug
Not applicable.
9.4.2.3
Labeling for Study Drug
Lenvatinib will be labeled in accordance with text that is in full regulatory compliance with 
each participating country and is translated into the required language(s) for each of those 
countries, if required.
The following information will be provided (but not limited to):

Name, address, and telephone number of the sponsor

Pharmaceutical dosage form, route of administration, quantity of dosage units, identifier, 
and potency

Lot number

Protocol number

Directions of use (if applicable)

Storage conditions

Storage restrictions (if applicable)

Expiration date (if applicable)

Caution: New Drug-Limited by Federal (US) Law to Investigational Use


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9.4.2.4
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 or designee (if regionally required, 
the head of the medical institution) is responsible for ensuring that the temperature is 
monitored throughout the total duration of the study and that records are maintained; the 
temperature should be monitored continuously by using either an in-house validated data 
acquisition system, a mechanical recording device, such as a calibrated chart recorder, or by 
manual means, such that minimum and maximum thermometric values over a specific time 
period can be recorded and retrieved as required.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
Lenvatinib at 24 mg once daily is the recommended dose for locally recurrent or metastatic, 
progressive, radioactive iodine-refractory DTC (LENVIMA® US package insert/EU SmPC).
A Phase 2 study in Japan using 24 mg once a day (QD) of lenvatinib is ongoing in subjects 
with ATC, DTC, and MTC.  An interim analysis of this study has confirmed the safety and 
efficacy of 24 mg QD.
Based on the above, 24 mg QD will be used for the dose of lenvatinib in this study. 
9.4.5
Selection and Timing of Dose for Each Subject
Study drug capsules are to be taken orally QD at approximately the same time in the morning 
without regard to food intake from D1C1 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 a 
subject vomits after study drug administration, the subject should not take another dose until 
the next scheduled dose.
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of ICF) until 28 days after the final dose of study 


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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.
Aspirin, nonsteroidal antiinflammatory drugs, and low-molecular-weight heparin are 
permissible but should be used with caution.  Granulocyte colony-stimulating factor or 
equivalent may be used in accordance with American Society of Clinical Oncology, 
institutional, or national guidelines.  Erythropoietin may be used according to ASCO, 
institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell (RBC) counts.
If the 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 for 2 days before the procedure and restart it 2 
days after, once there is clear evidence of wound healing and no risk of bleeding, but 
at least 2 days after the procedure. 

For major procedures: hold lenvatinib for 1 week (5 half-lives) prior to surgery and 
then restart when there is clear evidence of wound healing and no risk of bleeding, 
but at least 1 week after the procedure.
If concomitant medication/therapy is administered for an AE, investigators will record that 
AE on the Adverse Events CRF.
9.4.7.1
Drug-Drug Interactions
No dose adjustment of lenvatinib is recommended when co-administered with CYP3A, PgP, 
and breast cancer resistance protein (BCRP) inhibitors, and with CYP3A and PgP inducers 
(LENVIMA® US Package Insert).  Similarly, lenvatinib at the proposed dose for clinical use 
is not expected to inhibit the cytochrome P450-mediated metabolism of other drugs 
administered concomitantly (CPMS-E7080-007R-v1, RDMPKA2013-156 REVISION NO. 
1).
The population pharmacokinetic analysis also indicated that agents that raise gastric pH (eg,
H2-blockers, proton pump inhibitors, antacids) do not have a significant effect on the 
absorption and bioavailability of lenvatinib (CPMS-E7080-007R-v1).  Please refer to 
http://medicine.iupui.edu/flockhart/table.htm for the most current information regarding 
inhibitors and inducers of CYP3A4.


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9.4.7.2
Prohibited Concomitant Therapies and Drugs
Subjects should not receive other antitumor therapies while on study.  If subjects receive 
additional antitumor therapies during the study, such as radiotherapy, other chemotherapy, or 
immunotherapy, this will be judged to represent evidence of disease progression, and 
continuation of study medication should be discussed with the sponsor.  Following this 
discussion, if the joint decision is made to discontinue study treatment, then such subjects 
will complete all end of treatment assessments and continue to be followed for survival in the 
Follow-Up Period.
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  The CRAs 
will review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572

Financial Disclosure form(s) for the PI and all subinvestigators listed on Form FDA 1572

A signed and dated curriculum vitae (CV)  of the PI including a copy of the PI’s current 
medical license (required in the US) or medical registration number on the CV

A signed and dated clinical trial agreement

A copy of the regulatory authority approval for the country in which the study is being 
conducted, including any other required country-specific documentation and the 
Importation License
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 drug 


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(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 drug to be used other than as 
directed by this protocol.  Study drug 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 
drug, dispensing of study drug to the subject, collection and reconciliation of unused study 
drug that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drug to the sponsor or (where applicable) destruction of 
reconciled study drug at the site.  This includes, but may not be limited to:  (a) 
documentation of receipt of study drug, (b) study drug dispensing/return reconciliation log, 
(c) study drug 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 drug 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, EMA, MHRA).  As applicable, all unused study drug and empty and partially 
empty containers from used study drug 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 drug that was 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 drug 
and containers at the site.  Destruction at the site will only occur under circumstances where 
regulation or supply type prohibits the return of study drug to the central or local depot(s).  
Approval for destruction to occur at the site must be provided by the sponsor in advance.  
Upon completion of drug accountability and reconciliation procedures by the site’s personnel 
and documentation procedures by the sponsor’s personnel, study drug that is 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 drug may be removed from the site and hand delivered to the central or local depot by 
sponsor representatives.  Where study drug is 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.


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9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity (record in accordance with 
prevailing regulations).  Baseline characteristics will include ECOG performance status and 
NYHA cardiac disease classification(see Appendix 3 and Appendix 5, respectively).
9.5.1.2
Medical History and Physical Examinations
Medical and surgical histories and current medical conditions will be obtained during the
Pretreatment Phase (Screen and Baseline), along with concomitant medications, and 
recorded in the CRF at the Screening Visit.
Physical examinations (PEs) will be performed as specified in the Schedule of Visits and 
Procedures/Assessments (Table 4).  A comprehensive PE 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 PE 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 PE 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 (Appendix 2) as defined in
Inclusion Criterion #4.  Subjects must also fulfill the medical and physical characteristics 
identified in the inclusion criteria and not otherwise meet any of the exclusion criteria.
9.5.1.3
Efficacy Assessments
The primary endpoint (ORR), secondary endpoints (12-week PFS, 6-month OS, median PFS 
and median OS), and exploratory endpoints (CBR, DCR, and DOR) will be evaluated by the 
investigator.  In addition, OS status will be assessed throughout the study.
9.5.1.3.1
TUMOR ASSESSMENTS
Tumor assessments will be performed using RECIST 1.1. Assessments are to be performed 
at the site by appropriately qualified personnel at each time point and results of the site 
interpretation are to be recorded on the appropriate CRFs. Historical standard of care scans 
that are performed with scanning parameters consistent with the requirements for this 
protocol within 21 days prior to dosing are acceptable.  Tumor assessments (CT chest and 
CT/MRI of neck, abdomen, pelvis, and other areas of known disease at screening plus any 
areas of newly suspected disease) should be performed at screening, every 6 weeks ±1 week


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for the first 24 weeks and every 8 weeks ±1 week  thereafter, or sooner if clinically indicated, 
until documentation of disease progression.  A bone scan and brain scan will be performed 
within 21 days prior to C1D1, and continuing from C1D1 every 24 weeks ±1 week, or as 
clinically indicated.  If PET/CT is performed, a bone scan is not necessary.  In addition, for 
subjects with a history of treated brain metastases, brain scans will be performed at tumor 
assessment time points, if clinically indicated. In subjects with CR based on body CT/MRI 
scans, a bone scan (or PET/CT, if performed at Screening) and brain scan assessment will be 
required at response confirmation.  All objective responses must be confirmed at least 28 
days following the initial achievement of the response. 
The CT scan should be a diagnostic quality spiral or multidetector CT with oral and iodinated 
IV contrast, and the MRI scan should be performed with IV gadolinium chelate.  Scans of the 
neck, abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest must be done with CT.  If iodinated IV contrast is contraindicated, the 
chest evaluation should be done with non-contrast CT, and the abdomen and pelvis 
evaluation should be performed using either CT with oral contrast (without IV contrast) or 
MRI with gadolinium chelate IV contrast (the latter is preferred).  Spiral/multidetector CT 
should be performed with a 5-mm contiguous slice reconstruction algorithm.  If body MRI 
scans are performed, contiguous slices of 5 mm are also recommended.
The same imaging modality and image-acquisition protocol (including use or nonuse of IV 
contrast) should be used consistently across all time points to allow consistent comparison of 
lesions.  Low-dose non-contrast CT transmission scans from a positron emission 
tomography-CT (PET-CT) combination scanner are not acceptable for RECIST 1.1 
measurements/non-target lesion assessments.  Ultrasound should not be used for radiographic 
tumor assessment.  A chest x-ray or skeletal x-ray which clearly demonstrates a new 
metastatic lesion may be used to document progression in lieu of the CT/MRI scans.
Brain scans should be performed by MRI with and without contrast enhancement or CT with 
contrast enhancement, with 5-mm contiguous slices recommended (maximum inter-slice gap 
of 1 mm on MRI).
Bone scans may be performed using either 99m-technetium methylene polyphosphonate (ie, 
methylene diphosphate or hydroxymethylene diphosphate) scintigraphy or whole body-bone 
MRI or 18F-sodium fluoride PET (NaF PET).  The same methodology and scan acquisition 
techniques used at screening should be used throughout the study to ensure comparability.
Lesions identified on bone scans should be followed with cross-sectional imaging.
If subcutaneous masses or nodes are palpable (eg, bulky) and are assessable by both clinical 
and radiographic techniques, the radiographic (CT/MRI) technique should be used for the 
assessment of target and non-target lesions.
Subjects going off lenvatinib treatment without disease progression in the Treatment Phase 
will continue to undergo tumor assessments according to the above schedule until disease 
progression is documented or another anticancer therapy is initiated.  


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All scans for tumor assessments performed during the study should be archived in 
accordance with the standard local practice.  The scans must be accessible in the event of a 
sponsor request to submit them for central review.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Not applicable.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Pharmacodynamic/Pharmacogenomic:
Blood samples for the development of exploratory predictive biomarkers will be collected 
prior to the first dose of study drug, on Cycle 1 Day 15, and on Day 1 of all subsequent 
cycles during Treatment Phase, and at the End of Treatment visit (or at the time of disease 
progression, whichever occurs first).  Biomarker discovery and/or validation may be 
performed to identify blood or tumor biomarkers which may be useful to predict subject 
response to lenvatinib, as determined by evaluation of response-related and/or safety-related 
outcomes as well as for potential use in diagnostic development.  Blood samples from 
subjects receiving lenvatinib  may be analyzed using global proteomic methods, 
enzyme-linked immunosorbent assay, multiplex bead-based immunoassay, or other 
assays/methods or new technology.  In addition, biomarkers identified in other lenvatinib
clinical studies  may also be assessed in the biomarker samples collected from subjects 
enrolled in this study. The decision to perform exploratory biomarker analysis may be based 
on the clinical outcome of this study and/or the signals observed in other clinical studies or 
other information available at that time.
Archival fixed tumor tissue will be collected from all subjects for potential assessment of 
mutations and other genetic alterations or genes and/or proteins that may be important in the 
development and progression of cancer as well as for potential use in diagnostic 
development. Appropriate technology/methodologies will be used based on the amount of 
tumor tissue available.  The same tumor tissue that is collected for diagnosis of ATC and 
study eligibility may also be used for the biomarker assessments. 
A plasma sample will be collected for potential analysis for circulating cell free nucleic acid 
(cf nucleic acid) from all enrolled subjects.  These plasma samples will be collected at the 
same time points described above for blood samples.  Cell free DNA isolated from plasma 
samples may be used to explore tumor genetic alterations such as mutations observed in 
archival tumor samples as well as those which develop during drug treatment. 
Data obtained will be used for research, to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject.  The DNA will not be used to determine or predict risks for diseases that an 


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individual subject does not currently have.  Any sample or derivatives (DNA, RNA, and 
protein) may be stored for up to 15 years to assist in any research scientific questions related 
to lenvatinib, cancer and/or for potential diagnostic development. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all Common 
Terminology Criteria for Adverse Events (CTCAE) v4.03 grades (for both increasing and 
decreasing severity), and serious adverse events (SAEs); regular monitoring of hematology, 
blood chemistry, and urine values; periodic measurement of vital signs and ECGs; and 
performance of PEs as detailed in Table 4.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
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. 
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE)

Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not
All AEs observed during the study will be 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 and for 28 days after the last dose of study treatment.  Subjects 
who fail screening primarily due to AE(s) must have the AE(s) leading to screen failure 


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reported on the Screening Disposition CRF.  SAEs will be collected for 28 days after the last 
dose.
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF. 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
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.
Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to CTCAE v4.03; see Appendix 
6. Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event


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Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
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)
Anaplastic thyroid cancer can rapidly invade surrounding tissues, including trachea and 
carotid artery. In the case of life-threatening trachea fistula or carotid artery (or other major 
vessels) invasion or bleeding, the investigator should discuss the case with the Eisai Medical 
Monitor, in addition to discontinuing lenvatinib per Table 2 for Grade 4 toxicity and treat the 
subject based on the institution’s standard practice.
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.


