A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of Lenvatinib in Combination With Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line Treatment of Subjects With Advanced Renal Cell Carcinoma (CLEAR)
Phase: PHASE3
Conditions: Renal Cell Carcinoma
Sponsor: Eisai Inc.

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1
TITLE PAGE
Clinical Study Protocol
Study Protocol 
Number:
E7080-G000-307
Study Protocol 
Title:
A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare 
the Efficacy and Safety of Lenvatinib in Combination with 
Everolimus or Pembrolizumab Versus Sunitinib Alone in First-Line 
Treatment of Subjects with Advanced Renal Cell Carcinoma
(CLEAR).
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, pembrolizumab, and sunitinib
Indication:
Renal Cell Carcinoma
Phase:
Approval Dates:
3
Original Protocol: 22 Jun 2016
Protocol Amendment 01: 26 Sep 2016
Protocol Amendment 02: 03 Feb 2017
Protocol Amendment 03: 10 Jan 2018
Protocol Amendment 04: 30 Jun 2018
Protocol Amendment 05: 19 Dec 2018
Protocol Amendment 06: 10 Sep 2019
Protocol Amendment 07: 06 Aug 2020
IND Number:
124564
EudraCT 
Number:
2016-000916-14
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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REVSION HISTORY
Amendment 07
Date: 06 Aug 2020
Overall reason for the amendment: to remove the immune-related Response Evaluation 
Criteria in Solid Tumors (irRECIST) exploratory analysis for Arm B subjects.
Change
Rationale
Affected Protocol Sections
Removed the exploratory objective: 
To assess PFS by IIR using immune-related 
RECIST (irRECIST) in subjects treated with 
lenvatinib in combination with 
pembrolizumab.
Removed the irRECIST 
exploratory analysis due 
to low pseudoprogression 
rate with pembrolizumab 
in the renal cell cancer 
(RCC) population
Synopsis, Objectives
Section 8.3
Removed the irRECIST assessment and criteria:
For subjects in Arm B only, tumor 
assessments will also be performed using 
irRECIST; this assessment will be performed 
by IIR following database lock for PFS 
analysis
Synopsis, Efficacy 
Assessments
Section 9.5.1.2.1
Section 12, Appendix 7 
(removed)
Removed the irRECIST exploratory endpoint
and analysis:
Progression-free survival (PFS) as 
determined by IIR using irRECIST for 
subjects receiving lenvatinib plus 
pembrolizumab (Arm B), and defined as the 
time from the date of randomization to the 
date of the first documentation of confirmed 
immune-related progressive disease (irPD) or 
death (whichever occurs first).
Synopsis, Statistical 
Methods
Section 9.7.1.1.3
Progression-free survival (PFS) using 
irRECIST as assessed by IIR for subjects 
receiving lenvatinib plus pembrolizumab 
(Arm B) will be summarized using K-M 
estimates.
Section 9.7.1.6.3

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DATE
Highlights of Major Changes
Sections/Changes
10 Sep 2019
Amendment 06:
Title page, List of Abbreviations, and Section 5.2:
Updated to current ICH name (International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use).
Synopsis and Sections 9.1, 9.1.2, 9.1.2.1, 9.1.2.2, 9.1.3.1, 9.5.1.2.1:
The end of the Randomization Phase, Treatment Period, and Follow-up period 
definitions are updated to reflect the changes in PFS analysis.
Synopsis and Sections 9.5.1.2. 9.7.1.1.2, 9.7.1.6.1, 9.7.1.6.2, 9.7.2:
Added an interim analysis of PFS projected to occur ~38 months after the first 
subject was randomized in study.  The final PFS analysis is projected to occur 
approximately ~45 months after the first subject was randomized in the study.  
Based on the results from the two recent available IO+VEGF studies, an interim 
analysis of PFS is added.  The number of interim analyses of OS is also increased 
from 1 to 3.  The alpha-spending functions for PFS and OS analyses are added or 
updated. The procedure to control familywise error rate is changed to a graphical 
approach. The powers of statistical testing are re-calculated under the graphical 
approach.    
Updated median OS assumption for sunitinib arm from 30 months to 37.9 months 
and updated the projected timing for interim analyses and final analysis of OS 
accordingly.  The projected timing for final analysis of OS is updated from 53 
months to 69 months after first subject randomized.  
Synopsis and Section 9.7.3:
Updated Table 9, Summary of Interim and Final Efficacy Analyses, to specify 
timing of interim and final analyses.
Synopsis and Section 9.7.4:
Multiplicity adjustment strategy changed from truncated Hochberg procedure to 
Graphical approach with initial alpha of 0.045 assigned to test PFS 
lenvatinib+pembrolizumab vs sunitinib and initial alpha of 0.0049 assigned to test 
PFS lenvatinib+everolimus vs sunitinib. The multiplicity test strategy was updated 
to optimize the probability of success of all hypothesis tests while to strongly 
control the familywise type I error rate under 0.05 (2-sided).  

