Clinical trial NCT03173560
Conditions: Renal Cell Carcinoma
Keywords: Renal Cell Carcinoma lenvatinib everolimus E7080 VEGF-targeted treatment
Sponsor: Eisai Inc.
Start date: 2017-08-17; Completion date: 2024-06-20
Enrollment: 343 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study E7080-G000-218 is a Randomized, open-label (formerly Double-blind), Phase 2 Trial conducted to assess whether a starting dose of lenvatinib 14 milligrams (mg) in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate \[ORR\] at 24 weeks \[ORR24W\]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent intolerable Grade 2, or any greater than or equal to (\>=) Grade 3 adverse events (AEs) in the first 24 weeks after randomization).

Detailed description:

Arms: arm 1: Participants will receive oral lenvatinib 14 mg once daily (QD) plus oral everolimus 5 mg QD as the starting dose for Cycle 1. If there are no intolerable Grade 2 or any \>= Grade 3 treatment-emergent adverse events (TEAEs) that require dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), the lenvatinib dose will be escalated to 18 mg QD (plus everolimus 5 mg) beginning in Cycle 2 or later (cycle length equal to \[=\] 28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles. arm 2: Participants will receive oral lenvatinib 18 mg QD plus oral everolimus 5 mg QD as the starting dose in Cycle 1 or later (cycle length =28 days) during randomization phase. After the data cutoff for the primary analysis, participants will receive study treatment as continuous 56-day cycles.
Interventions: intervention 1: lenvatinib intervention 2: everolimus
Intervention descriptions: intervention 1: lenvatinib capsules. intervention 2: everolimus tablets.

Protocol documents:
Prot_000.pdf: 
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-G000-218
Study Protocol 
Title:
A Randomized, Open-Label (formerly Double-Blind), Phase 2 Trial to 
Assess Safety and Efficacy of Lenvatinib at Two Different Starting 
Doses (18 mg vs 14 mg QD) in Combination With Everolimus (5 mg 
QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted 
Treatment
Sponsor:
Eisai Inc.
155 Tice Boulevard
Woodcliff Lake,
New Jersey 07677
USA
Eisai Ltd.
European Knowledge Centre
Mosquito Way
Hatfield, Hertfordshire
AL10 9SN 
UK
Eisai Co., Ltd.
4-6-10 Koishikawa
Bunkyo-Ku,
Tokyo 112-8088
Japan
Investigational 
Product Name:
Lenvatinib (E7080), everolimus
Indication:
Renal Cell Carcinoma
Phase:
Phase 2
Approval Date(s):
29 Sep 2016
(Original Protocol)
24 Apr 2017
(Protocol Amendment 01)
12 Jul 2017
(Protocol Amendment 02)
23 May 2018
(Protocol Amendment 03)
23 Jul 2018
(Protocol Amendment 04)
18 Oct 2018
(Protocol Amendment 05)
04 Jan 2019
(Protocol Amendment 06)
07 Feb 2020
11 Sep 2020
(Protocol Amendment 07)
(Protocol Amendment 08)
IND Number:
124564
EudraCT 
Number:
2016-002778-11
GCP Statement:
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 


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


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REVISION HISTORY
Revisions per Amendment 08
Date: 11 September 2020
Change
Rationale
Affected Protocol Sections
Updated the packaging section of 
lenvatinib. Sponsor may change 
the packaging from child-resistant 
wallets to child-resistant bottles at 
its discretion. No placebo will be 
included in bottles.
This is to allow the sponsor to 
adapt packaging in-line with
availability and cost.
Synopsis (Study Design), Section 
9.4.1 Treatments Administered
Table 1- footnote, Section 9.4.3 
Identity of Investigational 
Products, Section 9.4.10 Drug 
Supplies and Accountability
Updated study design to include 
study treatment, an off-treatment 
visit after the data cutoff for the 
primary analysis and if the study 
is terminated by the sponsor, 
study drug will be provided to 
subjects where commercial access 
is not available. Figure 8 is 
updated.
To outline the key assessments 
required for patients who remain 
on study post data cut-off. 
Synopsis (Study Design), Section
5.1 Institutional Review 
Boards/Independent Ethics 
Committees, Section 9.1 Overall 
Study Design and Plan, Section
9.1.2 Randomization Phase, 
Section 9.1.2.2 Follow-up Period, 
Section 9.4.1 Treatments 
Administered, Section 9.4.2.2 
Management of Hypertension, 
9.4.2.3. Management of 
Proteinuria, Section 9.4.2.8 
Management of Hepatoxicity, 
Section 9.4.6 Selection and 
Timing of Dose for Each Subject, 
Section 9.4.8.2 Prohibited 
Concomitant Therapy, Section
9.5.1.1 Demography and Baseline 
Assessments, Section 9.5.1.2 
Efficacy Assessments, Section
9.5.1.3.2 Pharmacodynamic and 
Other Biomarker Assessments, 
Section 9.5.1.4 Safety 
Assessments, Section 9.5.1.4.1 
Adverse Events and Events 
Associated with Special 
Situations, Section 9.5.1.4.2 SAEs 
and Events Associated with 
Special Situations, Section
9.5.1.4.3 Laboratory 
Measurements, Section 9.5.1.4.4 
Vital Signs and Weight 
Measurements, Section 9.5.1.4.5 
Physical Examinations, Section
9.5.1.4.6 Electrocardiograms, 
Section 9.5.1.4.7 Echocardiogram 
or Multiple Gated Acquisition 
Scan, Section 9.5.1.4.8 Pregnancy 
Test, Section 9.5.1.5 Other 
Assessments, Section 9.5.2 
Schedule of 
Procedures/Assessments, Section


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Change
Rationale
Affected Protocol Sections
9.5.2 Schedule of Assessments 
after the Data Cutoff for the 
Primary Analysis Table 7, Section 
9.5.2.1 Description of 
Procedures/Assessments 
Schedule, Section 9.5.5 
Completion/Discontinuation of 
Subjects, Section 9.7.1.1.2 
Secondary Endpoints.
Clarified the daily starting dose as 
lenvatinib 14 mg or 18 mg plus 
everolimus 5 mg
Synopsis (Sample Size Rationale), 
Section 7.3 Study Rationale, 
Section 9.2 Discussion of Study 
Design, Section 9.4.5 Selection of 
Doses in the Study, Section 9.7.2 
Determination of Sample Size
Added a blood pressure 
assessment after the data cutoff 
for the primary analysis, as one 
blood pressure assessment is 
defined as the mean of 2 
measurements at least 5 minutes 
apart.  Added a vital sign 
measurement (resting BP, heart 
rate, respiratory rate and body 
temperature).
Updated to align with most recent 
program requirements.
Section 9.4.2.2 Management of 
Hypertension, 9.5.1.4.4 Vital 
Signs and Weight Measurements, 
Table 7.


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Revisions per Amendment 07
Date: 07 February 2020
Revisions per Amendment 06
Date: 04 Jan 2019
Change
Rationale
Affected Protocol 
Sections
Clarify that the data cutoff for the primary 
analysis refers to the statistical end of the study 
for analysis purposes (end of the Randomization 
Phase) and that the End of Study refers to the 
last subject last visit after which all subjects will 
have completed their Off-treatment visits. It 
further makes clear that investigational product 
will be provided to ongoing subjects until they 
have had their Off-treatment visit to transition to 
commercial lenvatinib or everolimus outside the 
study or an access program, and that subjects 
should follow the Schedule of Procedures and 
Assessments while taking investigational 
product. The amendment also clarifies that at 
the End of Study, the Sponsor (or investigator 
where required) will ensure that all relevant 
IRBs/ECs and Competent Authorities are 
notified about the study completion per 
regulatory requirements in each country or 
region. 
It is also clarified that Follow-up assessments 
will not be performed after the data cutoff for
the primary analysis and the subject completes 
the Off-treatment visit assessments.
The term “final” analysis is changed to 
“primary” analysis, because there may be 
analyses conducted for a final report after the 
primary analysis.
To clarify the End of Study 
definition and that 
investigational product will 
be provided to ongoing 
subjects until they have had 
their Off-treatment visit to 
transition to commercial 
lenvatinib or everolimus 
outside the study or an access 
program.
Synopsis; Sections 5.1, 9.1, 
9.1.2, 9.1.2.1, 9.1.2.2, 
9.3.3, 9.5.1.2, 9.5.1.4.3,
9.5.2 (Schedule of 
Procedures/Assessments 
footnotes n, s, u), 9.7,
Appendix 13
Change
Rationale
Affected Protocol 
Sections
Added an exploratory objective:
To explore tumor response parameters 
(ORR24W, ORR, PFS) based on blinded 
independent imaging review (IIR) for efficacy 
assessment.
After consultation, the Health 
Authority recommended
response assessment by a 
blinded independent central 
review to corroborate the 
investigator assessment.
Synopsis, Section 8.3


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Revisions per Amendment 05
Date: 18 Oct 2018
Added process of blinded independent imaging 
review:
Copies of all tumor assessment scans will be 
sent to an Imaging Core Laboratory (ICL) 
designated by the sponsor for blinded 
independent efficacy assessment.  For subjects 
enrolled after implementation of Amendment 
06, tumor assessments will be carried out 
following the guidelines provided by the ICL.
Change made to add the
exploratory objective.
Synopsis, Section 9.5.1.2
Added exploratory endpoints:
Tumor response endpoints ORR24W, ORR, and 
PFS based on IIR assessment. These endpoints 
will be defined in the same way as those based 
on the investigator assessments.
Changed to include endpoints 
for the added exploratory 
objective.
Synopsis, Section 9.7.1.1.3
Added statistical analyses for the IIR 
assessments:
Exploratory efficacy response endpoints 
ORR24W, ORR, and PFS based on IIR 
assessment will be summarized using the same 
statistical methods as those used for the same 
response parameters based on the investigator 
assessments.
Changed to clarify statistical 
analysis methods used to 
assess the added exploratory 
endpoints.
Synopsis, Section 9.7.1.6.3
Change
Rationale
Affected Protocol Sections
Administrative changes
Correction of minor typographical 
errors.
Section 1, List of Abbreviations. 
Section 5.2, Investigator 
Signature Page
Clarified that lenvatinib in 
plasma and everolimus in blood 
will be used for pharmacokinetic 
assessments (PK), and that PK 
assessments will be done using 
the population PK approach.
Clarification of wording.
Synopsis
Updated total sample size to 
approximately 338 subjects (169 
subjects in each arm).
Adjusted to account for the 32 subjects 
who received ≥2 incorrect lenvatinib 
doses due to IxRS issues.
Synopsis, Section 9.1, Section 
9.3, Section 9.7.2
Clarified that HRQoL is to be 
assessed at Baseline, on Day 1 of 
each subsequent cycle, and at the 
Off-Treatment Visit.
Clarification of wording to ensure that 
HRQoL measurements are collected at 
the appropriate time points.
Synopsis, Section 9.5.1.5, Section 
9.5.2 (Table 6)
Full Analysis set changed from 
primary analysis set to a 
secondary analysis set. 
Change made as a consequence of the
Oracle Interactive Voice and Web 
Response System (IxRS) issues that 
resulted in 32 subjects receiving ≥2 
incorrect lenvatinib doses.
Synopsis, Section 9.7.1.2


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Divided Per-Protocol Analysis 
Set into 2 data sets, Per-Protocol 
Analysis Set 1 and Per-Protocol 
Analysis Set 2.  
Per-Protocol Analysis Set 1
includes all randomized subjects, 
but excludes the 32 subjects who 
received ≥2 incorrect lenvatinib 
doses due to IxRS issues. 
Per- Protocol Analysis Set 2
includes all randomized subjects 
who received at least 1 dose of 
study drug, had no major 
protocol deviations, and had 
both baseline and at least 1 post-
baseline tumor assessment.
Subjects for whom death 
occurred prior to the first post-
baseline tumor assessment will 
also be included.  The 32 
subjects who received 
≥2 incorrect lenvatinib doses due 
to IxRS issues are considered as 
having experienced major 
protocol deviations and will be 
excluded from Per-Protocol 
Analysis Set 2.
The 32 subjects who received ≥2 
incorrect lenvatinib doses due to IxRS 
issues are to be excluded from efficacy 
data sets as these subjects are 
considered to have a major protocol 
deviation.
There was an additional subject who 
was subsequently affected by the IxRS 
issue after the discovery of the 32 
subjects, but because this 33rd subject 
received only one incorrect lenvatinib 
dose, this subject will not be excluded 
from Per-Protocol Analysis Set 1 or 
Per-Protocol Analysis Set 2.
Synopsis, Section 9.7.1.2
Added Per-Protocol Safety 
Analysis Set which includes all 
treated subjects minus the 32 
subjects who received ≥2 
incorrect lenvatinib doses due to 
IxRS issues.
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses.
Synopsis, Section 9.7.1.2, Section 
9.7.2
Specified that the 2 interim 
efficacy analyses will be 
performed using only Per-
Protocol Analysis Set 1.  
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses.
Synopsis, Section 9.7.1.6, Section 
9.7.2, Section 9.7.3, Appendix 13
Specified that for the final 
efficacy analysis, the primary 
analysis will be done using Per-
Protocol Analysis Set 1, and the 
secondary efficacy analyses will 
be performed using the Per-
Protocol Analysis Set 2 and the 
Full Analysis Set. 
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses
Synopsis, Section 9.7.1.6,
Appendix 13.
Added text to clarify that the 
primary safety analysis using the
Per-Protocol Safety Analysis Set
will be performed at each 
interim analysis and at the final 
analysis, if the non-inferiority 
boundary of the primary efficacy 
endpoint is crossed. 
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses
Synopsis, Section 9.7.1.6, Section 
9.7.2


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Specified that determination of 
noninferiority in ORR24W will be 
based on the results using Per-
Protocol Analysis Set 1.
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses
Synopsis, Section 9.7.1.6.1
Clarified that secondary efficacy 
analyses will be summarized 
descriptively using the Per-
Protocol Analysis Set 1, the Per-
Protocol Analysis Set 2, and the 
Full Analysis Set.
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses
Synopsis, Section 9.7.1.6.2
Added text to specify that the 
safety analyses will be 
performed on the Per-Protocol 
Safety Analysis Set in addition 
to the Safety Analysis Set.
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses
Synopsis, Section 9.7.1.6.1, 
Section 9.7.1.8
The statistical analysis plans for 
the exploratory pharmacokinetic, 
pharmacodynamic, and other 
biomarker endpoints will specify 
if the analyses will or will not 
include the 32 subjects who 
received ≥2 incorrect lenvatinib 
doses due to IxRS issues.
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses
Synopsis, Section 9.7.1.2
Removed text from a Figure 8
label to indicate that the 
Randomization Phase is no 
longer double-blind.
Correction of a figure label error where 
the words “Double-blind” should have 
been deleted in Amendment 04.
Section 9.1
Updated text to indicate that the 
sites will receive lenvatinib in 
labeled bottles.
Clarification that once the current 
study drug supply is exhausted, 
subsequent supplies of lenvatinib will 
be packaged in labeled containers.
Section 9.4.3
Updated text to reflect the Per-
Protocol Analysis Set 1, Per-
Protocol Analysis Set 2, and Full 
Analysis Set will be used to 
summarize subject disposition 
and subject demographics and 
other baseline characteristics, 
and prior and concomitant 
therapy.
Change made as a consequence of the
IxRS issues that resulted in 32 subjects 
receiving ≥2 incorrect lenvatinib doses.
Section 9.7.1.3, Section 9.7.1.4,  
Section 9.7.1.5
Clarified the definition of prior 
medications to indicate that these 
are medications that were started 
and stopped prior to the first 
dose of study drug.
Correction of error.
Section 9.7.1.5


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Revisions per Amendment 04
Date: 23 Jul 2018
Change
Rationale
Affected Protocol Sections
Title
Protocol title changed to reflect change 
in study design.
Title page, Synopsis, Signature 
pages
Revised text to reflect change 
from double-blind to open-label 
study design
This is a safety-directed amendment.  
The protocol design was changed 
because of an unresolved error 
introduced by a programmatic update to 
the Oracle Interactive Voice and Web 
Response System (IxRS), which 
resulted in incorrect dose dispensing 
and assignment of lenvatinib to 
32 treated patients between 08 Mar 
2018 and 04 Apr 2018.  Because an 
additional patient was subsequently 
affected, Eisai decided that it is in the 
best interest of the patients to unblind 
participants (investigators and subjects) 
as to all subjects’ treatment assignment 
and to continue the conduct of the trial 
in an open-label fashion. This decision 
has been communicated to all 
regulatory health authorities, and all 
investigators received unblinding 
information as of 14 Jul 2018. Study 
enrollment will continue as planned and 
all subjects currently receiving study 
drug may continue participation in the 
study.
Synopsis and Sections 9.2, 
9.4.1, 9.4.2.1, 9.4.4, 9.4.7, 
9.5.4.5, 9.7, 9.7.1, and 9.7.3
Revised text regarding lenvatinib 
dispensing instructions.
To ensure that each subject is dispensed 
the correct dose of lenvatinib. 
Sections 9.4.2.1, 9.4.3, and 
9.4.4
Administrative changes
Correction of minor typographical 
and/or formatting errors per protocol.
List of Abbreviations; Synopsis;
Sections 5.3, 7.3, 9.2, 9.4.1, 
9.7.1.6.2, 9.7.2, and 9.7.3;
Table 2 and Table 6; Reference 
List


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Revisions per Amendment 03
Date: 23 May 2018
Change
Rationale
Affected Protocol Sections
Deleted the following text from 
Follow-up Period:
“Subjects who are being followed for 
survival at the time of data cutoff for 
the primary analysis (ie, at the
end of the Randomization/Treatment 
Phase)”
The sentence is revised following this 
deletion, and new text is presented in 
bold below:
“Following the Off-Treatment Visit,
subjects will continue to be followed 
every 12 weeks (±1 week) for survival 
and PFS2, and all anticancer 
treatments received will be recorded 
until the End of Study.”
Wording for Follow-up 
Period revised for clarity.
Protocol Synopsis (Study Design)
Section 9.1.2.2 (Follow-Up Period)
End of Study (EOS) text revised and 
new text presented in bold below:
“The End of Study is the date of the 
data cutoff for the final analysis when
all randomized subjects have 
completed Week 24 assessments or 
have discontinued study treatment 
prior to Week 24.
Alternative wording for
EOS definition is now 
preferred by Biostatistics
Group for consistency 
across the program.
Protocol Synopsis (Study Design)
Section 9.1 (Overall Study Design 
and Plan)
New paragraph added:
Prior therapy must be documented by 
the following criteria prior to entry into 
study:

Any single agent therapy, and any 
combination of cytotoxic, 
hormonal, biological targeted 
agents, and/or humanized 
antibodies, scheduled to be 
administered as a preplanned 
treatment, given concomitantly, 
sequentially or both, is considered 
1 regimen.

Planned neoadjuvant 
chemotherapy (to debulk the 
tumor prior to surgical 
intervention) plus postoperative 
adjuvant chemotherapy is 
considered 1 regimen.
To provide consistency in 
the counting of prior 
anticancer regimens in this 
study and to align with use 
in other protocols
Section 9.4.8.2 (Prohibited 
Concomitant Therapies and Drugs)


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Change
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Affected Protocol Sections

For chemotherapy: if, due to 
toxicity, the dosing of one or more 
of the components must be 
reduced, or one or more of the 
components of the regimen must 
be omitted, or one of the 
components must be replaced with 
another similar drug, the changed 
version of the original regimen is 
not considered a new regimen. 
However, if a new component, 
dissimilar to any of the original 
components, is added to the 
regimen, the new combination is 
considered a new regimen.

For prior VEGF/VEGFR-targeted 
agents, treatment with each agent 
will be counted individually, 
regardless of the duration of 
administration.

If the treatment is interrupted for 
surgery or radiotherapy or any 
other reason and then continues 
with an unchanged schedule and 
components, that treatment is 
considered as 1 regimen despite 
the interruption.
Removed all references related to 
Pharmacogenomic sampling and 
testing from Synopsis and Protocol.
Pharmacogenomic 
sampling references are 
removed as they are no 
longer deemed necessary.
Synopsis (Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Assessments; 
Pharmacokinetic, 
Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Analyses) 
List of Abbreviations
Section 5.3 (Subject Information 
and Informed Consent)
Section 9.5.1.3.2 
(Pharmacogenomic,
Pharmacodynamic, and Other 
Biomarker Assessments)
Section 9.5.2 (Table 6: Schedule of 
Procedures/Assessments in E7080-
G0000-218)
Section 9.7.1.7 (Pharmacokinetic, 
Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Analyses)
Appendix 12 (Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Research)


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Change
Rationale
Affected Protocol Sections
Pharmacokinetic sampling text revised 
and new text presented in bold below:
Sparse PK samples (plasma for 
lenvatinib and whole blood for 
everolimus) will be collected from all 
subjects and will be analyzed using a 
population PK approach (PopPK).  The 
timing for obtaining the 7 PK 
sampling time points (one tube each 
for lenvatinib and everolimus PK) is 
shown in the Schedule of 
Procedures/Assessments (Table 6) and 
Table 4.
Pharmacokinetic sampling 
text revised for clarity.
Section 9.5.1.3.1 (Pharmacokinetic 
assessments)
Revised footnote “a” in Table 6 and 
new text presented in bold below:
“Subjects must be screened within 28 
days prior to randomization.  The 
screening assessment can serve as the 
baseline assessment, if performed 
within 72 hours before randomization.  
Baseline assessments may be 
performed on Day -1 or on C1D1 prior 
to randomization.  Patients 
randomized after the baseline 
assessment must have all baseline 
assessments reviewed prior to C1D1.  
Informed consent may be obtained up 
to 4 weeks prior to randomization.”
Clarification
Section 9.5.2 (Table 6)
Revised footnote “b” in Table 6 and 
new text presented in bold below:
“Efforts should be made to conduct
study visits on the dayscheduled (±3
days).  The study visit (and safety 
assessments) still needs to occur 
regardless of a study medication hold 
per the visit schedule.”
Clarification
Section 9.5.2 (Table 6)
Revised footnote “k” in Table 6 and 
new text presented in bold below:
“Clinical chemistry and hematology 
results must be reviewed prior to 
administration of study drug on C1D1 
and within 2 business days of receipt 
of results for all subsequent cycles”.  
Clarification
Section 9.5.2 (Table 6)


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Revisions per Amendment 02
Date: 12 Jul 2017
Change
Rationale
Affected Protocol Sections
The new End of Study (EOS) 
definition has been inserted and the 
paragraph has been revised to: 
“The End of Study is the date of the 
data cutoff for the final analysis or last 
subject/last visit, including 
discontinuation from the study for any 
reason, whichever occurs later.  At the 
End of Study, subjects still receiving 
study treatment may continue taking 
lenvatinib and everolimus if available 
through their pharmacy (and if 
commercially available for that 
individual subject) or through an 
access program administered by the 
sponsor.”
Alternative wording for 
EOS definition is now 
preferred by Biostatistics
Group for consistency 
across the program.
Protocol Synopsis (Study Design)
Section 9.1 (Overall Study Design 
and Plan)
Text revised and new text presented in 
bold below:
Dose reductions and interruptions for 
subjects who experience lenvatinib-
everolimus combination therapy-
related toxicity (except hypertension 
and non-infectious pneumonitis) will 
be managed as described in the table 
below.  Investigators will decide the 
probability of the event being related 
to 1 or both drugs as to whether dose 
modification of 1 or both drugs is 
required. For treatment-related 
hypertension and non-infectious 
pneumonitis, refer to Management 
of Hypertension (Section 9.4.2.2) and 
Management of Non-infectious
Pneumonitis (Section 9.4.2.5) for 
dose modification guidelines.
Updates made to the Dose 
Reduction section to 
clarify that Table 2 (Dose 
Modification Guidelines 
for Lenvatinib-Everolimus 
Combination Treatment-
Related Toxicity) is not 
intended to be used for 
treatment related 
hypertension or non-
infectious pneumonitis 
(these sub-sections have 
their own independent and 
specific dose reduction 
guidelines/rules).
Protocol Synopsis (Dose Reduction)
9.4.2 (Criteria for Interruption of 
Treatment, Dose Reduction and 
Resumption of Treatment)
Removed all references related to 
central imaging from Synopsis and 
Protocol.
“Copies of all tumor assessment scans 
will be sent to an imaging core 
laboratory (ICL) designated by the 
Sponsor for quality assessment, 
archival and potential future review.  
Tumor assessments will be carried out 
following the guidelines provided by 
the ICL.”
Central imaging references
are removed as they are no 
longer deemed necessary.
Synopsis (Efficacy Assessments) 
List of Abbreviations
9.5.1.2
Efficacy Assessments


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Rationale
Affected Protocol Sections
ICL (imaging core laboratory) from the 
Abbreviations List was removed.
Following references related to central 
imaging was also deleted from the 
Protocol and revisions were made 
accordingly:
Revised text: “Historical CT or MRI 
scans performed within 28 days of 
randomization but before informed 
consent may be used as screening 
scans.”
Deleted: "as long as they meet 
minimum standards as separately 
defined by the ICL."
Deleted: "Copies of tumor assessment 
scans will no longer be sent to the ICL 
during the Follow-up Period."
Changed foot note "n" in the Table 6 to 
read: "Scans that were performed 
within this window but before 
informed consent may be used."
Deleted following texts from foot note 
"n": 
"Detailed image acquisition guidelines 
will be provided by the imaging core 
laboratory."
"if they were acquired consistent with 
the guidelines provided by the imaging 
core laboratory."
Central imaging references
are removed as they are no 
longer deemed necessary.
Section 9.5.2 (Table 6, footnote “n”)
Changed Footnote "e" in the Table 6 
and following text was removed: 
"Blood pressure assessments, in 
addition to those already scheduled in 
the protocol (as noted in the table 
above), will be performed:  just before 
each scheduled PK sample (0.5 to 4 
hours and 6 to 10 hours postdose on 
C1D1; predose and 0.5 to 4 hours and 
6 to 10 hours postdose on C1D15, and 
predose and 2 to 12 hours postdose on 
C2D1)." 
New modified footnote "e" in the 
Table 6 with insertion in bold: 
"Assessments will include vital signs 
(resting BP [including date and time of 
measurement], HR, RR and body 
There is no need to 
measure Blood Pressure 
(BP) just prior to every 
scheduled PK sample, but 
only one per protocol BP 
assessment on the PK draw 
days. 
It was further confirmed 
that it is perfectly 
acceptable that the Time of 
the BP assessment 
recorded is the Time the 
site staff first began to 
perform BP measures. 
The additional wording in 
footnote “e” which already 
appears in the body of the 
Section 9.5.2 (Table 6, footnote "e”)


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Affected Protocol Sections
temperature), weight, and height.  
Height will be measured at the 
Screening visit only.  One BP 
assessment is defined as the mean 
value of 3 measurements at least 
5 minutes apart. An elevated BP 
assessment (ie, systolic BP ≥140 
mmHg or diastolic BP ≥90 mmHg 
should be confirmed by a repeat 
assessment after a minimum of 1 hour.  
Subjects with systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg must have 
their BP monitored every 2 weeks (on 
Day 1 and 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.  A diary will be 
provided to the subject to capture the 
blood pressure evaluations between 
study visits.  See subsection for 
management of hypertensive subjects."
protocol, is added here for 
greater emphasis.
Deleted the words "the date" in each 
section of SAE/Pregnancy reporting, 
section of the synopsis, and protocol 
body.
Changed to read: “no later than 24 
hours from when the investigator 
becomes aware of the event”.
Correction to make the 
SAE/Pregnancy reporting 
time frame consistent with 
guidelines (without 
unnecessary words)
Revision History Table in Protocol 
Amendment 01 (dated 24 Apr 2017)
9.5.4.1
(Reporting of Serious 
Adverse Events)
9.5.4.2
(Reporting of Pregnancy 
and Exposure to Study Drug Through 
Breastfeeding)
Following text revised in the Synopsis 
and Protocol, with insertions in the 
bold:
“Concentrations of lenvatinib in 
plasma and everolimus in whole blood 
will be pooled with existing data 
from other completed studies and
analyzed using a population PK 
approach to estimate population PK 
parameters for each drug. “
Inserted new text "whenever possible 
using a mechanism-based approach."
PK/PD model was fixed 
for Ang-2, but not VEGF, 
on data from Study 205. 
Data used was from the 
lenvatinib arm alone and 
the lenvatinib+ everolimus 
arm from the Phase 2. This 
was followed by 
simulations and re-
estimation for optimal 
sampling for Ang-2 in 
studies 218 and 307. Based 
on the simulation/re-
estimation results, 7 
biomarkers samples 
collected in each subject 
post-dosing, in addition to 
a baseline sample are 
sufficient to adequately 
characterise the PK/PD 
relationship for Ang-2.
Synopsis (Pharmacokinetic, 
Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Analyses)
9.7.1.7 (Pharmacokinetic, 
Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Analyses)


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Change
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Affected Protocol Sections
Following statement shifted to second 
paragraph for alignment:
"For the exposure-response 
relationship for biomarkers (eg, VEGF, 
Ang-2) data will be analyzed using a 
model-based approach with indirect 
PK/PD models."
Synopsis 
(Pharmacokinetic/Pharmacodynamic 
Analyses)
9.7.1.7.1 
(Pharmacokinetic/Pharmacodynamic 
Analysis)
Revised following statement in the 
Synopsis and Protocol: "The analysis 
will be detailed in the biomarker 
analysis plan (BAP) and reported 
separately.
Based on comments from 
the EMA word “may”
changed to “will be.”
Synopsis (Biomarker Analysis)
9.7.1.7.2 (Biomarker Analyses)
Revised foot note “v” with 
insertions in bold: 
“A blood sample for 
biomarkers will be 
collected at Baseline (pre-
treatment) and at predose 
at the following time 
points: C1D15, C2D1, 
C3D1, C4D1, C5D1 and 
C6D1.  A sample should 
also be collected at the 
Off-treatment visit.”
Removal of PD biomarker 
samples after cycle 6, off 
treatment and after post 
dose samples at C1D1.
The optimal sample are as 
in the Table 6 without 
sampling needed on C1D1, 
C1 D7/8, C1 D21/22, and 
beyond C6 D1
Section 9.5.2 (Table 6, footnote "e”)


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Revisions per Amendment 01
Date: 24 Apr 2017
Change
Rationale
Affected Protocol Sections
Amended section to add additional
safety results regarding dose 
modifications and reasons for 
treatment discontinuation due to 
toxicity.
Regulatory request from 
CHMP RAP
Section 7.1
Removed the following text: “The 
current approved dose in subjects 
with advanced predominant clear 
cell RCC following 1 prior 
VEGF-targeted treatment is 18 mg 
lenvatinib in combination with 5 mg 
everolimus daily.”
Added new text:  “Lenvatinib 
18 mg daily in combination with 
everolimus 5 mg daily is approved 
in the US and EU for the treatment 
of adult patients with advanced
RCC following 1 prior 
VEGF-targeted therapy.”
Clarification prompted by 
Regulatory question under 
Voluntary Harmonisation 
Procedure (VHP)
Section 9.1
Added the following text:
“Lenvatinib 18 mg daily in 
combination with everolimus 5 mg 
daily is approved in the US and EU 
for the treatment of adult patients 
with advanced RCC following 1 
prior VEGF-targeted therapy.”
Deleted the following text: “In 
subjects with advanced predominant 
clear cell RCC following 1 prior 
VEGF-targeted treatment, the 
current approved dose is 18 mg 
lenvatinib in combination with 5 mg 
everolimus.”
Consistency with Section 9.1
Section 9.2
For Exclusion Criterion 15, 
added the text “Left ventricular 
ejection fraction (LVEF) below the 
institutional normal range as 
determined by screening multigated 
acquisition (MUGA) scan or 
echocardiogram”
Regulatory request from 
CHMP RAP
Protocol Synopsis
Section 9.3.2 - Exclusion Criterion 15
Exclusion Criterion 19,
Changed “28 days” to “up to 
8 weeks after study drug 
discontinuation”
Regulatory request under VHP 
for consistency with 
Afinitor/everolimus SmPC
Protocol Synopsis
Section 9.3.2 - Exclusion Criterion 19
“Administrative reasons” changed 
to “other reasons”
Clarification prompted by 
Regulatory question under the 
VHP
Section 9.3.3


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Deleted “hemorrhage”
Correction; there is no 
corresponding hemorrhage 
management section
Protocol Synopsis (Dose Reductions),
Section 9.4.2
Revised footnote “b” in Table 2 to 
include hypertension.
Added the following text:  “For 
treatment-related hypertension and 
non-infectious pneumonitis, refer to 
Management of Hypertension 
(Section 9.4.2.2) and Management 
of Non-infectious Pneumonitis 
(Section 9.4.2.5) for dose 
modification guidelines.”
Clarifications, since more 
specific dose modification 
guidelines for those toxicities 
are contained therein.
Protocol Synopsis
Section 9.4.2
At the second bullet point the 
following text was added:
“Investigators will decide the 
probability of the event being 
related to 1 or both drugs as to 
whether dose modification of 1 or 
both drugs is required.”
At the third bullet point “Study 
medication” was changed to 
“Everolimus” and the following text 
was added: “Investigators will 
decide the probability of the event 
being related to 1 or both drugs as 
to whether discontinuation of 1 or 
both drugs is required.”
Repeated a pre-existing 
sentence from paragraph 1 of 
Section 9.4.2 at suggestion of 
Protocol Steering Committee 
for greater clarity.
Protocol Synopsis (Management of 
Non-Infectious Pneumonitis),
Section 9.4.2.5
Third paragraph has been changed 
to read:
“If a subject is discontinued from
the study for disease progression or 
toxicity, the PI may request the 
subject’s last dispensed lenvatinib 
dose level if this is needed for 
planning of future non-study
anticancer therapy.  The PI will 
request this from the IxRS after 
entering confirmation that the 
information is needed for planning 
future anticancer therapy. This 
information will be provided by the 
PI to the treating medical 
professional.”
Clarification prompted by 
Regulatory question from 
CHMP RAP
Section 9.4.7
Changed “exposure parameters“ to 
“concentrations”
Correction
Protocol Synopsis (Pharmacokinetic 
Analyses),
Section 9.7.1.7


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Removed “sTie 2 and FGF23” from 
biomarker assessments
Correction to align with the 
PK/PD Analysis Plan
Protocol Synopsis
(Pharmacodynamic, 
Pharmacogenomic, and Other 
Biomarker Assessments,
Pharmacokinetic/Pharmacodynamic 
Analyses),
Section 9.5.1.3.2
Section 9.7.1.7.1
Changed footnote “e” in Table 5 to 
read: “If urine dipstick testing 
suggests a urinary tract infection, a 
urinalysis with microscopy and/or 
urine culture with sensitivities 
should be considered if felt 
clinically indicated at the 
institution’s laboratory.”
Clarification
Section 9.5.1.4.3 (Table 5, 
footnote “e”)
Changed footnote “f” in Table 5 to 
read:  “If urine protein by dipstick 
is…”
Correction
Section 9.5.1.4.3 (Table 5)
Changed footnote “b” in Table 6 
from ±1 day to ±3 days
Correction
Section 9.5.2 (Table 6)
Changed from “subjects must be” to 
“subjects are suggested to be”
Clarification
Section 9.5.1.4.6
Section 9.5.2 (Table 6, footnote “h”)
Changed footnote “q” in Table 6 to 
read:  “…on Day 1 of each 
subsequent cycle starting with 
Cycle 2….”
Clarification
Section 9.5.2 (Table 6)
Changed footnote “k” to state that 
electrolyte abnormalities should be 
corrected before starting treatment 
“per the Investigator’s discretion”
Clarification
Section 9.5.2 (Table 6)
Footnote “m”: Deleted “PK blood 
samples” and replaced with “Blood 
samples for PK profiling lenvatinib 
and everolimus…”
Added the following sentence at the 
end of footnote “m”:
“If possible, a blood sample for the 
measurement of the concentration
of lenvatinib should be drawn at the 
first report of an SAE or a severe 
unexpected AE.”
Repeats a similar sentence that 
appears in Section 9.5.1.4.2 for 
greater emphasis.
Section 9.5.2 (Table 6)
Removed NYHA assessments at 
Visits 5, 7, and 9.  NYHA 
assessments are done only at 
Screening Visit only.
Correction to align footnote c 
of Table 6 with the Table.
Section 9.5.2 (Table 6)
28 days changed to 8 weeks 
Correction for consistency with 
Afinitor/everolimus SmPC
Section 9.5.4.2
Changed to read:  “no later than 
24 hours from the date when the 
investigator becomes aware of the 
event”
Regulatory request from 
CHMP RAP and Regulatory 
request under the VHP
Section 9.5.2 (Table 6, footnote “t’’)
Section 9.5.4.1
Section 9.5.4.2


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Changed “Functional Assessment of 
Cancer Therapy Kidney Syndrome 
Index-Disease-Related Symptoms”
to “Functional Assessment of 
Cancer Therapy-Kidney Symptom 
Index-Disease Related Symptoms”
Correction
Protocol Synopsis
Abbreviation list
Section 8.2
Section 9.5.1.5
Section 9.7.1.1.2
Added details on sensitivity analysis 
to be performed for primary 
endpoints to explore homogeneity 
of treatment effect across study 
centers/regions.
To address Regulatory request 
under the VHP (Added in 
response to Regulatory 
question under the VHP)
Clinical Protocol Synopsis and 
Section 9.7.1.6.1
Added new sub-section on handling 
of missing data for efficacy 
analyses
To address Regulatory request 
under the VHP (Added in 
response to Regulatory 
question under the VHP)
Clinical Protocol Synopsis and 
Section 9.7.1.6.4
Added details/explanation on 
estimation of non-inferiority margin
To address Regulatory request 
under the VHP (Added in 
response to Regulatory 
question under the VHP)
Clinical Protocol Synopsis and 
Section 9.7.2
Added cross-references to:
Rothmann et al 2003
East 6 User Manual, 2014
Consistency, Regulatory 
request under the VHP
Section 9.7.2
Added cross-references to:
Lan and DeMets, 1983
DeMets and Ware, 1980
Consistency, Regulatory 
request under the VHP
Section 9.7.3
Added the following references to 
the reference list:
DeMets and Ware 1980
East 6 User Manual
Lan and DeMets, 1983
Rothmann et al 2003
To support statistical analysis,
Regulatory request under the 
VHP
Section 10
Changed “any other reason” to 
“futility”
Regulatory request under the 
VHP
Section 11.11
Added definitions for N, Q1, and 
Q3
Regulatory request under the 
VHP
Abbreviation list
Editorial revisions 
Consistency
Throughout document


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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
A Randomized, Open-Label (formerly Double-Blind), Phase 2 Trial to Assess Safety and Efficacy of 
Lenvatinib at Two Different Starting Doses (18 mg vs 14 mg QD) in Combination With Everolimus 
(5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment
Investigator(s)
Unknown
Site(s)
Approximately 100 sites worldwide
Study Period and Phase of Development
Approximately 48-month duration
Phase 2
Objectives
Primary Objective

To assess whether a starting dose of lenvatinib 14 mg in combination with everolimus 5 mg
once daily (QD) will provide comparable efficacy (based on objective response rate [ORR]
at 24 weeks [ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in
combination with everolimus 5 mg (based on treatment-emergent intolerable Grade 2, or 
any ≥Grade 3 adverse events (AEs) in the first 24 weeks after randomization).
Secondary Objectives

To assess progression-free survival (PFS).

To assess ORR.

To determine the tolerability and safety profile of lenvatinib in combination with everolimus.

To assess the proportion of subjects who discontinued treatment due to toxicity.

To assess time to treatment failure due to toxicity.

To assess pharmacokinetic (PK) profiles of lenvatinib and everolimus during
combination therapy and to assess PK and pharmacodynamic (PD) drug-drug 
interactions.

To evaluate overall survival (OS).

To evaluate the impact of disease and treatment on patients' Health-Related Quality of Life 
(HRQoL) as assessed by using the Functional Assessment of Cancer Therapy-Kidney 
Symptom Index-Disease Related Symptoms (FKSI-DRS), the European Organization for the 
Research and Treatment of Cancer (EORTC) QLQ-C30 and the European Quality of Life 
(EuroQol) EQ-5D-3L.

To evaluate the PFS after next line of treatment (PFS2).
Exploratory Objectives

To explore tumor response parameters (ORR24W, ORR, PFS) based on blinded independent 
imaging review (IIR) for efficacy assessment.


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
To explore blood biomarkers that correlate with efficacy-related endpoints of this study.