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The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before ICF (where the condition requiring the hospitalization has 
not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 3. Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Visits and Procedures/Assessments (Table 4) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis will be 
collected in the study.
Efforts should be made to conduct study visits on the day scheduled.  If necessary, study 
visits may be held up to 3 days sooner or later than the scheduled day that clinical laboratory 
assessments may be conducted according to Table 4.
Table 3
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), ANC, INRb
Chemistry
Electrolytes
Bicarbonate, chloride, magnesium, potassium, sodium
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function testsa
TSH and free T4 
Pregnancy test
Serum β-hCG (if urine not tested)
Other
Albumin, glucosec, lactate dehydrogenase,  total protein,  uric 
acid, calcium,  phosphorus
Urinalysis
Glucosec, ketones, pH, protein, RBCs, specific gravity
Pregnancy test
Urine β-hCG (if serum not tested)
ALT = alanine aminotransferase, ANC= absolute neutrophil count, AST = aspartate aminotransferase, β 


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Table 3
Clinical Laboratory Tests
Category
Parameters
hCG = beta-human chorionic gonadotropin,  INR = International Normalized Ratio, RBC = red blood cells, 
T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = white blood cells
a:  Thyroid function will be assessed at the Screening Visit and then every 2 cycles (starting at C2) 
throughout the study.
b: INR only at screening/baseline and when clinically indicated
c: Fasting glucose at Screen, only
Clinical laboratory tests during the study will be performed by trained staff at the study sites.  
Local laboratories will perform tests throughout the study.  Laboratory certification as 
available will be included in the final clinical study report (CSR) for this study.
All hematology, blood chemistry, urinalysis, and pregnancy test (serum or urine) samples are 
to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle. Refer to 
Table 2 for the management of clinically significant laboratory abnormalities.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1 and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the Schedule of Visits and Procedures/Assessments (Table 
4) by a validated method.  Height will be measured at the Screening Visitonly.  Blood 
pressure and pulse will be measured after the subject has been sitting for 5 minutes.  All BP 
measurements should be performed on the same arm, preferably by the same person, if 
feasible. For subjects with an elevated BP (systolic BP ≥140 mmHg or diastolic BP ≥90 
mmHg), confirmation should be obtained by repeat measurements after 1 hour to obtain a 
mean value.  .
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of Visits and 
Procedures/Assessments (Table 4) and as described in Section 9.5.1.2.  Documentation of the 
PE will be included in the source documentation at the site.  Only changes from screening PE
findings that meet the definition of an AE will be recorded on the Adverse Events CRF.


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9.5.1.5.6
ELECTROCARDIOGRAMS
Electrocardiograms will be obtained as designated in the Schedule of Visits and 
Procedures/Assessments (Table 4). 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 9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the Adverse Events CRF.
9.5.1.5.7
OTHER SAFETY ASSESSMENTS
Eastern Cooperative Oncology Group Performance Status
Eastern Cooperative Oncology Group performance status will be assessed at the Screening 
Visit, Day 1 of each treatment cycle, and at End of Treatment Visits.  The table in Appendix 
3 will be used to assess performance status.
Echocardiogram or Multigated Acquisition (MUGA) Scan
Echocardiograms or MUGA scans should be performed only for subjects who had prior 
anthracycline treatment.  In such instances, the echocardiogram or MUGA must be 
performed during the Screening visit and at the End of Treatment Visit, or sooner, if 
clinically indicated (see Schedule of Visits and Procedures/Assessments, Table 4).
Pregnancy Test 
At the Screening Visit, a serum (6-mL sample of blood will be collected) or urine β-hCG test 
will be performed for premenopausal women and postmenopausal women who have been 
amenorrheic for less than 12 months.  A separate baseline assessment will be required if a 
negative screening pregnancy test was obtained more than 72 hours before the planned first 
dose of study drug.  Pregnancy testing (urine test is acceptable) must be performed on Day 1 
of each cycle (beginning with Cycle 2) for as long as the subject remains on the study.  
Please refer to the Schedule of Visits and Procedures/Assessments (Table 4).
9.5.2
Schedule of Procedures/Assessments 
9.5.2.1
Schedule of Procedures/Assessments
Table 4 presents the schedule of visits and procedures/assessments for the E7080-M000-213
study.


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Table 4
Schedule of Visits and Procedures/Assessments in E7080-M000-213 Pretreatment and Treatment 
Phases
Phase
Pretreatmenta
Treatmentb
All cycles are 28 days in duration
Posttreatmentc 
Period
Screening
Baseline
Cycle 1
Cycle 2 
Cycle 3–
Last Cycle
End of 
Treatment
Follow-Up Period 
Day
-21 to-2
-1
Day 1a
Day 8
Day 15
Day 1
Day 15
Day 1
Within 30 
days of last 
dose
Every 12 weeksd
Visit
1
2
3
4
5
6
7
8, 9, 10, 11, 
etc.
Informed consent
X
Inclusion/Exclusione
X
X
Demographic dataf
X
Archival/Fresh tumor 
block or slidesg
X
Blood samples for 
biomarker analysesh
X
X
X
X
X
Plasma sample for 
cfDNAh
X
X
X
X
X
ECOGi
X
X
X
X
X
TNM stagingj
X
Medical/surgical 
history
X
X
Vital signsk,l
X
X
X
X
X
X
X
X
Physical examinationm
X
X
X
X
X
12-Lead ECGn
X
X
X
X
X
Echocardiogram or 
MUGA scano
X
X
Clinical chemistry and 
hematologyp
X
X
X
X
Xq
X
X
TSH and free T4 
X
X
X
Xr
X


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Table 4
Schedule of Visits and Procedures/Assessments in E7080-M000-213 Pretreatment and Treatment 
Phases
Phase
Pretreatmenta
Treatmentb
All cycles are 28 days in duration
Posttreatmentc 
Period
Screening
Baseline
Cycle 1
Cycle 2 
Cycle 3–
Last Cycle
End of 
Treatment
Follow-Up Period 
Day
-21 to-2
-1
Day 1a
Day 8
Day 15
Day 1
Day 15
Day 1
Within 30 
days of last 
dose
Every 12 weeksd
Visit
1
2
3
4
5
6
7
8, 9, 10, 11, 
etc.
levelsr
Urinalysis (Dipstick)s
X
X
X
X
X
X
X
Pregnancy testt
X
X
X
X
Telephone contact
Xd
Lenvatinib treatment
Once Daily
Tumor assessments: 
CT/MRIu
X
CT chest and CT/MRI of neck/abdomen/pelvis and other areas of known disease at screening plus any areas of newly 
suspected disease should be performed every 6 weeks ±1 week  after C1D1 for the first 24 weeks and every 8 weeks ±1 
week thereafter, or sooner if clinically indicated, until documentation of disease progression.
Bone Scan and Brain 
Scanv
X
Bone scans and brain scans will be performed every 24 weeks after C1D1, or sooner if clinically indicated.  If PET/CT is 
performed, a bone scan is not necessary. In subjects with CR based on body CT/MRI scans, a bone scan (or PET/CT, if 
performed at Screening) and brain scan assessment will be required at response confirmation.  In addition, for subjects with 
a history of treated brain metastases, brain scans will be performed at tumor assessment time points, if clinically indicated
Survival
Throughout
Concomitant 
medicationsw
Throughout
AEs/SAEsx
Throughout
AEs = adverse events, BP = blood pressure, C1D1 = Cycle 1/Day 1, C1D15 = Cycle 1/Day 15, cfDNA = cell free DNA, CR = complete response, CT = computerized tomography, 
ECG = electrocardiogram, ECOG = Eastern Cooperative Oncology Group, h = hour, HR = heart rate, med = medical/medication(s), MRI = magnetic resonance imaging, MUGA = 
multigated acquisition, PET = positron-emission tomography, PR = partial response, RECIST = Response Evaluation Criteria In Solid Tumors, RR = respiratory rate, SAEs = 
serious adverse events, surg = surgical, T4= thyroxine TNM = tumor-mode-metastasis, TSH= thyroid stimulating hormone, Tx = treatment, w/in = within.


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a.
The results of all screening assessments and evaluations must be completed and reviewed by the investigator prior to the Baseline Visit.  Baseline assessments can be 
performed on Day -1 or on C1D1 prior to treatment.  Informed consent must be obtained up to 21 days prior to C1D1.
b.
Efforts should be made to conduct study visits on the day scheduled (3 day).  Clinical laboratory assessments may be conducted anytime within 72 hours prior to the 
scheduled visit, unless otherwise specified.
c.
The Posttreatment Phase will start at the End of the Treatment visit and will continue as long as the subject is alive or until the subject withdraws consent or is lost to 
follow-up.  Subjects who discontinue study treatment before disease progression will continue to undergo tumor assessment every 6 weeks ±1 week for the first 24 weeks 
and every 8 weeks ±1 week thereafter, until documentation of disease progression or start of another anti-cancer therapy.  Follow-up assessment for survival will be 
performed every 12 weeks ±1 week.
d.
Subjects will be followed for survival every 12 weeks (1 week) after the End of Treatment Visit.  If a clinic visit is not feasible, follow-up information may be obtained 
via telephone or email.
e.
New York Heart Association (NYHA) cardiac disease classification should be performed at Screening only, if needed.
f.
Demographic information includes date of birth (or age), sex, and race/ethnicity.
g.
Archival tumor sample(s) from the most recent surgery or biopsy for central pathology confirmation of ATC will be collected during the Pretreatment Phase and may also 
be used for potential biomarker research (see Section 9.5.1.4.2).  Fresh tumor biopsies (re-biopsy) should be obtained, whenever feasible.  If the results of central 
pathology review are not available prior to study entry, the confirmation of diagnosis of ATC at the local laboratory is mandatory prior to scheduled start of treatment 
with lenvatinib.  
h.
A blood sample for biomarkers and plasma sample for cell free DNA (cfDNA) must be collected prior to start of study drug, on C1D15, on Day 1 of all subsequent 
cycles during the Treatment Phase, and at the End of Treatment visit (or at the time of disease progression, whichever occurs first).
i.
ECOG will be performed at the Screening and Baseline Visits, on Cycle 2/Day 1, on Day 1 of every subsequent cycle thereafter, and at the End of Treatment Visit.
j.
TNM staging will be performed at Screening (see Appendix 1). 
k.
Assessments will include vital signs (resting BP, HR, RR, and body temperature), weight, and height.  Height will be measured at the Screening Visit only.  Vital signs 
will be performed at Screening, Baseline, C1D8, C1D15, C2D1, C2D15, Day 1 of every cycle thereafter, all unscheduled visits, and at the End of Treatment Visit. 
Elevated BP (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) should be confirmed by repeat measurements after 1 hour to obtain a mean value.    
l.
Subjects with systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg must have their BP monitored every 2 weeks (on Day 15 or more frequently as clinically indicated) 
until systolic BP has been ≤ 150 mmHg and diastolic BP has been ≤ 95 mmHg for 3 consecutive months.  If a new event of systolic BP ≥ 160 mmHg or diastolic BP 
≥100 mmHg occurs, the subject must resume the Day 15 evaluation until systolic BP has been ≤ 150 mmHg and diastolic BP has been ≤ 95 mmHg for 3 consecutive 
months.  
m.
A comprehensive PE (including a neurological examination) will be performed at the Screening Visit, on Cycle 1/Day 15, on Day 1 of each subsequent cycle, and at the 
End of Treatment assessment.  A symptom-directed PE will be performed on Baseline (Day -1) or on C1D1 prior to treatment, and at any time during the study, as 
clinically indicated.
n.
Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.
o.
For subjects who had prior anthracyclines, an echocardiogram or MUGA scan will be performed during Screening Visit and at the End of Treatment Visit or sooner, 
if clinically indicated. 
p.
Clinical chemistry and hematology results must be reviewed prior to administration of lenvatinib on C1D1 and within 48 hours after dispensing lenvatinib for all 
subsequent cycles.  Scheduled assessments (Screen, Baseline, Cycle 1/Day 15, Day 1 of each subsequent cycle starting with Cycle 2 and at the End of Treatment Visit) 
may be performed within 72 hours prior to the visit.  If there is a clinically relevant hematologic or clinical chemistry toxicity of ≥Grade 3, repeat laboratory test and AE
assessment at least every 3 days (until improvement to < Grade 3). An INR will be performed at screening/baseline and when clinically indicated.
q.
On C2D15, only liver function (ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin) should be performed.  Note: liver function should be assessed 