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DATE
Highlights of Major Changes
Section/Change
19 Dec 2018
Amendment 05:
Synopsis and Section 9.5.1.2:
During the EU member states Voluntary Harmonisation Procedure (VHP) regulatory 
authority review, the assessors’ requested removal of the second course retreatment 
phase option for pembrolizumab.  Since there are many second-line options available 
for advanced RCC, including checkpoint inhibitors, this has been agreed to be 
removed.
Section 9.5.2:
Removed Table 9, Schedule of Visits and Procedures in E7080-G000-307 – Second 
Course (Pembrolizumab Retreatment) Phase.  Renumbered subsequent tables.
Section 9.7.3:
Updated Table 9, Summary of Interim and Final Efficacy Analyses, to clarify that the 
results of the planned interim analysis (IA1) of ORR and DOR may be considered for 
an early submission in regions outside of EMA jurisdiction.

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DATE
Highlights of Major Changes
Section/Change
30 Jun 2018
Amendment 04:
Synopsis, Section 6, and Section 9.3:
Increased the planned number of investigational sites to 200 to accommodate the 
delay in study enrollment.
Synopsis, Sections 8.2 and 8.3:
Updated secondary and exploratory objectives for consistency with the endpoints in 
Sections 9.7.1.1.2 and 9.7.1.1.3
Synopsis, Section 9.1, Section 9.3, and Section 9.7.2: 
Increased the planned enrollment to 1050 subjects (approximately 350 subjects per 
arm) to address slow enrollment in the first 12 months and high loss of PFS event 
rate, and provide adequate power for intergroup comparisons of overall survival (OS).
Synopsis, Section 9.1 and Section 9.7.2:
Increased the estimated duration of the Study Randomization Period to 43 months
(29-month enrollment period; 14-month follow-up period).  Increased total study 
period to 53 months.
Synopsis and Sections 9.1.2 and 9.1.3:
Added reference to the Second Course (Pembrolizumab Retreatment) Phase and 
defined conditions for continuation of pembrolizumab with or without lenvatinib after 
discontinuation or completion of study treatment in Arm B.
New Section 1.1.1:
Added section to describe specific conditions under which subjects in Arm B may 
receive retreatment with pembrolizumab with or without lenvatinib, referred to as the 
Second Course Phase, after discontinuation or completion of pembrolizumab in this 
study.
Synopsis and Section 9.3.2:  
Revised Exclusion Criterion no. 2 to clarify that central nervous system (CNS)
metastases (not just brain metastases) must be stable for at least 4 weeks before 
starting study treatment.
Added Exclusion Criterion no. 28 to exclude subjects who have had an allogenic 
tissue/solid organ transplant in accordance with current pembrolizumab label.
Section 9.5.1.2:
Added subheadings and included new Section 1.1.1.1.1 to provide requirements for 
tumor imaging during the Second Course (Pembrolizumab Retreatment) Phase
Section 9.5.2:
Added schedule of assessments and visits for the Second Course (Pembrolizumab 
Retreatment) Phase. Renumbered subsequent tables.
Synopsis and Section 9.4.2.2:
Added Management of Proteinuria subheading; added text to clarify that 
lenvatinib/sunitinib must be discontinued in the event of nephrotic syndrome, and to 
align with guidance in the current lenvatinib global investigator brochure.
Synopsis and 9.7.1.6.1:
For the primary analysis of PFS, α was decreased to 0.0499 for all comparisons, due 
to the addition of an interim analysis to which an α of 0.0001 was allocated.
For the multiplicity adjustment, the P-value thresholds for the primary analysis of 
PFS were changed because of the addition of an interim analysis.