To develop exposure/biomarker/clinical endpoint models (whenever possible, using a 
mechanism-based approach) for both efficacy and safety data that will allow exploration 
of alternative dosing regimens with a better efficacy/safety profile than the lenvatinib 
18-mg plus everolimus 5-mg dose.
Study Design
Originally, this was a multicenter, randomized, double-blind study conducted as a postmarketing 
requirement by the US Food and Drug Administration (FDA) and the European Medicines Agency 
(EMA) to evaluate an alternate dose regimen for lenvatinib in combination with everolimus. As of 
14 Jul 2018, all ongoing subjects’ treatment assignment has been unblinded to investigational site 
personnel, and the study will be conducted in an open-label fashion. The investigational site 
personnel and study subjects will be unblinded as to the treatment assignment for all newly enrolled 
subjects.  
In subjects with advanced renal cell carcinoma (RCC) following one prior anti-angiogenic treatment, 
the current approved lenvatinib dose is 18 mg daily in combination with everolimus 5 mg daily.  This 
study will evaluate the combination of lenvatinib and everolimus in subjects with advanced 
predominant clear cell RCC following one prior vascular endothelial growth factor (VEGF)-targeted 
treatment at 14-mg starting dose of lenvatinib and allow up-titration of lenvatinib to determine 
whether this regimen provides comparable efficacy but has a better safety profile than the 18-mg 
starting dose. The 14-mg starting dose will be escalated to 18 mg if no Grade 2 (intolerable) or any 
≥Grade 3 treatment-emergent adverse events (TEAEs) that require dose reduction are observed in the 
first cycle (4 weeks) of treatment. If Grade 2 (intolerable) or Grade 3 or 4 TEAEs are observed, the
lenvatinib dose will be reduced, as described below in the dose reduction section.  Both lenvatinib 
and everolimus will be administered orally (PO) and once daily (QD).
Eligible subjects will have measurable disease according to Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) and will be randomly assigned to each treatment arm in a 
1:1 ratio.  The total sample size will be approximately 338 subjects. Randomization will follow a 
predefined randomization scheme based on the following stratification factors: Memorial Sloan-
Kettering Cancer Center (MSKCC) prognostic groups (favorable, intermediate, or poor risk); and 
whether subjects have had a prior PD-1/PD-L1 treatment (yes or no).
Subjects will receive study treatment as continuous 28-day cycles. Treatment cycles will be counted 
continuously regardless of dose interruptions. Subjects will undergo safety and efficacy assessments 
as defined in the Schedule of Procedures/Assessments and in the Schedule of Assessments after the 
Data Cutoff for the Primary Analysis.  After the data cutoff for the primary analysis subjects, will be 
eligible to receive study treatment as continuous 56-day cycles.  
Subjects will discontinue study treatment upon evidence of progressive disease, as judged by the 
Investigator. After disease progression, subjects will be followed for survival and PFS2 until data 
cutoff for the primary analysis.
This study will consist of 2 phases, the Prerandomization Phase, and the Randomization Phase with 
treatment continuing after the data cutoff for the primary analysis.  
The Prerandomization Phase will last no longer than 28 days and will include a Screening Period to 
establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease 
characteristics prior to randomization and treatment. Repeated laboratory evaluation to establish 
eligibility is not allowed unless discussed and agreed upon with the sponsor.
The Randomization Phase will consist of a Treatment Period and a Follow-up Period. It will begin 
at the time of randomization of the first subject and will end at the data cutoff for the primary
analysis, which is defined as when all randomized subjects complete the Week-24 tumor assessments 
or discontinue study treatment before Week 24. Subjects will be randomly assigned to treatment in a 


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1:1 ratio.
The Treatment Period for an individual subject will begin at the time of randomization and will end 
upon completion of the Off-Treatment Visit, which will occur within 28 days after the final 
administration of study drug.  The Treatment Period consists of open-label treatment with study drug 
in 28-day treatment cycles that will be counted continuously regardless of dose interruptions.  Serious 
adverse events (SAEs) and AEs must be captured for 28 days after the last dose of study drug. 
Subjects will undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments and will continue to receive study treatment until disease progression.  The 
Follow-up Period will begin immediately after the Off-Treatment Visit and will continue as long as 
the subject is alive, unless the subject withdraws consent, or until the data cutoff for the primary
analysis. Subjects who discontinue study drug treatment prior to disease progression will continue to 
have tumor assessments performed every 8 weeks until documentation of disease progression or 
initiation of another anticancer treatment. Following the Off-treatment Visit, subjects will continue 
to be followed every 12 weeks (±1 week) for survival and PFS2, and all anticancer treatments 
received will be recorded until the data cutoff for the primary analysis (ie, Follow-up ends at the end 
of the Randomization Phase). This information will be recorded unless this information is not 
allowed to be provided due to confidentiality.  
If a subject discontinues study treatment and does not consent to continued follow-up, the 
investigator must not access confidential records that require the subject’s consent. However, an 
investigator may consult public records to establish survival status.
While receiving investigational product, subjects should continue with the same assessments as noted 
in the Schedule of Assessments/Procedures.
All subjects who are still on study treatment after the data cutoff for the primary analysis (ie, at the 
end of the Randomization Phase) will continue to receive investigational product until they complete 
the Off-Treatment Visit.
After the data cutoff for the primary analysis, the Treatment Period will consist of 56-day 
treatment cycles and an Off-Treatment Visit, where subjects still on study treatment following the 
data cutoff of the planned primary analysis (ie, at the end of the Randomization Phase) will continue 
to receive the same treatment they received during the Randomization Phase.  Study treatment will 
continue until confirmed disease progression, development of unacceptable toxicity, subject request, 
withdrawal of consent, lost to follow up or study termination by the sponsor.  If the study is 
terminated by the sponsor, study drug (s) will be provided to subjects where commercial access is not 
available.  Tumor assessments will be performed according to the local standard of care, and scans 
will no longer be required to be sent to the imaging core laboratory (ICL).  The Off-Treatment Visit 
will occur within 28 days after the final dose of study treatment. After the data cutoff for the primary 
analysis, all AEs leading to study drug discontinuation and SAEs will be recorded until 28 days after 
the last dose of study drug.
The definition of the End of the Study is the last subject’s last assessment (Off-Treatment Visit)
after the data cutoff for the primary analysis.
The data obtained after the data cutoff for the primary analysis will be summarized and included in 
the CSR at the end of study as an addendum.   
Number of Subjects
Approximately 338 subjects will be randomized (169 subjects in each treatment arm).
Inclusion Criteria
1.
Histological or cytological confirmation of predominant clear cell RCC (original tissue diagnosis 
of RCC is acceptable).


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2.
Documented evidence of advanced RCC.
3.
One prior disease progression episode on or after VEGF-targeted treatment (for example, but not 
limited to, sunitinib, sorafenib, pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, 
AV951/tivozanib) administered for the treatment of RCC. Prior PD-1/PD-L1 treatment in 
addition to 1 prior VEGF-targeted treatment is allowed.
4.
At least 1 measurable target lesion according to RECIST 1.1 meeting the following criteria:

Lymph node (LN) lesion that measures at least 1 dimension as ≥1.5 cm in the short axis

Non-nodal lesion that measures ≥1.0 cm in the longest diameter

The lesion is suitable for repeat measurement using computerized tomography/magnetic 
resonance imaging (CT/MRI).  Lesions that have had external beam radiotherapy (EBRT) or 
locoregional therapy must show radiographic evidence of disease progression based on 
RECIST 1.1 to be deemed a target lesion.
5.
Male or female subjects age ≥18 years (or any age >18 years if that age is considered to be an 
adult per the local jurisdiction) at the time of informed consent.
6.
Karnofsky Performance Status (KPS) of ≥70.
7.
Adequately controlled blood pressure (BP) with or without antihypertensive medications, defined 
as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications within 1 week 
before Cycle 1/Day 1.
8.
Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the Cockcroft 
and Gault formula (Appendix 1).
9.
Adequate bone marrow function defined by:

Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 x 109/L)

Platelets ≥100,000/mm3(≥100 x 109/L)

Hemoglobin ≥9 g/dL.
10. Adequate blood coagulation function defined by International Normalized Ratio (INR) ≤1.5 
(except for subjects on warfarin therapy where INR must be ≤3.0 prior to randomization).
11. Adequate liver function defined by:

Total bilirubin ≤1.5 times the ULN except for unconjugated hyperbilirubinemia of Gilbert’s 
syndrome.

Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase 
(AST) ≤3×ULN (in the case of liver metastases ≤5×ULN). Subjects with bone metastases 
with ALP values greater than 3 times can be included. 
12. Subject must voluntarily agree to provide written informed consent.
13. Subject must be willing and able to comply with all aspects of the protocol.
Exclusion Criteria
1.
More than 1 prior VEGF-targeted treatment for advanced RCC.
2.
Subjects with Central Nervous System (CNS) metastases are not eligible, unless they have 
completed local therapy for at least 4 weeks and have discontinued the use of corticosteroids for 
this indication or are on a tapering regimen of corticosteroids (defined as ≤10 mg prednisolone 
equivalent) before starting treatment in this study. Any signs (eg, radiologic) or symptoms of 
brain metastases must be stable for at least 4 weeks before starting study treatment.
3.
Active malignancy (except for RCC or definitively treated basal or squamous cell carcinoma of 


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the skin, or carcinoma in-situ of the cervix or bladder) within the past 24 months.
4.
Any anti-cancer treatment (except for radiation therapy, see exclusion #5) within 21 days, or any 
investigational agent within 30 days prior to the first dose of study drug; subjects should have 
recovered from any toxicity related to previous anti-cancer treatment to CTC grade 0 or 1.
5.
Prior radiation therapy within 21 days prior to start of study treatment with the exception of 
palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to study 
treatment start.
6.
Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity to 
rapamycins (eg, sirolimus, everolimus, temsirolimus) or any of the excipients.
7.
Subjects with proteinuria >1+ on urinalysis will undergo 24-h urine collection for quantitative 
assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be ineligible.
8.
Fasting total cholesterol ˃300 mg/dL (or ˃7.75 mmol/L) and/or fasting triglycerides level ˃2.5 x 
ULN. NOTE: these subjects can be included after initiation or adjustment of lipid-lowering 
medication.
9.
Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. NOTE: these subjects 
can be included after initiation or adjustment of glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity and/or complications from major 
surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might 
affect the absorption of lenvatinib or everolimus.
13. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of tumor 
invasion/infiltration of major blood vessels (eg, carotid artery) should be considered because of 
the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following 
lenvatinib therapy.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study 
drug.
15. Significant cardiovascular impairment within 6 months prior to the first dose of study drug; 
history of congestive heart failure greater than New York Heart Association (NYHA) Class II, 
unstable angina, myocardial infarction or stroke, cardiac arrhythmia associated with significant 
cardiovascular impairment, or left ventricular ejection fraction (LVEF) below the institutional 
normal range as determined by screening multigated acquisition (MUGA) scan or 
echocardiogram. 
16. Active infection (any infection requiring systemic treatment).
17. Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.
18. 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.
19. Females of childbearing potential* who:

do not agree to use a highly effective method of contraception for the entire study period and 
for up to 8 weeks after study drug discontinuation, ie:
-
total abstinence (if it is their preferred and usual lifestyle)


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-
an intrauterine device (IUD) or hormone releasing system (IUS)
-
a contraceptive implant
-
an oral contraceptive** (with additional barrier method)
OR

do not have a vasectomized partner with confirmed azoospermia.
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.
NOTES:
*All females will be considered to be of childbearing potential unless they are postmenopausal 
[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause] or have been sterilized surgically [ie, bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing].
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 weeks 
before dosing with study drug and for the duration of the study.
Study Treatment
Originally, all study subjects, investigator site personnel, and the sponsor were blinded as to 
lenvatinib treatment assignment.  As of 14 Jul 2018, all investigational site personnel have been
unblinded as to the subjects’ treatment assignment, and the study continues as an open-label trial.
Lenvatinib will be administered as 3 capsules daily. These 3 capsules will consist of 10-mg and 4-mg 
capsules of lenvatinib or matching placebos provided in the appropriate configuration based on their 
assigned dose. Investigators will provide the lenvatinib pack containing the prescribed dose and the 
subject will take all capsules, including any placebo.  The sponsor may substitute drug supply without 
placebo capsules when resupplying study drug.  Everolimus is provided as 5-mg tablets. In addition, 
the sponsor may make changes to the packaging of lenvatininb clinical supplies at their discretion. 
Changes may include the use of child-resistant bottles rather than child-resistant wallets.  Child-
resistant bottles will not include placebo.  If changes to packaging are required, appropriate 
communication will be provided to the investigator at the study sites.  
Lenvatinib 18 mg or 14 mg QD plus everolimus 5 mg QD will be taken orally in each 28-day cycle
and after the data cutoff for the primary analysis in 56-day cycles. Study drug should be taken at 
approximately the same time each morning. Study drug may be taken in a fasting state or following a 
meal.
Dose Up-Titrations (14-mg Arm Only)
For subjects in the 14-mg QD (+ everolimus 5-mg) arm, if there are no intolerable Grade 2 or any 
≥Grade 3 TEAEs that require dose reduction in the first 28-day cycle (ie, the first 4 weeks of 
treatment), lenvatinib dose will be escalated to 18 mg QD (+ everolimus 5 mg).  See the Interactive 
Voice and Web Response System (IxRS) Manual and revised Pharmacy Manual for further 
instructions.
Dose reductions for toxicity may be instituted at any time as necessary.
Dose Reductions
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version 4.03.
Dose reductions and interruptions for subjects who experience lenvatinib-everolimus combination 
therapy-related toxicity (except hypertension and non-infectious pneumonitis) will be managed as 
described in the table below. Investigators will decide the probability of the event being related to 1
or both drugs as to whether dose modification of 1 or both drugs is required. For treatment-related 
hypertension and non-infectious pneumonitis, refer to Management of Hypertension (Section 9.4.2.2) 
and Management of Non-infectious Pneumonitis (Section 9.4.2.5) for dose modification guidelines.
Lenvatinib dose reductions occur in succession based on the previous dose level. The lenvatinib and 
everolimus dose may not be increased at a later date, unless the dose was mistakenly decreased; in 
this situation, the Sponsor’s approval is required to increase the dose. Subjects in either arm will be 
allowed a maximum of 3 lenvatinib dose reductions for lenvatinib-related toxicity.
Refer to the subsections below for management of proteinuria, diarrhea, infections, blood 
glucose/lipids, hepatotoxicity, thromboembolic events, posterior reversible encephalopathy 
syndrome/reversible posterior leukoencephalopathy syndrome (PRES/RPLS), and hypocalcemia as 
appropriate, in addition to consulting the dose modification table below.
Dose Modification Guidelines for Lenvatinib-Everolimus Combination Treatment-Related 
Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d,e or Grade 3f
First occurrence
Interrupt lenvatinib and everolimus 
until resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose 1 level and 
resume everolimus at the same 
dose as prior to dose interruption
Second occurrence
(Same toxicity or new toxicity)
Interrupt lenvatinib and everolimus 
until resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose 1 level. 
Dose reduction of everolimus to 
5 mg every other day may be 
considered for Grade 3 toxicitye
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib and everolimus 
until resolved Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose 1 level.
Dose reduction of everolimus for 
Grade 3 toxicity may be considered 
as follows:e
i) if 5 mg daily everolimus at event 
onset, reduce to 5 mg every other 
day or
ii) if 5 mg every other day 
everolimus at event onset, 
discontinue
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib and everolimus
Discontinue study treatment
Grade 4g: Discontinue Study Treatment
Note: For grading see CTCAE version 4.03. Collect all CTC grades of adverse events, decreasing and 
increasing grade.
a.
An interruption of study treatment for more than 28 days will require Sponsor`s approval before treatment 
can be resumed.
b.
Initiate optimal medical management for nausea, vomiting, hypothyroidism, hypertension and/or diarrhea 
before any study treatment interruption or dose reduction. For treatment-related hypertension and 


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non-infectious pneumonitis, refer to Management of Hypertension (Section 9.4.2.2) and Management of 
Non-infectious Pneumonitis (Section 9.4.2.5) for dose modification guidelines.
c.
Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d.
Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie,
Grade 1 weight loss). These subjects will restart the study drug(s) at a lower dose once their weight 
remains stable for at least 1 week and they reached the normal body mass index (BMI) (if the weight loss 
occurred but it is still above normal BMI, they can restart the study treatment at a lower dose once the 
weight has been stable for at least 1 week). Normal BMI should be used as the new baseline for further 
dose reductions.
e.
For Grade 2 toxicity, resume everolimus at the same dose as prior to dose interruption. For Grade 3 
toxicity, investigator will decide the probability of the event being related to one or both drugs as to 
whether dose modification of 1 or both drugs is required.
f.
For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor.
g.
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
Lenvatinib Dose Reduction Schedule For Intolerable Toxicities
Lenvatinib dose reductions occur in succession based on the previous dose level (18, 14, 10, 8, and 
4 mg/day), as shown in the table below.
Dose Reductions for Lenvatinib in Combination with 5 mg Everolimus
Current Dose (QD)
Dose Reduction
18 mg
14 mg QD
14 mg
10 mg QD
10 mg
8 mg QD
8 mg
4 mg QD
MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects enrolled to receive treatment with lenvatinib have 
BP of ≤150/90 mmHg at the time of study entry and, if known to be hypertensive, have been on a 
stable dose of antihypertensive therapy for at least 1 week before Cycle 1/Day 1. Early detection and 
effective management of hypertension are important to minimize the need for lenvatinib dose 
interruptions and reductions.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mmHg or 
diastolic BP ≥90 mmHg) is confirmed on 2 assessments a minimum of 30 minutes apart. One BP 
assessment is defined as the mean value of 3 measurements at least 5 minutes apart. After the data 
cutoff for the primary analysis, one BP assessment is defined as the mean value of 2 measurements at 
least 5 minutes apart.  The choice of antihypertensive treatment should be individualized to the 
subject’s clinical circumstances and follow standard medical practice. For previously normotensive 
subjects, appropriate antihypertensive therapy should be started when systolic BP ≥140 mmHg or 
diastolic BP ≥90 mmHg is first observed on 2 assessments a minimum of 30 minutes apart. For those 
subjects already on antihypertensive medication, treatment modification may be necessary if 
hypertension persists.
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop a 
hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mmHg, significant risk factors for cardiac disease, intracerebral 
hemorrhage, or other significant co-morbidities). Once the subject has been on the same hypertensive 


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medications for at least 48 hours and the BP is controlled, lenvatinib should be resumed as described 
below.
During the Treatment Period, subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
must have their BP monitored on Day 15 or more frequently as clinically indicated until systolic BP 
has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 1 treatment cycle (ie, 56-day cycle). 
If a repeat event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must 
resume the Day-15 evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 
mmHg for 1 treatment cycle (ie, 56-day cycle).
The following guidelines should be followed for the management of systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg confirmed on repeat measurements after 30 minutes:
1.
Continue lenvatinib and institute antihypertensive therapy for subjects not already receiving this.
2.
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.
3.
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted. It should be 
restarted at 1 dose level reduction only when systolic BP ≤150 mmHg and diastolic BP 
≤95 mmHg and the subject has been on a stable dose of antihypertensive medication for at least 
48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first dose reduction 
despite optimal management of hypertension with antihypertensive medications (either by 
dose increase or the addition of a different class of antihypertensive), then lenvatinib 
administration should be interrupted. It should be restarted at an additional dose reduction 
only when systolic BP is ≤150 mmHg and diastolic BP is ≤95 mmHg and the subject has 
been on a stable dose of antihypertensive medication for at least 48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose reduction 
despite optimal management of hypertension with antihypertensive medications (either by 
dose increase or the addition of a different class of antihypertensive), then lenvatinib
administration should be interrupted. It should be restarted at a third dose reduction only 
when systolic BP is ≤150 mmHg and diastolic BP is ≤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):
1.
Institute appropriate medical management
2.
Discontinue study treatment
MANAGEMENT OF PROTEINURIA
Regular assessment of proteinuria should be conducted as detailed in the Schedule of
Procedures/Assessments. Guidelines for assessment and management of proteinuria:
1.
Grading will be based on the 24-hour urinary protein result. Management of lenvatinib 
administration will be based on the grade of proteinuria according to the “Dose Modification 
Guidelines for Lenvatinib-Everolimus Combination Treatment-Related Toxicity.”
2.
A 24-hour urine collection (within 72 hours) to verify the grade of proteinuria for protein 
quantitation is required in the following situations:
-
The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug


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-
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the urine protein 
dipstick result is 2+, 3+, or 4+
3.
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 1 treatment 
cycle (ie, 56-day cycle).
MANAGEMENT OF DIARRHEA
An anti-diarrheal agent should be recommended to the subject at the start of study treatment and 
subjects should be instructed and educated to initiate anti-diarrheal treatment at the first onset of soft 
bowel movements. The choice of anti-diarrheal agent should be individualized to the subject’s 
clinical circumstances and follow standard medical practice. If signs/symptoms of diarrhea persist 
despite optimal medical management, instructions contained in the “Dose Modification Guidelines 
for Lenvatinib-Everolimus Combination Treatment-Related Toxicity” should be followed.
MANAGEMENT OF NON-INFECTIOUS PNEUMONITIS
Non-infectious pneumonitis is a recognized class effect of rapamycin derivatives, including 
everolimus. Non-infectious pneumonitis was described in 19% of subjects taking everolimus 
(AFINITOR® Package Insert). Some cases were severe and on rare occasions, a fatal outcome was 
observed. Investigators should therefore consider a diagnosis of non-infectious pneumonitis in 
subjects presenting with non-specific respiratory signs and symptoms and in whom infectious, 
neoplastic, and other non-medicinal causes have been excluded by means of appropriate 
investigations.
Subjects who develop radiological changes suggestive of non-infectious pneumonitis and have few or 
no symptoms (CTCAE Grade 1) may continue study dosing without dose adjustments.

If symptoms are moderate (CTCAE Grade 2):
-
Lenvatinib-everolimus combination therapy should be interrupted and the use of 
corticosteroids may be indicated until symptoms abate (resolved to CTCAE Grade 0-1) and 
may then be restarted at the same doses prior to study treatment interruption. 
-
If Grade 2 non-infectious pneumonitis recurs despite optimal management, then lenvatinib-
everolimus combination therapy administration should be interrupted, and the use of 
corticosteroids may be indicated until symptoms abate (resolved to CTCAE Grade 0-1).  

If symptoms are severe (CTCAE Grade 3):
-
Lenvatinib-everolimus combination therapy should be interrupted and the use of 
corticosteroids may be indicated until clinical symptoms resolve (to CTCAE Grade 0-1).  
Investigators will decide the probability of the event being related to 1 or both drugs as to 
whether dose modification of 1 or both drugs is required.

If symptoms are life-threatening (CTCAE Grade 4):
-
Everolimus should be discontinued. Investigators will decide the probability of the event 
being related to 1 or both drugs as to whether discontinuation of 1 or both drugs is required.
MANAGEMENT OF INFECTIONS


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Everolimus has immunosuppressive properties and may predispose subjects to infections.  Therefore,
it is important to monitor for signs and symptoms of infection and treat promptly.  Dose alterations of 
everolimus may be required in accordance with prescribing information.
MANAGEMENT OF BLOOD GLUCOSE AND LIPIDS
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia are recognized class effects of rapamycin 
derivatives, including everolimus. Glycemic and lipids control should be optimized before starting a 
subject on this study. 
Blood glucose will be monitored as specified in the Schedule of Procedures/Assessments.  For 
subjects with blood glucose >ULN, a fasting (>6h, water only) blood glucose sample will be 
obtained.  Grading according to CTCAE v4.03 will be based on the fasting blood glucose result.  The 
choice of hypoglycemic agent should be individualized to the subject’s clinical circumstances and 
follow standard medical practice. 
Dose alterations of everolimus may be required in accordance with prescribing information.
MANAGEMENT OF HEPATOTOXICITY
Liver function tests (ALT, AST, bilirubin levels) should be monitored at baseline, every 2 weeks for 
the first 2 months and monthly thereafter, and as clinically indicated (see Schedule of 
Procedures/Assessments). If signs/symptoms indicating liver injury occur, instructions contained in 
the “Dose Modification Guidelines for Lenvatinib-Everolimus Combination Treatment-Related 
Toxicity” should be followed. Appropriate supportive care should be provided together with close 
monitoring. If hepatic failure occurs, the study drug must be discontinued.
MANAGEMENT OF THROMBOEMBOLIC EVENTS
Subjects should be advised to pay attention to symptoms suggestive of venous thromboembolic 
events, which include acute onset of shortness of breath, dyspnea, chest pain, cough, hemoptysis, 
tachypnea, tachycardia, cyanosis, and deep-vein thrombosis (DVT) signs including lower-extremity 
swelling and warmth to touch or tenderness. In case any of these symptoms appear, subjects should 
be instructed to report such symptoms promptly to the treating physician. If a thromboembolic event 
is confirmed, instructions contained in the “Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity” should be followed. Appropriate supportive care should 
be provided together with close monitoring. If a subject experiences life-threatening (Grade 4) 
thromboembolic reactions, including pulmonary embolism, the study drug must be discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial infarction, 
transient ischemic attack, and cerebrovascular accident) of any grade require study treatment 
discontinuation.
MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME /
REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME (PRES/RPLS)
In clinical studies with lenvatinib, events of PRES/RPLS were reported in less than 1% of 
lenvatinib-treated subjects. PRES/RPLS is a neurological disorder that can present with headache, 
seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological 
disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is 
necessary to confirm the diagnosis of PRES/RPLS. Appropriate measures should be taken to control 
BP. In subjects with signs or symptoms of PRES/RPLS, “Dose Modification Guidelines for 


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Lenvatinib-Everolimus Combination Treatment-Related Toxicity” should be followed.
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored per the Schedule of Procedures/Assessments. Corrected serum 
calcium should be used to assess the grade of hypocalcemia per CTCAE v 4.03, using the following 
formula:
Corrected calcium = ([4 – serum albumin in g/dL] x 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in such 
situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
Duration of Treatment
A subject will remain on study treatment until 1 or more of the following events occur(s):

Progressive Disease (as determined by investigator assessment)

Unacceptable toxicity

Subject request

Lost to follow-up

Withdrawal of consent

Termination of the study by the Sponsor

End of study
Concomitant Drug/Therapy
The following therapies are prohibited during the Screening and Treatment Period of this study:

Concurrent anticancer therapies such as: chemotherapy, tyrosine kinase inhibitors (TKIs), 
radiotherapy (except for palliative radiotherapy of up to 2 painful pre-existing, non-target bone
metastases), antitumor interventions (surgical resection, thoracentesis, etc.), or immunotherapy

Concurrent other investigational drugs

Live vaccines while participating in the study.  Examples of live vaccines include, but are not 
limited to the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed.  However, intranasal influenza vaccines (eg. Flu-Mist®) are live 
attenuated vaccines, and are not allowed.
For further information on the prohibited concomitant therapies for everolimus, please refer to the 
respective Prescribing Information.
Treatment (including blood products, blood transfusions, fluid transfusions, antibiotics, and 
antidiarrheal drugs, etc.) of complications of AEs or therapy to ameliorate symptoms may be 
administered at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study medication.
For clarification, the following concomitant therapies are also allowed:

Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer

Bisphosphonates or denosumab


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
Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases will be 
permitted without being considered progressive disease
If the subject requires surgery during the study, the stop time and restart time of study treatment 
should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at least 
2 days after, once there is evidence of adequate healing and no risk of bleeding

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and then 
restart it at least 1 week after, once there is evidence of adequate healing and no risk of bleeding
Any additional procedural or patient-specific particularities should be discussed with the Sponsor.
Assessments
Efficacy Assessments
Tumor assessments will be performed using RECIST 1.1. Investigator-determined response 
assessments will be performed at each assessment time point and entered onto the case report form.
Copies of all tumor assessment scans will be sent to an ICL designated by the sponsor for blinded 
independent efficacy assessment until data cutoff for the primary analysis. For subjects enrolled after 
implementation of Amendment 06, tumor assessments will be carried out following the guidelines 
provided by the ICL. 
Tumor assessments (CT chest, and CT or MRI abdomen, pelvis and other known or suspected sites of 
disease) will be performed during the Prerandomization Phase and then during the Randomization 
Phase every 8 weeks (within the 8th week) until documentation of progressive disease as determined 
by the investigator and on a schedule as determined by the treating physician after the data cutoff for 
the primary analysis, but not less frequently than every 12 weeks or earlier if clinically indicated.  All 
responses must be confirmed no less than 4 weeks following the initial indication of response. A 
chest x-ray or a skeletal x-ray that clearly demonstrates a new metastatic lesion may be used to 
document progression in lieu of the CT/MRI scans.
A bone scan will be performed during the Prerandomization Phase to establish a baseline (a historical 
bone scan performed within 6 weeks prior to randomization is acceptable), every 24 weeks after 
randomization, within a target of 1 week, but no more than 2 weeks following a complete response 
(CR) as assessed by the investigator, and as clinically indicated after the data cutoff for the primary 
analysis. Lesions identified on bone scans should be followed at all tumor assessment time points 
with cross-sectional imaging.
A brain scan will be performed at screening and as clinically indicated thereafter, and within a target 
of 1 week, but no more than 2 weeks following achievement of a confirmed CR.  For subjects with a 
history of protocol-eligible treated brain metastases, a brain scan will be required at all protocol-
specified tumor assessment time points (ie, every 8 weeks).  Subjects with protocol-eligible treated brain 
metastases should also have brain CT/MRI performed as per local standard of care. For other subjects, brain 
scans should be performed as clinically indicated.
Subjects going off treatment without disease progression in the Treatment Period during the 
Randomization Phase, will continue to undergo tumor assessments in the Follow-up Period per the 
above schedule until disease progression is documented, another anticancer therapy is initiated, or 
data cutoff for the primary analysis.
Pharmacokinetic Assessments
Sparse PK samples will be collected from all subjects and will be analyzed using the population 
pharmacokinetics approach.
Pharmacodynamic and Other Biomarker Assessments
Samples will be collected at protocol-specified time points as indicated in the Schedule of 


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Procedures/Assessments and may undergo enzyme-linked immunosorbent assay (ELISA), multiplex 
bead- based immunoassay, and/or other appropriate analysis procedures to explore blood biomarkers 
(eg, VEGF, Ang-2).
Safety Assessments
Safety assessments will consist of monitoring and recording of all AEs, including all CTCAE v4.03 
grades (for both increasing and decreasing severity), and SAEs; regular laboratory evaluation for 
hematology, blood chemistry, and urine values; periodic measurement of vital signs and ECGs; and 
the performance of physical examinations.  An echocardiogram or a MUGA scan including LVEF 
will be performed at screening, and as clinically indicated.
Other Assessments
Health-Related Quality of Life (HRQoL) will be assessed at Baseline (prior to first dose of study 
drug), on Day 1 of each subsequent cycle, and at the Off-Treatment Visit. Every effort should be 
made to administer HRQoL surveys prior to study drug administration and before other assessments 
and procedures.  Subjects will complete the Cancer Therapy Kidney Symptoms Index-Disease
Related Symptoms (FKSI-DRS), the European Organization for the Research and Treatment of 
Cancer (EORTC) QLQ-C30 and the European Quality of Life (EuroQol) EQ-5D-3L instruments.
Bioanalytical Methods
Lenvatinib in plasma and everolimus in blood will be quantified by use of validated High 
Performance Liquid Chromatography-tandem mass spectroscopy methods.
Statistical Methods
Study Endpoints
Primary Endpoints

Objective response rate (ORR) at Week 24 (ORR24W) as assessed by the investigator according to 
RECIST 1.1. ORR24W is defined as the proportion of subjects with best overall response (BOR) 
of complete response (CR) or partial response (PR) at the Week 24 (after randomization) time 
point or earlier. To be considered a BOR, all responses must be confirmed no less than 4 weeks 
after the initial assessment of response.

Proportion of subjects with intolerable Grade 2 and any ≥ Grade 3 TEAEs within 24 weeks after 
randomization (as of the Week 24 time point).
Secondary Endpoints

Progression-free survival (PFS), defined as the time from the date of randomization to the date of 
first documentation of disease progression or date of death or the date of data cutoff for the 
primary analysis, whichever occurs first. PFS censoring rules will be defined in the statistical 
analysis plan (SAP) and will follow FDA guidance.

ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment.  ORR is 
defined as the proportion of subjects with BOR of CR or PR at the end of treatment.  To be 
considered BOR, all responses must be confirmed no less than 4 weeks after the initial 
assessment of response.

Overall safety profile and tolerability of lenvatinib in combination with everolimus.

Proportion of subjects who discontinue treatment due to toxicity, defined as the proportion of 
subjects who discontinue study treatment due to TEAEs.

Time to treatment failure due to toxicity, defined as the time from the date of randomization to 
the date that a subject discontinues study treatment due to TEAEs.

Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions.


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
Overall survival (OS), measured from the date of randomization until date of death from any 
cause. In the absence of confirmation of death, subjects will be censored either at the date that 
the subject was last known to be alive or the date of data cutoff for the primary analysis, 
whichever comes earlier.

Health-Related Quality of Life (HRQoL) will be assessed using the Functional Assessment of 
Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS), the European 
Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European 
Quality of Life (EuroQol) EQ-5D-3L instruments.

PFS2, defined as the time from randomization to the date of disease progression after next line of 
therapy or death from any cause, or the date of data cutoff for the primary analysis whichever 
occurs first.  PFS2 censoring rules will be defined in the SAP.
Exploratory Endpoints

Tumor response endpoints ORR24W, ORR, and PFS based on IIR assessment. These endpoints 
will be defined in the same way as those based on the investigator assessments.

Associations between blood biomarker and efficacy-related endpoints.

Development of exposure/biomarker/clinical endpoint models (whenever possible, using a 
mechanism-based approach) for both efficacy and safety data.
Analysis Sets
Full Analysis Set will include all randomized subjects.  This will be a secondary analysis set for 
efficacy endpoints, which will be analyzed according to the treatment randomized, regardless of the 
treatment actually received.
Per-Protocol Analysis Set 1 will include all randomized subjects minus the 32 subjects who had 
received ≥2 incorrect lenvatinib doses due to IxRS issues.  This will be the primary analysis set for 
efficacy endpoints, which will be analyzed according to the treatment randomized.
(A 33rd subject received a single incorrect lenvatinib dose due to IxRS issues, but given the brief 
exposure of the incorrect (slightly higher) dose before detection and correction, and because there 
were no adverse effects, this subject will not be excluded from this Per-Protocol Analysis Set 1.)
Per-Protocol Analysis Set 2 will include all subjects who received at least 1 dose of study drug, had 
no major protocol deviations, and had both baseline and at least 1 post-baseline tumor assessment.  
Subjects for whom death occurred prior to the first post-baseline tumor assessment will also be 
included.  The Per-Protocol Analysis Set 2 will be a secondary analysis set for efficacy endpoints.  
The 32 subjects who received ≥2 incorrect lenvatinib doses due to IxRS issues are considered as 
having experienced major protocol deviations and will be excluded from the Per-Protocol Analysis 
Set 2. 
Safety Analysis Set will include all subjects who were randomized and received at least 1 dose of 
study drug. This will be the analysis set for all safety evaluations, which will be analyzed according 
to the treatment actually received.
Per-Protocol Safety Analysis Set will include all treated subjects in Per-Protocol Analysis Set 1. 
This will be the primary analysis set for the primary safety endpoint, which will be analyzed 
according to the treatment actually received. 
Pharmacokinetic (PK) Analysis Set will include all subjects who received at least 1 dose of study 
drug with documented dosing history and have at least 1 evaluable lenvatinib plasma or everolimus 
whole blood concentration data.  
Pharmacodynamic Analysis Set will include all subjects who received at least 1 dose of study drug 
with documented dosing history and have at least 1 evaluable pharmacodynamic data.
For the Pharmacokinetic, Pharmacodynamic and other Biomarker endpoints, their respective analysis 


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plans will specify if the analysis set will or will not include the 32 subjects who received ≥2 incorrect 
lenvatinib doses due to IxRS issues.
Quality of Life (QoL) Analysis Set will consist of all subjects who have any QoL data.  
Efficacy Analyses
Analyses of Primary Endpoint:
Primary analysis of ORR24W will be based on a non-inferiority test. At each interim analysis and 
primary analysis, the point estimate of ORR24Wfor each treatment group (18 mg and 14 mg) will be 
summarized with the corresponding 95% confidence interval (CI). The odds ratio of ORR24W (14 mg 
vs 18 mg) along with the 90% CI will be calculated using the Cochran-Mantel-Haenszel (CMH) 
method stratified by MSKCC prognostic groups and prior PD-1/PD-L1 treatment. 
The first and second interim analysis will be performed only in the Per-Protocol Analysis Set 1. The 
primary analysis will be performed in the Per-Protocol Analysis Set 1 as the primary analysis set, and 
will also be performed in the Per-Protocol Analysis Set 2 and the Full Analysis Set as secondary 
analysis sets.
Non- inferiority in ORR24W will be claimed if the O’Brien-Fleming non-inferiority boundary is 
crossed at either interim analysis or primary analysis based on the result from the Per-Protocol 
Analysis Set 1. If the 1-sided P-value is ≤0.005 at the first interim analysis, or ≤0.014 at the second 
interim analysis, or ≤0.045 at the primary analysis, non-inferiority in ORR24W will be claimed. 
Futility will be claimed if the futility boundary is crossed. If the 1-sided P-value is ≥0.776 at the first 
interim analysis, or ≥0.207 at the second interim analysis, futility will be claimed. The treatment 
difference in ORR24W for 14 mg vs. 18 mg will also be estimated along with 90% CIs based on the 
asymptotic normal approximation. 
The safety endpoint for the primary analyses is the proportion of subjects with intolerable Grade 2
and any ≥ Grade 3 TEAEs within 24 weeks after randomization (as of the Week 24 time point).  
Frequency (number and percentage) will be summarized for intolerable Grade 2 and any ≥ Grade 3
TEAEs within 24 weeks after randomization by treatment. The proportions will be tested using the 
CMH test (2-sided alpha=0.05), stratified by MSKCC prognostic groups and prior PD-1/PD-L1 
treatment. At each interim analysis and the primary analysis, if the noninferiority boundary of the 
primary efficacy endpoint is crossed, the analysis of the primary safety endpoint will be performed 
for Per-Protocol Safety Analysis Set.  The proportions will also be summarized descriptively for 
Safety Analysis Set.
To explore homogeneity of treatment effect across centers/regions, sensitivity analyses will be 
conducted to adjust center/region effect for the primary endpoints of ORR24W and proportion of 
subjects with intolerable Grade 2 and any ≥Grade 3 TEAEs within 24 weeks after randomization 
using logistic regression models, including center/region as a covariate. 
Determination of whether 14 mg lenvatinib can be used as an alternative dosing strategy will be 
based on clinical judgment by the Sponsor in consultation with the independent Data Monitoring 
Committee (DMC) (as specified in the DMC charter) by assessing risks and benefits according to the 
totality of the safety and efficacy data.
Analysis of Secondary Endpoints:
All secondary efficacy endpoints will be summarized descriptively for the Per-Protocol Analysis Set 
1, Per-Protocol Analysis Set 2, and Full Analysis Set. The median PFS and PFS2 will be calculated 
using the Kaplan-Meier (KM) product-limit estimates for each treatment group and presented with 2-
sided 95% CIs. The KM estimate of PFS will also be plotted over time for each treatment group.
Point estimate of ORR and 95% CI will be summarized for each treatment arm.  Odds ratio with 90% 
CI will be estimated using the CMH method stratified by MSKCC prognostic groups and prior 
PD-1/PD-L1 treatment.