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every 2 weeks for the first two months (Baseline, C1D1, C1D15, C2D1, and C2D15) and then monthly thereafter (Day 1 of each subsequent cycle).
r.
Assessment of TSH and free T4 levels are to be performed at the Screening/Baseline Visit and then every 2 cycles (starting at Cycle 2) throughout the study.
s.
Urinalysis will be performed at Screening, Baseline, Cycle 1/Day 15, Cycle 2/Day 1, Cycle 2/Day 15, Day 1 of every cycle thereafter, all unscheduled visits, and at the 
End of Treatment Visit.  Urinalysis will include glucose (fasting at Baseline, only), ketones, pH, protein, RBCs, and specific gravity. If urinalysis suggests a urinary tract 
infection, or if clinically indicated, a urine microscopy, culture, and sensitivity should be performed at the site’s laboratory. If urine protein is ≥2+ on urinalysis, 
lenvatinib 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.  Urine 
dipstick testing for subjects with proteinuria ≥2+ should be performed every 2 weeks (on Day 1 and Day 15 of each cycle or more frequently as clinically indicated) until 
the results have been 1+ or negative for 3 consecutive months. If a new event of proteinuria ≥2+ occurs, the subject must resume urine dipstick testing for evaluation of 
proteinuria every 2 weeks until results are 1+ or negative for 3 consecutive months.
t.
A serum or urine pregnancy test will be performed in women of childbearing potential (ie, premenopausal and perimenopausal women who have been amenorrheic for 
less than 12 months) at the Screening Visit.  If a negative screening pregnancy test is obtained more than 72 hours before the planned first dose of lenvatinib, a separate 
serum or urine sample must be obtained and tested at the Baseline Visit assessment. Pregnancy testing (urine test is acceptable) must be performed on Day 1 of each 
cycle (beginning with Cycle 2) for as long as the subject remains on the study.   
u.
Tumor assessments will be performed using RECIST 1.1.  Screening tumor assessments using contrast-enhanced CT of the chest and contrast-enhanced CT or MRI of 
the neck/abdomen/pelvis and other areas of known disease or newly suspected disease should be performed within 21 days prior to C1D1.  Treatment Phase:  tumor 
assessments of the chest/neck/abdomen/pelvis and other areas of known disease at screening or newly suspected disease should be performed every 6 weeks (±1 week)
for the first 24 weeks and every 8 weeks ±1 week thereafter, or sooner if clinically indicated, until documentation of disease progression and should utilize the same 
methodology and scan acquisition techniques used at screening to ensure comparability.  If a subject discontinues from the study prior to the Week 6 scan, then a 
CT/MRI scan should be performed as close as possible to 6 weeks after C1D1 but before another anticancer therapy is initiated.  Detailed image acquisition guidelines 
will be provided by the imaging core laboratory.
Follow-up Period: Subjects who discontinue treatment without disease progression should continue tumor assessments every 6 weeks (±1 week) for the first 24 weeks 
and every 8 weeks ±1 week  thereafter, until disease progression or beginning another anticancer therapy.
v.
A brain scan and bone scan (99m-technetium polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF) to assess brain and bone metastases will be performed 
within 3 weeks prior to C1D1 (historical scans are acceptable) and then every 24 weeks (±1 week), or sooner if clinically indicated.  If PET/CT is performed, a bone scan 
is not necessary.  For subjects with a history of treated brain metastases, brain scans will be performed at tumor assessment time points, if clinically indicated.  In 
subjects with CR based on body CT/MRI scans, a bone scan (or PET/CT, if performed at Screening) and brain scan assessment will be required at response confirmation. 
All objective responses must be confirmed at least 28 days following the initial achievement of the response.  The same methodology and acquisition techniques used at 
screening should be used throughout the study to ensure comparability.  Lesions identified on bone scans should be followed with cross-sectional imaging.
w.
Concomitant medications will be recorded throughout and for 28 days after last dose of lenvatinib.  All anticancer therapy will be recorded until time of death or 
termination of survival follow-up.
x.
Throughout the study from the signature of ICF, SAE irrespective of relationship to study treatment must be reported as soon as possible but not later than 24 h.  AEs 
will be recorded for 28 days after last dose of lenvatinib.  During treatment interruption due to AEs, repeat AE assessments at least every 7 days (until restarting 
lenvatinib administration).


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9.5.2.2
Description of Procedures/Assessments Schedule
Refer to Table 4 for a description and timing of each procedure and assessment in the 
Prerandomization and Randomization Phase.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies ofRR-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 subjectsafety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from when the investigator becomes aware of the event.
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 sponsor 
to be filed in the sponsor’s Trial Master File.
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 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 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects


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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 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.4.3.2
REPORTING OF STUDY-SPECIFIC EVENTS
Study-specific events, consisting of clinically significant tumor bleeding or bleeding due to 
major artery invasion, should always be considered as serious important medical events, 
which will be entered on the Adverse Event CRF and reported using the procedures detailed 
in Reporting of Serious Adverse Events (Section 9.5.4.1), even if the study-specific event 
does not meet other serious criteria.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European GCP 
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 European member states.
9.5.5
Completion/Discontinuation of Subjects
The investigator may withdraw the subject from the study at any time for safety or 
administrative reasons.  A subject may elect to discontinue the study at any time for any 
reason.  All subjects who discontinue the study are to complete the study’s early 


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discontinuation procedures indicated in the Schedule of Visits and Procedures/Assessments 
(Table 4).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice (ie, subject chooses to discontinue from the 
treatment but is willing to participate in the Follow-Up portion of the study), progression of 
disease, withdrawal of consent (ie, subject no longer wishes to participate in the study and be 
contacted), pregnancy, sponsor discontinuation of the study, or other.  In addition to the 
primary reason, the subject may indicate 1 or more secondary reason(s) for discontinuation.  
Study disposition information will be collected on the Subject Disposition CRF.  Subjects 
will be judged as lost to follow-up only if they cannot be reached after 3 documented 
attempts (at least 1 week apart) by the site to contact them.
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
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.


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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.
The Data Management Plan defines and documents the procedures necessary to ensure data 
quality.  These activities must be followed to ensure that data are properly entered, validated, 
coded, integrated, reconciled, and reviewed.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released.  Statistical analyses will be performed 
using SAS software or other validated statistical software as required.  Details of the 
statistical analyses will be included in a separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT

The primary efficacy endpoint is ORR as determined by investigator review, using 
RECIST 1.1. ORR is the proportion of subjects who have best overall response 
(BOR) of CR or PR.
9.7.1.1.2
SECONDARY ENDPOINTS

Twelve-week PFS is the percentage of subjects in the analysis population who remain 
alive and progression-free at 12 weeks.

Six-month OS is defined as the percentage of subjects in the analysis population who 
are alive at 6 months.  It will be estimated using the KM method. 

Median PFS and median OS.


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9.7.1.1.3
EXPLORATORY ENDPOINTS

CBR is the proportion of subjects who have best overall response of CR or PR or 
durable SD. Stable disease must be achieved at ≥ 23 weeks after first lenvatinib 
administration to be considered durable SD. 

DCR is the proportion of subjects who have best overall response of CR, PR or SD.
Stable disease must be achieved at ≥5 weeks after the first lenvatinib administration 
to be considered BOR.

DOR is defined as the time from the date that the criteria are met for CR or PR, 
whichever is recorded first, to the date that PD is objectively documented or death, 
whichever occurs first.

Evaluate the association of tumor and blood biomarkers with clinical outcomes, 
including efficacy.
All above primary, secondary and exploratory endpoints based on tumor measurement will 
be assessed according to RECIST 1.1.
9.7.1.2
Definitions of Analysis Sets
Full Analysis Set (FAS) will include all subjects who received at least one dose of lenvatinib.
The FAS will be the population for the safety analysis.  Some selected efficacy endpoints 
will also be summarized in the FAS. 
Evaluable Analysis Set (EAS) will include FAS subjects with histological diagnosis of ATC 
that is confirmed by central pathology review.  The EAS will be the primary population for 
the efficacy analysis.
9.7.1.3
Subject Disposition
The number of subjects enrolled, treated, prematurely discontinued from study treatment 
(defined as those who discontinued study treatment due to any reason except for progressive 
disease) and those with major protocol deviations will be counted.  The primary reason for 
study drug discontinued will be summarized according to the categories in the CRF.  The end 
of study status (alive, death, withdrew consent or lost to follow-up) at the data cutoff date 
will be summarized using the data from the survival follow-ups.
Major protocol deviations will be summarized and listed by each category.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized in both Full Analysis Set 
and Evaluable Analysis Set, using descriptive statistics.  Continuous variables include age, 
weight, vital signs, time since ATC diagnosis; categorical variables include sex, age group, 
race, disease stage, ECOG-PS, prior line of chemotherapy for ATC and region.


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9.7.1.5
Prior and Concomitant Therapy
Concomitant medications will be assigned an 11-digit code using the World Health 
Organization Drug Dictionary drug codes.  Concomitant medications will be further coded to 
the appropriate ATC code indicating therapeutic classification.  Prior and concomitant 
medications will be summarized and listed by drug and drug class in the CSR for this 
protocol.  Prior medications will be defined as medications that stopped before the first dose 
of study drug.  Concomitant medications will be defined as medications that (1) started 
before the first dose of study drug and were continuing at the time of the first dose of study 
drug, or (2) started on or after the date of the first dose of study drug up to 28 days after the 
subject’s last dose.  A listing of prior and concomitant medications will be included in the 
CSR of this protocol.
9.7.1.6
Efficacy Analyses
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
In this population, ORR in the historical control is assumed to be approximately 10% based 
on recent trials. The ORR in this trial is estimated as 27%, which is deemed a clinical 
meaningful improvement. Hence, the null and alternative hypotheses are set as follows:
                                                     H0: ORR=10%
                                                     Ha: ORR ≥27%
A binomial exact test will be performed for hypothesis testing in the Evaluable Analysis Set.  
If the obtained p-value is less than or equal to 0.025, it will be concluded that the single agent 
lenvatinib statistically significantly increases ORR compared with historical control.  
Therefore, the superiority of single agent lenvatinib will be demonstrated.
Clopper Pearson 95% CI of ORR will also be constructed to assess the precision of the rate 
estimate.
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
PFS is defined as the time from the date of beginning of lenvatinib administration to the date 
of first documentation of disease progression or death, whichever occurs first. 
PFS censoring rule will follow FDA Guidance for Industry, Clinical Trial Endpoints for 
Approval of Cancer Drugs and Biologics (2007). 
Subjects who have a clinical determination of progression should undergo an MRI, if 
possible, to correlate radiographic findings with the clinical findings.  If a clinical 
determination of progression for a subject is confirmed by an MRI scan, the date of the MRI 
scan will be considered as the progression date for that subject.  Data for subjects without 
disease progression or death at the time of analysis will be censored at the time of the last 
tumor assessment.  Data for subjects who are lost to follow-up prior to documented disease 
progression will be censored at the last tumor assessment date when the subject is known to 