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DATE
Highlights of Major Changes
Section/Change
30 Jun 2018
Amendment 04:
Synopsis and Section 9.7.2:
Added justification for the sample size recalculation and power determination for 
ORR.  
Synopsis, 9.7.3:
Two interim analyses were added: 
1.
A planned interim analysis of objective response rate (ORR) and duration of 
response (DOR) was added to include the first 88 treated subjects from the 
lenvatinib + pembrolizumab arm who complete a median follow-up of 12 months 
and have a minimum of 6 months follow-up for duration of response.
2.
A planned interim analysis of OS was added to be performed at the time of the 
primary analysis for PFS.
Section 9.4.8:
Clarified the instructions for a missed dose of either lenvatinib or everolimus for 
subjects receiving lenvatinib + everolimus (Arm A).
For subjects receiving lenvatinib + pembrolizumab (Arm B), the schedule for 
lenvatinib administration after pembrolizumab administration on Day 1 of Cycles 1 
and 2 was revised for ease of study drug administration.
Section 9.5.1.4.3:
Clarified that urine microscopy should be performed at the institution’s laboratory.
Section 9.5.2, Table 7:
A time window for the multigated acquisition (MUGA) scan and echocardiogram was 
added in footnote “l” for consistency with the Extension Phase.
A time window for pharmacokinetic sampling was added in footnote “p.”
Section 9.7.1.6:
Moved Figure 4 to Section 9.7.4.
Section 9.7.2:
Added information on the number of required death events and statistical analysis 
parameters for analysis of the key secondary endpoint of OS. 
Section 9.7.3:
Specified that efficacy interim analyses will be conducted by the independent 
statistical group, that has no other responsibilities for the study.
Added new Section 9.7.4:
Added strategy to adjust for multiplicity and control of the overall family-wise error 
rate (FWER).
Administrative changes to correct minor errors:
Updated title page, List of Abbreviations, Section 5.2, and the Investigator signature 
page to add current ICH name (International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use).
Section 9.4.2.2, Section 9.5.1.2: minor text edits for consistency.  Table 7 and Table 8: 
minor edits, including correction of cross-reference to footnote “c” in Table 8 for 
Day 15 assessment of vital signs and weight.
Updated Reference List.

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DATE
Highlights of Major Changes
Section/Change
10 Jan 2018
Amendment 03:
Sections 7.1.4, 7.2, and 9.4.7:  Per EMA request, revised sections with updated data 
for Phases 1b/2 for the RCC cohort in Study 111, based on new cutoff date of 
31 May 2017.
Sections 8.2, 9.5.1.3, 9.7.1.1.2, 9.7.1.2, and 9.7.1.7.1, Table 7, and Synopsis: Text
revised to clarify that no population pharmacokinetic (PK) analyses will be 
performed using pembrolizumab data in this study.  Only comparisons to historical 
data will be performed.  Pharmacodynamic (PD) data for pembrolizumab will not 
be measured.  Per EMA request, added text that PK/PD analyses will be detailed in 
a separate analysis plan and references for the PK/PD analysis plan (CPMS-E7080-
012P-v1) and the biomarker analysis plan (TSBM-E7080-307-ANA-1P) included 
in Section 9.5.1.3.2 of the protocol.
Section 9.1.1.2: Revised time window for baseline assessments from Day 1 to 
within 72 hours prior to randomization
Sections 9.1.2.1 and 9.1.3.1 and Synopsis:  Revised text to clarify the conditions 
under which subjects will continue to receive study treatment
Sections 9.1.2.2 and 9.1.3.2: Added text that defines the circumstances under which 
a subject is considered to be “lost to follow-up” and identifies the documentation 
needed to support this classification.
Added text clarifying collection of survival status data.
Section 9.3.1 and Synopsis:  
Revised inclusion criterion no. 7 for further clarity on adequate renal function.
Added note to inclusion criterion no. 8, adequate bone marrow function, clarifying 
that conditions must be met without erythropoietin dependency or blood 
transfusion. 
Revised inclusion criterion no. 9 for further clarity.
Section 9.3.2 and Synopsis:  Revised exclusion criterion no. 6 (vaccination with 
live organism) for further clarity. 
Per EMA request, revised exclusion criterion no. 15 to change CV impairment 
window from 6 months to 12 months.  Revised exclusion criterion no. 22, 
immunodeficiency, for further clarity.
Section 9.3.3, Section 9.4.10.2 and Synopsis:  Added text to clarify that subjects 
will continue to undergo tumor assessments and bone scans, and will be followed 
for survival unless lost to follow-up.
Section 9.4.2.1, Section 9.5.1.4.4, Schedules of Assessments (Table 7 and Table 8) 
and Synopsis:  Revised guidelines for management of hypertension as follows:

Requirement of repeat blood pressure (BP) measurements has changed.  Repeat 
BP measurement now required only for subjects who have an elevated initial
BP measurement as follows: systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg.

Definition of a BP assessment changed from 3 BP measurements to 2 BP 
measurements taken at least 5 minutes apart.

Time between BP assessments required for confirmation of hypertension 
changed from 2 BP assessments taken at least 1 hour apart to 2 BP assessments 
at least 30 minutes apart.

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
Clarified that subjects with uncontrolled hypertension (BP ≥160 mmHg or 
diastolic ≥100 mmHg) must have their BP monitored on Day 15 (or more 
frequently if clinically indicated) for 2 consecutive treatment cycles.
Clarified that CTCAE grade is to be based solely on BP measurements.
Section 9.4.2.2, Tables 6, 7 and 8, and Synopsis: Revised guidelines for 
management of proteinuria as follows:

Clarified that CTCAE grading for proteinuria will be based on a 24-hour urine 
result if available.

Added the option to use an immediate spot urine protein-to-creatinine ratio 
(UPCR) test as an alternative to a 24-hour urine protein test to quantify the 
24-hour urine excretion if urine protein is ≥2+ (first occurrence or a subsequent 
increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib/sunitinib dose level, or at the new dose level when there has been a 
lenvatinib/sunitinib dose reduction).

Specified that a 24-hour urine protein test is required if the UPCR result is ≥2.4

Clarified that subjects with proteinuria ≥ 2+ should be tested on Day 15 (or 
more frequently as clinically indicated) until the results have been 1+ or 
negative for 2 consecutive treatment cycles.
Section 9.4.2.11 and Synopsis:  Revised guidelines for management of hemorrhage
for further clarity.
Section 9.4.3, Table 3, and Synopsis: Updated dose modification guidelines for 
pembrolizumab.  
Section 9.4.10.2 and Synopsis: Revised text pertaining to use of systemic 
glucocorticoids for further clarity.
Section 9.5.1.2 and Synopsis:  Clarified timing of screening scans.
Section 9.7.1.2 and Synopsis:  Added Pembrolizumab Pharmacokinetic Analysis 
Set
Section 9.7.3: Per EMA request, clarified that DMC closed minutes will be 
provided after the end of the study.
Administrative changes made throughout protocol:  Updated List of Abbreviations, 
labeled Figure 1 in Section 7.1, corrected error in Figure 2, revised Tables 7 and 8 
for consistency with text, corrected typographical errors, minor formatting changes.
DATE
Highlights of Major Changes
Section/Change
03 Feb 2017
Amendment 02:
Administrative changes made throughout the protocol:
Minor reordering of text for consistency, minor text edits to sentences, paragraphs, 
table footnotes and sections throughout the protocol. 
Assessment of PFS based on investigator assessment per RECIST v.1.1 was added 
as a secondary objective and a secondary endpoint in the Synopsis, Section 8.2, 
and Section 9.7.1.1.2, as requested by the regulatory authorities. 
The following bullet was added as a Secondary Endpoint:  “Progression-free 
survival (PFS) by investigator assessment is defined as the time from the date of 
randomization to the date of first documentation of disease progression based on 