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The median survival time and the survival rates at 12, 18, and 24 months will be calculated using KM 
product-limit estimates for each treatment group and presented with 2-sided 95% CIs.  The KM 
estimates of OS will be plotted over time.
All safety analyses will be performed on the Per-Protocol Safety Analysis Set and the Safety Analysis 
Set and summarized by treatment group.
The proportion of subjects who discontinue treatment due to toxicity will be summarized by 
frequency counts and percentages.  Median, upper, and lower quintiles of time-to-treatment failure 
due to toxicity will be summarized for subjects who discontinue study treatment due to TEAEs.
For HRQoL analyses, summary statistics of the scores for the derived functional / symptom scales 
according to the scoring manual and global health status scores will be summarized by treatment arm 
at each time point.  A separate pre-specified HRQoL analysis following FDA and EMEA PRO 
Guidelines will be performed and detailed in a separate SAP and HRQoL report.  Scoring of 
EQ-5D-3L and derivation of utility for health economic analysis will also be accomplished in a 
separate analysis and described in a separate HRQoL report.
Analysis of Exploratory Endpoints:
All exploratory endpoints will be summarized descriptively. Exploratory efficacy response endpoints 
ORR24W, ORR, and PFS based on IIR assessment will be summarized using the same statistical 
methods as those used for the same response parameters based on the investigator assessments.   
Pharmacokinetic, Pharmacodynamic and Other Biomarker Analyses 
Pharmacokinetic Analyses
Lenvatinib and everolimus concentrations will be summarized by use of descriptive statistics and 
plotted as appropriate for each treatment group.
Concentrations of lenvatinib in plasma and everolimus in whole blood will be pooled with existing 
data from other completed studies and analyzed using a population PK approach to estimate 
population PK parameters for each drug. The analyses will be detailed in a separate analysis plan.
Pharmacokinetic/Pharmacodynamic Analyses
Lenvatinib and everolimus exposure parameters (AUC or concentration at the time of the event or 
cumulative AUC, as appropriate) derived from the population PK analysis will be related to 
biomarker, safety, and efficacy data using a model-based approach. For some PK/PD analyses, data 
from this study will be pooled with data from the Phase 2 Study E7080-G000-205 (Study 205).
For the exposure-response relationship for biomarkers (eg, VEGF, Ang-2) data will be analyzed 
using a model-based approach with indirect PK/PD models.
For efficacy, a tumor growth inhibition model based on longitudinal tumor size measurements of 
target lesions will be included. Study drug exposure for lenvatinib and everolimus and/or measured 
biomarkers (eg, VEGF, Ang-2) will be investigated as predictors and/or correlations with tumor 
burden changes in the tumor growth inhibition model, whenever possible using a mechanism-based 
approach.
Other analyses will include logistic regression analysis for ORR24W, KM plots of PFS data, and 
Cox-regression analysis.  For the Cox-regression analysis of PFS, adjustment will be made for 
subject’s baseline characteristics or tumor-related features. In addition to lenvatinib and everolimus 
exposure, changes in biomarker concentrations and/or tumor burden will be related to PFS, whenever 
possible using a mechanism-based approach.
For the exposure-response relationship of safety, the model-based analysis will include the following 
AEs: hypertension (systolic and diastolic BP), triglyceridemia (and cholesterolemia), glycemia, 
proteinuria, weight loss, fatigue, nausea, vomiting and diarrhea. For hypertension, triglyceridemia 
(and cholesterolemia) and glycemia, data will be analyzed using an indirect-response model. For 
proteinuria, urine dipstick and/or 24-hour urine data will be analyzed using a longitudinal categorical 


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logistic regression analysis with Markov element. For weight loss, fatigue, nausea, vomiting, and 
diarrhea, data will be analyzed using a longitudinal categorical logistic regression analysis. For time 
to treatment discontinuation due to an AE and time to first dose reduction, KM plots stratified by 
lenvatinib exposure will be prepared.
Population PK and PK/PD analyses will be detailed in a separate analysis plan.
Biomarker Analysis
The effect of lenvatinib and everolimus combination treatment on exploratory biomarkers will be 
summarized by treatment group. Associations between clinical outcomes and baseline biomarker 
levels, and/or change in levels from baseline will be explored. The analysis will be detailed in the 
biomarker analysis plan (BAP) and reported separately.
For exploratory endpoints, Pharmacokinetic, Pharmacodynamic and Other Biomarker endpoints, their 
respective analysis plans will specify if the analyses will and will not include the 32 subjects who 
received ≥2 incorrect lenvatinib doses due to IxRS issues.
Safety Analyses
All safety analyses will be performed by treatment group for the Per-Protocol Safety Analysis Set and 
Safety Analysis Set. The incidence of TEAEs, intolerable Grade 2 TEAEs that lead to dose 
interruption, dose reduction, or drug discontinuation, and SAEs will be summarized and rates will be 
summarized descriptively.
Time to treatment discontinuation due to an AE, number of dose reductions, and time to first dose 
reduction will be summarized.
Laboratory test results, vital signs and their changes from baseline, and 12-lead ECG results will be 
summarized using descriptive statistics. Abnormal values will be flagged. Prior and concomitant 
medications, medical/surgical history and subject demographics will be summarized and listed.
Interim Analyses
Safety and efficacy monitoring will be performed by an independent DMC. The function and 
membership of the DMC will be described in the DMC charter.  Minutes from the open meetings of 
the DMC will be provided to regulatory agencies, if requested.
Two interim analyses will take place when 150 and 200 total subjects in Per-Protocol Analysis Set 1 
have completed 24 weeks follow-up or discontinue earlier. Each interim analysis will test both non-
inferiority and futility of the 14-mg arm ORR24W compared with the 18-mg arm ORR24W. An 
O’Brien-Fleming stopping boundary will be used for non-inferiority. An interpolated non-binding 
stopping boundary will be used for futility.
Sample Size Rationale
The objective of the study is to assess whether a starting dose of lenvatinib 14 mg QD in combination 
with everolimus 5 mg will provide comparable efficacy with an improved safety profile compared 
with lenvatinib 18 mg in combination with everolimus 5 mg. Determination of whether 14 mg 
lenvatinib can be used as an alternative dosing strategy will be based on clinical judgment by the 
Sponsor in consultation with the independent DMC (as specified in the DMC charter) by assessing
risks and benefits according to the totality of data at either of the interim or primary analyses.
Nevertheless, the sample size is guided by the plan of testing non-inferiority on primary efficacy 
endpoint and superiority on primary safety endpoint. The details and assumptions are provided 
below.
Sample size is based on detecting both the non-inferiority of ORR24W and superiority of the primary 
safety endpoint of the proportion of subjects with intolerable Grade 2 and any ≥ Grade 3 TEAEs 
within 24 weeks after randomization in comparison of 14-mg arm to 18-mg arm.


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Non-inferiority of ORR24W comparing the 14-mg arm to the 18-mg arm:
Based on the assumption from Study E7080-G000-205 that the confirmed ORR for 18 mg lenvatinib 
+ 5 mg everolimus arm is 37% (19 responders out of N=51) vs. 6% for the everolimus arm 
(3 responders out of N=50), the 95% CI comparing everolimus vs. lenvatinib 18 mg + everolimus 
arm is (0.029, 0.395).  The non-inferiority margin is chosen to ensure that a reasonable fraction of the 
lenvatinib 18 mg + everolimus vs. everolimus treatment effect is preserved. A 70% retention of the 
treatment effect of lenvatinib 18 mg + everolimus vs. everolimus is used for this design. Following 
the approach in Rothmann et al. (2003), using the 95% CI upper limit method based on logarithm of 
the odds ratio, the non-inferiority margin is estimated as exp((1 −
) ∗
(   95%   log   ! (" #" 18 % +  " 
⁄
))),
      where 0 < 
 < 1 is the retention rate. 
To retain 70% of the lenvatinib 18 mg + everolimus vs. everolimus treatment effect, the 
non-inferiority margin of the odds ratio is estimated to be exp((1 −0.7) ∗ %(0.395)) = 0.76 
(ie, Ha: OR (14 mg/18 mg)> M).
The table below lists the non-inferiority margins on the scale of difference in ORR24W between the 
lenvatinib 14-mg + everolimus arm and the lenvatinib 18-mg + everolimus arm corresponding to a 
0.76 non-inferiority margin on the odds ratio scale for a different ORR24W in the lenvatinib 18-mg 
+everolimus arm.
ORR24W in the lenvatinib 18-mg arm
Non-inferiority margin on difference scale (lenvatinib 
14-mg arm - lenvatinib 18-mg arm)
10%
-0.02
20%
-0.04
30%
-0.05
40%
-0.06
50%
-0.07
60%
-0.07
Two interim analyses will take place when 150 and 200 total subjects in the Per-Protocol Analysis 
Set 1 have completed 24 weeks follow-up or discontinue earlier. Each interim analysis will test both 
non-inferiority and futility of the 14-mg-arm ORR24W compared to the 18-mg-arm ORR24W. An 
O’Brien-Fleming stopping boundary will be used for non-inferiority. An interpolated non-binding 
stopping boundary will be used for futility, which will spend β = 0.005 and β = 0.10 at the first and 
second interim analysis, respectively. Assuming 37% ORR24W in the lenvatinib 18-mg arm and 45% 
ORR24W in the lenvatinib 14-mg arm, and adjusting for the interim analyses, a total of 306 subjects 
(153 per arm) is required to achieve 80% statistical power at one-sided α = 0.05.
The stopping boundaries on the P-value scale and the cumulative error probabilities spent at each 
interim analysis and primary analysis are shown in the table below. For example, at the second 
interim analysis, non-inferiority in ORR24W will be claimed if the P-value is ≤0.014; futility will be 
claimed if the P-value is ≥0.207.
Analysis #
Cumulative α 
Spent
Efficacy Boundary 
(P-value)
Cumulative β 
Spent
Futility Boundary 
(P-value)
Interim Analysis #1
0.005
0.005
0.005
0.776
Interim Analysis #2
0.015
0.014
0.10
0.207
Primary Analysis
0.05
0.045
0.2
0.045
Superiority of primary safety endpoint comparing the 14-mg arm to the 18-mg arm:
At each interim analysis and the primary analysis, safety will be evaluated if the non-inferiority


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boundary is crossed. Assuming 75% of subjects with intolerable Grade 2 or above TEAEs within 
24 weeks after randomization in the 18-mg arm, with a total of 306 subjects, a superiority test at 
2-sided α = 0.05 will give 80% statistical power to detect a 15% drop in proportion of subjects with 
intolerable Grade 2 or above TEAEs within 24 weeks after randomization in the 14-mg arm.
In consideration of both the primary efficacy and safety endpoints, a total of approximately 
306 subjects was originally planned to be randomized in a 1:1 ratio to both treatment arms. Since 
there were 32 subjects who received ≥2 incorrect lenvatinib doses due to IxRS issues, the number of 
subjects to be randomized will be increased by 32 to a total of approximately 338. Thus, 
approximately 306 subjects will be included in the Per-Protocol Analysis Set 1. Randomization will 
be stratified by MSKCC prognostic groups (favorable, intermediate, and poor risk) and whether 
subjects have had a prior PD-1/PD-L1 treatment (yes or no).


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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................21
3
TABLE OF CONTENTS.............................................................................................41
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................47
5
ETHICS.......................................................................................................................50
5.1
Institutional Review Boards/Independent Ethics Committees.............................50
5.2
Ethical Conduct of the Study..............................................................................51
5.3
Subject Information and Informed Consent ........................................................51
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................52
7
INTRODUCTION AND STUDY RATIONALE.........................................................52
7.1
Clinical Results Obtained with the Combination of Lenvatinib with 
Everolimus.........................................................................................................52
7.2
Results of Exposure-Response Analyses for Lenvatinib plus Everolimus ...........54
7.3
Study Rationale..................................................................................................58
8
STUDY OBJECTIVES................................................................................................58
8.1
Primary Objective ..............................................................................................58
8.2
Secondary Objectives.........................................................................................59
8.3
Exploratory Objectives.......................................................................................59
9
INVESTIGATIONAL PLAN ......................................................................................59
9.1
Overall Study Design and Plan...........................................................................59
9.1.1
Prerandomization .....................................................................................63
9.1.1.1
Screening Period...............................................................................63
9.1.1.2
Baseline Period.................................................................................63
9.1.2
Randomization Phase ...............................................................................63
9.1.2.1
Treatment Period ..............................................................................64
9.1.2.2
Follow-Up Period .............................................................................64
9.2
Discussion of Study Design, Including Choice of Control Groups......................65
9.3
Selection of Study Population ............................................................................65
9.3.1
Inclusion Criteria......................................................................................65
9.3.2
Exclusion Criteria.....................................................................................67
9.3.3
Removal of Subjects from Therapy or Assessment ...................................69
9.4
Treatments.........................................................................................................69
9.4.1
Treatments Administered..........................................................................69
9.4.2
Criteria for Interruption of Treatment, Dose Reduction and Resumption 
of Treatment.............................................................................................70
9.4.2.1
Dose Reduction Schedule for Intolerable Toxicities..........................72
9.4.2.2
Management of Hypertension ...........................................................73


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9.4.2.3
Management of Proteinuria...............................................................74
9.4.2.4
Management of Diarrhea ..................................................................75
9.4.2.5
Management of Non-Infectious Pneumonitis ....................................75
9.4.2.6
Management of Infections ................................................................76
9.4.2.7
Management of Blood Glucose and Lipids........................................76
9.4.2.8
Management of Hepatotoxicity.........................................................76
9.4.2.9
Management of Thromboembolic Events..........................................76
9.4.2.10
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Posterior Leukoencephalopathy Syndrome .....77
9.4.2.11
Management of Hypocalcemia..........................................................77
9.4.3
Identity of Investigational Products ..........................................................77
9.4.3.1
Chemical Name, Structural Formula of Lenvatinib ...........................78
9.4.3.2
Comparator Drug..............................................................................78
9.4.3.3
Labeling for Study Drug ...................................................................78
9.4.3.4
Storage Conditions ...........................................................................78
9.4.4
Method of Assigning Subjects to Treatment Groups.................................79
9.4.5
Selection of Doses in the Study ................................................................79
9.4.6
Selection and Timing of Dose for Each Subject........................................80
9.4.7
Blinding ...................................................................................................80
9.4.8
Prior and Concomitant Therapy................................................................80
9.4.8.1
Drug-Drug Interactions.....................................................................81
9.4.8.2
Prohibited Concomitant Therapies and Drugs ...................................81
9.4.9
Treatment Compliance .............................................................................83
9.4.10
Drug Supplies and Accountability ............................................................83
9.5
Study Assessments.............................................................................................84
9.5.1
Assessments .............................................................................................84
9.5.1.1
Demography and Baseline Assessments............................................84
9.5.1.2
Efficacy Assessments .......................................................................85
9.5.1.3
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Assessments .....................................................................................86
9.5.1.3.1
Pharmacokinetic assessments......................................................86
9.5.1.3.2
Pharmacodynamic and Other Biomarker Assessments ................86
9.5.1.4
Safety Assessments...........................................................................87
9.5.1.4.1
Adverse Events and Events Associated with Special Situations...87
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations....................................................................................89
9.5.1.4.3
Laboratory Measurements...........................................................90
9.5.1.4.4
Vital Signs and Weight Measurements........................................92
9.5.1.4.5
Physical Examinations ................................................................93


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9.5.1.4.6
Electrocardiograms .....................................................................93
9.5.1.4.7
Echocardiogram or Multiple Gated Acquisition Scan..................93
9.5.1.4.8
Pregnancy Test ...........................................................................93
9.5.1.5
Other Assessments............................................................................94
9.5.2
Schedule of Procedures/Assessments........................................................94
9.5.2.1
Description of Procedures/Assessments Schedule ...........................102
9.5.3
Appropriateness of Measurements..........................................................102
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations .........................................................102
9.5.4.1
Reporting of Serious Adverse Events..............................................102
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................103
9.5.4.3
Reporting of Events Associated with Special Situations..................103
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error.........................103
9.5.4.4
Expedited Reporting .......................................................................104
9.5.4.5
Breaking the Blind..........................................................................104
9.5.4.6
Regulatory Reporting of Adverse Events ........................................104
9.5.5
Completion/Discontinuation of Subjects.................................................104
9.5.6
Abuse or Diversion of Study Drug..........................................................105
9.5.7
Confirmation of Medical Care by Another Physician..............................105
9.6
Data Quality Assurance....................................................................................105
9.6.1
Data Collection.......................................................................................105
9.6.2
Clinical Data Management .....................................................................106
9.7
Statistical Methods...........................................................................................106
9.7.1
Statistical and Analytical Plans...............................................................106
9.7.1.1
Study Endpoints..............................................................................106
9.7.1.1.1
Primary Endpoints ....................................................................106
9.7.1.1.2
Secondary Endpoints.................................................................106
9.7.1.1.3
Exploratory Endpoints ..............................................................107
9.7.1.2
Definitions of Analysis Sets............................................................107
9.7.1.3
Subject Disposition.........................................................................109
9.7.1.4
Demographic and Other Baseline Characteristics............................109
9.7.1.5
Prior and Concomitant Therapy ......................................................109
9.7.1.6
Efficacy Analyses...........................................................................110
9.7.1.6.1
Primary Efficacy Analysis.........................................................110
9.7.1.6.2
Secondary Efficacy Analyses....................................................111
9.7.1.6.3
Exploratory Efficacy Analyses..................................................111
9.7.1.6.4
Handling of Missing Data for Efficacy Analyses.......................111


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9.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Analyses.........................................................................................112
9.7.1.7.1
Pharmacokinetic/pharmacodynamic Analyses...........................112
9.7.1.7.2
Biomarker Analyses..................................................................113
9.7.1.8
Safety Analyses ..............................................................................113
9.7.1.8.1
Extent of Exposure....................................................................113
9.7.1.8.2
Adverse Events.........................................................................113
9.7.1.8.3
Laboratory Values.....................................................................114
9.7.1.8.4
Vital Signs ................................................................................114
9.7.1.8.5
Electrocardiograms ...................................................................114
9.7.1.8.6
Other Safety Analyses...............................................................115
9.7.2
Determination of Sample Size ................................................................115
9.7.3
Interim Analyses ....................................................................................117
9.7.4
Other Statistical/Analytical Issues ..........................................................117
9.7.5
Procedure for Revising the Statistical Analysis Plan...............................117
10
REFERENCE LIST...................................................................................................118
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....120
11.1
Changes to the Protocol....................................................................................120
11.2
Adherence to the Protocol................................................................................120
11.3
Monitoring Procedures.....................................................................................120
11.4
Recording of Data............................................................................................121
11.5
Identification of Source Data............................................................................121
11.6
Retention of Records........................................................................................122
11.7
Auditing Procedures and Inspection .................................................................122
11.8
Handling of Study Drug ...................................................................................122
11.9
Publication of Results ......................................................................................123
11.10 Disclosure and Confidentiality .........................................................................123
11.11 Discontinuation of Study..................................................................................123
11.12 Subject Insurance and Indemnity......................................................................124
12
APPENDICES...........................................................................................................125


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LIST OF IN-TEXT TABLES
Table 1.
Study Treatments....................................................................................70
Table 2
Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity...............................................71
Table 3
Dose Reductions for Lenvatinib in Combination With 5 mg 
Everolimus .............................................................................................72
Table 4
Pharmacokinetic Sampling Time Points..................................................86
Table 5
Clinical Laboratory Tests........................................................................91
Table 6
Schedule of Procedures/Assessments in E7080-G0000-218....................95
Table 7
Schedule of Assessments After the Data Cutoff for the Primary 
Analysis ...............................................................................................100
LIST OF IN-TEXT FIGURES
Figure 1
Kaplan-Meier Plot Of Progression-Free Survival – Full Analysis Set 
(Phase 2) ................................................................................................53
Figure 2
Tumor Growth Inhibition PK/PD Model.................................................54
Figure 3
Case 1 – Effect Of Starting Dose Levels Less Than 18 Mg Lenvatinib* 
With No Allowance For Lenvatinib Dose Escalation..............................55
Figure 4
Case 2 - Simulated Average Tumor Reductions With Starting Dose Of 
18 Mg Lenvatinib* With And Without Drug Holiday (One Week 
Break In Lenvatinib Administration After Two-Week Continuous 
Lenvatinib Administration With Continuous Everolimus 
Administration) ......................................................................................56
Figure 5
Case 3 - Simulated Average Tumor Reductions With Lenvatinib* 
Dose Escalation......................................................................................57
Figure 6
Simulated Average Dose And Proportion Of Subjects With At Least 
One Dose Modification During 24 Weeks (Median Of 500 Replicates 
For 46 Subjects) .....................................................................................57
Figure 7
Utility of Allowing a Second 4-mg Up-titration of the Lenvatinib Dose 
to 22 mg .................................................................................................58
Figure 8
Study Design for Study E7080-G000-218...............................................62
LIST OF APPENDICES
Appendix 1
Creatinine Clearance Estimate by Cockcroft-Gault Formula .................126
Appendix 2
Clinical Studies Evaluating Drug-Drug Interactions with Lenvatinib ....127
Appendix 3
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03.........................................................................................128
Appendix 4
Karnofsky Performance Status..............................................................129
Appendix 5
New York Heart Association Cardiac Disease Classification ................130
Appendix 6
MSKCC Risk Model Criteria................................................................131


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Appendix 7
Tumor, Node, and Metastasis Staging of Renal Cell Carcinoma ...........132
Appendix 8
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 ...............134
Appendix 9
Health-Related Quality of Life Questionnaire FKSI-DRS.....................135
Appendix 10
Health-Related Quality of Life Questionnaire EORTC QLQ-C30.........136
Appendix 11
Health-Related Quality of Life Questionnaire EQ-5D-3L .....................138
Appendix 12
Pharmacodynamic and Other Biomarker Research................................140
Appendix 13
Efficacy and Futility Boundaries at Each Interim Analysis and the 
Primary Analysis ..................................................................................142


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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE(s)
adverse event(s)
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BOR
Best overall response
BP
blood pressure
CA
Competent Authority
CFR
Code of Federal Regulations
CMH
Cochran-Mantel-Haenszel
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT/MRI
computerized tomography/magnetic resonance imaging
CTCAE
Common Terminology Criteria for Adverse Events
CV
curriculum vitae 
CYP
cytochrome P
DMC
data monitoring committee
DOR
duration of response
EBRT
external beam radiotherapy
ECG
electrocardiogram
EMA
European Medicines Agency
EORTC
European Organization for the Research and Treatment of Cancer
EuroQol
European Quality of Life
FDA
Food and Drug Administration


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Abbreviation
Term
FKSI-DRS
Functional Assessment of Cancer Therapy-Kidney Symptom
Index-Disease Related Symptoms
GCP
Good Clinical Practice
HRQoL
Health-Related Quality of Life
ICF
informed consent form
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ICL
imaging core laboratory
IEC
Independent Ethics Committee
INR
international normalized ratio 
IRB
Institutional Review Board
IxRS
Interactive voice and web response system
KM
Kaplan-Meier
KPS
Karnofsky Performance Status
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
MSKCC
Memorial Sloan-Kettering Cancer Center
MUGA
multigated acquisition scan
N
number of subjects
NSAID
non-steroidal anti-inflammatory drug
NYHA
New York Heart Association
ORR
objective response rate
ORR24W
objective response rate at 24 weeks
OS
Overall survival
PRES/RPLS
posterior reversible encephalopathy syndrome/
reversible posterior leukoencephalopathy syndrome
PD
progressive disease or pharmacodynamic
PFS
progression-free survival
PFS2
progression-free survival after next line of therapy
PI
principal investigator or package insert
PR
partial response
PRO
patient-reported outcomes


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Abbreviation
Term
PK
pharmacokinetics
PO
orally (per os)
PT
preferred term
Q1
first quartile
Q3
third quartile
QD
once daily
RBC
red blood cell
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria In Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SOC
system organ class
SOPs
standard operating procedures
SUSAR
suspected unexpected serious adverse reaction
TEAE(s)
treatment-emergent adverse event(s)
TEMAV
treatment-emergent markedly abnormal laboratory values 
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
WHO 
World Health Organization 


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5
ETHICS
5.1
Institutional Review Boards/Independent Ethics Committees
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) constituted and functioning in accordance with ICH E6 (Good Clinical 
Practice), Section 3, and any local regulations.  Any protocol amendment or revision to the 
ICF will be resubmitted to the IRB/IEC for review and approval, except for changes 
involving only logistical or administrative aspects of the study (eg, change in clinical 
research associates [CRAs], change of telephone number[s]).  Documentation of IRB/IEC 
compliance with the ICH E6 and any local regulations regarding constitution and review 
conduct will be provided to the sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) (or if regionally required, the head of the medical institution) with a copy to 
the sponsor before study start and the release of any study drug to the site by the sponsor or 
its designee (ICH E6, Section 4.4).  If the IRB/IEC decides to suspend or terminate the study, 
the investigator (or if regionally required, the head of the medical institution) will 
immediately send the notice of study suspension or termination by the IRB/IEC to the 
sponsor.
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC (or if regionally required, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per ICH 
guidelines and local IRB/IEC standards of practice.  Upon completion of the study, the 
investigator will provide the IRB/IEC with a brief report of the outcome of the study, if 
required.
The data cutoff for the primary analysis will occur at the end of the Randomization Phase, 
which is defined as the time the last subject enrolled completes the Week-24 tumor 
assessments or discontinues study treatment before Week 24. Subjects will continue to 
receive investigational product until they complete the Off-treatment visit. All subjects who 
are still on study treatment after the data cutoff for the primary analysis (ie, at the end of the 
Randomization Phase) will continue to receive investigational product until they complete 
the Off-Treatment Visit.  The definition of the End of Study is the last subject’s last 
assessment (Off-Treatment Visit) after the data cutoff for the primary analysis. At the End of 
Study, the Sponsor (or investigator where required) will ensure that all relevant IRBs/ECs 
and Competent Authorities are notified about the study completion per regulatory 
requirements in each country or region.
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In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.
5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice 
(GCP) guidelines as required by the following:

Principles of the World Medical Association Declaration of Helsinki (2013)

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use

Title 21 of the United States Code of Federal Regulations (US 21 CFR) regarding clinical 
studies, including Part 50 and Part 56 concerning informed subject consent and IRB 
regulations and applicable sections of US 21 CFR Part 312

European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 
2001/20/EC for studies conducted within any EU country.  All suspected unexpected 
serious adverse reactions (SUSARs) will be reported, as required, to the Competent 
Authorities of all involved EU member states

Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 
145, 1960) for studies conducted in Japan, in addition to Japan’s GCP

Other applicable regulatory authorities’ requirements or directives
5.3
Subject Information and Informed Consent
As part of administering the informed consent document, the investigator must explain to 
each subject the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved, any potential discomfort, potential 
alternative procedure(s) or course(s) of treatment available to the subject, and the extent of 
maintaining confidentiality of the subject’s records.  Each subject must be informed that 
participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF at the 


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Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.
An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations. Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.  
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 100 investigational site(s) worldwide.
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor and of the contract research organizations (CROs) are listed in the Investigator 
Study File provided to each site.
7
INTRODUCTION AND STUDY RATIONALE
7.1
Clinical Results Obtained with the Combination of Lenvatinib with 
Everolimus
The safety and efficacy of lenvatinib and everolimus in combination was investigated in 
Study E7080-G000-205 (hereafter referred to as “Study 205”) in subjects with predominant 
clear cell renal cell carcinoma (RCC) following 1 prior vascular endothelial growth factor 
(VEGF)-targeted treatment.  The combination significantly prolonged progression-free 
survival (PFS) compared with either agent as monotherapy, as shown in the Kaplan-Meier 
(KM) (Kaplan and Meier, 1958) curve presented in Figure 1.


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Source: Study 205 CSR, Figure 4
Figure 1
Kaplan-Meier Plot Of Progression-Free Survival – Full Analysis 
Set (Phase 2)
The treatments studied were lenvatinib plus everolimus (18 mg plus 5 mg, respectively, once 
daily [QD]), lenvatinib (24 mg QD), and everolimus (10 mg QD).
The safety profile for lenvatinib plus everolimus was consistent with the known toxicities of 
each individual agent, with no unexpected treatment-emergent adverse events (TEAEs)
observed (AFINITOR® Package Insert and LENVIMA® Package Insert). The most common 
TEAEs of any grade in the lenvatinib plus everolimus arm were diarrhea and fatigue or 
asthenia. Grade 3 and 4 AEs occurred in 36/51 (71%) of the subjects in the lenvatinib plus 
everolimus cohort. The most common Grade 3 or 4 TEAE in the lenvatinib plus everolimus 
cohort was diarrhea (10/51 [20%]). 
The percentage of subjects with lenvatinib dose reduction and/or dose interruption was 
similar in the combination and lenvatinib arms (84.3% and 78.8%, respectively). The 
percentage of subjects with study treatment discontinuation was similar in both lenvatinib 
containing arms (23.5% for the combination and 25.0% for the lenvatinib arm).
Diarrhea and vomiting were the most frequently reported AEs that led to dose reduction 
and/or interruption in the combination arm. These events resulted in dose reduction and/or 
interruption more often in the combination than in the lenvatinib arm: 41.2% vs 28.8%, 
respectively, for diarrhea and 19.6% vs 5.8%, respectively, for vomiting.
The percentages of subjects with study treatment discontinuation due to AEs were similar in 
both the combination and lenvatinib arms (23.5% and 25.0%, respectively) and were 
approximately 2-fold higher than in the everolimus arm (12.0%).


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The percentage of subjects who had everolimus dose interruptions due to AEs was higher in 
the combination arm than in the everolimus arm (76.5% vs 54.0%), while the percentage of 
subjects with everolimus dose reductions was higher in the everolimus arm (26.0%) than in 
the combination arm (2.0%). The percentage of subjects with study treatment 
discontinuation due to AEs was higher in the combination arm (23.5%) compared to 
everolimus arm (12.0%).
Two deaths were deemed related to study drug, 1 cerebral hemorrhage in the lenvatinib plus 
everolimus group and 1 myocardial infarction with single-agent lenvatinib (Motzer, et al., 
2015).
7.2
Results of Exposure-Response Analyses for Lenvatinib plus 
Everolimus
The intent of the current study is to determine whether a different dosing regimen can 
maintain the significant efficacy (objective response rate at 24 weeks; ORR24W) while 
reducing the frequency of Grade 3 and 4 AEs.  To that end, using data from Study 205, Eisai 
and the FDA have collaboratively developed a tumor-growth PK/PD model, as depicted in 
Figure 2, which incorporates tumor suppression by both lenvatinib and everolimus and tumor 
resistance to lenvatinib for the purpose of evaluating, in terms of safety and efficacy, the 
effect of (1) lower lenvatinib starting doses, (2) lenvatinib drug holidays (eg. 2-week 
on/1-week off), and (3) different lenvatinib starting doses with the option of up-titrations of 
the lenvatinib dose.  The model (shown below) incorporates terms for the natural growth rate 
of the clear cell RCC tumors and the growth suppressing effects of both lenvatinib and 
everolimus. Additionally, an exposure-AE binary model was developed for the relationship 
between exposure to lenvatinib and any AE leading to drug reduction, interruption or 
discontinuation (data on file; Modeling and Simulation Report CPMS-E7080-008ADD).
Figure 2
Tumor Growth Inhibition PK/PD Model


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The FDA and Eisai both utilized these models to explore various exposure-response analyses 
for the time course of tumor burden (size) and dose-altering AEs to aid in the design of the 
current study.  
The three cases modeled were: (Case 1) where lenvatinib starting doses less than 18 mg QD 
in combination with 5 mg QD everolimus were administered and doses were reduced as 
necessary to control AEs; (Case 2) where a lenvatinib drug holiday was incorporated into the 
dosage regimen; and (Case 3) Case 1 with the additional caveat that a subject’s lenvatinib 
dose could be subsequently raised as long as the subject tolerated the current dose.  Note that 
Study 205 followed Case 1.  
The modeling results showed that in Case 1, lenvatinib daily doses less than 18 mg were less 
effective, ie, the simulated percent reduction in tumor size was less and occurred later than 
with the 18-mg dose (see Figure 3), and the predicted ORR24W was lower.
*  In combination with 5 mg QD everolimus.
Figure 3
Case 1 – Effect Of Starting Dose Levels Less Than 18 Mg 
Lenvatinib* With No Allowance For Lenvatinib Dose Escalation
In Case 2 (see Figure 4), the efficacy of regimens utilizing a lenvatinib drug holiday proved 
less effective than continuous dosing, and the predicted ORR24W was lower.


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*  In combination with 5 mg QD everolimus.
Figure 4
Case 2 - Simulated Average Tumor Reductions With Starting Dose 
Of 18 Mg Lenvatinib* With And Without Drug Holiday (One Week 
Break In Lenvatinib Administration After Two-Week Continuous 
Lenvatinib Administration With Continuous Everolimus 
Administration)
In Case 3 (see Figure 5), the efficacy of regimens that utilize lower starting doses (ie, 12 mg 
or 14 mg) but allow up titration of doses showed equivalent or superior tumor reduction and 
comparable predicted ORR24W to an 18-mg starting dose that only allowed dose reduction of 
lenvatinib.


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*  In combination with 5 mg QD everolimus.
Figure 5
Case 3 - Simulated Average Tumor Reductions With Lenvatinib* 
Dose Escalation
Simulations of the 2 dose regimens to be investigated in this study suggest that the 14-mg 
lenvatinib starting dose (while maintaining the 5-mg QD everolimus dose) can also result in 
fewer dose reductions (see Figure 6).
Starting Dose: 18 mg w/o dose escalation              Starting Dose: 14 mg w/ dose escalation
Figure 6
Simulated Average Dose And Proportion Of Subjects With At 
Least One Dose Modification During 24 Weeks (Median Of 500 
Replicates For 46 Subjects)
The utility of allowing a second 4-mg up-titration of the lenvatinib dose to 22 mg was also 
modeled.  As shown in Figure 7, there was no added benefit to increasing the dose to 22 mg 
from the 14-mg starting dose: 


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Figure 7
Utility of Allowing a Second 4-mg Up-titration of the Lenvatinib 
Dose to 22 mg
7.3
Study Rationale
Based on the results of Study 205 and the exposure-response models, the current Study 218 
was designed as a 2-arm study to investigate daily starting doses of lenvatinib 14 mg or
lenvatinib 18 mg both in combination with everolimus 5 mg in subjects with RCC.  The 
reference 18-mg lenvatinib dose regimen will only allow reduction of the dose as necessary 
to control AEs.  In contrast, the 14-mg lenvatinib dose regimen will require one 4-mg/day 
increase (ie, to 18 mg) on Day 1 of Cycle 2, if the subject is tolerating the 14-mg dose (while 
also allowing reduction of the dose whenever necessary to control AEs).  The objective of the 
study is to determine whether the lower lenvatinib starting dose regimen provides equivalent 
efficacy (as assessed by ORR24W) with increased safety to the subjects with RCC. 
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to assess whether a starting dose of lenvatinib 14 mg in 
combination with everolimus 5 mg QD will provide comparable efficacy (based on ORR24W)
with an improved safety profile compared to lenvatinib 18 mg in combination with 
everolimus 5 mg (based on treatment-emergent intolerable Grade 2 or any ≥Grade 3 AEs in 
the first 24 weeks after randomization).


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8.2
Secondary Objectives
The secondary objectives of the study are:

To assess progression-free survival (PFS)

To assess ORR

To determine the tolerability and safety profile of lenvatinib in combination with
everolimus

To assess the proportion of subjects who discontinued treatment due to toxicity

To assess time to treatment failure due to toxicity

To assess pharmacokinetic (PK) profiles of lenvatinib and everolimus during combination
therapy and to assess PK and pharmacodynamics (PD) drug-drug interactions

To evaluate overall survival (OS)

To evaluate the impact of disease and treatment on patients' Health-Related Quality of 
Life (HRQoL) as assessed by using the Functional Assessment of Cancer Therapy -
Kidney Symptom Index-Disease Related Symptoms (FKSI-DRS), the European 
Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 and the 
European Quality of Life (EuroQol) EQ-5D-3L

To evaluate the PFS after next line of treatment (PFS2)
8.3
Exploratory Objectives
The exploratory objectives of the study are:

To explore tumor response parameters (ORR24W, ORR, PFS) based on blinded 
independent imaging review (IIR) for efficacy assessment

To explore blood biomarkers that correlate with efficacy-related endpoints of this study

To develop exposure/biomarker/clinical endpoint models (whenever possible, using a 
mechanism-based approach) for both efficacy and safety data that will allow exploration 
of alternative dosing regimens with a better efficacy/safety profile than the lenvatinib 
18-mg plus everolimus 5-mg dose
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
Originally, E7080-G000-218 was designed as a multicenter, randomized, double-blind study,
conducted as a postmarketing requirement of the US Food and Drug Administration (FDA) 
and the European Medicines Agency (EMA) to evaluate an alternate dose regimen for 
lenvatinib in combination with everolimus. As of 14 Jul 2018, all ongoing subjects’ 
treatment assignment has been unblinded and the study will be conducted in an open-label 
fashion.  The investigational site personnel will be unblinded as to treatment assignment for 
all newly enrolled subjects. Lenvatinib 18 mg daily in combination with everolimus 5 mg 


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daily is approved in the US and EU for the treatment of adult patients with advanced RCC 
following 1 prior VEGF-targeted therapy.
This study will evaluate the combination of lenvatinib and everolimus at a 14-mg starting 
dose of lenvatinib and allow up-titration of lenvatinib to determine whether this alternate 
dose regimen provides comparable efficacy but has a better safety profile than the 18-mg 
starting dose in this subject population. The 14-mg starting dose will be escalated to 18 mg if 
no Grade 2 (intolerable) or any ≥Grade 3 TEAEs that require dose reduction are observed in 
the first cycle (4 weeks) of treatment. If Grade 2 (intolerable) or Grade 3 or 4 TEAEs are 
observed, the lenvatinib dose will be reduced, as described in the dose reduction section
(Section 9.4.2). Both lenvatinib and everolimus will be administered orally (PO) and daily 
(QD).
Eligible subjects will have measurable disease according to Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) and will be randomly assigned to each treatment 
arm in a 1:1 ratio.  The total sample size will be approximately 338 subjects. Randomization 
will follow a predefined randomization scheme based on the following stratification factors: 
Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic groups (favorable, 
intermediate, or poor risk); and whether subjects have had a prior PD-1/PD-L1 treatment (yes 
or no).
Subjects will receive study treatment as continuous 28-day cycles. Treatment cycles will be 
counted continuously regardless of dose interruptions. Subjects will undergo safety and 
efficacy assessments as defined in the Schedule of Procedures/Assessments (Table 6) and in 
the Schedule of Assessments After the Data Cutoff for the Primary Analysis (Table 7). After 
the data cutoff for the primary analysis subjects will be eligible to receive study treatment as 
continuous 56-day cycles.  
Subjects will discontinue study treatment upon evidence of progressive disease, as judged by 
the investigator. After disease progression, subjects will be followed for survival and PFS2
until the data cut-off for the primary analysis.
This study will consist of 2 phases, the Prerandomization Phase and the Randomization 
Phase with treatment continuing after the data cutoff for the primary analysis.  An overview 
of the study design is presented in Figure 8.
The data cutoff for the primary analysis will occur when all randomized subjects in the 
Randomization Phase have completed Week 24 assessments or have discontinued study 
treatment prior to Week 24. After the primary analysis is completed, subjects still receiving 
study treatment may continue taking lenvatinib and everolimus after the data cutoff for the 
primary analysis. Subjects will continue to receive investigational product after the data 
cutoff for the primary analysis until 
they complete the Off-treatment visit. The definition of the End of Study is the last subject’s 
last assessment (Off-Treatment Visit) after the data cutoff for the primary analysis.
The data obtained after the data cutoff for the primary analysis will be summarized and 
included in the CSR at the end of study as an addendum.


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PHASE:
Prerandomization 
Randomization Phase
After the Data 
Cutoff for the 
Primary Analysis
PERIOD:
Screening
Baseline
Treatment Period
(until radiographic PD)
Follow-up Period
Treatment Period
(until radiographic 
PD)
Lenvatinib 18 mg QD plus Everolimus 5 mg 
QD
(Cycle 1 Day 1)
ICF signed
Follow-up every 12 weeks for 
survival and PFS2
R
Lenvatinib 14 mg QD plus Everolimus 5 mg 
QDa
(Cycle 1 Day 1)
If no intolerable Grade 2 or Grade 3 or 4 AEs 
that require dose reduction occur in the first 4 
weeks, lenvatinib dose will increase to 18 mg 
QD starting in Cycle 2 Day 1
Day -28 to 
Day -3
Day -3 
to -1
Cycle 1 
Day 1
Tumor Assessment 
every 8 weeks 
(until radiographic PD)
Off Treatment Visit
(28 days after last 
dose)
Data Cutoff 
for Primary 
Analysis
Off Treatment 
Visit (28 days 
after the final 
dose)


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Figure 8
Study Design for Study E7080-G000-218
R = randomization
PD = progressive disease
PFS2 = PFS after next line of therapy 


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9.1.1
Prerandomization
The Prerandomization Phase will last no longer than 28 days and will include a Screening 
Period to establish protocol eligibility and a Baseline Period to confirm eligibility and 
establish disease characteristics prior to randomization and treatment. 
9.1.1.1
Screening Period
Screening will occur between Day -28 and Day -3.  The purpose of the Screening Period is to 
obtain informed consent and to establish protocol eligibility according to the inclusion and 
exclusion criteria listed in Sections 9.3.1 and 9.3.2, respectively.  The screening assessment 
can serve as the baseline assessment if performed within 72 hours before randomization.  
Informed consent will be obtained after the study has been fully explained to each subject 
and before the conduct of any screening procedures or assessments.  Procedures to be 
followed when obtaining informed consent are detailed in Section 5.3.
Subjects must have a histological or cytological confirmed diagnosis of predominant clear 
cell RCC (original tissue diagnosis is acceptable) and documented evidence of advanced 
RCC.
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 baseline assessment can be performed from Day -3 through Day -1 or prior to 
randomization on Cycle 1/Day1.  The screening assessment can serve as the baseline 
assessment if performed within 72 hours before randomization.  Laboratory tests and a 
pregnancy test (for female subjects of childbearing potential) may be performed up to 
72 hours before randomization.  
Subjects who complete the Baseline Period and meet the criteria for inclusion and exclusion 
(Sections 9.3.1 and 9.3.2, respectively) will begin the Randomization/Treatment Phase.
9.1.2
Randomization Phase
The Randomization Phase will begin at the time of randomization of the first subject and will 
include both a Treatment Period and a Follow-Up Period.  The data cut off for the primary
analysis will occur at the end of the Randomization Phase, which is defined as when the last 
subject enrolled completes the Week-24 tumor or discontinues study treatment prior to Week 
24.  Subjects will be randomized in a 1:1 ratio. After the data cut off for the primary analysis, 
subjects who are still on study treatment will continue to receive investigational product until 
they complete the Off-Treatment Visit. The last subject last visit will be the date of the Off-
Treatment Visit for the last subject’s last assessment after the data cutoff for the primary 
analysis.