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be progression-free.  Data for subjects who start to receive new anticancer therapy will be 
censored at the last tumor assessment date prior to the introduction of new therapy.  More 
details will be given in the SAP. 
A 12-week PFS of ≥70% in single agent lenvatinib and 50% in the historical control 
(corresponding to a median PFS improvement of approximately 3 months assuming 
exponential distribution) are assumed in the hypothesis testing:
                                                     H0: 12-week PFS=50%
                                                     Ha: 12-week PFS ≥70%
Kaplan-Meier (KM) method will be used to estimate 12-week PFS, along with the 
corresponding 95% CI constructed using Greenwood’s formula (Greenwood, 1926; Collett, 
1994).  The CI approach will be used to demonstrate the superiority of 12-week PFS in the 
single agent lenvatinib over historical control.  If the lower bound is above 50%, it will be 
concluded that the single agent lenvatinib statistically significantly increases 12-week PFS 
compared with historical control.
Overall survival is defined as the time from the date of beginning of lenvatinib administration 
until date of death from any cause.  Six-month OS is assumed to be approximately 44% in 
the historical control (corresponding to a median OS of approximately 5 months assuming an 
exponential distribution).  Six-month OS and its 95% CI will be calculated using the same 
methods as described in the 12-week PFS analyses.  If the lower bound of 95% CI for 6-
month OS is above 44%, it will be concluded that the single agent lenvatinib statistically 
significantly increases 6-month OS compared with historical control.
Median PFS and median OS will be estimated using the KM method.  Their 2-sided 95% CIs 
will be constructed with a generalized Brookmeyer and Crowley method (1982).  KM 
estimates of PFS and OS will be plotted over time.
Secondary efficacy endpoints will be analyzed sequentially, as listed above.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
CBR, DCR, and DOR will be analyzed using the statistical methods as described above.
Tumor and blood biomarkers will be analyzed to assess the correlation with clinical 
endpoints, including efficacy.  The analysis plan will be described in a separate report.


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9.7.1.6.4
FORMAL ANALYSES
A formal analysis will be carried out approximately 6 months following the enrollment of the 
last subject.  The timing of the formal analysis is chosen such that the secondary endpoints, 
12-week PFS and 6-month OS, will be adequately described.  The primary population for 
efficacy analysis is EAS.  Efficacy and safety analysis will also be performed in FAS.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Not applicable.
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Exploratory analyses of tumor and blood biomarkers will be performed to assess the 
correlation with clinical endpoints, including efficacy, and reported separately.  Details of 
these analyses may be described in a separate analysis plan.
9.7.1.8
Safety Analyses
Safety, using the FAS, will be assessed by monitoring and recording of all AEs including all 
CTCAE v4.03 grades (both increasing and decreasing severity), regular monitoring of 
hematology and clinical chemistry, urinalysis, regular measurement of vital signs, 12-lead 
ECGs, echocardiogram or MUGA scan results (only for subjects who had prior 
anthracyclines) including left ventricular ejection fraction and performance of PEs.
9.7.1.8.1
EXTENT OF EXPOSURE
Extent of exposure to study drug will be summarized descriptively as the number of cycles 
received (number and percentage of subjects), duration of exposure (days), cumulative total 
dose received per subject (mg), dose intensity (mg/day) and percent of planned dose 
received.
The number (percentage) of subjects requiring dose reductions, dose interruption, dose delay, 
and drug discontinuation due to AEs will be summarized. The cycle in which the first dose 
reduction/interruption occurred will be summarized using descriptive statistics.  Frequency of 
reductions and dose interruptions will be summarized by categories. 
Time to the first dose reduction (from 24 mg to 20 mg) is defined from the date of the first 
dose (24 mg) to the date of the first dose reduction (20 mg), or first dose interruption if 
subjects had dose interruption followed by dose reduction, or the date of drug discontinuation 
if AE was leading to it. 
Subject data listings will be provided for all dosing records and for calculated summary 
statistics.  


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9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using Medical Dictionary for Regulatory Activities 
(MedDRA®).  Adverse events will be coded to MedDRA (Version 17 or higher) lower level 
term closest to the verbatim term.  The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database.
A TEAE is defined as an AE that had an onset date or a worsening in severity from baseline 
(pretreatment) on or after the first dose of study drug up to 28 days following study drug 
discontinuation.  Only those AEs that were treatment emergent will be included in summary 
tables.  All AEs, treatment emergent or otherwise, will be presented in subject data listings.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT.  A subject will be counted only once by the highest severity grade according 
to CTCAE v4.03 within an SOC and PT, even if the subject experienced more than 1 TEAE 
within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by relationship to the study drug.  Treatment-related AEs include those events 
considered by the investigator to be possibly or probably related to study treatment or with 
missing assessment of the causal relationship.  Serious adverse events, deaths, TEAE with 
grade 3 or above, and TEAEs that led to treatment discontinuation, dose reduction or dose 
interruption will be summarized.
9.7.1.8.3
LABORATORY VALUES
Clinical laboratory (ie, hematology, serum chemistry and qualitative urinalysis) values will 
be evaluated for each laboratory parameter by subject.  Abnormal laboratory values will be 
flagged and identified as those outside (above or below) the normal range.  Reference 
(normal) ranges for laboratory parameters will be included in the CSR for this protocol.  
Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n[%] for categorical variables) for laboratory parameters 
and their changes from baseline will be calculated. Laboratory values will be summarized by 
visit and by worst postbaseline visit.
Laboratory parameters that are graded in CTCAE (v4.03) will be summarized by CTCAE 
grade. In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low directions (eg, calcium, glucose, magnesium, potassium, 
sodium) will be summarized separately.
Please see Appendix 7 for sponsor’s grading of laboratory values.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital sign parameters (systolic and diastolic BP, heart rate, 
respiratory rate, temperature, weight) and changes from baseline will be presented by visit 
for all visits.  Vital signs will be listed by subject and visit.


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9.7.1.8.5
ELECTROCARDIOGRAMS
Electrocardiogram assessments were performed at Screening and End of Treatment visit.  
Descriptive statistics for ECG parameters and changes from baseline will be presented.
9.7.1.8.6
OTHER SAFETY ANALYSES
9.7.1.9
Other Analyses
Primary, secondary and exploratory endpoints will be summarized in the evaluable analysis 
set in which central confirmed ATC is required.  In the analyses described above and any 
other sensitivity analysis, subjects with missing data will be considered as non-responders 
and will be included in the denominator when calculating ORR, DCR, and CBR.  Non-
responders will be excluded in the analysis of DOR.
Any other statistical/ analytical issues will be discussed in the SAP.
9.7.2
Determination of Sample Size
The sample size calculation was based on the assumed ORR of 27% in the trial as compared 
to 10% in the historical control.  Using a binomial exact text, the power is 0.932 with 57 
evaluable subjects to demonstrate statistical significance at a 1-sided alpha of 0.025.  To 
evaluate the power in the secondary endpoint 12-week PFS, an exponential distribution 
assuming 12-week PFS being 70% was used to simulate PFS data. Censoring times were 
generated such that the average number of observed PFS events was approximately 45 in the 
57 evaluable subjects.  In the 5,000 simulation runs, the lower bound of 95% CI for PFS at 
12 weeks was greater than 50% (historical control), 87.7% of the time.  Hence, the power is 
0.877 in demonstrating statistical superiority of the 12-week PFS in single agent lenvatinib.
Similarly, approximately 35 observed OS events in 57 evaluable subjects yield a power of 
approximately 0.857 in demonstrating a statistically significant increase in 6-month OS over 
historical control.  Assuming ATC confirmation rate is 75% in the enrolled subjects, 
approximately 76 subjects will need to be enrolled.  Subjects deemed to have another 
diagnosis (not ATC) will be replaced for the purpose of efficacy analyses.
9.7.3
Interim Analysis
One interim analysis will be performed after the first 20 evaluable subjects complete at least 
2 tumor assessments or discontinue treatment due to any reason. The trial will be halted if 
the number of responders is 3 or less (ORR ≤15%). Since type I error calculation for the 
primary efficacy analysis does not factor in this descriptive interim analysis, the interim 
decision will not affect the overall type I error in the formal primary analysis. Further action 
regarding enrollment will be taken after evaluating other efficacy and safety outcomes in the 
treated subjects. The probabilities of not passing interim threshold are 0.87, 0.41, and 0.17 
when underlying true ORR are 10%, 20%, and 27%, respectively.
The study team will define the datasets for the interim analysis.  The study team will assess 
the impact of any issues such as unsolved data queries, missing data or data entry delays on 


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the interim results.  The study statistician will perform the interim analysis, which includes 
calculating ORR per protocol.
9.7.4
Other Statistical/Analytical Issues
Not applicable. 
9.7.5
Procedure for Revising the Statistical Analysis Plan
The SAP will be finalized prior to the database lock in this trial.  Any deviation from analysis 
plan described in the protocol will be documented in the SAP.


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Shimaoka K, Schoenfeld D, DeWys W, Creech R, DeConti R. A randomized trial of 
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22(11): 1104-39.


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Sosa J, Elisei R, Jarzab B, Balkissoon J, Lu S, Bal C, et al. Randomized Safety and Efficacy 
Study of Fosbretabulin with Paclitaxel/Carboplatin Against Anaplastic Thyroid Carcinoma. 
Thyroid. 2014; 24(2): 232-40.
Takahashi S, Tahara M, Kiyota N, Yamazaki T, Chayahara N, Nakano K, et al. Phase II 
study of lenvatinib, a multitargeted tyrosine kinase inhibitor, in patients with all histologic 
subtypes of advanced thyroid cancer (differentiated, medullary, and anaplastic). Presented at 
the European Society for Medical Oncology 2014 congress; 26-30 September 2014; Madrid, 
Spain.
Eisai Clinical Study Reports
Report Number: CPMS-E7080-007R-v1. Population pharmacokinetic analysis of lenvatinib 
(pooled data) and pharmacokinetic/pharmacodynamic analyses of lenvatinib efficacy, 
biomarker (Study E7080-G000-303) and safety (Studies E7080-G000-201, E7080-G000-303, 
E7080-J081-208) in subjects with Iodine-131 refractory, unresectable differentiated thyroid 
cancer. 20 May 2014.
Report Number: RDMPKA2013-156 REVISION NO. 1.  Study Report: Simulation of drug-
drug interaction between lenvatinib and CYP3A4 substrate midazolam, and CYP2C8 
substrate repaglininide. 12 Sep 2014


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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, serum or urine pregnancy test 
result documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs

CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source
11.4
Recording of Data
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following item(s), the data recorded directly on the CRF are to be considered source data:

Study treatment 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 treatment, 
outcome)


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11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572), ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drug 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 
along with all other study conduct documents at appropriate intervals once study drug has 
been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist) will return all used 
and unused drug containers, drug labels, and a copy of the completed drug disposition form 
to the sponsor’s CRA or designated contractor or, when approval is given by the sponsor, 
will destroy supplies and containers at the site.


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


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11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.


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12 APPENDICES


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Appendix 1
Anaplastic Thyroid Cancer Tumor-Node-Metastasis Staging System
The TNM Staging System (tumor-node-metastasis) is the most widely used system forcancer
staging in the world. Staging of ATC in this clinical study will be based on the article by
Smallridge et al, 2012, entitled “American Thyroid Association Guidelines for Management 
of Patients with Anaplastic Thyroid Cancer.”  
Primary Tumor
T4a
Intrathyroidal
T4b
Extrathyroidal
Regional Nodesa
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 beassessed
M0
No distant metastasis
M1
Distant metastasis
Anaplastic Thyroid Cancer
Stage Group
T Stage
N Stage
M Stage
IVA
T4a
N0
M0
IVB
T4b
Any N
M0
IVC
Any T
Any N
M1
a.
Regional nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.