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Highlights of Major Changes
Section/Change
03 Feb 2017
Amendment 02:
the investigator assessment per RECIST v.1.1 or death (whichever occurs first).”
The following bullet was added under Secondary Objectives: “To assess PFS 
based on investigator assessment per RECIST v.1.1.”
A bullet under Secondary Objectives was revised to read “To compare safety and 
tolerability of treatment with lenvatinib in combination with everolimus or 
pembrolizumab versus sunitinib, including the assessment of the proportion of 
subjects who discontinued treatment due to toxicity and time to treatment failure 
due to toxicity.” (See Synopsis and Section 8.2.)
Exclusion criterion 13 was adapted for the study indication (ie, carotid artery 
reference was deleted) in the Synopsis and Section 9.3.2.
Exclusion criterion 27 was added to capture “known intolerance to any of the 
study drugs (or any of the excipients),” in the Synopsis and Section 9.3.2, as 
requested by the regulatory authorities.  
As requested by the regulatory authorities, “may be” was replaced with “if 
possible, will be” to confirm this intent in all appropriate and relevant sections.  
This change is reflected in the Synopsis, Section 9.5.1.3.2, and Section 9.7.1.7.3, 
as it applies to the various PK/pharmacodynamic evaluations, including 
PK/pharmacodynamic relationships (ie, exposure-efficacy, exposure-safety, and 
exposure-biomarker relationships) modeling. 
Dose-modification guidelines for holding treatment for pneumonitis were amended 
from Grade “3-4” to “3-4 or Recurrent 2.”  This change was made in the Synopsis 
and Table 3, Section 9.4.3.
Synopsis and Section 9.7.1.2: The definition of The Pharmacodynamic Analysis 
Set was revised as follows:  “…is the group of subjects who received at least 1 
dose of study drug and had sufficient pharmacodynamic data to derive at least 1 
pharmacodynamic measurement and with documented dosing history.”
Section 9.5.2, Table 7 and Table 8:
As requested by the regulatory authorities, pregnancy assessment was added to the 
Follow-up Period.  Footnote “n” in Table 7: “A serum or urine pregnancy test will 
be performed in women of childbearing potential (ie, premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months) at 
the Screening and Baseline Visits, on Day 1 of each cycle from Cycle 2 onwards, 
at the Off-Treatment Visit, and every 30 days up to 120 days post last dose of 
study medication or the start of a new anticancer therapy, whichever comes first.”
In footnote “y,” Table 7 and footnote “n” in Table 8, the statement “for subjects 
receiving treatment with pembrolizumab (Arm B)” was deleted.
Footnote “i” in Table 8 was also revised to reflect this change.
For consistency, Section 9.5.4.2 and the synopsis were amended to reflect this 
change.