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9.1.2.1
Treatment Period
The Treatment Period will begin with the first dose of study drug administration in Cycle 1 
and continue in 28-day cycles until completion of the Off-Treatment Assessments (within 
28 days after the last study drug administration).  Subjects will undergo safety and efficacy 
assessments as defined in the Schedule of Procedures/Assessments (Table 6).  Subjects will 
continue to receive study drug until confirmed disease progression, lost to follow-up, 
development of unacceptable toxicity, subject request, withdrawal of consent, or study 
termination by the sponsor.  Subjects who discontinue treatment before the data cutoff for the 
primary analysis will enter the Follow-up Period and will be followed every 12 weeks (±1 
week) after the Off-Treatment Visit.  If a clinic visit is not feasible, follow-up information 
may be obtained via telephone or email.
9.1.2.2
Follow-Up Period
The Follow-Up Period will begin immediately after the off-treatment assessments have been 
completed and will continue as long as the study subject is alive, until the study subject 
withdraws consent, or until the data cutoff for the primary analysis.  Subjects who 
discontinue study treatment before disease progression will continue to undergo tumor
assessments every 8 weeks and as of Amendment 06, send these to the imaging core 
laboratory (ICL) until documentation of disease progression or start of another anticancer 
therapy. Following the Off-Treatment Visit, subjects will continue to be followed every 12 
weeks (±1 week) for survival and PFS2, and all anticancer treatments received will be 
recorded until the data cutoff for the primary analysis.  This information will be recorded 
unless the information is not allowed to be provided due to confidentiality.
If a subject discontinues study treatment and does not consent to continued follow-up, the 
investigator must not access confidential records that require the subject’s consent.  
However, an investigator may consult public records to establish survival status. Copies of 
tumor assessment scans will no longer be sent to the ICL and independent review will not be 
carried out during the Follow-Up Period.
All subjects who are still on study treatment following the data cutoff for the primary 
analysis (ie, at the end of the Randomization Phase) will continue to receive the same study 
treatment.  Tumor assessments will be performed according to the local standard of care, but 
not less frequently than every 12 weeks or earlier if clinically indicated, and scans will no 
longer be required to be sent to the ICL.  Subjects will continue to receive study treatment 
until confirmed disease progression, development of unacceptable toxicity, subject request, 
withdrawal of consent, lost to follow up or study termination by the sponsor.  If the study is 
terminated by the sponsor, study drug (s) will be provided to subjects where commercial 
access is not available.
The Off-Treatment Visit will occur within 28 days after the final dose of study treatment.  
All AEs and SAEs will be captured up to 28 days after last dose of study drug (Table 7).  


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9.2
Discussion of Study Design, Including Choice of Control Groups
Originally, this was a multicenter, randomized, double-blind study, conducted as a 
postmarketing requirement by the US Food and Drug Administration (FDA) and the 
European Medicines Agency (EMA).  Following the unblinding on 14 Jul 2018, Study 218 
will be conducted in an open-label fashion; all ongoing and newly enrolled subjects, as well 
as investigational site personnel, will be unblinded as to the subjects’ treatment assignment.  
Lenvatinib 18 mg daily in combination with everolimus 5 mg daily is approved in the US and 
EU for the treatment of adult patients with advanced renal cell carcinoma (RCC) following 1
prior VEGF-targeted therapy. The safety and efficacy of lenvatinib and everolimus in 
combination was investigated in Study E7080-G000-205 (hereafter referred to as “Study 
205”) in subjects with predominant clear-cell RCC following 1 prior VEGF-targeted 
treatment.  The combination significantly prolonged PFS compared with either agent as 
monotherapy, and the safety profile for the combination treatment was consistent with the 
known toxicities of each individual agent, with no unexpected TEAEs observed.  Grade 3 
and Grade 4 AEs occurred in 36/51 (71%) of the subjects in the lenvatinib plus everolimus 
cohort.
The intent of the current 2-arm study is to determine whether a different dosing regimen for 
lenvatinib in combination with everolimus can maintain the significant efficacy (ORR24W) 
while reducing the frequency of Grade 3 and Grade 4 AEs. To that end, Eisai and the FDA 
have collaboratively developed a tumor-growth inhibition model that incorporates tumor 
suppression by both lenvatinib and everolimus and tumor resistance to lenvatinib for the 
purpose of evaluating safety and efficacy.  Eisai and the FDA both utilized this model to 
explore various exposure-response analyses for the time course of tumor burden (size) and 
dose-altering AEs with data from Study 205. The modeling results showed that daily starting 
doses of lenvatinib 14 mg or lenvatinib 18 mg in combination with everolimus 5 mg were 
indicated.  The reference 18-mg lenvatinib dose regimen will only allow reduction of the 
dose as necessary to control AEs.  In contrast, the 14-mg lenvatinib dose regimen will require 
one 4 mg/day increase in the dose on Day 1 of Cycle 2, if the subject is tolerating the dose 
(while also allowing reduction of the dose whenever necessary to control AEs).
Randomization will be used in this study to avoid bias in the assignment of subjects to 
treatment, to increase the likelihood that known and unknown subject attributes (eg,
demographics and baseline characteristics) are balanced across treatment groups, and to 
ensure the validity of statistical comparisons across treatment groups.  
9.3
Selection of Study Population
Approximately 338 subjects will be randomized (169 subjects in each treatment arm) at 
approximately 100 sites worldwide.  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:


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1. Histological or cytological confirmation of predominant clear cell RCC (original tissue 
diagnosis of RCC is acceptable).
2. Documented evidence of advanced RCC.
3. One prior disease progression episode on or after vascular endothelial growth factor 
(VEGF)-targeted treatment (for example, but not limited to, sunitinib, sorafenib, 
pazopanib, cabozantinib, bevacizumab, axitinib, vatalanib, AV951/ tivozanib)
administered for the treatment of RCC. Prior PD-1/PD-L1 treatment in addition to 
1 prior VEGF-targeted treatment is allowed.
4. At least 1 measurable target lesion according to RECIST 1.1 meeting the following 
criteria:
-
Lymph node (LN) lesion that measures at least 1 dimension as ≥1.5 cm in the short 
axis
-
Non-nodal lesion that measures ≥1.0 cm in the longest diameter
-
The lesion is suitable for repeat measurement using computerized 
tomography/magnetic resonance imaging (CT/MRI).  Lesions that have had external 
beam radiotherapy (EBRT) or locoregional therapy must show radiographic evidence 
of disease progression based on RECIST 1.1 to be deemed a target lesion.
5. Male or female subjects age ≥18 years (or any age >18 years if that age is considered to 
be an adult per the local jurisdiction) at the time of informed consent.
6. Karnofsky Performance Status (KPS) of ≥70.
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive 
medications within 1 week before the Cycle 1/Day 1.
8. Adequate renal function defined as calculated creatinine clearance ≥30 mL/min per the 
Cockcroft and Gault formula (Appendix 1).
9. Adequate bone marrow function defined by:
-
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5 x 109/L)
-
Platelets ≥100,000/mm3(≥100 x 109/L)
-
Hemoglobin ≥9 g/dL
10. Adequate blood coagulation function defined by International Normalized ratio (INR) 
≤1.5 (except for subjects on warfarin therapy where INR must be ≤3.0 prior to 
randomization).
11. Adequate liver function defined by:
-
Total bilirubin ≤1.5 x ULN except for unconjugated hyperbilirubinemia of Gilbert’s 
syndrome
-
Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3 × ULN (in the case of liver metastases ≤5 × ULN) 
Subjects with bone metastases with ALP values greater than 3 times can be included. 
12. Subject must voluntarily agree to provide written informed consent.
13. Subject must be willing and able to comply with all aspects of the protocol.


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9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. More than 1 prior VEGF-targeted treatment for advanced RCC.
2. Subjects with Central Nervous System (CNS) metastases are not eligible, unless they 
have completed local therapy for at least 4 weeks and have discontinued the use of
corticosteroids for this indication or are on a tapering regimen of corticosteroids (defined 
as ≤10 mg prednisolone equivalent) before starting treatment in this study.  Any signs 
(eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks 
before starting study treatment.
3. Active malignancy (except for RCC or definitively treated basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within the past 
24 months.
4. Any anti-cancer treatment (except for radiation therapy, see exclusion #5) within 21 days
or any investigational agent within 30 days prior to the first dose of study drug; subjects 
should have recovered from any toxicity related to previous anti-cancer treatment to
Common Terminology Criteria (CTC) grade 0 or 1.
5. Prior radiation therapy within 21 days prior to start of study treatment with the exception 
of palliative radiotherapy to bone lesions, which is allowed if completed 2 weeks prior to 
study treatment start.
6. Known intolerance to study drug (or any of the excipients) and/or known hypersensitivity 
to rapamycins (eg, sirolimus, everolimus, temsirolimus) or any of the excipients.
7. Subjects with proteinuria >1+ on urinalysis will undergo 24-h urine collection for 
quantitative assessment of proteinuria. Subjects with urine protein ≥1 g/24 h will be 
ineligible.
8. Fasting total cholesterol ˃300 mg/dL (or ˃7.75 mmol/L) and/or fasting triglycerides level 
˃2.5 x ULN. NOTE: these subjects can be included after initiation or adjustment of 
lipid-lowering medication.
9. Uncontrolled diabetes as defined by fasting glucose >1.5 times the ULN. NOTE: these 
subjects can be included after initiation or adjustment of glucose-lowering medication.
10. Prolongation of QTc interval to >480 ms.
11. Subjects who have not recovered adequately from any toxicity and/or complications from 
major surgery prior to starting therapy.
12. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib or everolimus.
13. Bleeding or thrombotic disorders, or subjects at risk for severe hemorrhage. The degree 
of tumor invasion/infiltration of major blood vessels (eg, carotid artery) should be 
considered because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis following lenvatinib therapy.
14. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose 
of study drug.


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15. Significant cardiovascular impairment within 6 months of the first dose of study drug; 
history of congestive heart failure greater than New York Heart Association (NYHA) 
Class II, unstable angina, myocardial infarction or stroke, cardiac arrhythmia associated 
with significant cardiovascular impairment, or left ventricular ejection fraction (LVEF) 
below the institutional normal range as determined by screening multigated acquisition 
(MUGA) scan or echocardiogram.
16. Active infection (any infection requiring systemic treatment).
17. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study.
18. 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.
19. Females of childbearing potential* who:
-
do not agree to use a highly effective method of contraception for the entire study 
period and for up to 8 weeks after study drug discontinuation, ie:
◦
total abstinence (if it is their preferred and usual lifestyle)
◦
an intrauterine device (IUD) or hormone releasing system (IUS
◦
a contraceptive implant
◦
an oral contraceptive** (with additional barrier method)
OR
-
do not have a vasectomized partner with confirmed azoospermia.
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.
NOTES:
*All females will be considered to be of childbearing potential unless they are 
postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause) or have been sterilized surgically (ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 
1 month before dosing).
**Must be on a stable dose of the same oral hormonal contraceptive product for at least 
4 weeks before dosing with study drug and for the duration of the study.


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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 other 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 PFS2 and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and PFS2 and 
survival follow-up, or whether the subject will withdraw consent.  If a subject withdraws 
consent, the date will be documented in the source documents. The Discontinuation from 
Treatment CRF page will be completed indicating the primary reason for discontinuation and 
all other reason(s) contributing to the subject’s discontinuation from treatment.  In addition, 
the date of last dose of study drug(s) will be recorded on the Study Drug Dosing CRF page.
During the Follow-Up Period, subjects who have discontinued study treatment without 
progression should have disease assessments every 8 weeks (±1 week) from the date of the 
last assessment until disease progression is documented, another anticancer therapy is 
initiated or the data cutoff for the primary analysis.
All subjects will be followed for PFS2 and survival until death, except where a subject 
withdraws consent or until the data cutoff for the primary analysis.
9.4
Treatments
9.4.1
Treatments Administered
Study subjects and investigator site personnel are unblinded as to lenvatinib treatment 
assignment.  Lenvatinib will be administered as 3 capsules daily. These 3 capsules will 
consist of 10-mg and 4-mg capsules of lenvatinib or matching placebos provided in the 
appropriate configuration based on the subject’s assigned dose. Investigators will provide 
the lenvatinib pack containing the prescribed dose and the subject will take all capsules, 
including any placebo.  The sponsor may substitute drug supply without placebo capsules 
when resupplying study drug. In addition, the sponsor may make changes to the packaging of 
lenvatininb clinical supplies at its discretion. Changes may include the use of child-resistant 
bottles rather than child-resistant wallets. Child-resistant bottles will not include placebo.  If 
changes to packaging is required, appropriate communication will be provided to the 
investigator at the study sites. Everolimus will be provided by the sponsor as 5-mg tablets, 
packaged in blisters. 


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Table 1.
Study Treatments
Capsule Allocation
Total Dose (QD)
10 mg Lenvatinib
10 mg Placebo
4 mg Lenvatinib
4 mg Placebo
18 mg
1
0
2
0
14 mg
1
0
1
1
10 mg
1
0
0
2
8 mg
0
1
2
0
4 mg
0
1
1
1
QD = once daily.
All subjects also receive one 5-mg dose of everolimus QD.
N.B For subjects transferred to child-resistant bottles, placebo will not be provided 
Lenvatinib 14 mg or 18 mg once daily plus everolimus 5 mg once daily will be taken orally 
in each 28-day cycle during the Randomization Phase and in 56-day cycles after the data 
cutoff for the primary analysis. Study drug should be taken at approximately the same time 
each morning. Study drug may be taken in a fasting state or following a meal.
Lenvatinib doses will be packaged in child-resistant wallets in a combination of active 4-mg 
and 10-mg capsules and/or matching placebo totaling 18 mg or 14 mg (or 10 mg, 8 mg, or 
4 mg, depending on the assigned starting dose, and in the event the investigator decides that 
dose reduction is needed for treatment-related toxicity).  The sponsor may substitute drug 
supplies without placebo capsules when resupplying study drug.  The sponsor may also 
change the packaging of lenvatininb from child-resistant wallets to child-resistant bottles. 
Child-resistant bottles will not include placebo.
Dose Up-Titrations (14-mg Arm Only)
For subjects in the 14-mg QD (+everolimus 5 mg) arm, if there are no intolerable Grade 2 or 
any ≥ Grade 3 TEAEs that require dose reduction in the first 28-day cycle (ie, the first 
4 weeks of treatment), lenvatinib dose will be escalated to 18 mg QD (+everolimus 5 mg).
See the Interactive Voice and Web Response System (IxRS) Manual and revised Pharmacy 
Manual for further instructions.
9.4.2
Criteria for Interruption of Treatment, Dose Reduction and Resumption of 
Treatment
Dose reductions for toxicity may be instituted at any time as necessary.
Adverse events will be graded using Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
Dose reduction and interruptions for subjects who experience lenvatinib-everolimus 
combination therapy-related toxicity (except hypertension and non-infectious pneumonitis) 


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will be managed as described in Table 2, “Dose Modification Guidelines for Lenvatinib-
Everolimus Combination Treatment-Related Toxicity.” For treatment-related hypertension 
and non-infectious pneumonitis, refer to Management of Hypertension (Section 9.4.2.2) and 
Management of Non-infectious Pneumonitis (Section 9.4.2.5) for dose modification 
guidelines. Investigators will decide the probability of the event being related to 1 or both 
drugs as to whether dose modification of 1 or both drugs is required.
Lenvatinib dose reductions will occur in succession based on the previous dose level. The 
lenvatinib and everolimus dose may not be increased at a later date, unless the dose was 
mistakenly decreased; in this situation, the sponsor’s approval is required to increase the 
dose.  Subjects in either arm will be allowed a maximum of 3 lenvatinib dose reductions for 
lenvatinib-related toxicity.
Refer to the subsections below for management of proteinuria (Section 9.4.2.3), diarrhea
(Section 9.4.2.4), infections (Section 9.4.2.6), blood glucose/lipids (Section 9.4.2.7), 
hepatotoxicity (Section 9.4.2.8), thromboembolic events (Section 9.4.2.9), posterior 
reversible encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome 
(PRES/RPLS) (Section 9.4.2.10), and hypocalcemia (Section 9.4.2.11), as appropriate, in 
addition to consulting the dose modification table (Table 2).
Table 2
Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d,e or Grade 3f
First occurrence
Interrupt lenvatinib and everolimus 
until resolved to Grade 0 - 1 or 
tolerable Grade 2
Reduce lenvatinib dose 1 level and 
resume everolimus at the same 
dose as prior to dose interruptionb
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib and everolimus 
until resolved to Grade 0 – 1 or 
tolerable Grade 2 
Reduce lenvatinib dose 1 level. 
Dose reduction of everolimus to 
5 mg every other day may be 
considered for Grade 3 toxicitye
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib and everolimus
until resolved to Grade 0 - 1 or 
tolerable Grade 2
Reduce lenvatinib dose 1 level. 
Dose reduction of everolimus for 
Grade 3 toxicity may be considered 
as follows:e
i)  if 5 mg daily everolimus at 
event onset, reduce to 5 mg every 
other day or
ii)  if 5 mg every other day 
everolimus at event onset, 
discontinue


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Table 2
Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib and everolimus
Discontinue study treatment
Grade 4g: Discontinue Study Treatment
For grading, see Common Terminology Criteria for Adverse Events (CTCAE v4.03. (Appendix 3).  Collect all 
CTC grades of AEs, decreasing and increasing grade.
a: Interruption of study treatment for more than 28 days (due to treatment-related toxicities) will require 
Sponsor’s approval before treatment can be resumed.
b: Initiate optimal medical management for nausea, vomiting, hypothyroidism, hypertension and/or diarrhea 
before any study treatment interruption or dose reduction. For treatment-related hypertension and 
non-infectious pneumonitis, refer to Management of Hypertension (Section 9.4.2.2) and Management of 
Non-infectious Pneumonitis (Section 9.4.2.5) for dose modification guidelines.
c: Applicable only to those Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d:Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie,
Grade 1 weight loss). These subjects will restart the study drug(s) at a lower dose once their weight remains 
stable for at least 1 week and they reached the normal body mass index (BMI) (if the weight loss occurred but 
it is still above normal BMI, they can restart the study treatment at a lower dose once the weight has been 
stable for at least 1 week). Normal BMI should be used as the new baseline for further dose reductions.
e: For Grade 2 toxicity, resume everolimus at the same dose as prior to dose interruption.  For Grade 3 toxicity, 
investigator will decide the probability of the event being related to one or both drugs as to whether dose 
modification of one or both drugs is required.
f: For asymptomatic laboratory abnormalities, such as Grade ≥3 elevations of amylase and lipase that are not 
considered clinically relevant by the investigator, continuation of treatment should be discussed with the 
Sponsor.
g:
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
9.4.2.1
Dose Reduction Schedule for Intolerable Toxicities
Lenvatinib dose reductions occur in succession based on the previous level (18, 14, 10, 8, 
and 4 mg/day) as shown in the table below:
Table 3
Dose Reductions for Lenvatinib in Combination With 5 mg 
Everolimus
Current Dose (QD)
Dose Reductiona
18 mg
14 mg QD
14 mg
10 mg QD
10 mg
8 mg QD
8 mg
4 mg QD
a:  Subjects in either arm will be allowed a maximum of 3 lenvatinib dose 
reductions for lenvatinib-related toxicity.
Note: Subjects in either arm will be allowed a maximum of 3 lenvatinib dose reductions for 
lenvatinib-related toxicity.


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At every dose change, the investigator or a designee will call the Interactive Voice and Web 
Response System (IxRS) to register the subject’s visit (see the IxRS Manual for further 
instructions).  At each of these postrandomization visits, the investigator will select the 
subject’s appropriate treatment dose in accordance with the protocol.  As of 01 Oct 2020, the 
IxRS will be discontinued.  Refer to the revised Pharmacy Manual for complete instructions. 
9.4.2.2
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mmHg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before Cycle 1/Day 1.  Early detection and effective management of hypertension are 
important to minimize the need for lenvatinib dose interruptions and reductions.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mmHg 
or diastolic BP ≥90 mmHg) is confirmed on 2 assessments a minimum of 30 minutes apart.  
One BP assessment is defined as the mean value of 3 measurements at least 5 minutes apart.  
After the data cutoff for the primary analysis, one BP assessment is defined as the mean 
value of 2 measurements at least 5 minutes apart.  The choice of antihypertensive treatment 
should be individualized to the subject’s clinical circumstances and follow standard medical 
practice.  For previously normotensive subjects, appropriate antihypertensive therapy should 
be started when systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg is first observed on 2 
assessments a minimum of 30 minutes apart.  For those subjects already on antihypertensive 
medication, treatment modification may be necessary if hypertension persists.  
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop 
a hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mmHg, significant risk factors for cardiac disease, 
intracerebral hemorrhage, or other significant co-morbidities).  Once the subject has been on 
the same hypertensive medications for at least 48 hours and the BP is controlled, lenvatinib 
should be resumed as described below.
During the Treatment Period, subjects with systolic BP ≥160 mmHg or diastolic BP 
≥100 mmHg must have their BP monitored on Day 15 or more frequently as clinically
indicated until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 1 
treatment cycle (ie, 56-day cycle).  If a repeat event of systolic BP ≥160 mmHg or diastolic 
BP ≥100 mmHg occurs, the subject must resume the Day-15 evaluation until systolic BP has 
been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 1 treatment cycle (ie, 56-day 
cycle).
The following guidelines should be followed for the management of systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg confirmed on repeat measurements after 30 minutes:
1. Continue lenvatinib and institute antihypertensive therapy for subjects not already 
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2. For those subjects already on antihypertensive medication, the dose of the current agent 
may be increased, if appropriate, or 1 or more agents of a different class of 
antihypertensive should be added.
3. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted. It should 
be restarted at 1 dose level reduction only when systolic BP ≤150 mmHg and diastolic 
BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive medication 
for at least 48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the first dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted. It should be 
restarted at an additional dose reduction only when systolic BP ≤150 mmHg and 
diastolic BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.
-
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib administration should be interrupted. It should be 
restarted at a third dose reduction only when systolic BP ≤150 mmHg and diastolic 
BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.
-
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):
1. Institute appropriate medical management
2. Discontinue study treatment
9.4.2.3
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments (Table 6) and the Schedule of Assessments After the Data Cutoff 
for the Primary Analysis (Table 7).  Guidelines for assessment and management of 
proteinuria:
1. Grading will be based on the 24-hour urinary protein result. Management of lenvatinib 
administration will be based on the grade of proteinuria according to instructions 
contained in Table 2, “Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity,”
2. A 24-hour urine collection (within 72 hours) to verify the grade of proteinuria for protein 
quantitation is required in the following situations:
-
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-
A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib dose level
-
When there has been a lenvatinib dose reduction and at the new dose level the urine 
protein dipstick result is 2+, 3+, or 4+
3. 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 1 treatment cycle (ie, 56-day cycle).
9.4.2.4
Management of Diarrhea
An antidiarrheal agent should be recommended to the subject at the start of study treatment 
and subjects should be instructed and educated to initiate antidiarrheal treatment at the first 
onset of soft bowel movements. The choice of antidiarrheal agent should be individualized 
to the subject’s clinical circumstances and follow standard medical practice. If 
signs/symptoms of diarrhea persist despite optimal medical management, instructions 
contained in Table 2, “Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity,” should be followed.
9.4.2.5
Management of Non-Infectious Pneumonitis
Non-infectious pneumonitis is a recognized class effect of rapamycin derivatives, including 
everolimus.  Non-infectious pneumonitis was described in 19% of subjects taking everolimus
(AFINITOR® Package Insert).  Some cases were severe and on rare occasions, a fatal 
outcome was observed.  Investigators should therefore consider a diagnosis of non-infectious 
pneumonitis in subjects presenting with non-specific respiratory signs and symptoms and in 
whom infectious, neoplastic and other non-medicinal causes have been excluded by means of 
appropriate investigations.
Subjects who develop radiological changes suggestive of non-infectious pneumonitis and 
have few or no symptoms (CTCAE Grade 1) may continue study dosing without dose 
adjustments.

If symptoms are moderate (CTCAE Grade 2):
-
Lenvatinib-everolimus combination therapy should be interrupted and the use of 
corticosteroids may be indicated until symptoms abate (resolved to CTCAE 
Grade 0-1) and may then be restarted at the same doses prior to study treatment 
interruption. 
-
If Grade 2 non-infectious pneumonitis recurs despite optimal management, then 
lenvatinib-everolimus combination therapy administration should be interrupted and 
the use of corticosteroids may be indicated until symptoms abate (resolved to CTCAE 
Grade 0-1).  

If symptoms are severe (CTCAE Grade 3):
-
Lenvatinib-everolimus combination therapy should be interrupted and the use of 
corticosteroids may be indicated until clinical symptoms resolve (to CTCAE 


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Grade 0-1).  Investigators will decide the probability of the event being related to 1 or 
both drugs as to whether dose modification of 1 or both drugs is required.

If symptoms are life-threatening (CTCAE Grade 4):
-
Everolimus should be discontinued. Investigators will decide the probability of the 
event being related to 1 or both drugs as to whether discontinuation of 1 or both drugs 
is required.
9.4.2.6
Management of Infections
Everolimus has immunosuppressive properties and may predispose subjects to infections.  
Therefore, it is important to monitor for signs and symptoms of infection, and treat promptly.  
Dose alterations of everolimus may be required in accordance with prescribing information.
9.4.2.7
Management of Blood Glucose and Lipids
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia are recognized class effects of 
rapamycin derivatives, including everolimus.  Glycemic and lipids control should be 
optimized before starting a subject on this study. 
Blood glucose will be monitored as specified in the Schedule of Procedures/Assessments.  
For subjects with blood glucose > ULN, a fasting (>6 h, water only) blood glucose sample 
will be obtained.  Grading according to CTCAE v4.03 will be based on the fasting blood 
glucose result.  The choice of hypoglycemic agent should be individualized to the subject’s 
clinical circumstances and follow standard medical practice. 
Dose alterations of everolimus may be required in accordance with prescribing information.
9.4.2.8
Management of Hepatotoxicity
Liver function tests (ALT, AST, bilirubin levels) should be monitored at baseline, every 
2 weeks for the first 2 months, and monthly thereafter, and as clinically indicated (see 
Schedule of Procedures/Assessments, Table 6) and the Schedule of Assessments After the 
Data Cutoff for the Primary Analysis (Table 7). If signs/symptoms indicating liver injury 
occur, instructions contained in Table 2, “Dose Modification Guidelines for Lenvatinib-
Everolimus Combination Treatment-Related Toxicity,” should be followed. Appropriate 
supportive care should be provided together with close monitoring. If hepatic failure occurs 
the study drug must be discontinued.
9.4.2.9
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, and deep-vein thrombosis (DVT)
signs including lower-extremity swelling, and warmth to touch or tenderness.  In case any of 
these symptoms appear, subjects should be instructed to report such symptoms promptly to 
the treating physician.  If a thromboembolic event is confirmed, instructions contained in 


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Table 2, “Dose Modification Guidelines for Lenvatinib-Everolimus Combination Treatment-
Related Toxicity,” should be followed.  Appropriate supportive care should be provided 
together with close monitoring.  If a subject experiences life-threatening (Grade 4) 
thromboembolic reactions, including pulmonary embolism, the study drug must be 
discontinued.
Arterial thromboembolic events (eg, new onset, worsening, or unstable angina, myocardial 
infarction, transient ischemic attack, and cerebrovascular accident) of any grade require study 
treatment discontinuation.
9.4.2.10
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome 
In clinical studies with lenvatinib, events of posterior reversible encephalopathy 
syndrome/reversible posterior leukoencephalopathy syndrome (PRES/RPLS) were reported 
for less than 1% of lenvatinib-treated subjects. PRES/RPLS is a neurological disorder that 
can present with headache, seizure, lethargy, confusion, altered mental function, blindness, 
and other visual or neurological disturbances. Mild to severe hypertension may be present. 
MRI is necessary to confirm the diagnosis of PRES/RPLS. Appropriate measures should be 
taken to control BP. In subjects with signs or symptoms of PRES/RPLS, instructions 
contained in Table 2, “Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity,” should be followed.
9.4.2.11
Management of Hypocalcemia
Serum calcium should be monitored per the Schedule of Procedures/Assessments.  Corrected 
serum calcium should be used to assess the grade of hypocalcemia per CTCAE v4.03, using 
the following formula:
Corrected calcium = ([4 – serum albumin in g/dL] x 0.8 + serum calcium)
The formula is not applicable when serum albumin concentration is normal (˃4 g/dL); in 
such situations, the total (uncorrected) serum calcium should be used instead.
Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
9.4.3
Identity of Investigational Products
The study drug under evaluation in this study is lenvatinib 14 mg and 18 mg in combination 
with everolimus 5 mg.  Lenvatinib will be packaged in a double-blind configuration (until the 
current supply is exhausted) and will be supplied as 4-mg and 10-mg capsules (and matching 
placebo) by the sponsor.  The sponsor may substitute drug supply without placebo capsules 
when resupplying study drug.  In addition, the sponsor may make changes to the packaging 
of lenvatininb at its discretion. Changes may include the use of child-resistant bottles rather 
than child-resistant wallets. Child-resistant bottles will not include placebo.  Lenvatinib is 
formulated with calcium carbonate, d-mannitol, microcrystalline cellulose, 


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hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and talc.  Everolimus will 
be supplied by the sponsor as 5-mg tablets, packaged in blisters.
9.4.3.1
Chemical Name, Structural Formula of Lenvatinib

Test drug code:  E7080

Generic name:  lenvatinib

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido)phenoxy]-7-methoxyquinoline-
6-carboxamide methanesulfonate

Molecular formula:  C21H19ClN4O4•CH3SO3H

Molecular weight: 522.96

Structural formula:
9.4.3.2
Comparator Drug
Not applicable.
9.4.3.3
Labeling for Study Drug
Lenvatinib, identical placebo, and everolimus will be labeled in accordance with text that is 
in full regulatory compliance with each participating country and is translated into the 
required language(s) for each of those countries.
The following information will be provided (but not limited to):

Name and address of the sponsor

Chemical name/drug identifier

Lot number/batch number

Unique package number

Storage conditions, expiration date if necessary
9.4.3.4
Storage Conditions
Study drugs will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator (or if regionally required, the head 
of the medical institution) or designee is responsible for ensuring that the temperature is 


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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.
9.4.4
Method of Assigning Subjects to Treatment Groups
Eligible subjects will be randomly assigned to each treatment arm in a 1:1 ratio.
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: MSKCC prognostic groups (favorable, intermediate, and poor risk); 
and whether subjects have had a prior PD-1/PD-L1 treatment (yes and no).
The randomization scheme and identification for each subject will be included in the final 
clinical study report for this study.
Randomization will be performed centrally by an Interactive Voice and Web Response 
System (IxRS).  At enrollment (and after successful completion of Visit 1), the investigator 
or designee will call the IxRS to register the subject information.  At randomization (Visit 2), 
the IxRS will assign each subject a unique 6-digit randomization number.  
At every subsequent dose change, the investigator or a designee will call the IxRS to register 
the subject’s visit (see the IxRS Manual for further instructions).  At each of these
postrandomization visits, the investigator will select the subject’s appropriate treatment dose 
in accordance with the protocol. As of 01 Oct 2020, the IxRS will be discontinued.  Refer to 
the revised Pharmacy Manual for complete instructions.
9.4.5
Selection of Doses in the Study
In subjects with advanced predominant clear RCC following 1 prior VEGF-targeted 
treatment, the current approved dose is 18 mg lenvatinib in combination with 5 mg 
everolimus.  Study 205 demonstrated that the combination significantly prolonged PFS 
compared with either agent as monotherapy.
The intent of the current study is to determine whether an alternate dosing regimen can 
provide comparable efficacy (based on ORR24WK) with an improved safety profile compared 
to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent 
intolerable Grade 2 or any ≥ Grade 3 AEs in the first 24 weeks after randomization).  A 
tumor-growth model that was developed collaboratively by Eisai and the FDA was used to 
explore various exposure-response analyses for the time course of tumor burden (size) and 
dose-altering AEs with data from Study 205.  The modeling results showed that lenvatinib 
daily doses less than 18 mg were less effective, ie, the simulated percent reduction in tumor 
size was less and occurred later than with the 18-mg dose.  Further, the modeling results 
showed that efficacy regimens that utilize lower starting doses (ie, 12 mg or 14 mg) but 
allowed up-titration of doses showed equivalent or superior tumor reduction to an 18-mg 
starting dose that allowed only dose reduction of lenvatinib.  The utility of an up-titration to 


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22 mg was also modeled; there was no added benefit to increasing the dose to 22 mg from 
the 14-mg starting dose.
Based on these simulations, daily starting doses of lenvatinib 14 mg or 18 mg in combination 
with everolimus 5 mg were chosen.  The reference 18-mg lenvatinib dose regimen will only 
allow reduction of the dose as needed to control AEs.  The 14-mg lenvatinib dose regimen 
will require one 4-mg per day increase in the dose on Day 1 of Cycle 2, if the subject 
tolerates the dose).  
9.4.6
Selection and Timing of Dose for Each Subject
Lenvatinib will be administered as 3 capsules daily.  These 3 capsules will consist of 10-mg 
and 4-mg capsules of lenvatinib or matching placebos provided in the appropriate 
configuration based on their assigned dose (18 mg or 14 mg).  Everolimus is provided as 
5-mg tablets (See Section 9.4.1, Table 1). 
Study drugs are to be taken orally once a day continuously from Day 1/Cycle 1 onward at 
approximately the same time in the morning without regard to food intake.  A cycle is 
considered 28 days during the Randomization Phase and 56 days after the data cutoff for the 
primary analysis.  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.
9.4.7
Blinding
As of 14 Jul 2018, the study is no longer blinded.
9.4.8
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 28 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the evaluation of 
or interact with lenvatinib may be continued during the study.
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) lenvatinib.
Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Granulocyte colony-stimulating 
factor (g-CSF) or equivalent may be used in accordance with American Society of Clinical 


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Oncology (ASCO), institutional, or national guidelines.  Erythropoietin may be used 
according to ASCO, institutional, or national guidelines, but the subject should be carefully 
monitored for increases in red blood cell (RBC) counts.
9.4.8.1
Drug-Drug Interactions
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 (CYP 
P450) enzymes (Study No. XT063020) suggests a low risk of lenvatinib interference with the 
PK of other drugs metabolized by CYP P450 enzymes that are co-administered in usual 
clinic practice.  Nonclinical studies identify CYP3A4 as the important CYP isozyme 
responsible for human hepatic metabolism of lenvatinib.  However, clinical studies 
conducted showed that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp) 
inhibitors or inducers is not of clinical concern.  The main metabolic pathways for lenvatinib 
in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic 
processes (LENVIMA® Package Insert).  Please refer to Appendix 2 and 
http://medicine.iupui.edu/clinpharm/ddis/ for the most current information.
For subjects receiving everolimus, drugs or substances (including herbal supplements or 
grapefruit juice) known to be potent inhibitors of CYP3A4/P-gp should not be used.  Potent 
inducers of CYP3A4/P-gp should not be used unless there is no alternative treatment 
available.  Moderate/ weak inhibitors or inducers or substrates of CYP3A4 and/or P-gp 
should be used with caution.  Dose reduction of everolimus may be considered when co-
administering moderate CYP3A4 or P-gp inhibitors.  For further information please refer to 
the prescribing information.
9.4.8.2
Prohibited Concomitant Therapies and Drugs
Prior therapy must be documented by the following criteria prior to entry into study:

Any single agent therapy, and any combination of cytotoxic, hormonal, biological
targeted agents, and/or humanized antibodies, scheduled to be administered as a 
preplanned treatment, given concomitantly, sequentially or both, is considered 1 regimen.

Planned neoadjuvant chemotherapy (to debulk the tumor prior to surgical intervention) 
plus postoperative adjuvant chemotherapy is considered 1 regimen.

For chemotherapy: if, due to toxicity, the dosing of one or more of the components must 
be reduced, or one or more of the components of the regimen must be omitted, or one of
the components must be replaced with another similar drug, the changed version of the
original regimen is not considered a new regimen. However, if a new component,
dissimilar to any of the original components, is added to the regimen, the new
combination is considered a new regimen.

For prior VEGF/VEGFR-targeted agents, treatment with each agent will be counted 
individually, regardless of the duration of administration.

If the treatment is interrupted for surgery or radiotherapy or any other reason and then
continues with an unchanged schedule and components, that treatment is considered as 
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Subjects should not receive other antitumor therapies or other investigational drugs while on 
study.  If subjects receive additional antitumor therapies, such as chemotherapy, tyrosine 
kinase inhibitors (TKIs), hormone therapy, radiotherapy (except for palliative radiotherapy of 
up to 2 painful pre-existing, non-target bone metastases), antitumor interventions (surgical 
resection, thoracentesis, etc), or immunotherapy, this will be judged to represent evidence of 
disease progression, and study medication will be discontinued.  These subjects should 
complete all off-treatment assessments and continue to be followed for survival in the 
Follow-Up Period until death, except where a subject withdraws consent or until the data 
cutoff for the primary analysis (ie, follow-up ends at the end of the Randomization Phase), or 
to complete all off-treatment assessments after the data cutoff for the primary analysis. 
Live vaccines while participating in the study are prohibited.  Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow 
fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed.  However, intranasal influenza vaccines (eg. 
Flu-Mist®) are live attenuated vaccines and are not allowed.
For further information on the prohibited concomitant therapies for everolimus, please refer 
to the respective Prescribing Information.
Treatment (including blood products, blood transfusions, fluid transfusions, antibiotics, and 
antidiarrheal drugs, etc.) of complications of AEs or therapy to ameliorate symptoms may be 
administered at the discretion of the investigator, unless it is expected to interfere with the 
evaluation of (or to interact with) the study medication.  For clarification, the following 
concomitant therapies are also allowed:

Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer

Bisphosphonates or denosumab

Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases will be 
permitted without being considered progressive disease
If the subject requires surgery during the study, the stop time and restart time of study 
treatment should be as follows:

For minor procedures: stop lenvatinib at least 2 days before the procedure and restart it at 
least 2 days after, once there is evidence of adequate healing and no risk of bleeding

For major procedures: stop lenvatinib at least 1 week (5 half-lives) prior to surgery and 
then restart it at least 1 week after, once there is evidence of adequate healing and no risk 
of bleeding
Any additional procedural or patient specific particularities should be discussed with the
sponsor.


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9.4.9
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study, including the 
Follow-up Period.  Clinical Research Associates (CRAs) will review treatment compliance 
during site visits and at the completion of the study.
9.4.10
Drug Supplies and Accountability
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator (or if regionally required, the head of the medical institution or the designated 
pharmacist) until the following documentation has been received by the sponsor:

A signed and dated confidentiality agreement

A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator

Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted

A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study

The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated FDA Form FDA 1572 or Investigator and Site 
Information Form, where applicable

Financial Disclosure form(s) for the principal investigator (PI) and all sub-investigators 
listed on Form FDA 1572 or Investigator and Site Information Form, where applicable

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 studies agreement

A copy of the regulatory authority approval for the country in which the study is being 
conducted (if required), and the Import License (if required)
The investigator and the study staff (or if regionally required, the head of the medical 
institution or the designated pharmacist) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
Unused study drugs must be returned to the clinic by the subject in the original packaging.  
The site must maintain an accurate and timely record of the following:  receipt of all study 


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drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study drugs 
that occurs at the site.  All forms will be provided by the sponsor.  Any comparable forms 
that the site wishes to use must be approved by the sponsor.
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority (eg,
FDA, Medicines and Health Regulatory Agency [MHRA]).  As applicable, all unused study 
drugs and empty and partially empty blister packages, wallets or bottles from used study 
drugs are to be returned to the investigator (or if regionally required, the head of the medical 
institution or the designated pharmacist) by the subject and, together with unused study drugs 
that were shipped to the site but not dispensed to subjects, are to be returned to the sponsor’s 
designated central or local depot(s) during the study or at the conclusion of the study, unless 
provision is made by the sponsor for destruction of study drugs and containers at the site.  
Destruction at the site will only occur under circumstances where regulation or supply type 
prohibits the return of study drugs to the central or local depot(s).  Approval for destruction 
to occur at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 
procedures by the sponsor’s personnel, study drugs that are to be returned to the sponsor’s 
designated central or local depot(s) must be boxed, sealed, and shipped back to the central or 
local depot(s) following all local regulatory requirements.  In some regions, study drugs may 
be removed from the site and hand delivered to the central or local depot by sponsor 
representatives.  Where study drugs are approved for destruction at the site, destruction will 
occur following the site’s standard procedures and certificates of destruction will be provided 
to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography and Baseline Assessments
Subject demography and baseline characteristics will be collected during the 
Prerandomization Phase.  Demography information includes date of birth (or age), sex, and 
race/ethnicity (recorded in accordance with prevailing regulations).  Baseline characteristics 
will include Karnofsky Performance Status (KPS) (Appendix 4), NYHA cardiac disease 
classification (Appendix 5), MSKCC prognostic group (Appendix 6), and RCC American 
Joint Committee on Cancer (AJCC) staging at the time of diagnosis (Appendix 7).