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Appendix 2
Overview of RECIST v1.1 for Evaluation of Tumors Response
Tumor response assessments in this clinical study will use RECIST v1.1 guidelines based on 
the article by Eisenhauer, et al., 2009, entitled “New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1),” with the exception that chest disease 
may not be followed using chest x-ray and must be assessed with CT.  This appendix 
contains an overview of the RECIST v1.1 guidelines.  
Baseline Tumor Assessment
Subjects are required to have measurable disease, defined as the presence of at least 
1 measurable lesion, to be eligible for entry into the study.  Measurable and nonmeasurable 
lesions are defined as:
Measurable lesions: 
Tumor lesions: Must be accurately measured in at least 1 dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of:
10 mm by CT scan (CT scan slice thickness no greater than 5 mm
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as nonmeasurable)
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed.
MRI may be substituted for contrast enhanced CT for some sites, but not lung.  The 
minimum size for measurability is the same as for CT (10 mm) as long as the scans are 
performed with slice thickness of 5 mm and no gap.  In the event the MRI is performed with 
thicker slices, the size of a measurable lesion at baseline should be 2 times the slice 
thickness.  In the event there are interslice gaps, this also needs to be considered in 
determining the size of measurable lesions at baseline. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI can be 
considered as measurable lesions if the soft tissue component meets the definition of 
measurability.
A lesion located in a previously irradiated area, or in an area previously subjected to any 
locoregional therapy, will be considered measurable only if there has been a documented 
increase in lesion size subsequent to prior treatment but before study entry.
Clinical lesions: Clinical lesions will only be considered measurable when they are 
superficial and >10 mm diameter as assessed using calipers (eg, skin nodules).  For the case 
of skin lesions, documentation by color photography including a ruler to estimate the size of 


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the lesion is suggested.  When lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed 
at the end of the study.
Nonmeasurable lesions: All other lesions, including small lesions (longest diameter  
< 10 mm or pathological lymph nodes with a short axis of ≥10 mm to < 15 mm short axis), 
lesions that cannot be accurately measured with calipers, and truly nonmeasurable lesions:  
leptomeningeal disease, ascites, pleural or pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by PE that is not measurable by reproducible imaging techniques. Lymph nodes 
with a short axis <10 mm are considered nonpathological and should not be recorded or 
followed.
Simple cysts (cystic lesions) will not be considered malignant, and will be neither measurable 
nor nonmeasurable.  Cystic lesions believed to be metastases may be considered measurable 
if they meet the general definition of measurability, but noncystic lesions are preferred as 
target lesions.
All baseline tumor evaluations should be performed as closely as possible to the start of 
treatment and never more than 4 weeks before the first dose of study treatment.
Methods of Tumor Measurement
The same imaging modality and the same technique (including use or nonuse of oral and IV 
contrast) should be used to characterize each identified and reported lesion at 
Baseline/Screening and at reassessment time points during the study.  All measurements 
should be taken and recorded in metric notation, using calipers if clinically assessed.
Computed tomography and MRI are the best currently available and reproducible methods to 
measure target lesions selected for response assessment.  Computed tomography should be 
performed with slices of 5 mm or less in thickness (as a general rule, lesion diameter should 
be no less than double the slice thickness).  This applies to tumors of the chest, abdomen, and 
pelvis.  Magnetic resonance imaging is also acceptable in certain conditions (eg, for body 
scans).  A CT of the chest without contrast is preferred over MRI.
Bone scans, positron emission tomography (PET) scan, or plain films are not sufficient to 
measure bone lesions and document objective response but may be used to confirm the 
presence or disappearance of such lesions.  Bone scans should be performed using 
99m-technetium-labeled polyphosphonate scintigraphy, whole body bone MRI, or 18F-NaF-
PET.
Chest x-rays should not be used for baseline assessment of the chest or for follow-up of 
known lesions.  Chest CT should be used.
Ultrasound should not be used to measure tumor lesions.
Endoscopy and laparoscopy should not be used to measure tumor lesions.


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Documentation of "Target" and "Nontarget" Lesions
Lesions are evaluated and classified at Baseline as either target or nontarget and all are then 
followed throughout the study.
Target Lesions:
Target lesions are all measurable lesions up to a maximum of 2 lesions per organ and 
5 lesions in total, representative of all involved organs.  Target lesions should be selected on 
the basis of their size (those with the longest diameters) and their suitability for accurate 
repeated measurements.
The short axis (≥15 mm) of any lymph nodes selected as target lesions at Baseline will be 
measured and recorded at each evaluation time point, even if the nodes become 
nonpathological (short axis <10 mm).
The sum of the diameters of all target lesions (longest for non-nodal lesions, short axis for 
nodal lesions) will be calculated at Baseline and reported as the baseline sum diameter.  This 
baseline sum of diameters will be used as the reference by which to characterize objective 
tumor response.  
Target Lesions Too Small To Measure:
Lesions that become too small to measure during treatment should be assigned a default 
measurement of either 0 mm (if the investigator believes the lesion has disappeared) or 5 mm 
(if the lesion is believed to be present and is faintly visible).
Target Lesions That Split or Coalesce:
If a non-nodal target lesion fragments during treatment, the longest diameters of each 
fragment should be added together to calculate the total sum for that lesion.  When lesions 
coalesce, a plane between them may be maintained that would aid in obtaining maximal 
diameter measurements for each individual lesion.  If the lesions are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
coalesced lesion.
Nontarget Lesions:
All other lesions (or sites of disease) should be identified as nontarget lesions and should also 
be recorded at Baseline.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout Follow-up.


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New Lesions:
The finding of a new lesion should be unequivocal (ie, not attributable to a change in 
scanning technique or imaging modality, and not thought to represent something other than a 
tumor).  If a possible new lesion is equivocal, treatment and radiographic evaluation should 
continue per this protocol until confirmation of PD or until additional scans confirm the 
presence of a new lesion.  In such a case, the date of progression will be the date of the initial 
scan.
A lesion identified on a Follow-up study of an anatomical location not studied as Baseline 
will be considered a new lesion.
Scanning with FDG-PET may be employed as a complement to CT scanning in the 
assessment of PD.  A negative FDG-PET scan at Baseline with a positive scan during the 
study will be evidence of PD.  If there is no FDG-PET scan at Baseline and a positive 
FDG-PET scan during the study, it will be considered evidence of PD if the positive 
FDG-PET corresponds to a new site of disease confirmed by CT scan.  A positive 
postbaseline FDG-PET result corresponding to a pre-existing site of disease with no 
radiographic evidence of progression will not be considered evidence of PD.
Evaluation of Response for an Individual Assessment Time Point
To determine tumor response, the sum of all target lesions is calculated at Baseline and at 
each subsequent assessment time point (ie, every 6 weeks until progression in this study).  
Each response parameter (target, nontarget, and new lesions) will be reported independently 
at each radiographic reading as shown in Table 1 for target lesions and Table 2 for nontarget 
lesions.  The investigator will then make a determination of OR for each assessment time 
point based on a composite evaluation of target, nontarget, and new lesions, as shown in 
Table 3.
Table 1 Evaluation of Target Lesions
Complete Response (CR)
Disappearance of all target lesions.  All pathological lymph nodes (whether 
target or nontarget) must have a reduction in their short axis to <10 mm.
Partial Response (PR)
At least a 30% decrease in the sum of the LD of target lesions, taking as 
reference the Baseline sum diameters
Progressive Disease (PD)
At least a 20% increase in the sum of the LD of target lesions, taking as 
reference the smallest sum LD recorded at Baseline or during treatment.  
The sum must also have an absolute increase of ≥5 mm.  
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum LD since the treatment 
started
Not Evaluable (NE) 
No imaging/measurement done at all or only on a subset of lesions at a 
particular time point; a target lesion at Baseline that is subsequently not 
measured or that is unable to be evaluated.  Includes scans that are not 
performed at a specified time point to evaluate the target lesion(s).


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Table 2 Evaluation of Nontarget Lesions
Complete Response (CR)
Disappearance of all nontarget lesions.  All lymph nodes <10 mm (short 
axis)
Non-CR/Non-PD
Persistence of 1 or more nontarget lesion(s) 
Progressive Disease (PD)
Unequivocal progression (substantial worsening in nontarget disease such 
that overall tumor burden has increased sufficiently to warrant 
discontinuation of therapy); unequivocal progression of existing nontarget 
lesionsa
Not Evaluable (NE)
A nontarget lesion at Baseline that is subsequently not measured or that is 
unable to be evaluated
a: 
Although a clear progression of "nontarget" lesions only is exceptional, in such circumstances, the 
opinion of the site radiologist should prevail.
Table 3
Overall Response at Each Assessment Time Point for Subjects 
with Target (± Nontarget) Disease
Target Lesions
Nontarget Lesions
   New Lesions
Overall Response
CR
CR
No
CR
CR
Non-CR/Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
      Yes or No
PD
Any
PD
      Yes or No
PD
Any
                         Any
Yes
PD
CR = complete response, NE = not evaluable, PD = disease progression, PR = partial response, SD = stable 
disease.
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of PD at that time point assessment should be classified as having 
"symptomatic deterioration."  Every effort should be made to document objective 
progression after discontinuation of treatment.
In some circumstances, it may be difficult to distinguish residual disease from normal tissue.  
When the evaluation of CR depends on this determination, it is recommended that the 
residual lesion be investigated (fine needle aspirate/biopsy) before assigning a status of CR.
Evaluation of Best Overall Response (BOR) and Confirmation of Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements [nadir] 
recorded since the treatment started).  In general, the subject's best response assignment will 


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depend on the achievement of both measurement and confirmation criteria as shown in 
Table 4.
Confirmation: To be assigned a BOR of PR or CR, changes in tumor measurements must be 
confirmed by repeat assessments that should be performed no less than 4 weeks after the 
criteria for response are first met.  In this study, a bone scan should be done within 1 week 
after the CR confirmatory scanning time point to exclude new bone metastases.

The main goal of confirmation of the PR or CR objective response is to avoid 
overestimating the response rate.  

In the case of SD, follow-up measurements must have met the SD criteria at 
least once after study entry at a minimum interval of 5 weeks for this protocol.
Table 4 Best Overall Response With Confirmation
Unconfirmed response (First 
Time Point)
Confirmatory Response 
(Subsequent Time Point)
Best Overall Response of:
CR
CR
CR
CR
PR
SD, PD or PRa
CR
SD
SD or PDb
CR
PD
SD or PDb
CR
NE
SD or NEc
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SDb
PR
NE
SDc
NE
NE
NE
BL = baseline, CR = complete response, NE = not evaluable, PD = disease progression, PR = partial response, 
SD = stable disease.
a:  If a CR is truly met at the first time point, then any reappearance of disease seen at a subsequent time point 
(including disease meeting PR criteria relative to BL) makes the disease PD at that time point.
b:  Classify response as SD, provided that confirmatory scan a minimum of 5 weeks later is still "SD."  
Otherwise, response will be classified as PD.
c:  Classify response as SD, provided that confirmatory scan a minimum of 5 weeks later is still "SD."  
Otherwise, response will be classified as NE.


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Appendix 3
Eastern Cooperative Oncology Group Performance Status
Scale
ECOG Status
0
Fully active, able to carry on all predisease performance
without restriction.
1
Restricted in physically strenuous activity but ambulatory and ableto 
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


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


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Appendix 6
Common Terminology Criteria for AdverseEvents (v4.03)
The National Cancer Institute's CTCAE v4.0 published 28 May 2009 (v4.03: June 14, 2010) 
provides descriptive terminology to be used for AE 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 be correlated with single-concept, 
MedDRA terms.
Grades in CTCAEs v4.03 refer to the severity of the AE.  Grades of 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 interventionindicated.
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 02 Oct2014).
For further details regarding MedDRA, refer to the MedDRA website at: 
http://www.meddramsso.com.CTCAE   v4.0 is available online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 02 Oct 2014).