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DATE
Highlights of Major Changes
Section/Change
03 Feb 2017
Amendment 02:
Synopsis, Section 9.5.2 Table 7 (footnote “y”) and Table 8 (footnote “n”), and 
Section 9.5.4.1:  
As requested by the regulatory authorities, the follow-up period for collecting SAE 
data was lengthened as follows: “SAEs regardless of causality assessment must be 
collected through the last visit and for 120 days after the subject’s last dose, or 30 
days following the last dose if the subject initiates new anticancer therapy, 
whichever is earlier.”
Synopsis and Section  9.7.1.6.2:  The following statement was added to the 
discussion of secondary efficacy analyses: “PFS by investigator assessment per 
RECIST v1.1 will be analyzed similarly as for the primary endpoint of PFS by IIR 
per RECIST v1.1.”
Text regarding PFS2 analysis was moved to the end of the secondary analyses 
section, following discussion of HRQoL to remain consistent with the order in 
which secondary objectives are presented.
Synopsis and Section 9.7.1.7:  The following statement, which applies to all 
PK/PD/biomarker analyses, was added:  “The PK and PK/PD analyses will be 
detailed in a separate analysis plan that will be provided at a later date and the 
result will be provided in a standalone report.”
As requested by the regulatory authorities, Section 7.2 was revised from “Study 
Rationale” to “Study Rationale and Benefit Risk Assessment” and a benefit/risk 
statement was added.
As requested by the regulatory authorities, the protocol language in the Synopsis 
and Section 9.1.2.2 was revised to specify that the sponsor may discontinue 
survival follow-up after completion of the primary study analysis when 
appropriate, eg, when only a minimal number of subjects remain in follow up.
PK/PD objective was amended to read “To assess the PK/pharmacodynamic 
relationship between exposure and efficacy/biomarkers/safety, if possible, using a 
mechanistic approach.”
PK and PK/PD related exploratory objectives have been recategorized from 
exploratory to secondary, and the following secondary endpoints have been added 
to the Synopsis (Statistical Methods section) and Section 9.7.1.1.2 (Secondary 
Endpoints) as requested by the regulatory authorities:

Model-predicted clearance and AUC for lenvatinib in Arms A and B. 

Model-predicted clearance and AUC for everolimus in Arm A, and 
pembrolizumab in Arm B.
Text regarding PK and PK/PD analysis was moved to the end of the secondary 
analyses section in the Synopsis.

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DATE
Highlights of Major Changes
Section/Change
26 Sep 2016
Amendment 01:
Administrative changes made throughout the protocol:
Minor reordering of text for consistency, minor text edits to sentences, paragraphs, 
table footnotes and sections throughout the protocol. 
Replaced acronym for EMEA with EMA.
Revised definition of end of study to the date of data cutoff for the final analysis or 
last subject/last visit, including discontinuation from study for any reason, 
whichever occurs later.  This reflects the most recent definition in the protocol 
template.
Recategorized PFS2 and HRQoL from exploratory objectives to secondary 
objectives in Synopsis and Sections 8.2 and 8.3, as requested by the EMA.
Recategorized PFS2 and HRQoL from exploratory endpoints in Synopsis and 
Section 9.7.1.1.3 to secondary endpoints. Added proportion of subjects who 
discontinued treatment due to toxicity, and time to treatment failure due to toxicity 
as new secondary endpoints in Synopsis and Section 9.7.1.1.2 as requested by 
EMA.
Exclusion criterion 19 changed and Exclusion Criterion 20 added in the Synopsis 
and Section 9.3.2 to clarify exclusion of subjects with a history of (noninfectious)
pneumonitis requiring steroid treatment and exclusion of subjects with current 
pneumonitis.  Exclusion Criterion 26 was added to exclude men who do not agree 
to use the methods of contraception specified in the protocol.
Exploratory objective changed in the Synopsis and Sections 8.2 and 8.3 to indicate 
that duration of response will be summarized for subjects in all treatment groups 
and that no formal comparison will be performed.  
Text regarding the provision of DMC Meeting minutes has been added to the 
protocol in the Synopsis and Section 9.7.3 as requested by EMA.
Clarified that serious adverse event reports, reports of pregnancy, reports of 
exposure to study drug through breastfeeding, and any follow-up information must 
be reported within 24 hours (Sections 9.5.4.1 and 9.5.4.2).
More accurately described formulation, packaging, and supply of all investigational 
products in Synopsis and Section 9.4.5.
Removed text on management of hypertension from Synopsis and Section 9.4.2.1, 
and text on management of GI perforation and fistula formation from Synopsis and 
Sections 9.4.2, 9.4.3, and 9.4.4. The text was removed for consistency with other 
lenvatinib protocols and to align with the study drugs’ commercial labels.  
Hypertension and GI perforation/fistula formation should be managed at the 
discretion of the investigator.
Reference added for method to be used to adjust for multiplicity and control family 
wise error rate, and text added to clarify the gatekeeping procedure in Sections 0
and 10.