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Medical and surgical histories will be obtained during the Prerandomization Phase, along 
with a record of prior and concomitant medications.
Physical examinations (comprehensive or symptom-directed) will be performed as specified 
in the Schedule of Procedures/Assessments (Table 6) and the Schedule of Assessments After 
the Data Cutoff for the Primary Analysis (Table 7).  A comprehensive physical examination 
will include evaluations of the head, eyes, ears, nose, throat, neck, chest (including heart and 
lungs), abdomen, limbs, skin, and a complete neurological examination.  
A urogenital examination will only be required in the presence of clinical symptoms related 
to this region.  Documentation of the physical examination will be included in the source 
documentation at the investigational site.  Significant findings prior to the start of study drug 
will be recorded on the Medical History and Current Medical Conditions CRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events CRF.
Subjects must have measurable disease according to RECIST 1.1 as defined in Inclusion 
Criterion #4 (Appendix 8).  Subjects must also fulfill the medical and physical characteristics 
identified in the inclusion criteria and not otherwise meet any of the exclusion criteria.
9.5.1.2
Efficacy Assessments
Tumor assessments will be performed using RECIST 1.1 (Appendix 8).  Investigator-
determined response assessments will be performed at each assessment time point and 
entered onto the case report form (CRF). Copies of all tumor assessment scans will be sent to 
an ICL designated by the sponsor for blinded independent efficacy assessment until the data 
cutoff for the primary analysis. For subjects enrolled after implementation of Amendment 06,
tumor assessments will be carried out following the guidelines provided by the ICL. 
Tumor assessments (computed tomography [CT] chest, and CT or MRI abdomen, pelvis, and 
other known or suspected sites of disease) will be performed during the Prerandomization 
Phase and then, during the Randomization Phase, every 8 weeks (within the 8th week) until 
documentation of progressive disease as determined by the investigator and on a schedule as 
determined by the treating physician after the data cutoff for the primary analysis, but not 
less frequently than every 12 weeks or earlier if clinically indicated.  Historical CT or MRI 
scans performed within 28 days of randomization but before informed consent may be used 
as screening scans provided they meet minimum standards as separately defined by the ICL.
The same imaging modality and image-acquisition protocol (including use or nonuse of 
contrast) should be used consistently across all time points. All responses must be confirmed 
no less than 4 weeks following the initial indication of response.  A chest x-ray or a skeletal 
x-ray that clearly demonstrates a new metastatic lesion may be used to document progression 
in lieu of the CT/MRI scans.
A bone scan (99m-technetium-based scintigraphy, whole-body bone MRI, or 18F-sodium
fluoride positron emission tomography [NaF PET]) will be performed during the 
Prerandomization Phase to establish a baseline (a historical bone scan performed within 
6 weeks prior to randomization is acceptable), every 24 weeks after randomization, within a 


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target of 1 week but no more than 2 weeks following a complete response (CR) as assessed 
by the investigator, and as clinically indicated after the data cutoff for the primary analysis.  
Lesions identified on bone scans should be followed at all tumor assessment time points with 
cross-sectional imaging.
A brain scan will be performed at screening and as clinically indicated thereafter, and within 
a target of 1 week but no more than 2 weeks following achievement of a confirmed CR.  For 
subjects with a history of protocol-eligible treated brain metastases, a brain scan will be 
required at all protocol-specified tumor assessment time points (eg, every 8 weeks).  Subjects 
with protocol-eligible treated brain metastases should also have brain CT/MRI performed as 
per local standard of care.  For other subjects, brain scans should be performed as clinically 
indicated.
Stable disease must be achieved at ≥7 weeks after randomization to be considered best 
overall response. Subjects going off treatment without disease progression in the Treatment 
Period will continue to undergo tumor assessments in the Follow-up Period per the above 
schedule until disease progression is documented, another anticancer therapy is initiated, or 
data cutoff for the primary analysis.
9.5.1.3
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Assessments
9.5.1.3.1
PHARMACOKINETIC ASSESSMENTS 
Sparse PK samples (plasma for lenvatinib and whole blood for everolimus) will be collected 
from all subjects and will be analyzed using a population PK approach (PopPK). The timing 
for obtaining the 7 PK sampling time points (one tube each for lenvatinib and everolimus 
PK) is shown in the Schedule of Procedures/Assessments (Table 6) and Table 4. See the 
Laboratory Manual for a description of collection, handling, and shipping procedures for PK 
samples.  A separate statistical analysis plan will be developed for the PopPK analysis.  
Table 4
Pharmacokinetic Sampling Time Points
Time Point
Sample Number
Time (h)
Cycle 1/Day 1
1
0.5-4 h postdose
2
6-10 h postdose
Cycle 1/Day 15a
3
Predose on Day 15 (Cycle 1)
4
0.5-4 h postdose
5
6-10 h postdose
Cycle 2 Day 1
6
Predose on Day 1 (Cycle 2)
7
2-12 h postdose
h = hour(s).
a
If dose interruption is necessary in these time points, only predose sample should be collected.
9.5.1.3.2
PHARMACODYNAMIC AND OTHER BIOMARKER ASSESSMENTS
Pharmacodynamic and Other Biomarker Assessments


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Blood samples will be collected for peripheral blood mononuclear cell (PBMC) and plasma 
isolation from all study subjects at protocol specified time points, during the Randomization 
Phase of the study, as indicated in the Schedule of Procedures/Assessments (Table 6). There 
will be no further biomarker sample collection after the data cutoff for the primary analysis.
Biomarker discovery or validation will be performed to identify blood biomarkers that may 
be useful to measure subject response to study drug, to understand the underlying disease 
biology, to provide further insight into the mechanism of action of the study drug as well as 
for potential use in diagnostic development. 
These samples may undergo enzyme-linked immunosorbent assay (ELISA), multiplex bead-
based immunoassay and/or other appropriate analysis procedures to explore blood 
biomarkers (eg, VEGF, Ang-2).  In addition, other pharmacodynamics target engagement 
and response biomarkers related to study drug may be assessed.  See Appendix 12 for 
description of sample collection and handling, procedures for securing and retention of 
samples, and subject privacy information).  
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual (see also Appendix 12).
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE
v4.03 grades (for both increasing and decreasing severity) and SAEs; regular monitoring of 
hematology, blood chemistry, and urine values; periodic measurement of vital signs and 
electrocardiograms (ECGs); and performance of physical examinations during the 
Randomization Phase.  An echocardiogram or a MUGA scan including LVEF will be 
performed at screening, and as clinically indicated. After the data cutoff for the primary 
analysis, all AEs leading to study discontinuation, SAEs and concomitant medications will be 
monitored and recorded.  Hematology and blood chemistry will be monitored prior to 
administration of study drug and as clinically indicated. Urine dipstick testing will be 
monitored at each visit and as clinically indicated. A serum or urine pregnancy test will be 
performed during the study for women of childbearing potential.  A symptom-directed 
physical examination and vital signs (resting BP, HR, RR and body temperature) will be 
performed at each visit and as clinically indicated.  A 12-lead ECG and 
Echocardiogram/MUCA scan will be performed as clinically indicated (Table 7).
Progression of RCC and signs and symptoms clearly related to the progression of RCC 
should not be captured as an AE.  Disease progression is a study endpoint and should be 
captured in the CRF as per the guidelines for reporting disease progression.
9.5.1.4.1
ADVERSE EVENTS AND 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 drugs are lenvatinib and 
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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 through the last visit. Subjects who fail screening primarily due 
to AE(s) must have the AE(s) leading to screen failure reported on the Screening Disposition 
CRF.  All AEs and SAEs will be collected for 28 days after the last dose.
After the data cutoff for the primary analysis, all AEs leading to study drug discontinuation 
and SAEs will be recorded until 28 days after the last dose of study drug. SAEs, irrespective 
of relationship to study drug, must be reported as soon as possible but not later than 24 hours 
from the date when the investigator becomes aware of the event.
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. 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.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.


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Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 3).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  For Grade 2 AEs that lead to changes in study drug administration (dose held, dose 
reduced, or dosing discontinuation), the investigator will be required to confirm in the CRF 
that the AE is considered intolerable.
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
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 non-study treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.4.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization


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
Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
If possible, a blood sample for the measurement of study drug plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.  A 
blood sample to measure study drug plasma concentrations will no longer be needed after the 
data cutoff for the primary analysis.
9.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, urine dipstick 
testing, and a serum or urine pregnancy test (for female subjects of childbearing potential), 
are summarized in Table 5.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 6) and the Schedule of 
Assessments After the Data Cutoff for the Primary Analysis (Table 7) shows the visits and 
time points at which blood for clinical laboratory tests and urine for dipstick testing (and 
possible 24-hour urine collection to quantify the 24-hour urine protein excretion) will be 
collected in the study.


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Clinical laboratory tests during the Randomization Phase of the study will be performed by a 
central laboratory.  All blood and urine samples (except urine sample for urine dipstick) will 
be collected and sent to the central laboratory on the day of collection unless otherwise 
instructed.  In cases of a safety concern or to guide clinical dosing, a local laboratory may be 
used in addition to the central laboratory testing.  If central laboratory results are not 
available within the necessary timeframe to allow the subject to be enrolled, local 
laboratories will perform tests to qualify subjects for entry into the study.  Laboratory 
certification as available will be included in the final clinical study report for this study.  
After the data cutoff for the primary analysis, clinical laboratory tests can be performed by 
the local laboratory and samples will no longer be sent to the central laboratory.
Urine dipstick testing will be performed, preferably at the investigational site (but may be 
performed locally by the primary care physician or a local laboratory if the subject does not 
have to come for a visit to the site).
Table 5
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with automated differential (including absolute neutrophil count 
and absolute lymphocyte count)
INRa
Chemistry
Electrolytes
Bicarbonate, calcium, chloride, magnesium, phosphorous,
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 testsb
Thyroid stimulating hormone, free T4 level
Other
Albumin, cholesterol, glucosec, lactate dehydrogenase, total 
protein, triglycerides, amylase, lipase, creatine kinase
Serum or urine pregnancy testd (β-hCG or hCG)
Urine Dipstick Testinge
glucose, hemoglobin (or blood), ketones, pH, proteinf, specific
gravity


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Category
Parameters
RBC = red blood cell, WBC = white blood cell, INR = International Normalized Ratio.
a.
INR should only be performed as part of the screening assessment and when clinically indicated.
b.
Free T4 and TSH levels will be performed at the Screening Visit, at the Baseline Visit (or within 72 
hours prior to the first dose of study drug). TSH levels will be repeated at Day 1 of every other cycle 
(starting with Cycle 2) and at the Off-Treatment visit.
c.
For subjects with blood glucose >ULN, a fasting (>6 h, water only) blood glucose sample will be 
obtained.
d.
For women of childbearing potential (ie, premenopausal women and postmenopausal women who have 
been amenorrheic for less than 12 months)
e.
If urine dipstick testing suggests a urinary tract infection, a urinalysis with microscopy and/or urine 
culture with sensitivities should be considered, if clinically indicated, at the institution’s laboratory.
f.
If urine protein by dipstick is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick 
proteinuria occurring on the same lenvatinib dose level), then a 24-hour urine collection should be done 
to quantify the 24-hour urine protein excretion.
All hematology, clinical chemistry (including pregnancy test, as applicable), and 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 Cycle 1, and within 48 hours of 
Day 1 in each treatment cycle and within 72 hours of Day 1 after the data cutoff for the 
primary analysis.  Refer to Table 2 for 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 9.5.1.4.1 and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.
9.5.1.4.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 6) by a 
validated method.  Blood pressure and pulse will be measured after the subject has been
resting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person. One BP assessment is defined as the mean value of 
3 measurements at least 5 minutes apart. After the data cutoff for the primary analysis, one 
BP assessment is defined as the mean value of 2 measurements at least 5 minutes apart.  
Vital sign measurements (resting BP [including date and time of measurement], HR, RR and 
body temperature) will be obtained, excluding weight at the visits designated in the Schedule 
of Assessments After the Data Cutoff for the Primary Analysis (Table 7).
For subjects with an elevated BP (systolic BP ≥140 mm Hg or diastolic BP ≥90 mmHg), 
confirmation should be obtained by performing 2 assessments a minimum of 30 minutes
apart.  


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Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP 
monitored every 2 weeks (on Day 1 and Day 15 or more frequently, as clinically indicated) 
until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 1 treatment 
cycle (ie, 56-day cycle).  A diary will be provided to the subject to capture the BP
evaluations between study visits. See subsection for management of hypertensive subjects
(Section 9.4.2.2).
9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 6) and in the Schedule of Assessments After the Data Cutoff 
for the Primary Analysis (Table 7).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.  A symptom-directed physical examination will be performed as clinically 
indicated.
9.5.1.4.6
ELECTROCARDIOGRAMS
ECGs will be performed during screening and every 4 weeks on Day 1 of each cycle during 
the Randomization Phase beginning with Cycle 2 and at the Off-Treatment Visit (Table 6).
After the data cutoff for the primary analysis, ECGs may be performed as clinically indicated
(Table 7). Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be 
displayed on a single page with an accompanying lead II rhythm strip below the customary 3 
× 4 lead format are to be used.  In addition to a rhythm strip, a minimum of 3 full complexes 
should be recorded from each lead simultaneously.  Subjects are suggested to be in the 
recumbent position for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.4.7
ECHOCARDIOGRAM OR MULTIPLE GATED ACQUISITION SCAN
A MUGA scan (using technetium-99m-pertechnetate) or an echocardiogram to assess LVEF 
will be performed at Screening and as clinically indicated (Table 6) and (Table 7).  MUGA 
or echocardiogram scans should be performed locally in accordance with the institution’s 
standard practice.  MUGA scans are the preferred modality; however, whichever modality is 
used for an individual subject at Baseline should be repeated for all subsequent LVEF 
assessments for that subject.  LVEFs as assessed by the institution will be entered onto the 
CRF.  Investigator assessment will be based upon institutional reports.
9.5.1.4.8
PREGNANCY TEST
A serum or urine pregnancy test (β-hCG or hCG with a minimum sensitivity of 25 IU/L or 
equivalent units of β-hCG or hCG) will be performed in women of childbearing potential (ie,
premenopausal women and postmenopausal women who have been amenorrheic for less than 


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12 months).  Samples of blood or urine will be taken at designated time points as specified in 
the Schedule of Procedures and Assessments (Table 6) and Schedule of Assessments After 
the Data Cutoff for the Primary Analysis (Table 7).
9.5.1.5
Other Assessments
HRQoL will be assessed at Baseline (prior to first dose of study drug), on Day 1 of each 
subsequent cycle, and at the Off-Treatment Visit in the Randomization Phase. HRQOL will 
not be assessed after the data cutoff for the primary analysis. Every effort should be made to 
administer HRQoL surveys prior to study drug administration and before other assessments 
and procedures.  Subjects will complete the Cancer Therapy-Kidney Symptom Index-Disease
Related Symptoms (FKSI-DRS; Appendix 9), the European Organization for the Research 
and Treatment of Cancer (EORTC) QLQ-C30 (Appendix 10) and the European Quality of 
Life (EuroQol) EQ-5D-3L (Appendix 11) instruments.
The FKSI-DRS consists of 9 items that experts and patients have indicated are important 
targets for the treatment of advanced kidney cancer, and that clinical experts have indicated 
are primarily disease-related, as opposed to treatment-related.  Symptoms assessed on the 
FKSI-DRS include pain, fatigue, shortness of breath, fevers, weight loss, coughing, and 
blood in urine. The total score can range from 0 (worst) to 36 (best).
The QLQ-C30 measure comprises 9 multiple-item scales and 6 single items.  Multiple-item 
scales of QLQ-C30 consist of 6 functional scales (physical, role, emotional, cognitive, social 
and global QoL) and 3 symptom scales (fatigue, nausea and vomiting, pain).  Six single-item 
scales of QLQ-C30 involve dyspnea, sleep disturbance, appetite loss, constipation, diarrhea 
and financial impact.  All of the derived scales range in score from 0 to 100.  For the overall 
HRQoL and functioning scales, a higher score is correlated with better HRQoL, whereas a 
higher score represents worse HRQoL for symptom scales.
The EQ-5D-3L generic QoL questionnaire is comprised of 5 dimensions:  mobility, self-care, 
usual activities, pain or discomfort, and anxiety or depression.  Each dimension has 3 levels 
(1) no problem, (2) some problem, or (3) extreme problem.  Thus, the final scoring consists 
of 243 possible combinations or health states.  The utility value for each state is assigned on 
the basis of a set of preference weights (tariffs) elicited from the general population.
9.5.2
Schedule of Procedures/Assessments 
Table 6 presents the schedule of procedures/assessments for the study. Table 7 presents the 
schedule of procedures/assessments after the data cutoff for the primary analysis. 


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Table 6
Schedule of Procedures/Assessments in E7080-G0000-218
Phase
Prerandomization Phase
RandomizationPhase
All cycles are 28 days in duration
Period
Screeninga
Baselinea
Study TreatmentPeriodb
Off-Tx
Follow- Up
Visit
1
2
3
4
5
6
7, 9,
etc.
8, 10, 12,
14, etc.
Day
-28 to -3
-3 to -1
Cycle 1
Cycle 2
Cycles 3 - Last
1
8
15
1
15
1
15
99
Procedures/Assessments
Informedconsent
X
Medical/surgicalhistory
X
X
Demographicdata
X
KPSc
X
X
X
X
NYHAc
X
AJCCstagingd
X
Inclusion/exclusion
X
X
Randomization
X
Vital signse
X
X
X
X
X
X
X
X
X
Physical examinationf
X
Xg
X
X
X
X
12-leadECGh
X
X
X
X
Echocardiogram/MUGAscani
X
As clinicallyindicated
Pregnancytestj
X
X
X
X
X


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Phase
Prerandomization Phase
RandomizationPhase
All cycles are 28 days in duration
Period
Screeninga
Baselinea
Study TreatmentPeriodb
Off-Tx Follow-Up
Visit
1
2
3
4
5
6
7, 9,
etc.
8, 10, 12,
14, etc.
99
Day
-28 to -3
-3 to -1
Cycle 1
Cycle 2
Cycles 3 - Last
1
8
15
1
15
1
15
Procedures/Assessments
Clinicalchemistry/hematologyk
X
X
X
X
X
X
X
Urinedipstick testingl
X
X
X
X
X
Xl
X
Studydrugadministration
Once daily
PK blood samplesm 
X
X
X
Tumorassessments(CT/MRI)n
X
Performed every8 weeks (counting from date of randomization), or
sooner if clinically indicated, until documentation ofdisease
progression
X
X
Bone scano
X
Every24 weeks, and as clinicallyindicated, and to confirm CR
Brain scan (CT/MRI)p
X
X
HRQoLq
X
X
X
X
Phone contact or visitr
X
Prior /Concomitantmedss
Throughout
Only 
anticancer 
Tx 
recorded 
during 
Follow-up 
Period
AEs/SAEst
Throughout
PFS2 and Survivalu
X


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Phase
Prerandomization Phase
RandomizationPhase
All cycles are 28 days in duration
Period
Screeninga
Baselinea
Study TreatmentPeriodb
Off-Tx Follow-Up
Visit
1
2
3
4
5
6
7, 9,
etc.
8, 10, 12,
14, etc.
99
Day
-28 to -3
-3 to -1
Cycle 1
Cycle 2
Cycles 3 - Last
1
8
15
1
15
1
15
Procedures/Assessments
Blood sample for Biomarkersv
X
X
X
X
X
AEs = adverse events, BP = blood pressure, C1D1 = Cycle 1/Day 1, C1D15 = Cycle 1/Day 15, CT = computed tomography, ECG = electrocardiogram,
HR = heart rate, ICL = imaging core laboratory, meds = medications, KPS = Karnofsky Performance Status, MRI = magnetic resonance imaging, MUGA
= multigated acquisition, NYHA = New York Heart Association, PET = positron emission tomography, PFS2 = progression-free survival after next 
line of therapy, PK = pharmacokinetic, RECIST = Response Evaluation Criteria in Solid Tumors, RR = respiratory rate, SAEs = serious adverse events,
Tx = treatment.
a.
Subjects must be screened within 28 days prior to randomization.  The screening assessment can serve as the baseline assessment, if performed within 
72 hours before randomization.  Baseline assessments may be performed on Day -1 or on C1D1 prior to randomization.  Patients randomized after the 
baseline assessment must have all baseline assessments reviewed prior to C1D1.  Informed consent may be obtained up to 4 weeks prior to
randomization.
b.
Efforts should be made to conduct study visits on the dayscheduled (±3 days).  The study visit (and safety assessments) still needs to occur regardless of 
a study medication hold per the visit schedule.
c.
KPS assessment will be performed at the Screening and Baseline Visits, on C2D1, and on Day 1 of every subsequent cycle.  NYHA assessment will
only be performed at the Screening visit.  See protocol appendices for KPS assessments and NYHA Cardiac Disease Classification.
d.
TNM staging, according to AJCC criteria (Edge, et al., 2010), should be reported based on the initial diagnosis of RCC.
e.
Assessments will include vital signs (resting BP [including date and time of measurement], HR, RR and bodytemperature), weight, and height.
Height will be measured at the Screening visit only.
One BP assessment is defined as the mean value of 3 measurements at least 5 minutes apart. 
An elevated BP assessment (ie, systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg should be confirmed by a repeat assessment after a minimum of1
hour.
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored every 2 weeks (on Day 1 and 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. A 
diary will be provided to the subject to capture the blood pressure evaluations between study visits. See subsection for management of hypertensive 
subjects.
Note:  During Cycle 3 and subsequent cycles, subjects may return to the clinic for the Day 15 visit if BP monitoring testing is required as specified 
above.  The Day-15 visit is mandatory in Cycles 1 and 2.
f.
A comprehensive physical examination (including a neurological examination) will be performed at the Screening or Baseline Visits, on Cycle 1/Day
15, on Day1 of each subsequent cycle, and at the Off-Treatment assessment.  A symptom-directed physical examination will be performed on C1D1


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and at any time during the study, as clinically indicated.
g.
Required if screening physical examination was performed >7 days prior to C1D1.
h.
Single 12-lead ECG.  Subjects are suggested to be in the recumbent position for a period of 5 minutes prior to obtaining ECG.
i.
An echocardiogram or MUGA scan to assess LVEF will be performed at Screening and as clinicallyindicated.
j.
A serum or urine pregnancy test will be performed at the Screening Visit, at the Baseline Visit (or within 72 hours prior to the first dose of study drug),
at Day1 of everycycle (starting with Cycle 2), and at the Off-Treatment assessment in women of childbearing potential (ie, premenopausal and
perimenopausal women who have been amenorrheic for less than 12 months).
k.
Clinical chemistry and hematology results must be reviewed prior to administration of study drug on C1D1 and within 2 business days of receipt of 
results for all subsequent cycles.  Electrolytes such as potassium, calcium, and magnesium should be monitored and abnormalities should be corrected 
in all subjects before starting treatment per the Investigator’s discretion.  Clinical laboratory assessments may be conducted anytime within 72 hours 
prior to the scheduled visit, unless otherwise specified.  If there is ≥Grade 3 hematologic or clinical chemistry toxicity, repeat the specific laboratory 
test and AE assessment at least 3-7 days (until improvement to <Grade 3).  For subjects with blood glucose >ULN, a fasting (>6 h, water only) blood 
glucose sample will be obtained. 
l.
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed locally every 2 weeks (on Day 1 and Day 15 or more frequently as 
clinically indicated) until the results have been 1+ or negative for 3 consecutive months. Urine dipstick testing should be performed preferably at 
the investigational site (but may be performed locally by the primary care physician or a local laboratory if the subject does not have to come for a 
visit to the site). If a new event of proteinuria ≥2+ occurs, the subject must resume the Day-15 urine dipstick testing for evaluation of proteinuria 
until results are 1+ or negative for 3 consecutive months. For subjects with a history of dipstick proteinuria ≥2+, see subsection for management of 
proteinuria.
Note:  During Cycle 3 and subsequent cycles, subjects may return to the clinic for the Day-15 visit if urine dipstick testing is required as specified 
above.  The Day-15 visit is mandatory in Cycles 1 and 2.
m.
Blood samples for PK profiling of lenvatinib and everolimus will be drawn at 0.5-4 h and 6-10 h postdose on C1D1; predose and 0.5-4 h and 6-10 h
postdose on C1D15, and predose and 2-12 h postdose on C2D1.  If possible, a blood sample for the measurement of the concentration of lenvatinib 
should be drawn at the first report of an SAE or a severe unexpected AE. A blood sample to measure study drug plasma concentrations will no longer 
be needed after the data cutoff for the primary analysis.
n.
Screening: Screening tumor assessments using contrast-enhanced CT of the chest, and contrast-enhanced CT or MRI of the abdomen and pelvis, and other
areas of known or suspected disease should be performed within 28 days prior to randomization. Historical scans that were performed within this
window but before informed consent maybe used if consistent with imaging requirement per the ICL.
Randomization Phase:
Tumor assessments using contrast-enhanced CT of the chest and contrast-enhanced CT or MRI of the abdomen, pelvis and other
areas of known disease at screening or newly suspected disease should be performed every8 weeks (during the eighth week, starting from the date of
randomization), or sooner if clinically indicated, until progressive disease. For subjects enrolled after implementation of Amendment 06, detailed image 
acquisition guidelines will be provided by the ICL until data cut off for the primary analysis. All responses must be confirmed no less than 4 weeks
following the initial assessment of response.  Tumor assessment at the Off-Treatment Visit is only necessary for subjects who discontinue studydrug
without disease progression if more than 4 weeks have passed since the previous assessment (window for these assessments is within 1 week of the Off-
Treatment Visit).
Follow-up Period:  Ifa subject discontinues from studytreatment without disease progression, tumor assessments should continue to be performed
every8 weeks until documentation of disease progression,beginning a new anticancer treatment or data cut off for the primary analysist. During the 
Follow-Up Period, scans will no longer be sent to the ICL.


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o.
A bone scan (99m-technetium-based scintigraphy, whole body bone MRI, or 18F-NaF PET) to assess bone metastases will be performed within 6 weeks
prior to randomization (historical scans prior to signing informed consent are acceptable) to establish a baseline, and then every 24 weeks (within the 24th
week) from randomization, or sooner if clinicallyindicated. In subjects whose body CT/MRI scans indicate CR, a bone scan will be required within a target 
of 1 week but no more than 2 weeks after achievement of CR to exclude new bone metastases. 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 at all tumor assessment time points with cross-sectional imaging).
p.
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should be performed within 28 days of randomization. Subjects 
with protocol-eligible treated brain metastases must also have brain CT/MRI performed at all tumor assessment time points (eg, every 8 weeks). For 
other subjects, brain scans should be performed as clinically indicated and to confirm CR. The same methodology (CT or MRI) and scan acquisition 
techniques that were used for the screening assessments should be followed during the Randomization phase. A brain scan will be performed within a 
target of 1 week but no more than 2 weeks following achievement of a CR.
q.
HRQoL will be assessed at Baseline, on Day 1 of each subsequent cycle starting with Cycle 2, and at the Off-Treatment Visit. Every effort should be 
made to administer HRQoL surveys prior to study drug administration and before other assessments and procedures.  
r.
Telephone contact or clinic visit on Day 8 (±2 days) of Cycle 1 to assess subjects for development of early toxicity.  An unscheduled visit may be
requested bythe investigator if deemed necessary.
s.
Concomitant medications will be recorded from the Screening Visit through 28 days after the last dose of studydrug. All anticancer therapy
will be recorded until time of death or the data cutoff for the primary analysis unless not allowed to be provided due to confidentiality.
t.
AEs and SAEs will be recorded from the signature of Informed Consent until 28 days after the last dose of study drug. SAEs, irrespective of
relationship to studydrug, must be reported as soon as possible but not later than 24 hours from the date when the investigator becomes aware of
the event.  Signs/symptoms related to disease progression should not be reported as AEs.  During treatment interruption due to AEs, repeat AE
assessments should be performed at least every7 days (until restarting studydrug administration).
u.
PFS2 is defined as the time from randomization to the date of disease progression after next line of therapy or death from any cause, whichever 
occurs first.  Subjects who discontinue treatment before the data cutoff for the primary analysis will be followed for survival every12 weeks (±1
week) after the Off-Treatment Visit. If a clinic visit is not feasible, follow-up information may be obtained via telephone or email.
v.
A blood sample for biomarkers will be collected at Baseline (pre-treatment) and at predose at the following time points: C1D15, C2D1, C3D1, 
C4D1, C5D1 and C6D1.  A sample should also be collected at the Off-Treatment Visit. The biomarker sample at the Off-Treatment Visit will 
not be collected after the data cutoff for the primary analysis.


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Table 7
Schedule of Assessments After the Data Cutoff for the Primary Analysis
Phase
After the Data Cutoff for the Primary Analysis
All cycles are 8 weeks in duration
Period
Study Treatment Perioda
Off-Treatment Visit
Procedures/Assessments
Vital Signsb
X
As clinically indicated
Physical Examinationc
X
As clinically indicated
12-Lead ECGd
As clinically indicated
As clinically indicated
Echocardiogram/MUGA scane
As clinically indicated
As clinically indicated
Pregnancy Test for WOCBPf
X
X
Clinical Chemistry/hematology (local lab)g
X
As clinically indicated
Urine dipstick testingh
X
As clinically indicated
Study drug administration
Once daily
Tumor assessments (CT/MRI)i
As per local standard of care
Bone Scanj
As clinically indicated
Brain scan (CT/MRI)k
As clinically indicated
AE/SAEl
X
X
Concomitant medicationsm
X
X
a. Efforts should be made to conduct study visits on the day scheduled (±3 days). The study visit (and safety assessments) still needs to occur regardless of a 
study medication hold per the visit schedule.
b. Assessments will include vital signs (resting BP [including date and time of measurement], HR, RR and body temperature). After the data cutoff for the 
primary analysis, one BP assessment is defined as the mean value of 2 measurements at least 5 minutes apart. A diary will be provided to the subject to 
capture the blood pressure evaluations between study visits. See subsection for management of hypertensive subjects.
c. A symptom-directed physical examination during the study, as clinically indicated.
d. Single 12-lead ECG as clinically indicated. Subjects are suggested to be in the recumbent position for a period of 5 minutes prior to obtaining ECG.
e. An echocardiogram or MUGA scan to assess LVEF will be performed as clinically indicated
f. A serum or urine pregnancy test will be performed at Day 1 of every cycle, and at the Off-Treatment assessment in women of childbearing potential (ie,
premenopausal and perimenopausal women who have been amenorrheic for less than 12 months).
g. Clinical laboratory assessments will be conducted at a local laboratory. Clinical chemistry and hematology results should be reviewed prior to 


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administration of study drug for all cycles. Assessments may be performed within 72 hours prior to the visit.
h. Urine dipstick testing for subjects should be performed preferably at the investigational site (but may be performed locally by the primary care physician 
or a local laboratory if the subject does not have to come for a visit to the site). For subjects with a dipstick proteinuria ≥2+, see section 9.4.2.3 for 
management of proteinuria.
i. After the data cutoff for the primary analysis: Tumor assessments using contrast-enhanced CT of the chest and contrast-enhanced CT or MRI of the 
abdomen, pelvis and other areas of known disease at screening or newly suspected disease should be performed as per local standard of care but not less 
frequently than every 12 weeks or earlier if clinically indicated.  The same methodology (CT or MRI) and scan acquisition techniques that were used for the 
assessment during the Prerandomization and Randomization Phases should be used after the data cutoff for the primary analysis.  Scans will no longer be 
sent to the imaging core lab after the data cutoff for the primary analysis.
j. A bone scan to assess bone metastases should be performed as clinically indicated.
k. Subjects with protocol-eligible treated brain metastases should also have brain CT/MRI performed as per local standard of care. For other subjects, brain 
scans should be performed as clinically indicated.
l. All AEs leading to study drug discontinuation and SAEs will be recorded until 28 days after the last dose of study drug. SAEs, irrespective of relationship 
to study drug, must be reported as soon as possible but not later than 24 hours from the date when the investigator becomes aware of the event.
m. Concomitant medications will be recorded until 28 days after last dose.


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9.5.2.1
Description of Procedures/Assessments Schedule
Refer to Table 6 for a description and timing of each procedure and assessment in the 
Prerandomization and Randomization Phase and to Table 7 for procedures and assessments
after the data cutoff for the primary analysis. 
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies of metastatic 
RCC.  The safety assessments to be performed in this study, including hematology analyses, 
blood chemistry tests, urine dipstick testing, and assessment of AEs, are standard evaluations 
to ensure subject safety.
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations
9.5.4.1
Reporting of Serious Adverse Events
All SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 24 hours from when the investigator becomes aware of the event.
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for 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 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
For sites in the US, 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 


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forwarded to the sponsor and/or the designated CRO, depending on responsibility for 
regulatory documents, 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 8 weeks of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 8 weeks 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 24 hours from when the investigator becomes 
aware of the pregnancy.  The contact information for the reporting of pregnancies and 
exposure to study drug through breastfeeding is provided in the Investigator Study File.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from when the investigator becomes aware of the event 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
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 the 


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healthcare professional, subject, or consumer.  Such events may be 
related to professional practice, healthcare products, occupational 
exposure, procedures, or systems, including prescribing, order 
communication, product labeling/packaging/nomenclature,
compounding, dispensing, distribution, administration, education,
monitoring, or use.
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (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
As of 14 Jul 2018, the subjects’ treatment assignment is no longer blinded.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
SUSARs will be reported, as required, to the competent authorities of all involved European 
member states.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 6) and Schedule of Assessments After the 
Data Cutoff for the Primary Analysis (Table 7).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 


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measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, progression of disease, withdrawal of 
consent, pregnancy, study terminated by sponsor, or other.  In addition to the primary reason, 
the subject may indicate 1 or more secondary reason(s) for discontinuation.  Study 
disposition information will be collected on the Subject Disposition CRF.
A subject removed from the study for any reason may not be replaced.
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.
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness.
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities.


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9.6.2
Clinical Data Management
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system.
9.7
Statistical Methods
All statistical analyses will be performed by the sponsor or designee after the study is 
completed (based on the data cut off for the primary analysis) and the database is locked and 
released. The interim analyses will be performed by an independent statistical reporting 
team. 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 ENDPOINTS

Objective response rate at Week 24 (ORR24W) as assessed by the investigator according 
to RECIST 1.1 (Appendix 8). ORR24W is defined as the proportion of subjects with best 
overall response (BOR) of complete response (CR) or partial response (PR) at the 
Week-24 (after randomization) time point or earlier. To be considered a BOR, all 
responses must be confirmed no less than 4 weeks after the initial assessment of 
response.

Proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks 
after randomization (as of the Week-24 time point).
9.7.1.1.2
SECONDARY ENDPOINTS

Progression-free survival (PFS), defined as the time from the date of randomization to the 
date of first documentation of disease progression or date of death or the date of data cutoff 
for the primary analysis, whichever occurs first.  PFS censoring rules will be defined in the 
statistical analysis plan (SAP) and will follow FDA guidance.

ORR as assessed by the investigator according to RECIST 1.1 at the end of treatment.  
ORR is defined as the proportion of subjects with BOR of CR or PR at the end of 
treatment.  To be considered BOR, all responses must be confirmed no less than 4 weeks 
after the initial assessment of response.

Overall safety profile and tolerability of lenvatinib in combination with everolimus.

Proportion of subjects who discontinue treatment due to toxicity, defined as the 
proportion of subjects who discontinue study treatment due to TEAEs.


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
Time to treatment failure due to toxicity, defined as the time from the date of 
randomization to the date that a subject discontinues study treatment due to TEAEs.

Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions.

Overall survival (OS), measured from the date of randomization until date of death from 
any cause.  In the absence of confirmation of death, subjects will be censored either at the 
date that the subject was last known to be alive or the date of data cutoff for the primary 
analysis, whichever comes earlier.

Health-Related Quality of Life (HRQoL) will be assessed using the Functional 
Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms 
(FKSI-DRS), the European Organization for the Research and Treatment of Cancer 
(EORTC) QLQ-C30 and the European Quality of Life (EuroQol) EQ-5D-3L instruments.

PFS2, defined as the time from randomization to the date of disease progression after 
next line of therapy or death from any cause or the date of data cutoff for the primary 
analysis, whichever occurs first.  PFS2 censoring rules will be defined in the SAP.
9.7.1.1.3
EXPLORATORY ENDPOINTS 

Tumor response endpoints ORR24W, ORR, and PFS based on IIR assessment. These 
endpoints will be defined in the same way as those based on the investigator assessments. 

Associations between blood biomarker and efficacy related endpoints.

Development of exposure/biomarker/clinical endpoint models (whenever possible, using 
a mechanism-based approach) for both efficacy and safety data.
9.7.1.2
Definitions of Analysis Sets
Full Analysis Set will include all randomized subjects.  This will be a secondary analysis set 
for efficacy endpoints, which will be analyzed according to the treatment randomized, 
regardless of the treatment actually received.
Per-Protocol Analysis Set 1 will include all randomized subjects minus the 32 subjects who 
had received ≥2 incorrect lenvatinib doses due to IxRS issues.  This will be the primary 
analysis set for efficacy endpoints, which will be analyzed according to the treatment 
randomized.
Per-Protocol Analysis Set 2 will include all subjects who received at least 1 dose of study 
drug, had no major protocol deviations, and had both baseline and at least 1 post-baseline 
tumor assessment.  Subjects for whom death occurred before the first post-baseline tumor 
assessment will also be included.  The Per-Protocol Analysis Set 2 will be a secondary 
analysis set for efficacy endpoints. The 32 subjects who received ≥2 incorrect lenvatinib 
doses due to IxRS issues are considered as having experienced major protocol deviations and 
will be excluded from the Per-Protocol Analysis Set 2. (A 33rd subject received a single 
incorrect lenvatinib dose due to IxRS issues, but given the brief exposure of the incorrect 
[slightly higher] dose before detection and correction, and because there were no adverse 


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effects, this subject will be considered to have experienced a minor protocol deviation and 
will not be excluded from analysis sets.)
Safety Analysis Set will include all subjects who were randomized and received at least 
1 dose of study drug.  This will be the analysis set for all safety evaluations, which will be 
analyzed according to the treatment actually received.
Per-Protocol Safety Analysis Set will include all treated subjects in Per-Protocol Analysis 
Set 1. This will be the primary analysis set for the primary safety endpoint, which will be 
analyzed according to the treatment actually received. 
Pharmacokinetic (PK) Analysis Set will include all subjects who received at least 1 dose of 
study drug with documented dosing history and have at least 1 evaluable lenvatinib plasma or 
everolimus whole blood concentration data.
Pharmacodynamic Analysis Set will include all subjects who received at least 1 dose of 
study drug with documented dosing history and have at least 1 evaluable pharmacodynamic 
data.
For the Pharmacokinetic, Pharmacodynamic and other Biomarker endpoints, their respective 
analysis plans will specify if the analysis set will or will not include the 32 subjects who 
received ≥2 incorrect lenvatinib doses due to IxRS issues
Quality of Life (QoL) Analysis Set will consist of all subjects who have any QoL data.
The analysis sets are summarized in the following table.
Analyses for:
Efficacy Parameters
Safety Parameters
Analysis Set:
Full Analysis Set
Safety Analysis Set
Definition:
All subjects randomized
All randomized subjects who received 
at least 1 dose of study drug
Used as:
A secondary analysis set for efficacy 
endpoints
An analysis set for safety parameters
Analysis Set:
Per-Protocol Analysis Set 1
Per-Protocol Safety Analysis Set
Definition:
All randomized subjects minus the 32 
subjects who received ≥2 incorrect 
lenvatinib doses due to IxRS issues
All treated subjects minus the 32 
subjects who received ≥2 incorrect 
lenvatinib doses due to IxRS issues
Used as:
The primary analysis set for the primary 
efficacy endpoint
The primary analysis set for the 
primary safety endpoint
An analysis set for the secondary efficacy 
endpoints
An analysis set for other safety 
parameters
For interim 
analyses:
The analysis set for the planned 2 interim 
analyses of the primary efficacy endpoint
The analysis set for the planned two 
interim analyses of the primary safety 
endpoint


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Analysis Set
Per-Protocol Analysis Set 2
Definition
All randomized subjects who received at least one dose, had no major protocol 
deviation, and had both baseline and at least 1 post-baseline tumor assessment.  
Subjects for whom death occurred prior to the first post-baseline tumor assessment 
will also be included.
Used as
An analysis set for a sensitivity analysis of
the primary efficacy endpoint
An analysis set for a sensitivity 
analysis of the primary safety endpoint
An analysis set for the secondary efficacy 
endpoints
9.7.1.3
Subject Disposition
Subject disposition will be summarized for the Per-Protocol Analysis Set 1, Per-Protocol 
Analysis Set 2, and Full Analysis Set. All subjects who were screened for the study will be 
accounted for and reported in the study results.  The reasons for screen failures will be 
described and documented by subject and summarized by total number of subjects with 
screen failures.  If deemed relevant, the reasons for excluding subjects will be evaluated to 
determine if these reasons could help clarify the appropriate subject population for eventual 
drug use.
The number (percentage) of randomized and treated subjects will be summarized as well as 
subjects who completed the study/discontinued from the study and reasons for 
discontinuation by treatment arm.  The number (percentage) of subjects who completed the 
study treatment/discontinued from the study treatment and reasons for discontinuation will 
also be summarized by treatment arm.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics will be summarized for the Per-Protocol 
Analysis Set 1, Per-Protocol Analysis Set 2, and Full Analysis Set.  For continuous 
demographic/baseline variables including age, weight, and height, results will be summarized 
and presented as N, mean, standard deviation, median, Q1, Q3, and minimum and maximum 
values.  For categorical variables such as race/ethnicity, the number and percentage of 
subjects will be used.
9.7.1.5
Prior and Concomitant Therapy
Prior and concomitant therapy will be summarized for the Per-Protocol Analysis Set 1 and 
Full Analysis Set. All investigator terms for medications recorded on the CRF will be coded 
using the World Health Organization (WHO) Drug Dictionary.  Prior medications will be 
defined as medications that were started prior to the first dose of study drug and were stopped 
prior to the first dose of study drug. Concomitant medications will be defined as medications 
that (i) started before the first dose of study drug and were continuing at the time of the first 
dose of study drug, or (ii) started on or after the date of the first dose of study drug up to 28
days following the last dose in randomization phase.  Medications that cannot be determined 


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to be prior/concomitant/posttreatment due to missing or incomplete dates will be regarded as 
concomitant.
Prior medications will be summarized by anatomical class (Anatomical Therapeutic 
Chemical [ATC] Level 1), pharmacologic class (ATC Level 3), and World Health 
Organization (WHO, Geneva, Switzerland) generic drug name by frequency counts and 
percentages.  The same summary will be provided for concomitant medications except 
thyroxine suppression therapy and hypertensive therapy.  Concomitant thyroxine suppression 
therapy and hypertensive therapy will be summarized separately.  In addition, there also will 
be a separate summary for the concomitant medications of P-glycoprotein inhibitors and/or 
inducers.  Data listings will be provided for all prior and concomitant medications, for all 
concomitant thyroid suppression therapy, for all concomitant hypertensive therapy, and for 
all concomitant P-glycoprotein inhibitors and/or inducers.  
9.7.1.6
Efficacy Analyses
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Primary analysis of ORR24W will be based on a non-inferiority test. There will be two 
interim analyses and the primary analysis. The two interim analyses will be performed using 
only Per-Protocol Analysis Set 1. The primary analysis will be performed using the Per-
Protocol Analysis Set 1 as the primary analysis set and will also be performed using Per-
Protocol Analysis Set 2 and the Full Analysis Set as secondary analysis sets. At each interim 
analysis and primary analysis, the point estimate of ORR24W for each treatment group (18 mg 
and 14 mg) will be summarized with the corresponding 95% confidence interval (CI). The 
odds ratio of ORR24W (14 mg vs 18 mg) along with the 90% CI will be calculated using the 
Cochran-Mantel-Haenszel (CMH) method stratified by MSKCC prognostic groups and prior 
PD-1/PD-L1 treatment. Non- inferiority in ORR24W will be claimed if the O’Brien-Fleming 
efficacy boundary is crossed at either interim analysis or primary analysis based on the 
results from the Per-Protocol Analysis Set 1. If the 1-sided P-value is ≤0.005 at the first 
interim analysis, or ≤0.014 at the second interim analysis, or ≤0.045 at the primary analysis, 
non-inferiority in ORR24W will be claimed. Futility will be claimed if the futility boundary is 
crossed. If the 1-sided P-value is ≥0.776 at the first interim analysis, or ≥0.207 at the second 
interim analysis, futility will be claimed. The treatment difference in ORR24W for 14 mg vs 
18 mg will also be estimated along with 90% CIs based on the asymptotic normal 
approximation. 
At each interim analysis and at the primary analysis, if the noninferiority boundary of the 
primary efficacy endpoint is crossed, the analysis of the primary safety analysis will be 
performed for Per-Protocol Safety Analysis Set. The primary safety endpoint is the 
proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks 
after randomization (as of the Week-24 time point).  Frequency (number and percentage) will 
be summarized for intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after 
randomization by treatment. The proportions will be tested using the CMH test (2-sided 
alpha=0.05), stratified by MSKCC prognostic groups and prior PD-1/PD-L1 treatment. The 
proportions of the primary safety endpoint will also be summarized for Safety Analysis Set 
for descriptive purpose.