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Appendix 7
Sponsor’s Grading for Laboratory Values
Grade 1
Grade 2
Grade 3
Grade 4
BLOOD/BONE
MARROW
Hemoglobin
<LLN – 10.0 g/dL
<LLN – 100 g/L
<LLN – 6.2 mmol/L
<10.0 – 8.0 g/dL
<100 – 80 g/L
<6.2 – 4.9 mmol/L
<8.0 g/dL
<80 g/L
<4.9 mmol/L;
transfusion indicated
life-threatening
consequences;
urgent inter-
vention indicated
Leukocytes (total
WBCs)
<LLN – 3.0109/L
<LLN – 3000/mm3
<3.0 – 2.0109/L
<3000 – 2000/mm3
<2.0 – 1.0109/L
<2000 – 1000/mm3
<1.0109/L
<1000/mm3
Lymphocytes
<LLN – 800/mm3
<LLN – 0.8109/L
<800 – 500/mm3
<0.8 – 0.5109/L
<500 – 200/mm3
<0.5 – 0.2109/L
<200/mm3
<0.2109/L
Neutrophils
<LLN – 1.5109/L
<LLN – 1500/mm3
<1.5 – 1.0109/L
<1500 – 1000/mm3
<1.0 – 0.5109/L
<1000 – 500/mm3
<0.5109/L
<500/mm3
Platelets
<LLN – 75.0109/L
<LLN – 75,000/mm3
<75.0 – 50.0109/L
<75,000 –
50,000/mm3
<50.0 – 25.0109/L
<50,000 –
25,000/mm3
<25.0109/L
<25,000/mm3
METABOLIC/ LABORATORY
Albumin, serum- low
(hypoalbuminemia)
<LLN – 3 g/dL
<LLN – 30 g/L
<3 – 2 g/dL
<30 – 20 g/L
<2 g/dL
<20 g/L
life-threatening
consequences;
urgent inter-
vention indicated
Alkaline phosphatase
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
ALT
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
AST
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Bilirubin
(hyperbilirubinemia)
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 10.0ULN
>10.0ULN
Calcium, serum-low
(hypocalcemia)
<LLN – 8.0 mg/dL
<LLN – 2.0 mmol/L
<8.0 – 7.0 mg/dL
<2.0 – 1.75 mmol/L
<7.0 – 6.0 mg/dL
<1.75 – 1.5 mmol/L
<6.0 mg/dL
<1.5 mmol/L
Calcium, serum-high
(hypercalcemia)
>ULN – 11.5 mg/dL
>ULN – 2.9 mmol/L
>11.5 – 12.5 mg/dL
>2.9 – 3.1 mmol/L
>12.5 – 13.5 mg/dL
>3.1 – 3.4 mmol/L
>13.5 mg/dL
>3.4 mmol/L
Cholesterol, serum-high
(hypercholesterolemia)
>ULN – 300 mg/dL
>ULN – 7.75
mmol/L
>300 – 400 mg/dL
>7.75 – 10.34
mmol/L
>400 – 500 mg/dL
>10.34 – 12.92
mmol/L
>500 mg/dL
>12.92 mmol/L
Creatinine
>ULN – 1.5ULN
>1.5 – 3.0ULN
>3.0 – 6.0ULN
>6.0ULN


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Sponsor’s Grading for LaboratoryValues
Grade 1
Grade 2
Grade 3
Grade 4
GGT (γ-glutamyl
transpeptidase)
>ULN – 3.0ULN
>3.0 – 5.0ULN
>5.0 – 20.0ULN
>20.0ULN
Glucose, serum-high
Fasting glucose
Fasting glucose
>250 – 500 mg/dL;
>500 mg/dL;
value:
value:
>13.9 – 27.8 mmol/L;
>27.8 mmol/L;
(hyperglycemia)
>ULN – 160 mg/dL
>160 – 250 mg/dL
hospitalization
life-threatening
>ULN – 8.9 mmol/L
>8.9 – 13.9 mmol/L
indicated
consequences
Glucose, serum-low
(hypoglycemia)
<LLN – 55 mg/dL
<LLN – 3.0 mmol/L
<55 – 40 mg/dL
<3.0 – 2.2 mmol/L
<40 – 30 mg/dL
<2.2 – 1.7 mmol/L
<30 mg/dL
<1.7 mmol/L
life-threatening
consequences;
seizures
Phosphate, serum-low
<LLN – 2.5 mg/dL
<2.5 – 2.0 mg/dL
<2.0 – 1.0 mg/dL
<1.0 mg/dL
<0.3 mmol/L
(hypophosphatemia)
<LLN – 0.8 mmol/L
<0.8 – 0.6 mmol/L
<0.6 – 0.3 mmol/L
life-threatening
consequences
Potassium, serum-high
(hyperkalemia)
>ULN – 5.5 mmol/L
>5.5 – 6.0 mmol/L
>6.0 – 7.0 mmol/L
hospitalization
indicated
>7.0 mmol/L
life-threatening
consequences
Potassium, serum-low
(hypokalemia)
<LLN – 3.0 mmol/L
<LLN – 3.0 mmol/L;
symptomatic;
intervention
indicated
<3.0 – 2.5 mmol/L
hospitalization
indicated
<2.5 mmol/L
life-threatening
consequences
Sodium, serum-high
(hypernatremia)
>ULN – 150 mmol/L
>150 – 155 mmol/L
>155 – 160 mmol/L
hospitalization
indicated
>160 mmol/L
life-threatening
consequences
Sodium, serum-low
(hyponatremia)
<LLN – 130 mmol/L
N/A
<130 – 120 mmol/L
<120 mmol/L
life-threatening
consequences
Triglyceride, serum-high
150 – 300 mg/dL
>300 – 500 mg/dL
>500 – 1000 mg/dL
>1000 mg/dL
>11.4 mmol/L
(hypertriglyceridemia)
1.71 – 3.42 mmol/L
>3.42 – 5.7 mmol/L
>5.7 – 11.4 mmol/L
life-threatening
consequences
Uric acid, serum-high
>ULN – 10 mg/dL
N/A
>ULN – 10 mg/dL
>10 mg/dL
≤0.59 mmol/L
≤0.59 mmol/L with
>0.59 mmol/L
(hyperuricemia)
without physiologic
consequences
Physiologic
consequences
life-threatening
consequences
ALT = alanine aminotransferase (serum glutamic pyruvic transaminase), AST = aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase), GGT = γ-glutamyl transpeptidase, N/A = not applicable, LLN = lower limit of normal, ULN = upper limit of normal,
WBC = white blood cell.
Based on Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Published: May 28, 2009 (v4.03: June 14, 2010).


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-M000-213
Study Protocol Title:
An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of 
Lenvatinib for the Treatment of Anaplastic Thyroid Cancer 
(ATC)
Investigational Product
Name:
Lenvatinib (E7080)
IND Number:
113656
EudraCT Number:
2015-001929-17
SIGNATURES
Authors:
r
oba
ncology Business Unit
Date
Head, Global Clinical Research
Oncology Product Creation Unit
Date
Global Medical & Scientific Affairs
Global Oncology Business Unit
Eisai Inc.
Date
PPD
PPD
PPD
PPD
PP


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-M000-213
Study Protocol Title:
An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of 
Lenvatinib for the Treatment of Anaplastic Thyroid Cancer 
(ATC)
Investigational Product
Name:
Lenvatinib (E7080)
IND Number:
113656
EudraCT Number:
2015-001929-17
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) and all applicable 
local Good Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
<Name of institution>
Medical Institution
<Name, degree(s)>
Investigator
Signature
Date
.


 
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘GMT’Z) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E7080-M000-213 - Protocol Amendment 02
Medical Monitor Approval
27-May-2016 14:22 GMT-04
PPD

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7080-M000-213
Study Protocol 
Title:
An Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib 
for the Treatment of Anaplastic Thyroid Cancer (ATC)
Date:
18 Oct 2018
Version:
Final Version 1.0


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1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...................................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................4
3
INTRODUCTION .............................................................................................................6
3.1
Study Objectives ......................................................................................................6
3.1.1
Primary Objective..........................................................................................6
3.1.2
Secondary Objectives.....................................................................................6
3.1.3
Exploratory Objectives ..................................................................................6
3.2
Overall Study Design and Plan................................................................................6
4
DETERMINATION OF SAMPLE SIZE..........................................................................8
5
STATISTICAL METHODS..............................................................................................8
5.1
Study Endpoints.......................................................................................................8
5.1.1
Primary Endpoint...........................................................................................8
5.1.2
Secondary Endpoints .....................................................................................8
5.1.3
Exploratory Endpoints ...................................................................................9
5.2
Study Subjects..........................................................................................................9
5.2.1
Definitions of Analysis Sets...........................................................................9
5.2.2
Subject Disposition........................................................................................9
5.2.3
Protocol Deviations......................................................................................10
5.2.4
Demographic and Other Baseline Characteristics .......................................10
5.2.5
Prior and Concomitant Therapy...................................................................10
5.2.6
Treatment Compliance.................................................................................11
5.3
Data Analysis General Considerations ..................................................................11
5.3.1
Pooling of Centers........................................................................................11
5.3.2
Adjustments for Covariates..........................................................................11
5.3.3
Multiple Comparisons/Multiplicity .............................................................11
5.3.4
Examination of Subgroups...........................................................................11
5.3.5
Handling of Missing Data, Dropouts, and Outliers .....................................11
5.3.6
Other Considerations ...................................................................................12
5.4
Efficacy Analyses ..................................................................................................12
5.4.1
Primary Efficacy Analyses ..........................................................................12
5.4.2
Secondary Efficacy Analyses ......................................................................12
5.4.3
Other Efficacy Analyses ..............................................................................12
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...............................................................................................13
5.6
Safety Analyses......................................................................................................13
5.6.1
Extent of Exposure.......................................................................................13


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5.6.2
Adverse Events ............................................................................................13
5.6.2.1
Deaths ................................................................................................14
5.6.3
Laboratory Values........................................................................................14
5.6.4
Vital Signs....................................................................................................15
5.6.5
Electrocardiograms ......................................................................................15
5.6.6
Other Safety Analyses..................................................................................15
5.7
Other Analyses.......................................................................................................16
5.8
Exploratory Analyses.............................................................................................16
6
INTERIM ANALYSES...................................................................................................16
7
CHANGES IN THE PLANNED ANALYSES...............................................................16
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................16
9
PROGRAMMING SPECIFICATIONS ..........................................................................20
10
STATISTICAL SOFTWARE..........................................................................................20
11
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................20
12
REFERENCES ................................................................................................................20
13
APPENDICES .................................................................................................................21
13.1
Sponsor’s Grading for Laboratory Values.............................................................21


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC
anaplastic thyroid cancer
ß-hCG
beta-human chorionic gonadotropin
BOR
best overall response
BP
blood pressure
CBR
clinical benefit rate
CI
confidence interval
CR
complete response
CRF
case report form
CSR
clinical study report
CT
computerized tomography
CTCAE 
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DOR
duration of response
EAS
evaluable analysis set
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
full analysis set
FDA
Food and Drug Administration
ICF
Informed consent form
INR
International Normalized Ratio
KM
Kaplan-Meier
MedDRA®
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NYHA
New York Heart Association


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Abbreviation
Term
ORR
objective response rate
OS
overall survival
PE
physical examinations
PET
position emission tomography 
PFS
progression-free survival
PI
principal investigator
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PT
preferred term
QD
once a day
RBC
red blood cell count
RECIST
Response Evaluation Criteria in Solid Tumors
RR-DTC
radioiodine-refractory differentiated thyroid cancer
RTK
receptor tyrosine kinase
SAE
serious adverse events
SAP
statistical analysis plan
SD
stable disease
SmPC
Summary of Product Characteristics
SOC
system organ class
SUSAR
suspected unexpected serious adverse reactions 
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
TTP
time to progression
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor


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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-
M000-213, an Open-Label, Single-Arm, Multicenter, Phase 2 Trial of Lenvatinib for the 
Treatment of Anaplastic Thyroid Cancer (ATC).  The focus of this SAP is on all the analyses 
specified in the final protocol of the study (i.e., Version 3.0 dated on 24May2016, 
Amendment 02), which covers the both interim analyses and final analyses. This SAP will be 
finalized before the database lock of study completion.
3.1
Study Objectives
3.1.1
Primary Objective
To evaluate objective response rate ([ORR]: complete response [CR] or partial response 
[PR]) by investigator review in subjects with anaplastic thyroid cancer (ATC) treated with 
lenvatinib.
3.1.2
Secondary Objectives