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To explore homogeneity of treatment effect across centers/regions, sensitivity analyses will 
be conducted to adjust center/region effect for the primary endpoints of ORR24W and 
proportion of subjects with intolerable Grade 2 and any ≥Grade 3 TEAEs within 24 weeks 
after randomization using logistic regression models, including center/region as a covariate. 
Determination of whether 14 mg lenvatinib can be used as an alternative dosing strategy will 
be based on clinical judgment by the sponsor in consultation with the independent DMC (as 
specified in the DMC charter) by assessing risks and benefits according to the totality of the 
safety and efficacy data.
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
All secondary efficacy endpoints will be summarized descriptively for the Per-Protocol 
Analysis Set 1, Per-Protocol Analysis Set 2, and Full Analysis Set. The median PFS and 
PFS2 will be calculated using the KM product-limit estimates for each treatment group and 
presented with 2-sided 95% CIs. The KM estimate of PFS will also be plotted over time for 
each treatment group. 
Point estimate of ORR and 95% CI will be summarized for each treatment arm.  Odds ratio 
with 90% CI will be estimated using the CMH method stratified by MSKCC prognostic 
groups and prior PD-1/PD-L1 treatment.
The median survival time and the survival rates at 12, 18, and 24 months will be calculated 
using KM product-limit estimates for each treatment group and presented with 2-sided 95% 
CIs.  The KM estimates of OS will be plotted over time.
For HRQoL analyses, summary statistics of the scores for the derived functional/symptom
scales according to the scoring manual and global health status scores will be summarized by 
treatment arm at each time point.  A separate pre-specified HRQoL analysis following FDA 
and EMEA patient-reported outcome (PRO) guidelines will be performed and detailed in a 
separate SAP and HRQoL report.  Scoring of EQ-5D-3L and derivation of utility for health 
economic analysis will also be accomplished in a separate analysis and described in a 
separate HRQoL report.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
All exploratory endpoints will be summarized descriptively. Exploratory efficacy response 
endpoints ORR24W, ORR, and PFS based on IIR assessment will be summarized using the 
same statistical methods as those used for the same response parameters based on the 
investigator assessments.   
9.7.1.6.4
HANDLING OF MISSING DATA FOR EFFICACY ANALYSES
For efficacy endpoints related to ORR which summarizes the percentage of responders, 
missing responses will not be imputed and subjects with missing response will be considered 
as non-responders. For incomplete dates involving efficacy data, a conservative imputation 
rule will be used for calculation if needed. Details of handling missing data and imputation 
rules will be specified in SAP and further in the study analysis dataset specifications. 


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HRQoL analysis will follow FDA and EMEA PRO guidelines. Handling of missing values 
for HRQoL analyses will be detailed in a separate SAP and HRQoL report.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Analyses
Lenvatinib and everolimus concentrations will be summarized by use of descriptive statistics 
and plotted as appropriate for each treatment group.
Concentrations of lenvatinib in plasma and everolimus in whole blood will be pooled with 
existing data from other completed studies and analyzed using a population PK approach to 
estimate population PK parameters for each drug. The analyses will be detailed in a separate 
analysis plan.
9.7.1.7.1
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
Lenvatinib and everolimus exposure parameters (AUC or concentration at the time of the 
event or cumulative AUC, as appropriate) derived from the population PK analysis will be 
related to biomarker, safety, and efficacy data using a model-based approach.  For some 
PK/PD analyses, data from this study will be pooled with data from the Phase 2 Study 
E7080-G000-205 (Study 205).
For the exposure-response relationship for biomarkers (e.g., VEGF, Ang-2), data will be 
analyzed using a model-based approach with indirect PK/PD models.
For efficacy, a tumor growth inhibition model based on longitudinal tumor size 
measurements of target lesions will be included.  Study drug exposure for lenvatinib and 
everolimus and/or measured biomarkers (e.g., VEGF, Ang-2) will be investigated as 
predictors and/or correlations with tumor burden changes in the tumor growth inhibition 
model, whenever possible using a mechanism-based approach.
Other analyses will include logistic regression analysis for ORR24W, KM plots of PFS data, 
and Cox-regression analysis.  For the Cox-regression analysis of PFS, adjustment will be 
made for subject’s baseline characteristics or tumor-related features.  In addition to lenvatinib 
and everolimus exposure, changes in biomarker concentrations and/or tumor burden will be 
related to PFS, whenever possible using a mechanism-based approach.
For the exposure-response relationship of safety, the model-based analysis will include the 
following AEs:  hypertension (systolic and diastolic BP), triglyceridemia (and 
cholesterolemia), glycemia, proteinuria, weight loss, fatigue, nausea, vomiting and diarrhea.  
For hypertension, triglyceridemia (and cholesterolemia) and glycemia, data will be analyzed 
using an indirect-response model.  For proteinuria, urine dipstick and/or 24-hour urine data 
will be analyzed using a longitudinal categorical logistic regression analysis with Markov 
element.  For weight loss, fatigue, nausea, vomiting, and diarrhea, data will be analyzed 
using a longitudinal categorical logistic regression analysis.  For time to treatment 
discontinuation due to an AE and time to first dose reduction, KM plots stratified by 
lenvatinib exposure will be prepared.
Population PK and PK/PD analyses will be detailed in a separate analysis plan.


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9.7.1.7.2
BIOMARKER ANALYSES
The effect of lenvatinib and everolimus combination treatment on exploratory biomarkers 
will be summarized by treatment group. Associations between clinical outcomes and 
baseline biomarker levels, and/or change in levels from baseline will be explored. The 
analysis will be detailed in the biomarker analysis plan (BAP) and reported separately.
For exploratory endpoints, Pharmacokinetic, Pharmacodynamic and Other Biomarker 
endpoints, their respective analysis plans will specify if the analyses will and will not include 
the 32 subjects who received ≥2 incorrect lenvatinib doses due to IxRS issues.
9.7.1.8
Safety Analyses
All safety analyses will be performed on the Per-Protocol Safety Analysis Set and Safety 
Analysis Set.  All safety analyses will be summarized separately by treatment group.  The 
incidence of TEAEs, intolerable Grade 2 TEAEs that lead to dose interruption, dose 
reduction, or drug discontinuation, ≥ Grade 3 TEAEs, and SAEs will be summarized; rates 
will be summarized using descriptive statistics.  
Time to treatment discontinuation due to an AE, number of dose reductions, and time to first 
dose reduction will be summarized. The proportion of subjects who discontinue treatment 
due to toxicity will be summarized by frequency counts and percentages.  Median, upper, and 
lower quintiles of time to treatment discontinuation due to toxicity will be summarized for 
subjects who discontinue study treatment due to TEAEs.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation due to AEs will be summarized.
9.7.1.8.2
ADVERSE EVENTS
Adverse events will be graded using CTCAE v4.03.  The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology 
using the Medical Dictionary for Regulatory Activities (MedDRA).  Adverse events will be 
coded to the MedDRA lower level term (LLT) closest to the verbatim term.  The linked 
MedDRA preferred term (PT) and primary system organ class (SOC) are also captured in the 
database.
A TEAE is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 
•
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
•
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.


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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.
An overview table, including the incidence of and the number of subjects with TEAEs, 
SAEs, deaths, and those TEAEs that led to study drug discontinuation, dose modification, or 
dose interruption will be provided.
The incidence of TEAEs will be summarized by system organ class (SOC), preferred term 
(PT), CTCAE grade, and relatedness to study drug.  All summaries will be performed by 
treatment group.  Although a MedDRA term may be reported more than once for a subject, 
that subject will be counted only one time in the incidence count for that MedDRA term with 
the highest CTCAE grade (in the summary by CTCAE grade) or with the closest relationship 
to study treatment (in the summary by relatedness to study treatment).
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).
In addition, the overall proportion of subjects with TEAEs of CTCAE Grade 3 or higher and 
the overall proportion of subjects with intolerable CTCAE Grade 2 TEAEs that result in dose 
modification will be summarized.
9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.4.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment (defined as the last on-
treatment value) will be summarized by visit and treatment arm using descriptive statistics.  
Laboratory parameters will be categorized according to CTCAE v4.03. Grades, and shifts 
from baseline CTCAE Grade to worst postbaseline Grade will be assessed using shift tables.
Percentages will be based on the number of subjects with both nonmissing baseline and at 
least 1 postbaseline result.
Common Terminology Criteria for Adverse Events v4.03 (Appendix 3) will be used to 
identify subjects with treatment-emergent markedly abnormal laboratory values (TEMAV).  
A more detailed definition of TEMAV will be specified in the SAP.  A summary of 
TEMAVs will be presented by treatment arm.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit and treatment group.  Subjects will be included in the summary if they had both a 
Baseline value and at least 1 postbaseline value.
9.7.1.8.5
ELECTROCARDIOGRAMS
Descriptive statistics for ECG parameters and changes from baseline will be presented by 
visit and by treatment group. Shift tables will present changes from baseline in ECG 


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interpretation (categorized as normal; abnormal, not clinically significant; and abnormal 
clinically significant).
9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive summary statistics for LVEF assessed on echocardiogram or MUGA scans and
changes from baseline will be calculated and summarized by treatment group.
9.7.2
Determination of Sample Size
The objective of the study is to assess whether a starting dose of lenvatinib 14 mg QD in 
combination with everolimus 5 mg will provide comparable efficacy with an improved safety 
profile compared to lenvatinib 18 mg in combination with everolimus 5 mg.  Determination 
of whether 14 mg lenvatinib can be used as an alternative dosing strategy will be based on 
clinical judgment by the Sponsor in consultation with the independent DMC (as specified in 
the DMC charter) by assessing risks and benefits according to the totality of data at either of 
the interim or primary analyses.  Nevertheless, the sample size is guided by the plan of 
testing non-inferiority on the primary efficacy endpoint and superiority on the primary safety 
endpoint.  The details and assumptions are provided below.
Sample size is based on detecting both the non-inferiority of ORR24W and superiority of the 
primary safety endpoint of the proportion of subjects with intolerable Grade 2 or any 
≥Grade 3 TEAEs within 24 weeks after randomization in comparison of the 14-mg arm to 
the 18-mg arm (Appendix 13).
Non-Inferiority of ORR24W Comparing the 14-mg Arm to the 18-mg Arm
Based on the assumption from Study 205 that the confirmed ORR for the 18 mg lenvatinib + 
5 mg everolimus arm is 37% (19 responders out of N=51) vs 6% for the everolimus arm 
(3 responders out of N=50), the 95% CI of the odds ratio comparing everolimus vs. 
lenvatinib 18 mg + everolimus arm is (0.029, 0.395). The non-inferiority margin is chosen to 
ensure that a reasonable fraction of the lenvatinib 18 mg + everolimus vs. everolimus 
treatment effect is preserved. A 70% retention of the treatment effect of lenvatinib 18 mg + 
everolimus vs. everolimus is used for this design. Following the approach in Rothmann,
et al. (2003), using the 95% CI upper limit method based on logarithm of the odds ratio, the 
non-inferiority margin is estimated as 
exp((1 −
) ∗(   95%   log  ! (" #" 18 % +  " 
⁄
))), 
where 0 < 
 < 1 is the retention rate. 
To retain 70% of the lenvatinib 18 mg + everolimus vs. everolimus treatment effect, the 
non-inferiority margin of the odds ratio is estimated to be 
exp.(1 −0.7) ∗ %(0.395)/ = 0.76 (ie, Ha: OR (14 mg/18 mg)> M). Listed below are the 
non-inferiority margins on the scale of difference in ORR24W between the lenvatinib 14-mg +
everolimus arm and the lenvatinib 18-mg + everolimus arm corresponding to a 0.76 non-
inferiority margin on the odds ratio scale for a different ORR24W in the lenvatinib 18-mg +
everolimus arm.


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ORR24W in the Lenvatinib 
18-mg Arm
Non-inferiority Margin on Difference Scale (Lenvatinib 14-mg ARM –
Lenvatinib 18-mg ARM)
10%
-0.02
20%
-0.04
30%
-0.05
40%
-0.06
50%
-0.07
60%
-0.07
Two interim analyses will take place when 150 and 200 total subjects in the Per-Protocol
Analysis Set 1 have completed 24 weeks follow-up or discontinue earlier.  Each interim 
analysis will test both non-inferiority and futility of the 14-mg arm ORR24W compared to the 
18-mg arm ORR24W. An O’Brien-Fleming stopping boundary will be used for non-
inferiority.  An interpolated non-binding stopping boundary will be used for futility, which 
will spend β=0.005 and β=0.10 at the first and second interim analysis, respectively.  
Assuming 37% ORR24W in the lenvatinib 18-mg arm and 45% ORR24W in the lenvatinib 
14-mg arm, and adjusting for the interim analyses, a total of 306 subjects (153 per arm) in the 
Per-Protocol Analysis Set 1 is required to achieve 80% statistical power at 1-sided α = 0.05
(East 6 User Manual, 2014).
The stopping boundaries on the P-value scale and the cumulative error probabilities spent at 
each interim analysis and primary analysis are shown in the table below.  For example, at the 
second interim analysis, non-inferiority in ORR24W will be claimed if the 1-sided P-value is 
≤0.014; futility will be claimed if the 1-sided P-value is ≥0.207.
Analysis No.
Cumulative α 
Spent
Efficacy Boundary
(P-value)
Cumulative β 
Spent
Futility Boundary
(P-value)
Interim Analysis #1
0.005
0.005
0.005
0.776
Interim Analysis #2
0.015
0.014
0.10
0.207
Primary Analysis
0.05
0.045
0.2
0.045
Superiority of Primary Safety Endpoint Comparing 14-mg Arm to 18-mg Arm:
At each interim analysis and the primary analysis in the Per-Protocol Safety Analysis Set, 
safety will be evaluated if the non-inferiority boundary is crossed.  Assuming 75% subjects 
with intolerable Grade 2 or above TEAEs within 24 weeks after randomization in the 18-mg 
arm, with a total of 306 subjects, a superiority test at 2-sided α=0.05 will give 80% statistical 
power to detect a 15% drop in proportion of subjects with intolerable Grade 2 or above 
TEAEs within 24 weeks after randomization in the 14 mg-arm.
In consideration of both the primary efficacy and safety endpoints, a total of approximately 
306 subjects were originally planned to be randomized in a 1:1 ratio to both treatment arms.
Since there were 32 subjects who received ≥2 incorrect lenvatinib doses due to IxRS issues, 
the number of subjects to be randomized will be increased by 32 to a total of approximately 
338. Therefore, there will be approximately 306 subjects in the Per-Protocol Analysis Set 1.


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Randomization will be stratified by MSKCC prognostic groups (favorable, intermediate, and 
poor risk) and whether subjects have had a prior PD-1/PD-L1 treatment (yes or no).
9.7.3
Interim Analyses
Safety and efficacy monitoring will be performed by an independent DMC.  The function 
and membership of the DMC will be described in the DMC charter.  Minutes from the open 
meetings of the DMC will be provided to regulatory agencies, if requested.
Two interim analyses will take place when 150 and 200 total subjects in the Per-Protocol
Analysis Set 1 have completed 24 weeks follow-up or discontinue earlier.  Each interim 
analysis will test both non-inferiority and futility of the 14 mg-arm ORR24W compared to the 
18 mg-arm ORR24W.  An O’Brien-Fleming stopping boundary (Lan and DeMets, 1983; 
DeMets and Ware, 1980) will be used for efficacy.  An interpolated non-binding stopping 
boundary will be used for futility, which will spend β=0.005 and β=0.10 at the first and 
second interim analyses, respectively.  The interim analyses will be performed by an 
independent statistical reporting team. 
9.7.4
Other Statistical/Analytical Issues
Not applicable.
9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.


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10 REFERENCE LIST
AFINITOR® (everolimus) Package Insert: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s034lbl.pdf
LENVIMA® (lenvatinib) Package Insert:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/206947s003lbl.pdf
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16:31-41.
DeMets DL and Ware JH. Group sequential methods for clinical trials with a one-sided 
hypothesis. Biometrika. 1980;67:651-60.
East 6 User Manual (2014), Cytel Inc.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, et al. AJCC Cancer 
Staging Manual. 7th ed. New York, NY: Springer-Verlag; 2010.
Kaplan AE, Meier P. Nonparametric estimation from incomplete observations. J Am Stat 
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Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika,
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Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, 
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Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, et al. Prognostic factors for 
survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol. 
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Rothmann M, Li N, Chen G, Chi GYH, Temple RT, Tsou HH. Design and analysis of non-
inferiority mortality trials in oncology. Stat Med. 2003;22(2):239-64.
Shumaker RC, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effect of rifampicin on the 
pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014;34(9):651-9. 
Shumaker RC, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effects of ketoconazole 
on the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharm in Drug 
Dev. 2015;4(2):155-60.


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CTCAE Reference
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-1 4_QuickReference_8.5x11.pdf.
RECIST Reference
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). 
Eur J Cancer. 2009;45(2):228-47.


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


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


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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).  In addition, since the 
study was unblinded in July 2018, the sponsor will send a list of treatment codes by study 
subject to the investigator. 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 principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed to 
each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site.
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 futility 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
Creatinine Clearance Estimate by Cockcroft-Gault 
Formula
Male
(140-age) x weight (kg)
= XX mL/min 
Serum creatinine (mg/dL) x 72
Female
(140-age) x weight (kg) x 0.85
= XX mL/min
Serum creatinine (mg/dL) x 72
Adapted from Cockcroft DW and Gault MH.  Nephron 1976;16(1):31-41.
For serum creatinine measured in μmol/L:
Male
(140-age) x weight (kg) x 1.23
= XX mL/min
Creatinine (µmol/L)
Female
(140-age) x weight (kg) x 1.23 x 0.85
= XX mL/min
Creatinine (µmol/L)


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Appendix 2
Clinical Studies Evaluating Drug-Drug Interactions with 
Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme 
responsible for metabolism of lenvatinib.  Clinical studies were conducted to test these 
findings. 
Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly (15% to 
19%) increases systemic exposure to lenvatinib (Shumaker, et al., 2015).  Since no change 
was observed in half-life, tmax, or lag time (tlag), the slight increase in systemic exposure is 
probably related to a decrease in first pass metabolism.  However, since the magnitude of 
change is small, co-administration of lenvatinib with CYP3A4/P-gp inhibitors is not of 
clinical concern. 
The influence of P-gp inhibition on lenvatinib PK has been investigated.  P-gp inhibition was 
accomplished by co-administering a single dose of rifampin with a single dose of lenvatinib.  
Preliminary results suggest P-gp inhibition increases systemic exposure to lenvatinib 26% to 
32%.  Thus, co-administration of lenvatinib with P-gp inhibitors only causes a small increase 
in lenvatinib exposure. 
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been 
investigated.  Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK 
was accomplished by administering rifampin QD for 21 days (Shumaker, et al., 2014).  A 
single dose of lenvatinib was co-administered with the 15th dose of rifampin.  Based on 
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib 
exposure as mean Cmax increased about 8% while AUC decreased about 7%.  Co-
administration of lenvatinib with CYP3A4/P-gp inducers is not of clinical concern.
The main metabolic pathways for lenvatinib in humans were identified as enzymatic 
(CYP3A and aldehyde oxidase) and non-enzymatic processes (LENVIMA® Package Insert).


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Appendix 3
Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03
The Common Terminology Criteria for Adverse Events (CTCAE v4.03, published 14 June 
2010) provides descriptive terminology to be used for adverse event reporting in clinical 
trials.  A brief definition is provided to clarify the meaning of each AE term.  To increase the 
accuracy of AE reporting, all adverse event terms in CTCAE v4.03 have been correlated with 
single-concept Medical Dictionary for Regulatory Activities (MedDRA) terms.
The Common Terminology Criteria for Adverse Events v4.03 grading refers to the severity 
of the AE.  The Common Terminology Criteria for Adverse Events grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Grade
CTCAE Status
1
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated
2
Moderate:  minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADLb
4
Life-threatening consequences: urgent intervention indicated
5
Death related to adverse event
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Adapted from: Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-1 4_QuickReference_8.5x11.pdf.
For further details regarding MedDRA, refer to the MedDRA website at:  
http://www.meddra.org


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Appendix 4
Karnofsky Performance Status
Karnofsky Performance Status Scale
Definitions
Rating (%)
Criteria
Able to carry on normal activity and 
to work:  No special care needed
100
Normal no complaints; no evidence of 
disease
90
Able to carry on normal activity; minor 
signs or symptoms of disease
80
Normal activity with efforts; some signs or 
symptoms of disease
Unable to work; able to live at home 
and care for most personal needs; 
varying amount of assistance needed
70
Cares for self; unable to carry on normal 
activity or to do active work
60
Requires occasional assistance, but is able 
to care for most of his/her personal needs
50
Requires considerable assistance and 
frequent medical care
Unable to care for self.  Requires 
equivalent of institutional or hospital 
care; disease may be progressing 
rapidly
40
Disabled; requires special care and 
assistance
30
Severely disabled; hospital admission is 
indicated although death not imminent
20
Very sick; hospital admission necessary; 
active supportive treatment necessary
10
Moribund; fatal process progressing rapidly
0
Death
Source: Mor V, Laliberte L, Morris JN, et al. The Karnofsky Performance Status Scale. An examination of its reliability and 
validity in a research setting. Cancer 1984;53:2002-2007.


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Appendix 5
New York Heart Association Cardiac Disease 
Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for heart failure patients 
based on cardiac functional capacity.  Based on NYHA definitions, subjects are to be 
classified as follows:
Class
NYHA Status
Class I:
Patients with cardiac disease but without resulting limitation of physical 
activity; ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea or anginal pain.
Class II:
Patients with cardiac disease resulting in slight limitation of physical 
activity; they are comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea, or anginal pain.
Class III:
Patients with cardiac disease resulting in marked limitation of activity; 
they are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
Class IV:
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or angina 
syndrome may be present even at rest.  If any physical activity is 
undertaken, discomfort is increased.
NYHA = New York Heart Association.
Source: The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. 9th ed. Boston, Mass: Little, Brown & Co; 1994:253-256.
Note: NYHA Classification only applies to subjects with underlying cardiac disease.


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Appendix 6
MSKCC Risk Model Criteria
Determination of Prognostic Score in Previously-Treated Patients
Parameter
Risk Factor
Criteria Value
Subject 
Value
If subject value meets 
criteria value, enter 1
KPS
Low KPS
<80%
Corrected Calcium*
High Corrected 
Calcium
≥10 mg/dL
Hemoglobin
Low Hemoglobin
Males: ≤13 g/dL
Females: ≤11.5 g/dL
Sum total of above = 
MSKCC Prognostic 
Score:
* Corrected Calcium = ([4 – serum albumin in g/dL] x 0.8 + serum calcium)
Risk Group Based on MSKCC Prognostic Score
Risk Group
MSKCC Prognostic Score
Favorable Risk
0
Intermediate Risk
1
Poor Risk
2 or 3
Source:  Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously 
treated patients with metastatic renal cell carcinoma. J Clin Oncol 2004;22:454–63.


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Appendix 7
Tumor, Node, and Metastasis Staging of Renal Cell 
Carcinoma
Primary tumors (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor ≤7 cm in greatest dimension, limited to the kidney
T1a
Tumor ≤4 cm in greatest dimension, limited to the kidney
T1b
Tumor >4 cm but not >7 cm in greatest dimension, limited to the kidney
T2
Tumor >7 cm in greatest dimension, limited to the kidney
T2a
Tumor >7 cm but ≤10 cm in greatest dimension, limited to the kidney
T2b
Tumor >10 cm, limited to the kidney
T3
Tumor extends into major veins or perinephric tissues but not into the ipsilateral 
adrenal gland and not beyond the Gerota fascia
T3a
Tumor grossly extends into the renal vein or its segmental (muscle-containing) 
branches, or tumor invades perirenal and/or renal sinus fat but not beyond the Gerota 
fascia
T3b
Tumor grossly extends into the vena cava below the diaphragm
T3c
Tumor grossly extends into the vena cava above the diaphragm or invades the wall of 
the vena cava
T4
Tumor invades beyond the Gerota fascia (including contiguous extension into the 
ipsilateral adrenal gland)
Regional lymph nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in regional lymph node(s)
Distant metastasis (M)
M0
No distant metastasis
M1
Distant metastasis


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Anatomic stage/prognostic group
Stage
T
N
M
I
T1
N0
M0
II
T2
N0
M0
III
T1-2
N1
M0
T3
N0-1
M0
IV
T4
Any N
M0
Any T
Any N
M1
Source: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, et al. AJCC 
Cancer Staging Manual. 7th ed. New York, NY: Springer-Verlag; 2010.


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Appendix 8
Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1
Tumor response assessments in this clinical trial will use Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) based on the 2009 article by Eisenhauer, et al entitled, New 
Response Evaluation Criteria in Solid Tumors:  revised RECIST guideline (version 1.1).
The sole modification to RECIST 1.1 to be implemented in this study is that chest x-rays 
may not be used to follow disease; only CT scans may be used to follow chest disease.  
The Eisenhauer article, published in the European Journal of Cancer, is available online at:  
http://linkinghub.elsevier.com/retrieve/pii/S0959804908008733.


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Appendix 9
Health-Related Quality of Life Questionnaire FKSI-DRS


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Appendix 10
Health-Related Quality of Life Questionnaire EORTC 
QLQ-C30


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Appendix 11
Health-Related Quality of Life Questionnaire EQ-5D-3L
By placing a checkmark in one box in each group below, please indicate which statements 
best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or leisure 
activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain / Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety / Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



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


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Appendix 12
Pharmacodynamic and Other Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic and other biomarker analysis. These samples may be used for discovery 
and validation to identify biomarkers that may be used for exploratory evaluation of response 
and/or safety-related outcomes as well as for use in diagnostic development.
Sample collection for pharmacodynamic, and other biomarker analysis is required as per the 
study protocol unless the collection and use of the samples is prohibited by specific country 
laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All pharmacodynamic and other biomarker 
samples will be single coded.  Clinical data collected as part of the clinical trial will be 
cleaned of subject identifying information and linked by use of the sample ID “key.”


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The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:

Clinical research organizations retained by the sponsor 

Independent ethics committees or institutional review boards that have responsibility for 
this research study 

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report, which can include part 
or all of the coded data, in listing or summary format.  Other publication (eg, in peer-
reviewed scientific journals) or public presentation of the study results will only include 
summaries of the population in the study, and no identified individual results will be 
disclosed.
Given the research nature of the pharmacodynamic and other biomarker analysis, it will not 
be possible to return individual data to subjects.  The results that may be generated are not 
currently anticipated to have clinical relevance to the patients or their family members.  
Therefore, these results will not be disclosed to the patients or their physicians.
If at any time, pharmacodynamic and/or other biomarker results are obtained that may have 
clinical relevance, IRB review and approval will be sought to determine the most appropriate 
manner of disclosure and to determine whether or not validation in a Clinical Laboratory 
Improvement Amendments (CLIA)-certified setting will be required.  Sharing of research 
data with individual patients should only occur when data have been validated by multiple 
studies and testing has been done in CLIA-approved laboratories.


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Appendix 13
Efficacy and Futility Boundaries at Each Interim 
Analysis and the Primary Analysis
There will be 2 interim analyses and one primary analysis. The 2 interim analyses will be 
performed only in the Per-Protocol Analysis Set 1. The primary analysis will be performed 
in the Per-Protocol Analysis Set 1 as the primary analysis set, and will also be performed in 
the Per-Protocol Analysis Set 2 and in the Full Analysis Set as secondary analysis sets.  
The tables below list the treatment differences in ORR24w between the lenvatinib 14-mg + 
everolimus arm and the lenvatinib 18-mg + everolimus arm corresponding to the efficacy and 
futility boundaries at each interim analysis and primary analysis for different ORR24w in the 
lenvatinib 18-mg + everolimus arm. 
First interim analysis, non-inferiority stopping boundary OR = 1.788 (non-inferiority 
will be claimed if observed OR ≥1.788 at first interim analysis. Correspondingly, depending 
on ORR24W, non-inferiority will be claimed if observed treatment difference between the 
14-mg arm and the 18-mg arm is ≥
).
ORR24W in lenvatinib 18-mg arm

 = Treatment difference 
(lenvatinib 14-mg arm -
lenvatinib 18-mg arm)
10%
0.07
20%
0.11
30%
0.13
40%
0.14
50%
0.14
60%
0.13
First interim analysis, futility stopping boundary OR = 0.590 (futility will be claimed if 
observed OR ≤0.590 at first interim analysis. Correspondingly, depending on ORR24W, non-
inferiority will be claimed if the observed treatment difference between 14-mg arm and 
18-mg arm is ≤
)
ORR24W in lenvatinib 18-mg arm

 = Treatment difference 
(lenvatinib 14-mg arm -
lenvatinib 18-mg arm)
10%
-0.04
20%
-0.07
30%
-0.10
40%
-0.12
50%
-0.13
60%
-0.13


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Second interim analysis, non-inferiority stopping boundary OR = 1.436 (non-inferiority 
will be claimed if the observed OR ≥1.436 at second interim analysis. Correspondingly, 
depending on ORR24W, non-inferiority will be claimed if the observed treatment difference 
between the 14-mg arm and the18-mg arm is ≥
)
ORR24W in lenvatinib 18-mg arm

 = Treatment difference 
(lenvatinib 14-mg arm -
lenvatinib 18-mg arm)
10%
0.04
20%
0.06
30%
0.08
40%
0.09
50%
0.09
60%
0.08
Second interim analysis, futility stopping boundary OR = 0.962 (futility will be claimed if 
the observed OR ≤0.962 at the second interim analysis. Correspondingly, depending on 
ORR24W, non-inferiority will be claimed if the observed treatment difference between the 
14-mg arm and the18-mg arm is≤
)
ORR24W in lenvatinib 18-mg arm

 = Treatment difference 
(lenvatinib 14-mg arm -
lenvatinib 18-mg arm)
10%
-0.003
20%
-0.006
30%
-0.008
40%
-0.009
50%
-0.010
60%
-0.009
Primary analysis, OR = 1.128 (non-inferiority will be claimed if observed OR ≥1.128 at 
the primary analysis. Correspondingly, depending on ORR24W, non-inferiority will be 
claimed if the observed treatment difference between the 14-mg arm and the 18-mg arm is ≥

).


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ORR24W in lenvatinib 18-mg arm

 = Treatment difference 
(lenvatinib 14-mg arm -
lenvatinib 18-mg arm)
10%
0.01
20%
0.02
30%
0.03
40%
0.03
50%
0.03
60%
0.03


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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-G000-218
Study Protocol Title:
A Randomized, Open-Label (formerly Double-Blind),
Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at 
Two Different Starting Doses (18 mg vs 14 mg QD) in 
Combination With Everolimus (5 mg QD) in Renal Cell 
Carcinoma Following One Prior VEGF-Targeted Treatment
Investigational Product 
Name:
Lenvatinib (E7080), everolimus
IND Number:
124564
EudraCT Number:
2016-002778-11
SIGNATURES
Authors:
Associate Director, Clinical Research
Oncology Business Group, Eisai Inc.
Date
g & Simulation
Date
Vice President Biostatistics
Oncology Business Group, Eisai Inc.
Date
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-218
Study Protocol Title:
A Randomized, Open-Label (formerly Double-Blind),
Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at 
Two Different Starting Doses (18 mg vs 14 mg QD) in 
Combination With Everolimus (5 mg QD) in Renal Cell 
Carcinoma Following One Prior VEGF-Targeted Treatment
Investigational Product
Name:
Lenvatinib (E7080), everolimus
IND Number:
124564
EudraCT Number:
2016-002778-11
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council 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.
Medical Institution
Investigator
Signature
Date

SAP_001.pdf: 
Statistical Analysis Plan 
E7080-G000-218 
 
 
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Final Version 2.0: 29 Apr 2020 
Confidential 
Page 1 of 49 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7080-G000-218 
Study Protocol 
Title: 
A Randomized, Open-Label (formerly Double-Blind), Phase 2 Trial 
to Assess Safety and Efficacy of Lenvatinib at Two Different Starting 
Doses (18 mg vs 14 mg QD) in Combination With Everolimus (5 mg 
QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted 
Treatment 
 
Date: 
29 Apr 2020 
Version: 
2.0 


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REVISION HISTORY 
Revisions per Version 2.0 
Date: 29 Apr 2020 
Change  
Rational 
Affected 
Sections 
Updated that the data cutoff for the 
primary analysis refers to the end of the 
randomization phase) and that the End of 
Study refers to the last subject last visit 
after which all subjects will have 
completed their off-treatment visits. 
The term “final” analysis was changed to 
“primary” analysis according to the 
Protocol Amendment 07. 
 
Protocol was amended (Protocol 
Amendment 07), SAP updates were 
made accordingly. 
Section 3.2 
For the stratification factor of MSKCC 
prognostic group from IxRS, some 
subjects with MSKCC Prognostic Score 2 
were misclassified to intermediate risk on 
Interactive Response Technology (IRT) 
system which should have been classified 
to poor risk per protocol. Poor risk will be 
pooled with the intermediate risk in the 
relevant stratified analyses based on 
IxRS data, the favorable risk will remain 
intact.  
 
For the stratification factor of 
MSKCC prognostic group from 
IxRS, some subjects with MSKCC 
Prognostic 
Score 
2 
were 
misclassified to intermediate risk on 
IRT system which should have been 
classified to poor risk per protocol. 
It is then determined that poor risk 
group will be pooled with the 
intermediate risk group in the 
relevant stratified analyses based 
on IxRS data, the favorable risk 
group will remain intact. 
Section 5.3.2; 
Section 5.4 
Added hazard ratio estimates for PFS, OS 
and PFS2 analyses. 
Added hazard ratio estimates for 
PFS, OS and PFS2 analysis for 
descriptive purpose. 
Section 
5.4.2.1, 
5.4.2.3, and 
5.4.2.4 
Changed the major protocol deviations to 
important protocol deviations. 
Per new Standard Working Practice 
(SWP) 101-206.00-SWP, protocol 
deviation type will be classified as 
important or minor. 
 