To evaluate 12-week progression-free survival (PFS)

To evaluate 6-month overall survival (OS) 

To evaluate median PFS and median OS

To evaluate safety and tolerability of lenvatinib in subjects with ATC
3.1.3
Exploratory Objectives

To explore clinical benefit rate ([CBR]: CR, PR or durable stable disease [SD] 
≥23 weeks) 

To explore disease control rate ([DCR]: CR, PR or SD) 

To explore duration of response (DOR)

To identify and explore tumor and blood biomarkers that correlate with clinical 
outcomes, including efficacy
3.2
Overall Study Design and Plan
This was an open-label, single arm, multicenter, Phase 2 trial of lenvatinib (24 mg/day) to 
assess the efficacy and safety of lenvatinib in subjects with ATC. The study was designed 
primarily to provide additional efficacy and safety data for single-agent lenvatinib in a larger 
cohort of ATC subjects. Approximately a total of 76 subjects was planned to be enrolled into 
this study (i.e., signed informed consent) to be sure that out of the 76 subjects there would be 
57 subjects confirmed with ATC for the purpose of efficacy analyses. Also one interim 
analysis was planned to be performed after the first 20 evaluable subjects completed at least
2 tumor assessments or discontinue treatment due to any reason. While waiting for the 


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interim analysis results the enrollment would not be suspended so that no enrollment gap was 
in the study for the interim analysis. From the interim analysis the enrollment would be 
halted if the number of responders was 3 or less (ORR ≤15%, according to Response 
Evaluation Criteria in Solid Tumors (RECISIT) 1.1), and the safety and efficacy data would
be further evaluated before making the decision of stopping the study permanently.
This study would consist of the following three phases and the corresponding 
procedures/assessments to each was presented as Table 4 in the final protocol of the study in 
details, where as shown a 28-days during the treatment period was considered as one cycle of 
treatment and used  for study related visits/assessments: 

The Pretreatment Phase: including Screening period from Day -21 prior to the first 
study treatment of lenvatinib start. All analyses related baseline assessments would be 
defined as the last assessment obtained during this phase for each. 

The Treatment Phase: starting from the time of the first lenvatinib administration till 
the end of last lenvatinib administration. Subjects would be treated with lenvatinib 
dose of 24 mg once daily by oral administration, or dose following protocol on 
treatment adjustment.    

The Posttreatment Phase: starting after the last study dose, including End of 
Treatment visit (i.e., within 30 days of last dose), survival follow-ups (i.e., every 12 
(±1) weeks after End of Treatment visit). 
Treated subjects would discontinue treatment with lenvatinib until the time of disease 
progression (radiological or clinical), development of unacceptable toxicity, withdrawal of 
consent, lost to follow-up, pregnancy or study termination by the sponsor. 
During the Follow-Up Period, in subjects who had discontinued study treatment without
documented disease progression (radiological or clinical), every effort would be made to 
continue monitoring their disease status by radiologic imaging every 6 weeks ±1 week for 
the first 24 weeks and every 8 weeks ±1 week thereafter from the date of the last assessment 
until (1) the start of new anticancer treatment, (2) disease progression (3) death, or (4) the 
end of the study, whichever occurred first.
All subjects would be followed for survival until death, except where a subject withdrew
consent or the sponsor chose to halt survival follow-up after completion of the primary study 
analysis.


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4
DETERMINATION OF SAMPLE SIZE
The sample size calculation was based on the assumed objective response rate (ORR), 
defined in Section 5.1) of 27% in the trial as compared to 10% in the historical control.  
Using a binomial exact text, the power was 0.932 with 57 evaluable subjects to demonstrate 
statistical significance at a 1-sided alpha of 0.025. To evaluate the power in the secondary 
endpoint 12-week PFS (defined in Section 5.1), an exponential distribution assuming 12-
week PFS being 70% was used to simulate PFS data. Censoring times were generated such 
that the average number of observed PFS events was approximately 45 in the 57 evaluable 
subjects.  In the 5,000 simulation runs, the lower bound of 95% confidence interval for PFS 
at 12 weeks was greater than 50% (historical control), 87.7% of the time. Hence, the power 
was 0.877 in demonstrating statistical superiority of the 12-week PFS in single agent 
lenvatinib. Similarly, approximately 35 observed OS events in 57 evaluable subjects yielded
a power of approximately 0.857 in demonstrating a statistically significant increase in 6-
month OS over historical control. Assuming ATC confirmation rate was 75% in the enrolled 
subjects, approximately 76 subjects would need to be enrolled. Subjects deemed to have 
another diagnosis (not ATC) would be replaced for the purpose of efficacy analyses.
5
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported in mean, standard deviation 
(SD), median, 25 percentile (Q1), 75 percentile (Q3), minimum and maximum. Categorical 
variables will be summarized in number (percentage) of subjects. 
5.1
Study Endpoints
All tumor related endpoints, including timepoint tumor responses and the best overall 
responses (i.e., complete response, partial response, stable disease, disease progression), are 
from investigators based on RECIST 1.1.
5.1.1
Primary Endpoint
The primary efficacy endpoint is ORR as determined by investigator review, using RECIST 
1.1. ORR is the proportion of subjects who have best overall response (BOR) of CR or PR
(confirmed). Confirmation of CR or PR must be performed at least 28 days following the 
initial achievement of the response.
5.1.2
Secondary Endpoints
•
Twelve-week PFS is the percentage of subjects in the analysis population who remain 
alive and disease progression-free at 12 weeks post first study dose. This will be the 
Kaplan-Meier estimated rate of event (death or disease progression)-free at 12 weeks 
post first study dose (i.e., at the 84th day counting from the first dose date),
•
Six-month OS is defined as the percentage of subjects in the analysis population who 
are alive at 6 months post first study dose.  This will be the Kaplan-Meier estimated 


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rate of event (death)-free at 6 months post first study dose (i.e., at the 183th day 
counting from the first dose date, from 6 x 365.25/12),

Median PFS and Median OS. These will be the estimated median event-free time 
from Kaplan-Meier method (in day and month). The PFS is defined as the time from
the date of first dose of study drug to date of first documentation of disease 
progression (only from the radiological assessment) or death, whichever occurs first, 
and OS is defined as the time from the date of first dose of study drug until date of 
death from any cause.
5.1.3
Exploratory Endpoints

Clinical benefit rate (CBR) is the proportion of subjects who have the best overall 
response (confirmed) of CR or PR or durable SD. A stable disease (SD) must be at ≥ 
5 weeks after the first study dose. A durable SD is a subset of SD with the duration of 
≥ 23 weeks after the first study dose. 

Disease control rate (DCR) is the proportion of subjects who have the best overall 
response (confirmed) of CR, PR or SD. 

Duration of response (DOR) is defined as the time from the first objective response 
(i.e., the initial CR or PR that was confirmed) to the first documented disease 
progression or death. This endpoint is just defined for the subjects who had confirmed 
response during study.

Evaluate the association of tumor and blood biomarkers with clinical outcomes, 
including efficacy.
5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Full Analysis Set [FAS] will include all subjects who received at least one dose of 
lenvatinib. The FAS will be the population for the safety analysis. Some selected efficacy 
endpoints will also be summarized in the FAS.
The Evaluable Analysis Set [EAS] will include FAS subjects with histological diagnosis of 
ATC that was confirmed by central pathology review. The EAS will be the primary 
population for the efficacy analysis.
5.2.2
Subject Disposition
The number (percentage) of enrolled (i.e., signed informed consent) and treated subjects will 
be summarized as well as reasons for discontinuation from study treatment. Survival status at 
the last follow-up visit, and reasons for screen failure, will also be summarized.


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5.2.3
Protocol Deviations
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock for the primary 
analysis.
Major protocol deviations will be summarized and listed by each category. All protocol 
deviations identified according to the study entry criteria and during treatment will be listed.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for both the FAS and EAS will be 
summarized for lenvatinib treatment, using descriptive statistics. Continuous demographic 
and baseline variables include age, BMI, weight, and height; categorical variables include 
sex, age group (<65 years, 65-75, >75 years), region, ethnicity and race. Other variables at 
study entry include: pregnancy test, ECOG performance status, time since disease 
progression, prior radiotherapy (yes/no), ATC diagnosis confirmation by central pathology 
review (yes/no), TNM classification (T-Primary Tumor, N-Regional Lymph Nodes, M-
Distant Metastasis), Anaplastic Thyroid Cancer Stage (IVA, IVB, IVC), time from original 
histological diagnosis to first dose, NYHA, number of target lesions and sum of target lesion 
diameters.       
MEDICAL HISTORY
The number (percentage) of subjects in the FAS reporting a history of any medical condition
and current medical condition, as recorded on the CRF, will be summarized. A subject data 
listing will be provided. Medical History will be coded using MedDRA (version 21.0 or 
newer), and summarized on the FAS by System Organ Class and Preferred term.
5.2.5
Prior and Concomitant Therapy
All investigator terms (verbatim terms) for medications recorded in the CRF will be coded to
an 11-digit code using the World Health Organization Drug Dictionary (WHO DD) 
(WHODDMAR2018). The number (percentage) of subjects who took prior and concomitant 
medications will be summarized in FAS by Anatomical Therapeutic Chemical (ATC) class, 
and WHO DD preferred term.
Prior medications are defined as medications that stopped before the first dose of study drug.  
Concomitant medications are 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. All 
medications will be presented in subject data listings.
Frequencies [n (%)] of previous anti-cancer procedures will be summarized similarly by 
system organ class and preferred term.  In addition, previous anti-cancer medications will be 
summarized in terms of number of prior regimens, duration of last therapy, best response for 
last therapy, time from end of last therapy to first dose, and indication of previous medication 


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(neoadjuvant/adjuvant/metastatic/unknown). The following data on radiotherapy will be 
summarized: time from last radiotherapy to first dose, site of previous radiotherapy, 
progression of tumor lesion at the site since radiotherapy (yes/no), and number of all prior 
radiotherapy treatments.
5.2.6
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study. Clinical 
research associates will review treatment compliance during investigational site visits and at 
the completion of the study. Treatment compliance will not be summarized since the data 
will not be entered in the clinical database.
5.3
Data Analysis General Considerations
All efficacy analyses will be summarized with available data in the clinical database at the 
data cutoff.  
5.3.1
Pooling of Centers 
Subjects from all centers will be pooled for all analyses. 
5.3.2
Adjustments for Covariates
No adjustments for covariates will be performed in the study.
5.3.3
Multiple Comparisons/Multiplicity
Per protocol, the type I error calculation for the primary efficacy analysis did not factor in the 
descriptive interim analysis, the interim decision won’t affect the overall type I error in the 
formal primary analysis; no multiplicity adjustments for the tests of secondary endpoints will 
be made in this study.
5.3.4
Examination of Subgroups
No examination of subgroups is planned.
5.3.5
Handling of Missing Data, Dropouts, and Outliers
Rules of handling missing or partial missing dates are explained in Section 8. The censoring 
rules used in time-to-event analyses (PFS, OS, DOR) are also explained in Section 8. 
Potential outlier values will be investigated, and they will be analyzed as originally reported
in the locked database.
In the analyses on the endpoints described above and any sensitivity analysis, subjects with 
missing data will be considered as non-responders and will be included in the denominator 
when calculating ORR, DCR, and CBR. Non-responders will be excluded in the analysis of 
DOR.