Section 5.2.1, 
5.2.3 
 


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1 
TABLE OF CONTENTS 
REVISION HISTORY...............................................................................................................2 
1 
TABLE OF CONTENTS ...................................................................................................3 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................6 
3 
INTRODUCTION .............................................................................................................9 
3.1 
Study Objectives ......................................................................................................9 
3.1.1 
Primary Objective ..........................................................................................9 
3.1.2 
Secondary Objectives.....................................................................................9 
3.1.3 
Exploratory Objectives ................................................................................10 
3.2 
Overall Study Design and Plan ..............................................................................10 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................12 
5 
STATISTICAL METHODS ............................................................................................15 
5.1 
Study Endpoints .....................................................................................................15 
5.1.1 
Primary Endpoints .......................................................................................15 
5.1.2 
Secondary Endpoints ...................................................................................15 
5.1.3 
Exploratory Endpoints .................................................................................16 
5.2 
Study Subjects ........................................................................................................16 
5.2.1 
Definitions of Analysis Sets.........................................................................16 
5.2.2 
Subject Disposition ......................................................................................18 
5.2.3 
Protocol Deviations ......................................................................................19 
5.2.4 
Demographic and Other Baseline Characteristics .......................................19 
5.2.5 
Prior and Concomitant Therapy ...................................................................21 
5.2.6 
New Anticancer Therapies ...........................................................................22 
5.2.7 
Treatment Compliance .................................................................................22 
5.3 
Data Analysis General Considerations ..................................................................22 
5.3.1 
Pooling of Centers........................................................................................22 
5.3.2 
Adjustments for Covariates..........................................................................22 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................23 
5.3.4 
Examination of Subgroups ...........................................................................23 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................24 
5.3.6 
Other Considerations ...................................................................................24 
5.4 
Efficacy Analyses ..................................................................................................24 
5.4.1 
Primary Efficacy Analyses ..........................................................................25 
5.4.2 
Secondary Efficacy Analyses ......................................................................26 
5.4.2.1 
Progression-free Survival...................................................................26 
5.4.2.2 
Objective Response Rate ....................................................................28 
5.4.2.3 
Overall Survival .................................................................................29 
5.4.2.4 
Progression-free Survival on Next Line of Therapy ..........................30 


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5.4.3 
Other Efficacy Analyses ..............................................................................31 
5.4.3.1 
Duration of Response .........................................................................31 
5.4.3.2 
Disease Control Rate..........................................................................31 
5.4.3.3 
Clinical Benefit Rate ..........................................................................31 
5.4.4 
Subgroup Analysis for Efficacy/Safety Endpoints ......................................31 
5.5 
Pharmacokinetic, Pharmacodynamic, and Other Biomarker Analyses .................32 
5.6 
Safety Analyses ......................................................................................................32 
5.6.1 
Primary Safety Endpoint ..............................................................................32 
5.6.2 
Extent of Exposure .......................................................................................33 
5.6.2.1 
Extent of Exposure to Study Treatment .............................................33 
5.6.2.2 
Study Drug Administered ..................................................................33 
5.6.2.3 
Study Drug Dose Reductions and Interruptions ................................34 
5.6.3 
Adverse Events ............................................................................................35 
5.6.3.1 
Overview of TEAEs ...........................................................................35 
5.6.3.2 
All TEAEs ..........................................................................................36 
5.6.3.3 
Intolerable Grade 2 and ≥ Grade 3 TEAEs ........................................36 
5.6.3.4 
Treatment-related TEAEs ..................................................................36 
5.6.3.5 
Serious TEAEs ...................................................................................36 
5.6.3.6 
TEAEs Leading to Treatment Discontinuation..................................36 
5.6.3.7 
TEAEs Leading to Dose Reductions and Dose Interruptions ............37 
5.6.3.8 
Grade 3 or Higher TEAEs..................................................................37 
5.6.3.9 
TEAEs with Fatal Outcome ...............................................................37 
5.6.3.10 
Deaths ................................................................................................37 
5.6.3.11 
Adverse Events of Clinical Interest ...................................................37 
5.6.4 
Laboratory Values ........................................................................................38 
5.6.4.1 
Hematology and Clinical Chemistry ..................................................38 
5.6.4.2 
Urinalysis ...........................................................................................39 
5.6.5 
Vital Signs ....................................................................................................39 
5.6.6 
Electrocardiograms ......................................................................................40 
5.6.7 
Other Safety Analyses..................................................................................40 
5.6.7.1 
Karnofsky Performance Status ..........................................................40 
5.6.7.2 
Left Ventricular Ejection Fraction .....................................................41 
5.7 
Other Analyses .......................................................................................................41 
5.7.1 
Health-Related Quality of Life ....................................................................41 
5.8 
Exploratory Analyses .............................................................................................41 
5.8.1 
Efficacy Analysis Based on IIR Assessment ...............................................41 
5.8.2 
Exploratory Analysis for Subjects with Prior PD-1/PD-L1 Treatments ......41 
5.8.3 
Biomarker-related Analysis .........................................................................42 
6 
INTERIM ANALYSES ...................................................................................................42 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................43 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................43 


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8.1 
Visit Windows .......................................................................................................43 
8.2 
Baseline Definitions ...............................................................................................43 
8.3 
Imputation of Missing Data ...................................................................................44 
8.4 
Variable Derivations ..............................................................................................44 
8.4.1 
Duration of Events Prior to Randomization.................................................44 
8.5 
Pharmacokinetics/Pharmacodynamics Data Handling ..........................................44 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................44 
10 STATISTICAL SOFTWARE ..........................................................................................45 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................45 
12 REFERENCES ................................................................................................................45 
13 APPENDICES .................................................................................................................46 
13.1 
Efficacy and Futility Boundaries at Each Interim Analysis and Final Analysis ....46 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
AEoSI 
AEs of special interest 
AJCC 
American Joint Committee on Cancer 
ATC 
anatomical therapeutic class 
BLQ 
below limit of quantification  
BOR 
best overall response 
BMI 
body mass index 
CBR 
clinical benefit rate  
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CMQ 
customized MedDRA queries 
CR 
complete response 
CRF 
case report form 
CSAEs 
clinically significant adverse events 
CSR 
clinical study report 
CV 
coefficient of variation 
DCR 
disease control rate  
DMC 
data monitoring committee 
DOR 
duration of response  
ECGs 
electrocardiograms  
EMA 
European Medicines Agency  
EORTC 
European Organization for the Research and Treatment of Cancer  
EuroQol 
European Quality of Life  
FDA 
Food and Drug Administration  
FKSI-DRS 
Functional Assessment of Cancer Therapy - Kidney Symptom 
Index-Disease Related Symptoms  
HRQoL 
Health-Related Quality of Life   
ICL 
imaging core laboratory  
IIR 
independent imaging review   


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Abbreviation 
Term 
IRT 
interactive response technology 
IxRS 
interactive voice and web response system 
LDH 
lactate dehydrogenase  
LLT 
lower level term  
LVEF 
left ventricular ejection fraction  
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
multiple gate acquisition  
NA 
not applicable  
NE 
not evaluable  
NYHA 
New York Heart Association  
KPS 
Karnofsky performance status  
MSKCC 
Memorial Sloan-Kettering Cancer Center  
OR 
odds ratio 
ORR 
objective response rate 
ORR24w 
objective response rate as of Week 24 
OS 
overall survival 
PFS 
progression-free survival 
PFS2 
progression-free survival on next line of therapy 
PD 
progressive disease or pharmacodynamic 
PK 
pharmacokinetic 
PO 
orally 
PR 
partial response 
PT 
preferred term 
QD 
once daily 
QTc 
corrected QTc interval 
QTcF 
corrected for QTc interval using Frederica's correction factors 
RECIST 
Response Evaluation Criteria in Solid Tumors   
RBC 
red blood cell  
RCC 
renal cell carcinoma  
SAE 
serious adverse event 


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Abbreviation 
Term 
SAP 
statistical analysis plan 
SD 
standard deviation or stable disease 
SE 
standard error  
SGQs 
sponsor-generated queries 
SI 
Système International 
SMQs 
standardized MedDRA queries 
SOC 
system organ class 
SWP 
standard working practice  
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal values  
TLGs 
tables, listings, and graphs 
TNM 
tumor-node-metastasis  
TSH 
thyroid stimulating hormone 
VEGF 
vascular endothelial growth factor  
WBC 
white blood cell  
WHO 
World Health Organization 
 


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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 of the primary analysis for 
Eisai Protocol E7080-G000-218 (Amendment 07). Analyses on subjects’ Health-Related 
Quality of Life (HRQoL) data, pharmacokinetic (PK)/pharmacodynamics (PD), biomarkers, 
and relationships between PK and efficacy and safety will be included in separate statistical 
analysis plans.  
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective of this study is to assess whether a starting dose of lenvatinib 14 mg in 
combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on 
objective response rate [ORR] at 24 weeks [ORR24W]) with an improved safety profile compared 
to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment-emergent 
intolerable Grade 2, or any ≥ Grade 3 adverse events (AEs) in the first 24 weeks after 
randomization).    
3.1.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To assess progression-free survival (PFS) 
• 
To assess ORR 
• 
To determine the tolerability and safety profile of lenvatinib in combination with 
everolimus 
• 
To assess the proportion of subjects who discontinued treatment due to toxicity 
• 
To assess time to treatment failure due to toxicity 
• 
To assess pharmacokinetic (PK) profiles of lenvatinib and everolimus during combination 
therapy and to assess PK and pharmacodynamics (PD) drug-drug interactions 
• 
To evaluate overall survival (OS) 
• 
To evaluate the impact of disease and treatment on subjects' Health-Related Quality of Life 
(HRQoL) as assessed by using the Functional Assessment of Cancer Therapy - Kidney 
Symptom Index-Disease Related Symptoms (FKSI-DRS), the European Organization for 
the Research and Treatment of Cancer (EORTC) QLQ-C30 and the European Quality of 
Life (EuroQol) EQ-5D-3L 
• 
To evaluate the PFS on next line of therapy (PFS2) 


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3.1.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
• 
To explore tumor response parameters (ORR24W, ORR, PFS) based on blinded independent 
imaging review (IIR) for efficacy assessment 
• 
To explore blood biomarkers that correlate with efficacy-related endpoints of this study  
• 
To develop exposure/biomarker/clinical endpoint models (whenever possible, using a 
mechanism-based approach) for both efficacy and safety data that will allow exploration 
of alternative dosing regimens with a better efficacy/safety profile than the lenvatinib 18 
mg plus everolimus 5 mg dose 
3.2 
Overall Study Design and Plan 
Study E7080-G000-218 was designed as a multicenter, randomized, open-label (formerly 
double-blind) study, conducted as a postmarketing requirement of the US Food and Drug 
Administration (FDA) and the European Medicines Agency (EMA) to evaluate an alternate 
dose regimen for lenvatinib in combination with everolimus. Lenvatinib 18 mg daily in 
combination with everolimus 5 mg daily is approved in the US and EU for the treatment of 
adult subjects with advanced renal cell carcinoma (RCC) following 1 prior vascular endothelial 
growth factor (VEGF) targeted therapy.  
This study will evaluate the combination of lenvatinib and everolimus at a 14 mg starting dose 
of lenvatinib and allow up-titration of lenvatinib to determine whether this alternate dose 
regimen provides comparable efficacy but has a better safety profile than the 18 mg starting 
dose in this subject population. The 14 mg starting dose will be escalated to 18 mg if no Grade 
2 (intolerable) or any ≥ Grade 3 treatment-emergent adverse events (TEAEs) that require dose 
reduction are observed in the first cycle (4 weeks) of treatment. If Grade 2 (intolerable) or 
Grade 3 or 4 TEAEs are observed, the lenvatinib dose will be reduced, as described in the dose 
reduction section in protocol Section 9.4.2.1. Both lenvatinib and everolimus will be 
administered orally (PO) and QD. 
Eligible subjects will have measurable disease according to Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) and will be randomly assigned to each treatment arm 
in a 1:1 ratio. The total sample size will be approximately 338 subjects. Randomization will 
follow a predefined randomization scheme based on the following stratification factors: 
Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic groups (favorable, 
intermediate, or poor risk); and whether subjects have had a prior PD-1/PD-L1 treatment (yes 
or no). 
Subjects will receive study treatment as continuous 28-day cycles. Treatment cycles will be 
counted continuously regardless of dose interruptions. Subjects will undergo safety and 


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efficacy assessments as defined in the Schedule of Procedures/Assessments in Table 6 in 
protocol. Subjects will discontinue study treatment upon evidence of progressive disease, as 
judged by the investigator. After disease progression, subjects will be followed for survival 
and PFS2. 
This study consists of 2 phases, the Pre-randomization Phase and the Randomization Phase, as 
shown in Figure 1:  
 
Figure 1 
Study Design for Study E7080-G000-218 
R = randomization 
PD = progressive disease 
PFS2 = PFS on next line of therapy 
• 
The Pre-randomization Phase will last no longer than 28 days and will include a Screening 
Period to establish protocol eligibility and a Baseline Period to confirm eligibility and 
establish disease characteristics prior to randomization and treatment.  
• 
The Randomization Phase will consist of a Treatment Period and a Follow-up Period. It 
will begin at the time of randomization of the first subject and will end at the data cutoff 
for the primary analysis, which is defined as when all randomized subjects complete the 
Week-24 tumor assessments or discontinue study treatment before Week 24.   


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- 
The Treatment Period will begin with the first dose of study drug administration in 
Cycle 1 and continue in 28-day cycles until completion of the off-treatment 
assessments (within 28 days after the last study drug administration). Subjects will 
undergo safety and efficacy assessments as defined in the Schedule of 
Procedures/Assessments in protocol Table 6. Subjects will continue to receive study 
treatment until confirmed disease progression, development of unacceptable toxicity, 
subject request, withdrawal of consent, or study termination by the sponsor. Subjects 
who discontinue treatment before the data cut off for the primary analysis will enter the 
Follow-up Period, and will be followed every 12 weeks (±1 week) after the off-
treatment visit. If a clinic visit is not feasible, follow-up information may be obtained 
via telephone or email. 
- 
The Follow-up Period will begin immediately after the off-treatment assessments have 
been completed and will continue as long as the study subject is alive, until the study 
subject withdraws consent, or until the data cutoff for the primary analysis. Subjects who 
discontinue study treatment before disease progression will continue to undergo tumor 
assessments every 8 weeks and as of Amendment 06, send these to the imaging core 
laboratory (ICL) until  documentation of disease progression or start of another 
anticancer therapy. Following the off-treatment visit, subjects will continue to be 
followed every 12 weeks (±1 week) for survival and PFS2, and all anticancer 
treatments received will be recorded until the data cutoff for the primary analysis. This 
information will be recorded unless the information is not allowed to be provided due 
to confidentiality. 
The data cutoff for the primary analysis will occur at the end of the Randomization Phase, which 
is defined as the time when all randomized subjects have completed Week 24 assessments or 
have discontinued study treatment prior to Week 24.  
Subjects will continue to receive investigational product until they complete the off-treatment 
visit prior to their transition to commercial lenvatinib and everolimus or an access program. 
The last subject last visit for the End of Study will be the date of the off-treatment visit for the 
last subject. 
4 
DETERMINATION OF SAMPLE SIZE    
The objective of the study is to assess whether a starting dose of lenvatinib 14 mg QD in 
combination with everolimus 5 mg will provide comparable efficacy with an improved safety 
profile compared to lenvatinib 18 mg in combination with everolimus 5 mg. Determination of 
whether 14 mg lenvatinib can be used as an alternative dosing strategy will be based on clinical 
judgment by the Sponsor in consultation with the independent Data Monitoring Committee 
(DMC) as specified in DMC Charter by assessing risks and benefits according to the totality 
of data at either of the interim or final analyses. Nevertheless, the sample size is guided by the 


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plan of testing non-inferiority on the primary efficacy endpoint and superiority on the primary 
safety endpoint. Superiority on the primary safety endpoint will only be tested if the non-
inferiority on the primary efficacy endpoint is claimed. The details and assumptions are 
provided below. 
Sample size is based on detecting both the non-inferiority of ORR24W and superiority of the 
primary safety endpoint of the proportion of subjects with intolerable Grade 2 or any ≥ Grade 
3 TEAEs within 24 weeks after randomization in comparison of the lenvatinib 14 mg arm to 
the lenvatinib 18 mg arm. 
The “final analysis” stated in the sections of Determination of Sample Size, Primary Efficacy 
Analyses, Interim Analyses, and Appendix Section 13.1 refers to the last analysis when the 
statistical inference is made for the study, that is, at the data cutoff for the primary analysis. 
NON-INFERIORITY OF ORR24W COMPARING LENVATINIB 14 MG TO LENVATINIB 18 MG  
Based on the assumption from Study E7080-G000-205 that the confirmed ORR for the 18 mg 
lenvatinib + 5 mg everolimus arm is 37% (19 responders out of N=51) vs 6% for the everolimus 
arm (3 responders out of N=50), the 95% confidence interval (CI) of the odds ratio (OR) 
comparing everolimus vs. lenvatinib 18 mg + everolimus arm is (0.029, 0.395). The non-
inferiority margin is chosen to ensure that a reasonable fraction of the lenvatinib 18 mg + 
everolimus vs. everolimus treatment effect is preserved. A 70% retention of the treatment 
effect of lenvatinib 18 mg + everolimus vs. everolimus is used for this design. Following the 
approach in Rothmann, et al. (2003), using the 95% CI upper limit method based on logarithm 
of the odds ratio, the non-inferiority margin is estimated as: 
exp ((1−δ) כ (upper limit of 95% CI of log OR (everolimus/lenvatinib 18 mg + everolimus))), 
where 0<δ< 1 is the retention rate. 
To retain 70% of the lenvatinib 18 mg + everolimus vs. everolimus treatment effect, the non-
inferiority margin (M) of the odds ratio is estimated to be: 
M = exp ((1 − 0.7) כ log(0.395)) = 0.76 (i.e, Ha: OR (14 mg/18 mg)>M).  
Table 1 below lists the non-inferiority margins on the scale of difference in ORR24W between  
lenvatinib 14 mg + everolimus arm and lenvatinib 18 mg + everolimus arm corresponding to 
a 0.76 non-inferiority margin on the odds ratio scale for a different ORR24W in lenvatinib 18 
mg + everolimus arm. 
Table 1 
Non-inferiority Margins on Scale of Treatment Difference in ORR24W 
ORR24W in lenvatinib 18 mg arm 
Non-inferiority Margin on Difference Scale 
(lenvatinib 14 mg arm - lenvatinib 18 mg arm) 


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10% 
-2% 
20% 
-4% 
30% 
-5% 
40% 
-6% 
50% 
-7% 
60% 
-7% 
Two interim analyses will take place when 150 and 200 total subjects in the Per-Protocol 
Analysis Set 1 have completed 24 weeks follow-up or discontinue earlier. Each interim 
analysis will test both non-inferiority and futility of the 14 mg arm ORR24W compared to the 
18 mg arm ORR24W. An O’Brien-Fleming stopping boundary will be used for non-inferiority. 
An interpolated non-binding stopping boundary will be used for futility, which will spend 
β=0.005 and β=0.10 at the first and second interim analysis, respectively. Assuming 37% 
ORR24W in the lenvatinib 18 mg arm and 45% ORR24W in the lenvatinib 14 mg arm, and 
adjusting for the interim analyses, a total of 306 subjects (153 per arm) in the Per-Protocol 
Analysis Set 1 is required to achieve 80% statistical power at 1-sided α=0.05. 
The stopping boundaries on the P value scale and the cumulative error probabilities spent at 
each interim analysis and final analysis are shown in Table 2 below. For example, at the second 
interim analysis, non-inferiority in ORR24W will be claimed if the 1-sided P value is ≤0.014; 
futility will be claimed if the 1-sided P value is ≥0.207. 
Table 2 
Stopping Boundaries 
Analysis # 
Cumulative α 
Spent 
Efficacy 
Boundary  
(P value) 
Cumulative β 
Spent 
Futility 
Boundary  
(P value) 
Interim Analysis #1 
0.005 
0.005 
0.005 
0.776 
Interim Analysis #2 
0.015 
0.014 
0.10 
0.207 
Final Analysis 
0.05 
0.045 
0.2 
0.045 
SUPERIORITY OF PRIMARY SAFETY ENDPOINT COMPARING LENVATINIB 14 MG TO LENVATINIB 18 
MG 
At each interim analysis and the final analysis in the Per-Protocol Safety Analysis Set, 
superiority on the primary safety endpoint will be evaluated if the non-inferiority boundary is 
crossed. Assuming 75% subjects with intolerable Grade 2 or above TEAEs within 24 weeks 
after randomization in the 18 mg arm, with a total of 306 subjects, a superiority test at 2-sided 
α=0.05 will give 80% statistical power to detect a 15% drop in proportion of subjects with 
intolerable Grade 2 or above TEAEs within 24 weeks after randomization in the 14 mg-arm.  
In consideration of both the primary efficacy and safety endpoints, a total of approximately 
306 subjects were originally planned to be randomized in a 1:1 ratio to both treatment arms. 
Since there were 32 subjects who received ≥2 incorrect lenvatinib doses due to IxRS issues, 
the number of subjects to be randomized will be increased by 32 to a total of approximately 


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338. Therefore, there will be approximately 306 subjects in the Per-Protocol Analysis Set 1. 
Randomization will be stratified by MSKCC prognostic group (favorable, intermediate, and 
poor risk) and whether subjects have had a prior PD-1/PD-L1 treatment (yes or no). 
5 
STATISTICAL METHODS 
In general, continuous variables will be summarized using descriptive statistics such as 
mean, standard deviation (SD), median, and range (minimum and maximum). Categorical 
variables will be summarized using frequency and percentage. For time-to-event variables, 
which is defined as the time from the date of randomization to the date of the event, the 
Kaplan-Meier method will be used for descriptive summaries. For the calculation of time-
to-event or duration-of-event variables for on-study events, the difference between the start 
date and the end date plus 1 day will be used. For durations of events (eg, baseline disease 
characteristics or prior therapies) prior to randomization, the durations will be calculated as the 
date of randomization minus the date of the event, the details are specified in Section 8.4.1.  
5.1 
Study Endpoints 
5.1.1 
Primary Endpoints 
The primary endpoints are: 
x 
ORR24W as assessed by investigator according to RECIST 1.1.  ORR24W is defined as the 
proportion of subjects with best overall response (BOR) of complete response (CR) or 
partial response (PR) as of the Week 24 (after randomization) timepoint during treatment 
or within 28 days after the last dose date but on or prior to the start of new anticancer 
therapy. To be considered as BOR, all responses must be confirmed no less than 4 weeks 
after the initial assessment of response. 
x 
Proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks 
after randomization (as of the Week 24 timepoint). 
5.1.2 
Secondary Endpoints 
The secondary efficacy endpoints are defined as follows: 
x 
PFS, defined as the time from the date of randomization to the date of first documentation 
of disease progression or date of death, whichever occurs first. 
x 
ORR as assessed by investigator according to RECIST 1.1, defined as the proportion of 
subjects with BOR of CR or PR during treament or within 28 days after the last dose date 
but on or prior to the start of new anticancer therapy. To be considered as BOR, all 
responses must be confirmed no less than 4 weeks after the initial assessment of response. 


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x 
Overall safety profile and tolerability of lenvatinib in combination with everolimus. 
x 
Proportion of subjects who discontinue treatment due to toxicity, defined as the proportion 
of subjects who discontinue study treatment due to TEAEs. 
x 
Time to treatment failure due to toxicity, defined as the time from the date of randomization 
to the date that a subject discontinues study treatment due to TEAEs. 
x 
Lenvatinib and everolimus exposure parameters and PK and PD drug-drug interactions. 
x 
OS, measured from the date of randomization until date of death. In the absence of 
confirmation of death, subjects will be censored either at the date that the subject was last 
known to be alive or the date of data cutoff, whichever comes earlier. 
x 
HRQoL will be assessed using the FKSI-DRS, the EORTC QLQ-C30 and the EuroQol 
EQ-5D-3L instruments. 
x 
PFS2, defined as the time from randomization to the date of disease progression on next 
line of therapy or death, whichever occurs first. 
5.1.3 
Exploratory Endpoints  
The exploratory endpoints include: 
x 
Tumor response endpoints ORR24W, ORR, and PFS based on IIR assessments. These 
endpoints will be defined in the same way as those based on investigator assessments. 
x 
Associations between blood biomarker and efficacy related endpoints. 
x 
Development of exposure/biomarker/clinical endpoint models (whenever possible, using a 
mechanism-based approach) for both efficacy and safety data. 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
x 
Full Analysis Set will include all randomized subjects. This will be a secondary analysis 
set for efficacy endpoints, which will be analyzed according to the treatment arm to which 
subjects are randomized, regardless of the treatment actually received. 
x 
Per-Protocol Analysis Set 1 will include all randomized subjects minus the 32 subjects who 
had received ≥2 incorrect lenvatinib doses due to IxRS issues. This will be the primary 
analysis set for efficacy endpoints, which will be analyzed according to the treatment arm 
to which subjects are randomized. 


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x 
Per-Protocol Analysis Set 2 will include all subjects who received at least 1 dose of study 
drug, had no important protocol deviations, and had both baseline and at least 1 
postbaseline tumor assessment. Subjects who died before the first postbaseline tumor 
assessment will also be included. The Per-Protocol Analysis Set 2 will be a secondary 
analysis set for efficacy endpoints. The 32 subjects who received ≥2 incorrect lenvatinib 
doses due to IxRS issues are considered as having experienced important protocol 
deviations and will be excluded from the Per-Protocol Analysis Set 2. (A 33rd subject 
received a single incorrect lenvatinib dose due to IxRS issues, but given the brief exposure 
of the incorrect [slightly higher] dose before detection and correction, and because there 
were no adverse effects, this subject will be considered to have experienced a minor 
protocol deviation and will not be excluded from analysis sets.) 
x 
Safety Analysis Set will include all subjects who were randomized and received at least 1 
dose of study drug. This will be the analysis set for all safety evaluations, which will be 
analyzed according to the treatment actually received. 
x 
Per-Protocol Safety Analysis Set will include all treated subjects in Per-Protocol Analysis 
Set 1. This will be the primary analysis set for the primary safety endpoint, which will be 
analyzed according to the treatment actually received. 
x 
Pharmacokinetic Analysis Set will include all subjects who received at least 1 dose of study 
drug with documented dosing history and had at least 1 evaluable lenvatinib plasma or 
everolimus whole blood concentration data. 
x 
Pharmacodynamic Analysis Set will include all subjects who received at least 1 dose of 
study drug with documented dosing history and had at least 1 evaluable sample for  
pharmacodynamics data. 
For the Pharmacokinetic, Pharmacodynamic and other Biomarker endpoints, their 
respective analysis plans will specify if the analysis set will or will not include the 32 
subjects who received ≥2 incorrect lenvatinib doses due to IxRS issues. 
x 
Quality of Life (QoL) Analysis Set季will consist of all subjects who had any QoL data. 


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Table 3 
Analysis Sets in Data Analyses  
 
 
Tables 
All 
Screened 
Subjects 
 
Full 
Per-Protocol 
Analysis Set 
1 
Per-Protocol 
Analysis Set 
2 
 
 
Safety 
Per-Protocol 
Safety 
Analysis Set 
 
PK 
 
PD 
 
QoL 
Protocol Deviations 
 
• 
 
 
 
 
 
 
 
Disposition 
• 
• 
• 
• 
 
 
 
 
 
Demography & Baseline 
Characteristics 
 
• 
• 
• 
 
 
 
 
 
Disease History 
 
• 
 
 
 
 
 
 
 
Prior and concomitant 
medication 
 
• 
• 
 
 
 
 
 
 
New anticancer therapy 
 
• 
• 
 
 
 
 
 
 
Efficacy analysis  
 
• 
• 
• 
 
 
 
 
 
Primary safety endpoint 
- proportion of subjects 
with intolerable Grade 2 
or any ≥ Grade 3 TEAEs 
within 24 weeks after 
randomization 
 
 
 
• 
• 
• 
 
 
 
Safety analysis 
(including drug 
exposure, AEs, 
laboratory tests, vital 
signs, etc.) 
 
 
 
 
• 
• 
 
 
 
Pharmacokinetics 
 
 
 
 
 
 
• 
 
 
Pharmacodynamics 
 
 
 
 
 
 
 
• 
 
QoL 
 
 
 
 
 
 
 
 
• 
5.2.2 
Subject Disposition 
Subject disposition will be summarized for the Per-Protocol Analysis Set 1, Per-Protocol 
Analysis Set 2, and Full Analysis Set. All subjects who were screened for the study will be 
reported. The number of subjects who failed screening and the reasons for screen failures will 
be summarized. 
The number of subjects who were randomized, treated, discontinued study treatment, and the 
reasons for discontinuation of study treatment will be summarized 
Subject status (Alive, Death, Withdrew Consent, Lost to Follow-up, etc.) at the data cutoff for 
the primary analysis will also be summarized by treatment arm and overall.  


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5.2.3 
Protocol Deviations    
Protocol deviations will be identified and documented prior to database lock.    
Protocol deviations will be classified as important or minor. Subjects who have experienced 
important protocol deviations will be excluded from per protocol analysis sets and reported in 
the clinical study report (CSR). 
Important protocol deviations will be appropriately grouped into different categories and 
summarized by treatment arm.  
The summary of important protocol deviations will be performed on Full Analysis Set. A list 
of subjects with important protocol deviations will also be provided.  
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics will be summarized for the Per-Protocol Analysis 
Set 1, Per-Protocol Analysis Set 2, and Full Analysis Set.   
The following demographic and baseline characteristics will be summarized: 
• Age (years) 
• Age group (<65 years, ≥65 years) 
• Gender 
• Race  
• Race group (White, All Others) 
• Ethnicity   
• Region (Eastern Europe, Western Europe, North America, Asia/Pacific) 
• Height (cm) 
• Baseline weight (kg)  
• Baseline body mass index (BMI) (kg/m2) 
• Karnofsky performance status (KPS) 
• New York Heart Association (NYHA) classification  
• Prior PD-1/PD-L1 treatment (Yes, No) 
• MSKCC risk group (Favorable, Intermediate, and Poor risk) 
• Baseline hypertension status (Yes, No) 
The following disease history and characteristics at study entry will also be summarized:  
• 
Time since the first RCC diagnosis to date of randomization (months) 
• 
RCC diagnosis classification (predominant clear cell,  other) 


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• 
Age at diagnosis (years) 
• 
RCC American Joint Committee on Cancer (AJCC)  Tumor-node-metastasis (TNM) 
staging at diagnosis 
• 
Type of tumor lesions at screening (baseline): 
◦ 
Target lesions 
- Lymph node (Yes, No) 
- Non-lymph node (Yes, No) 
◦ 
Non-target lesions (Yes, No) 
The following prior anticancer therapies will also be summarized: 
• 
Number of prior therapy regimens 
• 
Prior VEGF-targeted therapy (Yes, No) 
• 
Prior biological agents (Yes, No) 
• 
Duration of last therapy (months) 
• 
Best response for last anticancer therapy (complete response (CR), partial response 
(PR), stable disease (SD), progressive disease (PD), not evaluable (NE), not 
applicable (NA), unknown) 
• 
Time from end of last therapy to date of randomization (months)  
• 
Prior treatment regimen (adjuvant, locally advanced, metastatic, neoadjuvant, 
unknown) 
• 
Prior radiotherapy (Yes, No)  
◦ 
Time from last radiotherapy to date of randomization (months)  
◦ 
Site of prior radiotherapy 
◦ 
Tumor lesion at the site progressed since last radiotherapy (Yes, No, Not 
evaluated) 
• 
Prior VEGF-targeted therapy  
◦ 
Duration of most recent VEGF-targeted therapy (months) 
◦ 
Best response for most recent VEGF-targeted therapy 
◦ 
Time from end of most recent VEGF-targeted therapy to date of randomization 
(months) 
◦ 
Type of prior VEGF-targeted therapy (adjuvant, locally advanced, metastatic, 
neoadjuvant, unknown) 
In addition, a summary of stratification factors used in the randomization (MSKCC prognostic 
group and prior PD-1/PD-L1 treatment) based on IxRS data will be provided to evaluate 
whether or not randomization process was appropriately executed in the study.  


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Demographic and baseline disease characteristics, prior anticancer therapies will also be listed 
for each subject. 
MEDICAL HISTORY   
General medical history will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 22.1 or higher and summarized by body system organ class (SOC) and 
preferred term (PT) for each treatment group and overall.  
A subject data listing of medical history will be provided, including SOC and/or PT, current 
medical condition, date of diagnosis or surgical procedure or onset of symptoms, and end 
date/on-going.  
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded on the case report form (CRF) will be coded 
using the World Health Organization Drug Dictionary (WHO DD) Version of March 2018 or 
later.  
Prior medications will be defined as the medications that were started prior to the first dose of 
study drug. Concomitant medications will be defined as the medications that (i) started before 
the first dose of study drug and were continuing at the time of the first dose of study drug, or 
(ii) started on or after the date of the first dose of study drug up to 28 days following the last 
dose in randomization phase. Medications that cannot be determined to be 
prior/concomitant/posttreatment due to missing or incomplete dates will be regarded as 
concomitant. 
Prior medications will be summarized by anatomical class (Anatomical Therapeutic Chemical 
[ATC] Level 1), pharmacologic class (ATC Level 3), and WHO DD preferred term. A similar 
summary will also be provided for concomitant medications except thyroxine suppression 
therapy and antihypertensive therapy. Concomitant thyroxine suppression therapy and 
antihypertensive therapy will be summarized separately. In addition, a separate summary for 
the concomitant medications of P-glycoprotein inhibitors and/or inducers will be provided. 
Data listings will be generated for all prior and concomitant medications, concomitant 
thyroxine suppression therapy, concomitant antihypertensive therapy, and concomitant P-
glycoprotein inhibitors and/or inducers.  
Prior and concomitant medications/therapies will be summarized for Per-Protocol Analysis Set 
1 and Full Analysis Set.  


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5.2.6 
New Anticancer Therapies 
The total number of subjects who received new anticancer therapies during Follow-up period 
will be reported for Per-Protocol Analysis Set 1 and Full Analysis Set in each treatment group. 
A summary of new anticancer therapy will be presented by anatomical class (ATC Level 1), 
pharmacologic class (ATC Level 3), and WHO DD preferred term. The number of anticancer 
regimens received, the duration of the first new anticancer regimen, and the primary reason for 
discontinuation of the first new anticancer regimen will also be summarized. 
The new anticancer procedures during Follow-up period will also be reported. 
5.2.7 
Treatment Compliance  
Records of treatment compliance for each subject will be kept during the study, including the 
Follow-up Period. Clinical research associates will review treatment compliance during 
investigational site visits and at the completion of the study. Received dose as percent of 
planned dose per subject (ie, relative dose intensity) will be summarized as described in Section 
5.6.2.2, no other analysis of treatment compliance is planned.  
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for analyses. For the subgroup analysis for region, 
subjects from all centers within each region will be pooled for the analysis. 
5.3.2 
Adjustments for Covariates   
For the analyses of primary efficacy endpoint of ORR24W and primary safety endpoint of 
proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after 
randomization, the CMH test stratified by the randomization stratification factors of MSKCC 
prognostic group and prior PD-1/PD-L1 treatment will be used.  
The stratified analyses will be performed using the stratification factors from IxRS data. For 
the stratification factor of MSKCC prognostic group from IxRS, some subjects with MSKCC 
Prognostic Score 2 were misclassified to intermediate risk on IRT system which should have 
been classified to poor risk per protocol. The poor risk group will be pooled with the 
intermediate risk group in the relevant stratified analyses based on IxRS data, the favorable 
risk group will remain intact. The analyses based on the stratification factors from CRF data 
in clinical database may also be performed as sensitivity analyses.  
To explore homogeneity of treatment effect across centers/regions, sensitivity analyses will be 
conducted to adjust center/region effect for the primary endpoints of ORR24W and the 
proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after 


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randomization using logistic regression models including center/region and stratification 
factors as covariates.  
Other demographic and baseline variables may be included and adjusted in the statistical 
models as sensitivity analyses if deemed necessary.  
5.3.3 
Multiple Comparisons/Multiplicity 
There will be two interim analyses and one final analysis for the non-inferiority test on the 
primary efficacy endpoint ORR24W. O’Brien-Fleming efficacy boundary is used to control the 
overall Type I error rate at the nominal level (α=0.05 one-sided). Specifically, if the 1-sided P 
value is ≤0.005 at the first interim analysis, or ≤0.014 at the second interim analysis, or ≤0.045 
at the final analysis, non-inferiority in ORR24W will be claimed.  
A non-binding futility will be also carried out at each interim analysis. If the 1-sided P value 
is ≥0.776 at the first interim analysis, or ≥0.207 at the second interim analysis, futility will be 
claimed.     
These stopping boundaries are based on the plan that the two interim analyses will take place 
when the total number of 150 subjects and 200 subjects in the Per-protocol Analysis Set 1 have 
completed 24 weeks of follow-up or discontinued early. 
Superiority on the primary safety endpoint will be tested at 2-sided α=0.05 only if the non-
inferiority on the primary efficacy endpoint ORR24W is claimed.  
All secondary efficacy endpoints will be analyzed descriptively, no formal statistical 
hypothesis tests will be performed on the secondary efficacy endpoints.   
5.3.4 
Examination of Subgroups 
In general, subgroup analyses on the prespecified subgroups in Table 4 will be performed for 
the efficacy endpoint ORR based on the investigator assessment and the primary safety 
endpoint of proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 
weeks after randomization.  
Exploratory analysis on the subgroup of subjects previously treated with PD-1/PD-1 will  be 
performed and is specified in the Section 5.8.2.  
Additional subgroup analyses may be performed as appropriate. 
Table 4:  Subgroup Analyses for Efficacy and Safety Endpoints 
Subgroup 
Definition 
Sex 
Male, Female 
Age  
<65, ≥65 years 


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Race 
White, Non-White 
Region 
Eastern Europe, Western Europe, North America, 
Asia/Pacific 
Baseline hypertension status  
Yes, No 
MSKCC risk group 
Favorable, Intermediate, and Poor risk 
Prior PD-1/PD-L1 treatment 
Yes, No 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
For efficacy endpoints related to ORR which summarize the percentage of responders, missing 
responses will not be imputed and subjects with missing responses will be considered as non-
responders.  
For incomplete dates involving efficacy and safety data such as adverse events, concomitant 
medications, laboratory assessments, vital signs, and echocardiogram/multigated acquisition 
(MUGA) data, a conservative imputation will be used for calculation if needed. The imputation 
rules will be specified in study analysis dataset specification with more details. 
HRQoL analysis will follow FDA and EMEA PRO guidelines. Handling of missing values for 
HRQoL analysis will be specified in details in a separate SAP and HRQoL report. 
5.3.6 
Other Considerations 
There are no other specific considerations that are not covered in other sections of this SAP.  
5.4 
Efficacy Analyses  
Tumor response will be assessed using RECIST 1.1 criteria (Eisenhauer, 2009). For this study, 
a confirmation of CR or PR is required by a consecutive tumor assessment no less than 4 weeks 
after the initial assessment of response.  
The primary efficacy analyses will be based on the investigator assessments. The stratification 
factors (ie, MSKCC prognostic group and prior PD-1/PD-L1 treatment) from IxRS data will 
be used for the primary analysis. For the stratification factor of MSKCC prognostic group from 
IxRS, some subjects with MSKCC Prognostic Score 2 were misclassified to intermediate risk 
on IRT system which should have been classified to poor risk per protocol. The poor risk group 
will be pooled with the intermediate risk group in the relevant stratified analyses based on IxRS 
data, the favorable risk group will remain intact.   
Sensitivity analyses may be performed using the stratification factors from CRF data in clinical 
database.  
Exploratory analyses for the primary efficacy endpoint ORR24w and secondary efficacy 
endpoints of ORR and PFS based on IIR assessments will also be performed (refer to Section 


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5.8.1). 
5.4.1 
Primary Efficacy Analyses 
The primary efficacy endpoint ORR24W is defined as the proportion of subjects with BOR of 
CR or PR as of the Week 24 (after randomization) timepoint based on investigator assessments, 
during treatment or within 28 days after the last dose date but on or prior to the start of new 
anticancer therapy. Subjects with responses achieved after the start of new anticancer therapy 
or after 28 days from the last dose date will not be considered as responders. 
The primary analysis of ORR24W will be based on a non-inferiority test. The study hypothesis 
is that the ORR24W for lenvatinib 14 mg QD in combination with everolimus 5 mg is non- 
inferior to the ORR24W for lenvatinib 18 mg QD in combination with everolimus 5 mg  in 
subjects with renal cell carcinoma following one prior VEGF-targeted treatment.  
For this study, the non-inferiority of lenvatinib 14 mg QD in combination with everolimus 5 
mg relative to lenvatinib 18 mg QD in combination with everolimus 5 mg is defined using 70% 
retention of the treatment effect of lenvatinib 18 mg QD in combination with everolimus vs. 
everolimus, which translated to the estimated odds ratio =0.76 for the non-inferiority margin 
following the approach of Rothmann et al. (2003).   
The non-inferiority hypothesis for ORR24W with the non-inferiority margin of odds ratio =0.76 
for the final analysis can be stated as follows:   
H0: Odds ratio of ORR24W-14mg vs ORR24W-18mg ≤0.76 
Ha: Odds ratio of ORR24W-14mg  vs ORR24W-18mg >0.76 (non-inferiority) 
The primary analysis of ORR24W will be performed on the Per-Protocol Analysis Set 1. The 
point estimate of ORR24W with the corresponding 95% CI for each treatment arm will be 
summarized. The odds ratio of ORR24W (lenvatinib 14 mg over lenvatinib 18 mg) along with 
the 90% CI will be calculated using the CMH method stratified by MSKCC prognostic group 
and prior PD-1/PD-L1 treatment. Non-inferiority in ORR24W will be claimed if the O’Brien-
Fleming efficacy boundary is crossed. If the 1-sided P value is ≤0.045 at the final analysis, 
non-inferiority in ORR24W will be claimed (interim analysis is specified in Section 6). The 
boundary P value ≤0.045 for the final analysis is based on the plan that the two interim analyses 
will take place when the total number of 150 subjects and 200 subjects in the Per-Protocol 
Analysis Set 1 have completed 24 weeks of follow-up or discontinued early. 
The treatment difference in ORR24W between lenvatinib 14 mg and lenvatinib 18 mg will also 
be estimated along with 90% CIs based on the asymptotic normal approximation. 
If non-inferiority in ORR24W is claimed, the superiority test at 2-sided α=0.05 for the primary 
safety endpoint will be performed. The details are specified in Primary Safety Endpoint Section 


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5.6.1. 
Sensitivity analyses of ORR24W based on Full Analysis Set and Per-Protocol Analysis Set 2 
will be performed in a similar manner as described above.   
To explore homogeneity of treatment effect across centers/regions, a sensitivity analysis of 
ORR24W using logistic regression model with center/region along with stratification factors as 
covariates will be conducted to adjust center/region effect.   
Sensitivity analyses of ORR24W based on the stratification factors  from CRF data in clinical 
database will also be performed on Per-Protocol Analysis Set 1, Full Analysis Set and Per-
Protocol Analysis Set 2. 
For this study, for subjects in the lenvatinib 14 mg QD with everolimus 5 mg arm, lenvatinib 
dose should be escalated to 18 mg QD (with everolimus 5 mg) as long as there are no 
intolerable Grade 2 or any ≥ Grade 3 TEAEs that require dose reductions in the first 28-day 
cycle. To evaluate any potential impact due to failing to up-titrate the doses for eligible subjects 
in the lenvatinib 14 mg QD with everolimus 5 mg arm, another sensitivity analysis may be 
performed on Per-Protocol Analysis Set 1 to exclude those subjects who should have been up-
titrated by protocol but were actually not up-titrated by investigators, if the number of such 
cases in the lenvatinib 14 mg QD with everolimus 5 mg arm is deemed high (eg, ≥10%).    
An analysis of ORR24W based on the data prior to when the protocol was amended to open-
label (from double-blinded) (ie, treatment assignments were unblinded to investigator sites on 
14 July 2018) will be performed on Per-Protocol Analysis Set 1 and Per-Protocol Analysis Set 
2 to check for consistency of study results before and after the protocol became un-blinded.  
5.4.2 
Secondary Efficacy Analyses  
The secondary efficacy endpoints include PFS, ORR, OS, PFS2. The analysis of secondary 
efficacy endpoints will be performed descriptively based on the Per-Protocol Analysis Set 1 as 
the primary analysis set, Per-Protocol Analysis Set 2 and Full Analysis Set as the secondary 
analysis sets.    
5.4.2.1 
Progression-free Survival 
DEFINITION  
PFS is defined as the time from the date of randomization to the date of first documentation of 
disease progression based on investigator assessments or date of death, whichever occurs first.  
Determination of the date of PFS event or censoring is summarized in Table 5 below. 
Table 5 
PFS Event and Censoring Rules  


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No. Situation 
Date of Progression or Censoring 
Outcome 
1 
No baseline or postbaseline adequate 
tumor assessments 
Date of randomization 
Censored 
 
2 
Progression documented between 
scheduled visits, on or prior to new 
anticancer therapy# and within 28 
days after the last dose of study 
treatment 
Date of first radiologic PD 
assessment 
 
PFS Event 
 
3 
No progression at the time of data 
cutoff 
Date of last adequate 
radiologic assessment on or 
prior to data cutoff 
 
Censored 
4 
New anticancer therapy started 
Date of last adequate radiologic 
assessment on or prior to the start of 
new anticancer therapy 
Censored 
5 
Death before first PD assessment, on 
or prior to start of new anticancer 
therapy# and within 28 days after the 
last dose of study treatment 
Date of death 
PFS Event 
6 
Death between adequate 
assessment#,* 
Date of death  
 
PFS Event 
 
7 
Death or progression after more than 
one missed visit/tumor assessment**  
 
Date of last adequate radiologic 
assessment before missed tumor 
assessments  
 
Censored 
8 
Death or progression after 28 days 
from the last dose of study treatment 
 
Date of last adequate radiologic 
assessment before the date of last 
dose of study treatment + 28 days  
 
Censored 
9 
No progression and treatment 
discontinuation for reasons other than 
PD 
Date of last adequate radiologic 
assessment before treatment 
discontinuation (ie, within last dose 
date + 28 days) 
Censored 
Note: 
# If documented PD and/or death occurs after the last dose, it is counted as a PFS event as long as the PD 
and/or the death occurs within 28 days since the date of the last dose of study treatment and provided that it 
does not violate other censoring rules (eg, start of new anticancer therapy before the PD or death). Otherwise 
the subject will be censored on the date of the last tumor assessment before the date of last dose of the study 
treatment. 
* Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD or PD as determined 
by investigators at regular interval as defined in the protocol. Any tumor assessments after new anticancer 
therapy starts or after 28 days from the last dose date will not be considered in the definition of PFS. 
** More than one missed visit/adequate tumor assessment is defined as having the duration between two 
consecutive tumor assessments or the duration between the last adequate tumor assessment and death/PD being 
longer than (>) 118 days (the visit schedule for tumor assessment is during every 8th week for this study).  
The priority of the censoring rules is described as follows: 
1. If the subject had PD or death, the following sequence will be applied: 


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• 
If a subject did not have baseline or postbaseline adequate tumor assessments (No. 1), the subject will 
be censored at the date of randomization. However, if the subject died within 118 days after 
randomization and did not receive any new anticancer therapy, it will be counted as a PFS event at the 
date of death. If a subject had new anticancer therapy before PD or death (No. 4), the subject will be 
censored at the date of the last adequate tumor assessment on or prior to the date of new anticancer 
therapy. If PD is reported after the date of the last dose + 28 days, the subject will be censored at the date 
of last tumor assessment before the date of last dose + 28 days (No. 8). If PD or death happened within 
28 days after the last dose date, it will be considered as a PFS event. 
• 
If a subject missed two or more tumor assessments before PD or death (No. 7), the subject will 
be censored at the date of the last adequate tumor assessment before the missed tumor assessments. 
Note that if a subject is censored by both of this criterion and start of new anticancer therapy criterion, 
the earliest censoring date will be used. 
• 
Otherwise, if a subject had PFS event (No. 2, No. 5 or No. 6), the earliest event date will be used. 
2. If a subject did not have PD or death, the censoring date will be the earliest censoring date if the subject 
met multiple censoring criteria (No. 1, No. 3, No. 4, No. 7). 
ANALYSIS METHOD 
The analysis of PFS will be performed based on the Per-Protocol Analysis Set 1 as the primary 
analysis set. The median PFS and the PFS rates at 6, 12, 18 months, and so on (depending on 
data adequacy) will be estimated using the Kaplan–Meier method and presented with 2-sided 
95% CIs. The hazard ratio of lenvatinib 14 mg over lenvatinib 18 mg and the corresponding 
90% CIs will be estimated using the Cox regression model with Efron's method for ties, 
stratified by MSKCC prognostic group and prior PD-1/PD-L1 treatment. The Kaplan-Meier 
curve of PFS will also be plotted over time for each treatment arm. 
Sensitivity analyses of PFS based on the Per-Protocol Analysis Set 2 and Full Analysis Set 
will be performed in a similar manner as described above. 
5.4.2.2 
Objective Response Rate 
ORR is defined as the proportion of subjects achieving a best overall response of confirmed 
CR or PR during treatment or within 28 days after the last dose date but on or prior to the start 
of new anticancer therapy at the time of clinical data cutoff. Subjects with overall responses 
achieved after the start of new anticancer therapy or after 28 days from the last dose date will 
not be considered as responders. Subjects who do not have a tumor response assessment for 
any reason will be considered non-responders and will be included in the denominator when 
calculating the response rate. 
The point estimate of ORR and corresponding 95% CI based on asymptotic normal 
approximation will be summarized for each treatment arm. Odds ratio with 90% CI will be 
estimated using the CMH method stratified by MSKCC prognostic group and prior 
PD-1/PD-L1 treatment. In addition, the treatment difference in ORR between lenvatinib 14 mg 
and lenvatinib 18 mg will also be estimated along with 90% CIs based on the asymptotic 


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normal approximation.  
A sensitivity analysis of ORR based on the Per-Protocol Analysis Set 2 and Full Analysis Set 
will be performed in a similar manner as described above.   
In addition, waterfall plot for the percentage changes from baseline to postbaseline nadir (ie, 
best percentage changes from baseline) in sum of diameters of the target lesions will be 
presented. The depth of response for >0%, ≥30%, ≥50% and ≥75% maximum reduction in sum 
of diameters will be summarized.  
5.4.2.3 
Overall Survival 
Overall survival is defined as the time from the date of randomization to the date of death. All 
deaths during the study will be considered as OS events.   
Subjects who were lost to follow-up or withdrew consent will be censored at the date the 
subject was last known to be alive. Subjects who are still alive at the clinical cut-off date will 
be censored at the date of data cutoff.   
Determination of date of OS event or censoring is summarized in Table 6 below. 
Table 6   OS Event and Censoring Method 
Situation 
Date of Event or Censoring 
Outcome 
Death during study 
Date of death 
OS Event 
Death after data cut-off  
Date of data cut-off 
Censored  
Subject still alive at data cut-off 
Date of data cut-off 
Censored  
Subject lost to follow-up or withdrawal of consent 
before data cut-off 
Date of last known to be alive  
Censored  
The analysis of OS will be performed on the Per-Protocol Analysis Set 1 as the primary 
analysis set. The median OS and the OS rates at 12, 18, and 24 months will be estimated using 
the Kaplan–Meier method and presented with 2-sided 95% CIs. The hazard ratio of lenvatinib 
14 mg over lenvatinib 18 mg and the corresponding 90% CIs will be estimated using the Cox 
regression model with Efron's method for ties, stratified by MSKCC prognostic group and 
prior PD-1/PD-L1 treatment. The Kaplan-Meier curve of OS will also be plotted over time for 
each treatment arm. 
Sensitivity analyses of OS based on the Per-Protocol Analysis Set 2 and Full Analysis Set will 
be performed in a similar manner as described above. 