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5.3.6
Other Considerations
Not applicable.
5.4
Efficacy Analyses
5.4.1
Primary Efficacy Analyses
In the study design, the ORR was estimated as 27% (deemed a clinical meaningful 
improvement), and its historical control on recent trials was assumed to be 10%. The study 
primary analysis was planned to be performed for the observed ORR using the binomial 
exact test, on evaluable analysis set, and based on the following hypotheses
H0: ORR=10%
Ha: ORR ≥27%.
And in the plan if the obtained p-value from the binomial exact test was less than or equal to 
0.025 (one-sided), it would be concluded that the superiority of single agent lenvatinib was
demonstrated. 
The 95% Clopper–Pearson confidence interval (95% CI) of ORR will be presented. The 
same primary efficacy analysis for ORR for evaluable analysis set will also be repeated for 
the full analysis set.
5.4.2
Secondary Efficacy Analyses
All analyses of secondary efficacy endpoints will be performed in FAS.
Progression-Free Survival (PFS) and Overall Survival (OS) will be analyzed using Kaplan-
Meier product-limit method. The Kaplan-Meier estimated rate of event-free will be presented 
at 12 weeks for PFS and at 6 months for OS, together with the corresponding two-sided 95% 
CI. In addition, the median, first and third quartiles of the Kaplan-Meier estimated event-free 
time will also be presented together with the corresponding 95% Brookmeyer-Crowley (or 
generalized Brookmeyer-Crowley) CI.
5.4.3
Other Efficacy Analyses
All the efficacy exploratory analyses will be performed in both evaluable analysis set and/or 
full analysis set.
The observed clinical benefit rate and the disease control rate will be presented along with 
their 95% CI of exact method.
Similarly, using the same method as the analyses to PFS and OS, the Duration of Response 
(DOR) will be analyzed using Kaplan-Meier method and the estimated median, first and third 
quartiles of the DOR will be presented with the 95% CI.


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5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
Not applicable.
5.6
Safety Analyses
All safety analyses will be performed based on Full Analysis Set.
5.6.1
Extent of Exposure
The analyses of extent of drug exposure will be performed for each subject on the duration of 
treatment, and total cumulative dose received (mg) (i.e., the sum of all doses actually taken), 
actual dose intensity (mg/day) received, and the relative dose intensity (%), and the 
definitions are:

Duration of treatment (day) is calculated as (Date of last study drug – Date of first 
study drug + 1)

Actual dose intensity (mg/day) is calculated as total cumulative dose received (mg) 
divided by treatment duration (day)

Relative dose intensity (%) is calculated as actual dose intensity (mg/day) divided by 
24 (mg/day).
For the data from the CRF page of Study Medication collected during treatment phase, the 
number (%) of subjects with dose reduced, dose interruption, and the time to the first dose 
reduction will be summarized.
5.6.2
Adverse Events
The adverse event (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 21.0 or 
higher) lower level term (LLT) closest to the verbatim term.  The linked MedDRA preferred 
term (PT) and primary system organ class (SOC) will also be captured in the database. All 
AEs will also be graded by the investigators using CTCAE v4.03.  
A treatment-emergent adverse event (TEAE) is defined as an AE that emerged during 
treatment (up to 28 days post the last study dose), having been absent at pretreatment 
(Baseline) or 
•
Reemerged during treatment (up to 28 days post the last study dose), having been present 
at pretreatment (Baseline) but stopped before treatment, or 
•
Worsened in severity during treatment (up to 28 days post the last study dose) relative to 
the pretreatment state, when the AE was continuous.


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Only those AEs that are treatment emergent will be included in summary tables.  All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC and PT. A subject will be counted only once within a SOC and PT, even if the 
subject experienced more than 1 TEAE within a specific SOC and PT. The number 
(percentage) of subjects with TEAEs will also be summarized by highest CTCAE grade.
The number (percentage) of subjects with treatment-related TEAEs will also be summarized 
by SOC and PT. Treatment-related TEAEs include those events considered by the 
investigator to be related to study treatment or with missing assessment of the causal
relationship.
The following TEAE summary analyses will be performed:
•
An overall summary table will include the number (%) of subjects with TEAEs, with 
treatment-related TEAEs, with TEAEs with CTCAE grade ≥3, with severe TEAEs (grade 
3 or 4), with serious TEAEs, treatment-related serious TEAEs, TEAEs leading to death, 
TEAEs leading to dose withdrawn/dose reduced/dose interrupted.
•
TEAEs will be summarized by SOC, PT and grade in number (%) of patients. Similarly, 
TEAEs that are serious, treatment-related, grade 3 or above, serious and related, leading 
to death/dose withdrawn/dose reduced/dose interrupted will also be summarized by SOC, 
PT and grade.
•
TEAEs will be summarized by PT in number (%) of subjects.
•
Additional summary on the TEAE of special interested will be presented by special 
interest, preferred term, and the worst CTCAE grade. 
5.6.2.1
Deaths
An overall summary of deaths will be presented: deaths within 28 days post last study drug, 
and deaths after 28 days post last study drug, and treatment-related deaths. A listing of all 
deaths will be provided.
5.6.3
Laboratory Values
Per protocol, the clinical laboratory tests in Table 1 were performed in the study. Abnormal 
laboratory values will be flagged and identified as those outside (above or below) the normal 
range, laboratory values will also be categorized by CTCAE v4.03 grades per Appendix 7, 
Sponsor’s Grading for Laboratory Values, of the study protocol. Laboratory values will be 
summarized by visit and by worst post-baseline visit. Laboratory parameters will be 
summarized by worst grade, and laboratory parameters with CTCAE grading in both high 
and low directions will be summarized separately. Shift tables from baseline grade to worst 
value will be presented.


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Table 1
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), ANC, INRb
Chemistry
Electrolytes
Bicarbonate, chloride, magnesium, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function tests
Blood urea/blood urea nitrogen, creatinine
Thyroid function testsa
TSH and free T4 
Pregnancy test
Serum β-hCG (if urine not tested)
Other
Albumin, glucosec, lactate dehydrogenase,  total protein,  uric 
acid, calcium,  phosphorus
Urinalysis
Glucosec, ketones, pH, protein, RBCs, specific gravity
Pregnancy test
Urine β-hCG (if serum not tested)
ALT = alanine aminotransferase, ANC= absolute neutrophil count, AST = aspartate aminotransferase, β 
hCG = beta-human chorionic gonadotropin,  INR = International Normalized Ratio, RBC = red blood cells, 
T4 = thyroxine, TSH = thyroid stimulating hormone, WBC = white blood cells
a:  Thyroid function will be assessed at the Screening Visit and then every 2 cycles (starting at C2) 
throughout the study.
b: INR only at screening/baseline and when clinically indicated
c: Fasting glucose at Screen, only
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiration rate, temperature, weight) and changes from baseline will be presented by visit.
5.6.5
Electrocardiograms
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit. 
Shift tables will present changes from baseline in ECG (categorized as normal; abnormal, not 
clinically significant; and abnormal, clinically significant) to the worst post-baseline (during 
treatment period). Other ECG values (Heart rate, QT Interval) and the changes from baseline 
will be summarized and presented by visit.
5.6.6
Other Safety Analyses
No other safety analyses are planned.


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5.7
Other Analyses
No other analysis is planned.
5.8
Exploratory Analyses
Additional exploratory analyses may be conducted as appropriate. Any exploratory analyses 
to be performed will be appropriately titled/labeled as exploratory and will be clearly 
distinguished from planned analyses when results are reported in the Clinical Study Report.
6
INTERIM ANALYSES
Per study protocol, one interim analysis was planned to be performed after the first 20 
evaluable subjects complete at least 2 tumor assessments or discontinue treatment due to any 
reason. From the interim analysis the enrollment would be halted if the number of responders 
is 3 or less (ORR ≤15%), and the safety and efficacy data would be further evaluated before 
making the decision of stopping the study permanently.
The study team would define the datasets for the interim analysis. The study team would
assess the impact of any issues such as unsolved data queries, missing data or data entry 
delays on the interim results. The study statistician would perform the interim analysis, 
which would include calculating ORR per protocol.
7
CHANGES IN THE PLANNED ANALYSES
Treatment duration will be analyzed in months instead of nominal cycles mentioned in the 
protocol. The exploratory analyses of identifying and exploring tumor and blood biomarkers 
that correlate with clinical outcomes, including efficacy will not be performed.
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
Baseline: in all analyses, the baseline value is defined as the non-missing value most recently 
collected before the first dose.
Study day calculation:  unless otherwise specified in outputs, the following convention will 
be used to calculate the study day used in the listings:  
-
Day 1 is the day of the first study drug taken  
-
Study Day (for an event/assessment, relative to the day of the first study drug taken) 
is defined as (date of assessment/event – date of the first study drug taken +1) for the 
event/assessment on or after the date of the first study drug, and as (date of 
assessment/event date of the first study drug) for the event/assessment before the first 
study drug.   


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Censoring rule for OS: Subjects who were lost to follow-up, or withdrew consent, will be
censored at the last date the subject was known to be alive, otherwise the censoring date will 
be the data cutoff date.
Censoring rule for PFS: Table 2 shows the censoring rules for subjects without documented 
PD or death in the derivation of PFS based upon investigator’s tumor assessment.  
Censoring rule for duration of response (DOR): considering the subjects with the confirmed 
best overall response of CR or PR and still alive without disease progression following the 
objective response.  The same censoring rule of PFS will be applied to the derivation of DOR 
for the cases applicable.


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Table 2  Censoring Rules for Analysis of Progression-Free Survival
No.
Situation
Date of Progression or Censoring
Outcome
1
No baseline tumor assessments
Date of first dose
Censored
2
Progression documented between scheduled 
visits
Date of first radiological PD assessment
Progressed
3
No progression at the time of data cut-off or 
withdrawal from study
Date of last adequate radiologic 
assessment prior to or on date of data 
cut-off or withdrawal from study, or 
date of the first dose if no adequate post 
baseline tumor assessment was 
conducted.   
Censored
4
New anticancer treatment started
Date of last adequate radiologic 
assessment prior to or on date of new 
anticancer treatment, or date of the first 
dose if no adequate post baseline tumor 
assessment was conducted.   
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 two or more missed 
visits**
Date of last adequate radiologic 
assessment before missed tumor 
assessments, or date of the first dose if 
no adequate post baseline tumor 
assessment was conducted.
Censored
8
No post-baseline tumor assessments but known 
alive
Date of first dose
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.
New anticancer treatment includes palliative radiotherapy. Any tumor assessments after new anticancer treatment 
started will be removed in the definition of PFS. 
** ‘More than two missed visits’ occurs if the duration between the last tumor assessment and death or PD is longer 
than the following: 
1.
12 weeks if the last tumor assessment is prior to week 24
2.
16 weeks if the last tumor assessment is on or after week 24 
Note: NE counts as a non-missing visit for No. 7.
Censoring rules are also described in Figure 1.


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Figure 1  PFS Censoring Rules
Note: If subject is censored in chart below, censoring time will be first dose date if no adequate post-
baseline assessments.
Progression (radiologically 
confirmed) or Death?
New anti-cancer medication?
New anti-cancer medication 
prior to event?
Yes
No
Censor at last adequate tumor 
assessment prior to start date of 
anti-cancer therapy
Yes
Yes
Censor at last 
adequate tumor 
assessment    
More than 2 missed visits 
between event and previous 
non-missing assessment?
[12 weeks if previous 
assessment before week 24, 
otherwise 16 weeks]
Note: NE not considered 
missing
No
Yes
Censor at last 
adequate tumor 
assessment prior to 
event    
Event date is 
earlier of PD or 
death    
No
No


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Handling of Adverse Events Dates missing or partial missing:
For an AE with start date missing, if the date cannot indicate that the AE started prior to the 
first study treatment or after the 28 days post the last study treatment then it will be 
considered as treatment emergent adverse event (TEAE), and will be flagged as TEAE in the 
dataset. No imputation on the dates will be made in the datasets.
Unscheduled Visits:
Data from unscheduled visits (eg, vital signs or laboratory tests) will be excluded from the 
by-visit summary but will contribute to the worst value in required in summary tables. 
Listings will include all, the scheduled and unscheduled. 
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in separate 
documents.
10 STATISTICAL SOFTWARE
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., 
Cary, NC, USA), version 9 or higher, and/or other validated statistical software as required.
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
The Study Protocol of E7080-M000-213 (Version 3.0, dated 24May2016, Amendment 02) 
and its corresponding case report form.
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, May 28, 2009.
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.
Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics.  Washington, DC: United States Food and Drug Administration; 2007.


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13 APPENDICES
13.1
Sponsor’s Grading for Laboratory Values 
See Appendix 7 of the final protocol of this study.


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SIGNATURE PAGE
Author:  
s 
isai Inc.
Date
Approval:
Date
Date
PPD
PPD
PPD