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5.4.2.4 
Progression-free Survival on Next Line of Therapy  
PFS2 is defined as the time from randomization to the date of disease progression on next line 
of therapy or death, whichever comes first.   
Subjects who started the next line of therapy and have not yet progressed on the next line of 
therapy and are still alive will be censored on the last date they are known to be alive. Subjects 
who did not have any new anticancer therapies and had no death documented before the data 
cutoff date will be censored at the last date they are known to be alive.  
Determination of date of PFS2 event or censoring is summarized in Table 7 below. 
Table 7   PFS2 Event and Censoring Method 
Situation 
Date of Event or Censoring 
Outcome 
Subjects who started the next line of 
therapy and have not yet progressed on 
the next line of therapy and are still alive 
Date of last known to be alive 
Censored 
Subjects who did not have any new 
anticancer therapies and had no death 
documented before the data cutoff date 
Date of last known to be alive 
Censored 
Disease progression on the next line of 
therapy or any death  
Minimum of earliest date that 
indicates progression on the next line 
of therapy and date of death 
PFS2 event 
Other, such as: 
o Lost to follow-up 
o Withdrawal of consent 
Date of last known to be alive 
Censored 
The analysis of PFS2 based on investigator assessment will be performed on Per-Protocol 
Analysis Set 1. The median PFS2 will be estimated using the Kaplan–Meier method and 
presented with 2-sided 95% CIs. The hazard ratio of lenvatinib 14 mg over lenvatinib 18 mg 
and the corresponding 90% CIs will be estimated using the Cox regression model with Efron's 
method for ties, stratified by MSKCC prognostic group and prior PD-1/PD-L1 treatment. The 
Kaplan-Meier curve of PFS2 will also be plotted for each treatment arm. 
Sensitivity analyses of PFS2 based on the Per-Protocol Analysis Set 2 and Full Analysis Set 
will also be performed in a similar manner.  


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5.4.3 
Other Efficacy Analyses 
Other efficacy analyses may be performed descriptively on duration of response (DOR), 
disease control rate (DCR), and clinical benefit rate (CBR). 
5.4.3.1 
Duration of Response  
Duration of response is calculated from the date of initial documentation of the best overall 
response of CR or PR to the date of first objectively documented progressive disease or death, 
whichever occurs first, for the subjects who had achieved a best overall response of CR or PR.  
Subjects who start new anticancer therapies without PD will be censored at the date of the last 
available tumor assessment prior to the start of new anticancer therapies. Subjects who have 
not progressed and subjects who did not die will be censored at the last tumor assessment date. 
Analysis of DOR will be performed on the subjects who achieved a best overall response of 
CR or PR. Median DOR with 2-sided 95% CI will be estimated using the Kaplan-Meier 
method.  
5.4.3.2 
Disease Control Rate 
The DCR is the proportion of subjects who achieved a best overall response of CR, PR or SD 
(minimum duration of SD ≥7 weeks). The DCR with corresponding 2-sided 95% CI based on 
the asymptotic normal approximation will be provided.    
5.4.3.3 
Clinical Benefit Rate 
The CBR is the proportion of subjects who achieved a best overall response of CR, PR or 
durable SD (duration of SD ≥23 weeks). The CBR with corresponding 2-sided 95% CI based 
on the asymptotic normal approximation will be provided.  
5.4.4 
Subgroup Analysis for Efficacy/Safety Endpoints  
To assess the internal consistency and investigation of homogeneity of the treatment effect 
across subgroups, subgroup analyses for the efficacy endpoint of ORR based on the 
investigator assessment and primary safety endpoint of proportion of subjects with intolerable 
Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after randomization based on predefined 
subgroups specified in Section 5.3.4 will be conducted.  
Forest plots of subgroup analyses will be generated.   
Additional subgroup analyses may be performed for selected efficacy and/or safety endpoints. 


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5.5 
Pharmacokinetic, Pharmacodynamic, and Other Biomarker 
Analyses 
Analyses related to PK, PD, and biomarkers will be detailed in separate analysis plans. 
5.6 
Safety Analyses 
The primary safety endpoint of the study is the proportion of subjects with intolerable Grade 2 
or any ≥ Grade 3 TEAEs within 24 weeks after randomization. The primary safety endpoint 
will be performed on the Per-Protocol Safety Analysis Set, Safety Analysis Set will be used 
for descriptive purpose. A sensitivity analysis for primary safety endpoint based on Per-
Protocol Analysis Set 2 will also be performed. Other safety assessments include TEAEs, 
clinical laboratory evaluations, vital signs, electrocardiograms (ECGs), and echocardiogram or 
MUGA scan including left ventricular ejection fraction (LVEF). All safety analyses will be 
performed on the Safety Analysis Set. Some selected safety analyses will also be performed 
on Per-Protocol Safety Analysis Set. 
5.6.1 
Primary Safety Endpoint 
If the boundary for the non-inferiority test on the primary efficacy endpoint ORR24W is crossed, 
the following superiority test at 2-sided α=0.05 on the primary safety endpoint (ie, the 
proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks after 
randomization) will be performed: 
H0: Δ14mg-18mg = 0 
Ha: Δ14mg-18mg ≠ 0 
where Δ14mg-18mg is the difference in the proportion of subjects with intolerable Grade 2 or any 
≥ Grade 3 TEAEs within 24 weeks after randomization between lenvatinib 14 mg and 
lenvatinib 18 mg arm. 
The proportion of subjects with intolerable Grade 2 or any ≥ Grade 3 TEAEs within 24 weeks 
after randomization will be tested using the CMH test at 2-sided ɑ=0.05, stratified by MSKCC 
prognostic group and prior PD-1/PD-L1 treatment from IxRS data.  
At each interim analysis and the final analysis, if the non-inferiority boundary of the primary 
efficacy endpoint is crossed, the analysis of the primary safety endpoint will be performed on 
Per-Protocol Safety Analysis Set. The proportions will also be summarized on Safety Analysis 
Set for descriptive purpose. A sensitivity analysis on primary safety endpoint will be performed 
on Per-protocol Analysis Set 2.
A sensitivity analysis for the primary safety endpoint based on the stratification factors from 
CRF data in clinical database will also be performed on Per-Protocol Safety Analysis Set. 


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To explore homogeneity of treatment effect across centers/regions, a sensitivity analysis for 
the primary safety endpoint using logistic regression model with center/region along with 
stratification factors as covariates will be conducted to adjust center/region effect.  
The summary of intolerable Grade 2 and ≥ Grade 3 TEAEs by SOC and PT is specified in 
Section 5.6.3.3. 
5.6.2 
Extent of Exposure 
Extent of exposure to study treatment, study drug administered, and study drug modifications 
will be summarized and presented for each individual drug and overall. The dosing and 
treatment exposure for those 32 subjects who had received ≥2 incorrect lenvatinib doses due 
to IxRS issue will also be summarized and listed. 
5.6.2.1 
Extent of Exposure to Study Treatment 
Treatment duration and the total number of treatment cycles will be summarized descriptively. 
The maximum number of treatment cycles for each subject is the largest cycle number in which 
a subject receives any non-zero dose of study drugs. The number and percentage of subjects 
treated within each cycle will also be summarized for each treatment arm.  
Treatment duration will be summarized descriptively for each individual drug and overall. The 
dosing end date will be imputed to the analysis cutoff date if the subject is still on treatment at 
the time of the data cutoff, and the dose will be imputed with the last dose recorded in the 
database for that subject.  
The duration of each individual drug in months will be calculated as (Date of the last non-zero 
dose – Date of the first non-zero dose + 1)/30.4375 for the specific drug, including drug 
interruption days. For overall treatment duration, it is defined as the duration between the 
earliest first dose start date of study drugs and the latest last dose end date of study drugs.  
In this study, study drugs refer to lenvatinib 14 mg, lenvatinib 18 mg, and everolimus 5 mg. 
5.6.2.2 
Study Drug Administered 
The total dose received per subject, dose intensity, and relative dose intensity will be 
summarized with descriptive statistics for each individual study drug.  
For each individual study drug, the total dose per subject (mg) will be calculated as the sum of 
all doses that subject has received during the study. The dose intensity (mg/day) will be 
calculated as the total dose (mg) received during the study divided by the treatment duration 
of the specific drug (days). The relative dose intensity, which is defined as the ratio (%) of total 
dose received and total planned dose (ie, received dose as a percentage of planned dose), will 
be calculated as the dose intensity divided by the daily planned dose.  


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5.6.2.3 
Study Drug Dose Reductions and Interruptions 
DOSE REDUCTIONS 
Dose reduction refers to a situation that a dose level was reduced from the previous dose level 
without going back. Dose reduction could apply to any of the study drugs: lenvatinib18 mg/day 
(could reduce to 14, 10, 8, and 4 mg/day), lenvatinib 14 mg/day (could reduce to 10, 8, and 4 
mg/day), and everolimus (5 mg every day could reduce to 5 mg every other day). 
DOSE INTERRUPTIONS 
Dose interruption refers to a situation that a subject had a planned temporary break from taking 
the study drug for a short period (ie, interruption period). Dose interruption could apply to any 
of the study drugs.  
Dose interruption only refers to the scenario that the dose levels or dosing frequencies before 
and after interruption period (defined as the period with dose=0) are the same. For example: 
18 mg lenvatinib followed by 0 mg and followed by 18 mg lenvatinib; 5 mg everolimus every 
day followed by 0 mg followed by 5 mg everolimus every day. If the dose level after dose 
interruption period was reduced from the dose level before the interruption period, it should be 
counted as dose reduction and should not be counted as dose interruption. The following 2 
scenarios are examples of dose reduction instead of dose interruption:  
(1) 18 mg lenvatinib followed by 0 mg followed by 14 mg lenvatinib;  
(2) 5 mg everolimus every day followed by 0 mg followed by 5 mg everolimus every other 
day;  
Please note, for the 2 scenarios above, the period with dose=0 should be counted as dose 
reduction period and not dose interruption (ie, the dose reduction date should be the date of 
dose=0). If the subject discontinued from treatment permanently after dose interruption with 
dose=0, it should be counted as treatment discontinuation instead of dose interruption. 
The number of subjects with dose reductions and dose interruptions for each individual study 
drug will be summarized. Number (ie, frequency) of dose reductions per subject will also be 
summarized.   
Time to first dose reduction is defined as the time period from the first dose date to the date of 
first dose reduction, or the time period from the first dose date to the date of first dose 
interruption for those subjects who had dose interruption first and then followed by dose 
reduction. Time to first dose reduction will be derived and summarized descriptively for each 
individual drug and overall for those subjects who had dose reduction during treatment period.  


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Median time to first dose reduction with 95% CI will also be estimated based on Kaplan-Meier 
method for all the treated subjects. Subjects who did not have dose reductions during treatment 
period will be censored at the date of last dose.     
5.6.3 
Adverse Events 
Adverse events will be graded according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03. The AE verbatim 
descriptions (investigator terms from the CRF) will be classified into standardized medical 
terminology using the MedDRA Version 22.1 or higher. Adverse events will be coded to the 
MedDRA lower level term (LLT) closest to the verbatim term, the linked MedDRA preferred 
term and primary system organ class are also captured in the database.  
A treatment-emergent AE is defined as any one of the followings: 
• 
An AE that emerges during treatment or up to 28 days after the last dose of study treatment, 
having been absent at pretreatment (baseline); or 
• 
An AE that reemerges during treatment or up to 28 days after the last dose of study 
treatment, having been present at pretreatment (baseline) but stopped before treatment; or 
• 
An AE that worsens in toxicity grade during treatment or up to 28 days after the last dose 
of study treatment, relative to the pretreatment state, when the AE is continuous; or 
• 
An AE with missing or partial onset date and is considered related to study treatment by 
investigator; or 
• 
An AE that is not treatment-related and with missing or partial onset date will be considered 
as treatment-emergent unless the onset of the AE can be determined as earlier than the first 
dose date or later than 28 days after the last dose of study treatment. 
Unless otherwise specified, a subject will be counted only once at each level of summary (eg, 
SOC and/or PT), even if the subject experienced more than 1 TEAE within a specific SOC 
and/or PT.  
5.6.3.1 
Overview of TEAEs 
An overview of TEAEs reported through the study will be provided for each treatment arm. 
Overall summary of TEAE will include the number and percentage of subjects with TEAEs, 
serious TEAEs, treatment-related TEAEs, intolerable Grade 2 TEAEs, TEAEs of Grade 3 or 
higher, TEAEs leading to treatment discontinuation (discontinuation of both study drugs in 
each treatment arm), TEAEs leading to dose reductions, TEAEs leading to dose interruptions, 
and TEAEs with fatal outcomes. Overview of TEAEs episodes adjusted by treatment duration 
will also be provided. 


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An overview of TEAEs reported for those 32 subjects who had received ≥2 incorrect lenvatinib 
doses due to IxRS issue will also be provided. 
5.6.3.2 
All TEAEs 
The following summaries will be provided for all TEAEs: 
• 
TEAEs by SOC and PT 
• 
TEAEs by decreasing frequency of PT 
• 
Most common (eg, ≥10%) TEAEs by SOC and PT 
• 
TEAEs by SOC, PT, and worst toxicity grade 
5.6.3.3 
Intolerable Grade 2 and ≥ Grade 3 TEAEs 
The intolerable Grade 2 and ≥ Grade 3 TEAEs will be summarized by SOC and PT.    
In addition, a listing of intolerable Grade 2 and ≥ Grade 3 AEs will be provided. 
5.6.3.4 
Treatment-related TEAEs 
The following treatment-related TEAEs will be summarized: 
• 
Treatment-related TEAEs by SOC, PT and worst toxicity grade  
• 
Most common (eg, ≥10%) treatment-related TEAEs by SOC and PT 
5.6.3.5 
Serious TEAEs 
The incidence of serious TEAEs will be summarized as below: 
• 
Serious TEAEs by SOC and PT  
• 
Treatment-related serious TEAEs by SOC and PT  
• 
Serious TEAEs by decreasing frequency of PT 
• 
Most commonly reported (eg, ≥5%) serious TEAEs by SOC and PT 
• 
Serious TEAEs adjusted by treatment duration 
In addition, a listing of serious AEs will be provided. 
5.6.3.6 
TEAEs Leading to Treatment Discontinuation 
The proportion of subjects who discontinued treatment due to toxicity and time to treatment 
discontinuation due to toxicity will be summarized descriptively. 
The TEAEs leading to treatment discontinuation (discontinuation of both study drugs in each 
treatment arm) will be summarized by SOC and PT for those subjects indicated as having 
discontinued study treatment due to an adverse event on the CRF treatment disposition page.  


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The TEAEs leading to study drug discontinuation for each individual drug will also be 
summarized. 
A listing of AEs leading to treatment discontinuation or any study drug discontinuation will be 
provided. 
5.6.3.7 
TEAEs Leading to Dose Reductions and Dose Interruptions 
The TEAEs leading to dose reductions and dose interruptions will be summarized by SOC and 
PT for each treatment arm. The TEAEs leading to dose reductions and dose interruptions will 
be summarized for each individual drug and overall. 
A listing of AEs leading to dose reductions and/or dose interruptions of any study drug will be 
provided.  
5.6.3.8 
Grade 3 or Higher TEAEs 
The following Grade 3 or higher TEAEs will be summarized: 
x 
Grade 3 or higher TEAEs by SOC and PT  
x 
Most commonly reported (eg, ≥5%) Grade 3 or higher TEAEs by SOC and PT  
x 
Grade 3 or higher TEAEs leading to treatment discontinuations, dose reductions and/or 
dose interruptions by SOC and PT  
In addition, a listing of Grade 3 or higher AEs will be provided. 
5.6.3.9 
TEAEs with Fatal Outcome 
The TEAEs with fatal outcome will be summarized by SOC and PT for each treatment arm. 
Treatment-related TEAEs with fatal outcome will also be summarized. 
A listing of AEs with fatal outcome will be provided. 
5.6.3.10 
Deaths  
The number of subjects who died during the study will be summarized. 
A listing of subjects who died during the study will be provided. 
5.6.3.11 
Adverse Events of Clinical Interest 
Clinically significant adverse events (CSAEs) for lenvatinib and treatment-emergent AEs of 
special interest (AEoSI) for everolimus will be identified based on a thorough review of safety 
data from the clinical and pharmacovigilance database.  


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Evaluations of the CSAEs and AEoSI will be based on standardized MedDRA queries (SMQs), 
customized MedDRA queries (CMQ), or sponsor-generated queries (SGQs), which included 
sponsor-specified PT either alone or in addition to those listed for an SMQ or CMQ. 
CSAEs and AEoSI will be summarized by overall, CTCAE grade and treatment cycle. The 
subjects with CSAEs and AEoSI leading to dose reductions, dose interruptions, and treatment 
discontinuations will also be provided.  
In addition, number of subject with hypertension leading to administration of concomitant 
medication and type of antihypertensive medication received will be summarized. Time to first 
onset of hypertension (defined as the time from the date of first dose date to the date of first 
onset of hypertension) will also be summarized. Similar analysis will also be provided for the 
subjects who had proteinuria. 
Hypertension based on vital sign data will also be summarized. Details are specified in the 
vital sign Section 5.6.5. 
Proteinuria based on urine dipstick data will also be summarized. Details are specified in the 
urinalysis Section 5.6.4.2. 
5.6.4 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units. Laboratory values 
that are non-missing and reported as ‘below the detectable limit’ of an assay will be replaced by 
half the detectable limit in the summary tables. Central laboratory test results will be used as the 
primary data source for laboratory analyses. Only when the central laboratory tests results are 
missing, the local laboratory test results will be used as substitute.  
On-treatment laboratory tests will be defined as the laboratory tests conducted from the start of 
treatment to no more than 28 days after the last dose of study treatment.  
5.6.4.1 
Hematology and Clinical Chemistry 
Laboratory parameters will be graded based on CTCAE Version 4.03. In the summary of laboratory 
parameters by CTCAE grade, for parameters with CTCAE grading in both high and low direction 
(eg, calcium, glucose, magnesium, potassium, sodium), CTCAE grades in both high and low 
directions will be summarized separately.  
The evaluation of clinical laboratory tests will focus on the following selected laboratory 
analytes: 


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Hematology Panel: 
• 
hematocrit, hemoglobin, red blood cell (RBC) counts, white blood cell (WBC) count, 
absolute neutrophil count, and absolute lymphocyte count, platelet count 
Chemistry Panel: 
• 
Electrolytes: bicarbonate, calcium, chloride, magnesium, phosphate, potassium, sodium 
• 
Liver function tests: alanine aminotransferase (ALT), alkaline phosphatase, aspartate 
aminotransferase (AST), direct bilirubin, total bilirubin 
• 
Renal function tests: blood urea/blood urea nitrogen (BUN), creatinine 
• 
Thyroid function tests:thyroid stimulating hormone (TSH), free T4 level 
• 
Other: albumin, cholesterol, triglycerides, glucose, calcium, lactate dehydrogenase (LDH), 
amylase, lipase, creatine kinase  
Descriptive statistics for values and changes from baseline at each scheduled visit for 
hematology and chemistry laboratory parameters will be provided. Box plots of laboratory 
values over time will also be provided for selected hematology and chemistry parameters. 
In addition, the worst CTCAE grade in hematology and chemistry during the treatment will be 
summarized by treatment arm and CTCAE grade. Shift tables from baseline to the worst 
CTCAE grade during treatment will be generated.  
Subjects with treatment-emergent markedly abnormal values (TEMAV) will be summarized. 
Treatment-emergent markedly abnormal value is defined as a value that is outside of the 
normal range and the CTCAE grade increased from baseline by 2 or more grades, except for 
phosphate which must have shifted by 3 or more grades.  
5.6.4.2 
Urinalysis 
Proteinuria: Shifts from baseline to worst postbaseline for proteinuria determined by dipstick 
(negative, trace, 1+, 2+, 3+, 4+) will be presented by treatment arm.  
The urinalysis results from 24-hour urine protein will also be summarized by worst Grade. 
5.6.5 
Vital Signs 
Descriptive statistics for vital sign parameters (systolic and diastolic blood pressure, pulse, 
respiratory rate, temperature, and weight) and changes from baseline at each scheduled visit 
will be presented.  
Blood pressure will also be summarized using a shift table from baseline to worst postbaseline 
CTCAE grade by the categories defined in Table 8 below based on CTCAE grades. 


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Table 8  Blood Pressure Grades 
 
Grade 
Blood Pressure (mm Hg) 
Systolic 
Diastolic 
0 (Normal) 
≤119 
≤79 
1 (Prehypertension) 
120–139 
80–89 
2 (Stage 1 Hypertension) 
140–159 
90–99 
3 (Stage 2 Hypertension) 
≥160 
≥100 
Subjects with systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg 
during treatment will be listed along with their hypertensive medications. 
5.6.6 
Electrocardiograms 
Descriptive statistics for ECG parameters and changes from baseline at each scheduled visit 
will be presented. 
Shift tables will be presented for the changes from baseline in ECG findings (categorized as 
normal; abnormal, not clinically significant; and abnormal clinically significant) for each 
scheduled visit. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia or QTc Bazett during treatment will be summarized. Clinically 
abnormal ECG results in QTc will be categorized as follows:  
• 
Absolute QTc interval prolongation:  
◦ 
QTc interval >450 msec  
◦ 
QTc interval >480 msec  
◦ 
QTc interval >500 msec   
• 
Change from baseline in QTc interval:  
◦ 
QTC interval increases from baseline >30 msec  
◦ 
QTC interval increases from baseline >60 msec 
A subject listing will also be provided. 
5.6.7 
Other Safety Analyses 
5.6.7.1 
Karnofsky Performance Status 
Karnofsky performance status (KPS) will be summarized by a shift table from baseline to worst 
postbaseline scale.  


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5.6.7.2 
Left Ventricular Ejection Fraction  
LVEF (%) assessed on echocardiogram or MUGA scans will be summarized. The lowest 
postbaseline value and change from baseline will be summarized descriptively.   
In addition, LVEF quantitative values will be classified into the following 5 categories:  
• 
Hyperdynamic = LVEF greater than 70%  
• 
Normal = LVEF 50% to 70% (midpoint 60%)  
• 
Mild dysfunction = LVEF 40% to 49% (midpoint 45%)  
• 
Moderate dysfunction = LVEF 30% to 39% (midpoint 35%)  
• 
Severe dysfunction = LVEF less than 30%  
A shift table from baseline to the worst postbaseline values may be generated.  
5.7 
Other Analyses  
5.7.1 
Health-Related Quality of Life   
The analysis of HRQoL will be performed on the QoL Analysis Set. 
For HRQoL analysis, summary statistics of the scores for the derived functional/symptom 
scales according to the scoring manual and global health status scores will be summarized by 
treatment arm at each time point. A separate prespecified HRQoL analysis following FDA and 
EMEA PRO Guidelines will be performed and detailed in a separate SAP and HRQoL report.  
Scoring of EQ-5D-3L and derivation of utility for health economic analysis will also be 
accomplished in a separate analysis and described in a separate HRQoL report. 
5.8 
Exploratory Analyses 
5.8.1 
Efficacy Analysis Based on IIR Assessment 
The efficacy endpoints ORR24W, ORR, and PFS based on blinded IIR assessment will be 
defined and analyzed in the same manner as those based on the investigator assessments that 
described in Section 5.4.  
5.8.2 
Exploratory Analysis for Subjects with Prior PD-1/PD-L1 Treatments 
Exploratory analysis on efficacy endpoints of PFS and OS may be performed descriptively for 
the subjects who had prior PD-1/PD-L1 treatments. 
The subgroup analyses on the efficacy endpoint ORR and primary safety endpoint for the 
subjects with prior PD-1/PD-L1 treatment are specified in Section 5.4.4. 


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5.8.3 
Biomarker-related Analysis 
For the biomarker-related exploratory analysis, such as the analyses to explore the associations 
between blood biomarker and efficacy-related endpoints and the development of 
exposure/biomarker/clinical endpoint models (whenever possible, using a mechanism-based 
approach) for both efficacy and safety data, the analysis methods will be specified in a separate 
analysis plan.  
Other exploratory analyses may be conducted as appropriate. 
6 
INTERIM ANALYSES 
Two interim analyses will take place when 150 and 200 total subjects in the Per-Protocol 
Analysis Set 1 have completed 24 weeks follow-up or discontinue earlier. Each interim 
analysis will test both non-inferiority and futility of lenvatinib 14 mg arm ORR24W compared 
to lenvatinib 18 mg arm ORR24W based on investigator assessment. An O’Brien-Fleming 
stopping boundary (Lan and DeMets, 1983; DeMets and Ware, 1980) will be used for efficacy. 
An interpolated non-binding stopping boundary will be used for futility, which will spend 
β=0.005 and β=0.10 at the first and second interim analyses, respectively.  
The stopping boundaries on the P value scale and the cumulative error probabilities spent at 
each interim analysis and final analysis are shown in Table below. For example, at the second 
interim analysis, non-inferiority in ORR24W will be claimed if the 1-sided P value is ≤0.014; 
futility will be claimed if the 1-sided P value is ≥0.207. 
Analysis # 
Cumulative 
α Spent 
Efficacy 
Boundary  
(P value) 
Cumulative β 
Spent 
Futility 
Boundary  
(P value) 
Interim Analysis #1 
0.005 
0.005 
0.005 
0.776 
Interim Analysis #2 
0.015 
0.014 
0.10 
0.207 
Final Analysis 
0.05 
0.045 
0.2 
0.045 
Safety and efficacy monitoring will be performed by an independent DMC. The function and 
membership of the DMC are described in the DMC charter. The recommendations concerning 
continuation or termination of the trial, or regarding modification of the trial or informed 
consent documents will be reached by the DMC based on the review of study safety and 
efficacy data. Determination of whether lenvatinib 14 mg can be used as an alternative dosing 
strategy will be based on clinical judgment by the Sponsor in consultation with the independent 
DMC (as specified in the DMC charter) by assessing risks and benefits according to the totality 
of data at either of the interim or final analyses. 
The interim analyses together with the safety monitoring DMC analyses will be performed by 
an independent statistical reporting team, such as a statistical contract research organization. 


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DMC meetings for the two protocol specified interim analyses have been carried out on 13 
Mar 2019 and 12 Jun 2019. The DMC reviewed the interim analyses results and the study 
continues as planned. 
7 
CHANGES IN THE PLANNED ANALYSES 
 Not applicable. 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Visit Windows 
Visit windows will be defined to be upper and lower bounds of 3 days of the scheduled visit, 
following the protocol, which states that efforts should be made to conduct study visits (and 
safety assessments) on the day scheduled (± 3 days).  
Tumor assessments are to be performed every 8 weeks (during the 8th week, starting from the 
date of randomization), or sooner if clinically indicated, until progressive disease during 
Randomization Phase. If a subject discontinues from study treatment without disease 
progression, tumor assessments should continue to be performed every 8 weeks until 
documentation of disease progression or beginning a new anticancer treatment during Follow-
up Period. 
In the calculation of descriptive statistics for laboratory values and vital signs, if a visit has 
multiple observations, the observation closest in date and time to the target visit day will be 
used in the analysis. If two or more observations have the same distance to the target visit day, 
the one that has the highest CTCAE grade or is furthest away from the normal range will be 
used.  
The purpose of this windowing is to provide a single record per subject per visit for the 
calculation of descriptive statistics per scheduled visit, and change from baseline per visit. 
Other safety analyses (eg, worst grade laboratory results and shift tables) will include all 
postbaseline assessments, including those scheduled and unscheduled visits. 
8.2 
Baseline Definitions 
For safety assessments, the baseline value is defined as the last non-missing measurement 
taken on or prior to the first dose date. The first dose date is defined as the earliest date of non-
zero dose administration of either study drug (ie, lenvatinib or everolimus). 
Study day is defined as date of assessment – first dosing date + 1 for any assessment done on 
or after first dosing date; otherwise, study day is defined as date of assessment – first dosing 
date.  


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8.3 
Imputation of Missing Data 
Unless specified otherwise, no data imputation will be applied for missing safety and 
efficacy evaluations. For analysis and reporting purpose, partial dates for adverse events, 
prior and concomitant therapies, disease diagnosis date, and start date of new anticancer 
therapy will be imputed if needed. Partial dates for laboratory values, vital signs, and ECGs 
will not be imputed. 
The imputation rules will be specified in study analysis dataset specification with more details. 
8.4 
Variable Derivations 
8.4.1 
Duration of Events Prior to Randomization 
For the following disease characteristics and prior therapies, the duration in months will be 
calculated as the date of randomization minus the date of event (disease diagnosis, disease 
progression, prior therapies, etc.) and then divided by 30.4375. 
The duration in years will be calculated as: (date of randomization – date of event)/365.25. 
• 
Time since the first RCC diagnosis to date of randomization (months) 
• 
Time since last disease progression to date of randomization (months) 
• 
Time from end of last therapy to date of randomization (months)  
• 
Time from prior surgery to date of randomization (months) 
• 
Time from last radiotherapy to date of randomization (months) 
8.5 
Pharmacokinetics/Pharmacodynamics Data Handling 
Details on calculating PK parameters, the way that the values of below limit of quantification (BLQ) 
to be treated, and the analyses to be conducted on PK/PD and exposure-response relationships will 
be specified in a separate plan.  
When developing individual concentration-time profiles, BLQ values will be replaced with 0 for 
the linear plot or missing for the semi-logarithm plot, respectively.  
When calculating the mean or median value for the concentration at a given time point, the BLQ 
values will be assigned to 0. If the proportion of values reported as BLQ is more than 50%, no 
summary statistics should be presented at that time point, and the value will be treated as missing 
in mean or median concentration profiles. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents.  


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10 STATISTICAL SOFTWARE 
Statistical programming and analyses will be performed using SAS® (SAS Institute, Inc., Cary, 
NC, USA), Version 9.4 or higher, and/or other validated statistical software as required.  
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study tables, listings, and graphs (TLGs) shells will be provided in a separate document, 
which will show the content and format of all the TLGs in details. 
12 REFERENCES 
Rothmann M, Li N, Chen G, Chi GYH, Temple RT, Tsou HH. Design and analysis of 
noninferiority mortality trials in oncology. Stat Med. 2003;22(2):239-64. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 
2009; 45(2):228-47. 
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika, 
1983;70:659-63. 
DeMets DL and Ware JH. Group sequential methods for clinical trials with a one-sided 
hypothesis. Biometrika. 1980;67:651-60. 
EMA Guideline on the Evaluation of Anticancer Medicinal Products in Man, July 2013. 
Available from: https://www.ema.europa.eu/documents/scientific-guideline/guideline-
evaluation-anticancer-medicinal-products-man_en.pdf 
FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007. Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/ucm071590.pdf. 


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13 APPENDICES 
13.1 Efficacy and Futility Boundaries at Each Interim Analysis and Final 
Analysis 
There will be 2 interim analyses and one final analysis. The 2 interim analyses will be 
performed only in the Per-Protocol Analysis Set 1 (based on investigator assessment). The 
final analysis will be performed in the Per-Protocol Analysis Set 1 as the primary analysis set, 
and will also be performed in the Per-Protocol Analysis Set 2 and in the Full Analysis Set as 
secondary analysis sets. 
The tables below list the treatment differences in ORR24w between lenvatinib 14 mg + 
everolimus arm and lenvatinib 18 mg + everolimus arm corresponding to the efficacy and 
futility boundaries at each interim analysis for different ORR24w in lenvatinib 18 mg + 
everolimus arm. 
First interim analysis, non-inferiority stopping boundary OR=1.788 (non-inferiority will 
be claimed if observed OR ≥1.788 at first interim analysis. Correspondingly, depending on 
ORR24W, non-inferiority will be claimed if observed treatment difference between lenvatinib 
14 mg arm and lenvatinib 18 mg arm is ≥δ). 
ORR24W in lenvatinib 18 mg arm 
ߜൌTreatment difference 
(lenvatinib 14 mg arm - lenvatinib 18 mg arm) 
10% 
7% 
20% 
11% 
30% 
13% 
40% 
14% 
50% 
14% 
60% 
13% 
First interim analysis, futility stopping boundary OR=0.590 (futility will be claimed if 
observed OR ≤0.590 at first interim analysis. Correspondingly, depending on ORR24W, futility 
will be claimed if the observed treatment difference between lenvatinib 14 mg arm and 
lenvatinib 18 mg arm is ≤δ). 


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ORR24W in lenvatinib 18 mg arm 
ߜൌTreatment difference  
(lenvatinib 14 mg arm - lenvatinib 18 mg arm) 
10% 
-4% 
20% 
-7% 
30% 
-10% 
40% 
-12% 
50% 
-13% 
60% 
-13% 
Second interim analysis, non-inferiority stopping boundary OR=1.436 (non-inferiority 
will be claimed if the observed OR ≥1.436 at second interim analysis. Correspondingly, 
depending on ORR24W, non-inferiority will be claimed if the observed treatment difference 
between lenvatinib 14 mg arm and lenvatinib 8 mg arm is ≥δ). 
ORR24W in lenvatinib 18 mg arm 
ߜൌTreatment difference  
(lenvatinib 14 mg arm - lenvatinib 18 mg arm) 
10% 
4% 
20% 
6% 
30% 
8% 
40% 
9% 
50% 
9% 
60% 
8% 
Second interim analysis, futility stopping boundary OR=0.962 (futility will be claimed if 
the observed OR ≤0.962 at the second interim analysis. Correspondingly, depending on 
ORR24W, futility will be claimed if the observed treatment difference between lenvatinib 14 
mg arm and lenvatinib 18 mg arm is ≤δ). 
ORR24W in lenvatinib 18 mg arm 
ߜൌTreatment difference 
(lenvatinib 14 mg arm - lenvatinib 18 mg arm) 
10% 
-0.3% 
20% 
-0.6% 
30% 
-0.8% 
40% 
-0.9% 
50% 
-1.0% 
60% 
-0.9% 
Final analysis, OR=1.128 (non-inferiority will be claimed if observed OR≥1.128 at the final 
analysis. Correspondingly, depending on ORR24W, non-inferiority will be claimed if the 
observed treatment difference between lenvatinib 14 mg arm and lenvatinib 18 mg arm is ≥δ). 


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ORR24W in lenvatinib 18 mg arm 
ߜൌTreatment difference  
(lenvatinib 14 mg arm - lenvatinib 18 mg arm) 
10% 
1% 
20% 
2% 
30% 
3% 
40% 
3% 
50% 
3% 
60% 
3% 
The above boundaries are based on the plan that the two interim analyses will take place when 
the total number of 150 subjects and 200 subjects in the Per-Protocol Analysis set 1 have 
completed 24 weeks of follow-up or discontinued early.  
Safety and efficacy monitoring will be performed by an independent DMC. The function and 
membership of the DMC are described in the DMC charter. The recommendations concerning 
continuation or termination of the trial, or regarding modification of the trial or informed 
consent documents will be reached by the DMC based on the review of study safety and 
efficacy data. Determination of whether lenvatinib 14 mg can be used as an alternative dosing 
strategy will be based on clinical judgment by the Sponsor in consultation with the independent 
DMC (as specified in the DMC charter) by assessing risks and benefits according to the totality 
of data at either of the interim or final analyses. 
The interim analyses together with the safety monitoring DMC analyses will be performed by 
an independent statistical reporting team, such as a statistical contract research organization. 


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SIGNATURE PAGE 
Author:   
 
 
 
  
 
 
 
 
Oncology Business Group, Eisai Inc. 
 
Date 
Approval: 
 
 
 
  
 
 
 
 
 
 
Oncology Business Group, Eisai Inc.  
  
 
Date 
 
  
 
 
 
 
 
 
Oncology Business Group, Eisai Ltd.    
 
 
 
 
Date 
 
PPD
PPD
PPD
PPD