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DATE
Highlights of Major Changes
Section/Change
26 Sep 2016
Amendment 01:
Characterization of the population pharmacokinetics of pembrolizumab was added 
as an exploratory objective, and text additions and clarifications were made in the 
Synopsis, Sections 9.5.1.3.1, 9.7.1.2, and 9.7.1.7.1 and Table 7.
Deleted FAST information that was inadvertently added to Appendix 3.
Clarification of the New York Heart Association Cardiac Disease Classification 
was done in Appendix 4.
Corrections to the Tumor, Node, and Metastasis Staging scheme were made in 
Appendix 5. 
Clarification in Appendix 7 that tumor assessment scans are performed every 8 
weeks.

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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.:  E7080
Name of Active Ingredient:  Lenvatinib
Study Protocol Title
A Multicenter, Open-label, Randomized, Phase 3 Trial to Compare the Efficacy and Safety of 
Lenvatinib in Combination with Everolimus or Pembrolizumab Versus Sunitinib Alone in First-
Line Treatment of Subjects with Advanced Renal Cell Carcinoma (CLEAR)
Investigators
Unknown
Sites
Approximately 200 sites worldwide
Study Period and Phase of Development
Approximately 69 months
Phase 3
Objectives
Primary Objective
The primary objective of the study is to demonstrate that lenvatinib in combination with 
everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone (Arm C) 
in improving progression-free survival (PFS) (by independent imaging review [IIR] using 
Response Evaluation Criteria in Solid Tumors [RECIST 1.1]) as first-line treatment in subjects 
with advanced renal cell carcinoma (RCC).
Secondary Objectives

To compare objective response rate (ORR) by IIR using RECIST 1.1 of subjects treated with 
lenvatinib in combination with everolimus or pembrolizumab versus sunitinib.

To compare overall survival (OS) of subjects treated with lenvatinib in combination with 
everolimus or pembrolizumab versus sunitinib.

To compare safety and tolerability of treatment with lenvatinib in combination with everolimus 
or pembrolizumab versus sunitinib, including the assessment of the proportion of subjects who 
discontinued treatment due to toxicity and time to treatment failure due to toxicity.

To compare the impact of treatment on Health-Related Quality of Life (HRQoL) as assessed 
by using the Functional Assessment of Cancer Therapy Kidney Index-Disease-Related 
Symptoms (FKSI-DRS), the European Organization for the Research and Treatment of Cancer 
(EORTC) QLQ-30, and the European Quality of Life (EuroQOL) EQ-5D-3L instruments, for 
subjects treated with lenvatinib in combination with everolimus or pembrolizumab versus 
sunitinib

To assess PFS on next-line of therapy (PFS2) as reported by investigator.

To assess PFS based on investigator assessment per RECIST v.1.1

To characterize the population pharmacokinetics (PK) of lenvatinib when co-administered with 
everolimus or pembrolizumab.

To compare the PK of pembrolizumab from this study to historical data.

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
To characterize the population PK of everolimus when co-administered with lenvatinib.

To assess the PK/pharmacodynamic relationship between exposure and 
efficacy/biomarkers/safety, if possible using a mechanistic approach.
Exploratory Objectives

To compare ORR by investigator assessment using RECIST 1.1.

To assess the duration of response (DOR) by IIR and investigator assessment using RECIST 
1.1 for subjects in all treatment arms.

To compare the disease control rate (DCR) (complete response [CR] + partial response [PR] + 
stable disease [SD]) and clinical benefit rate (CBR) (CR, PR + durable SD) by IIR and 
investigator assessment using RECIST 1.1 of subjects treated with lenvatinib in combination 
with everolimus or pembrolizumab versus sunitinib.

To compare PFS by IIR and investigator assessment using RECIST 1.1 in subjects treated with 
lenvatinib in combination with everolimus (Arm A) versus lenvatinib in combination with 
pembrolizumab (Arm B).

To investigate the relationship between candidate tumor and blood biomarkers and clinical 
outcome measures including antitumor activity of study treatment.
Study Design
This is a multicenter, randomized, open-label, Phase 3 study to compare the efficacy and safety of 
lenvatinib in combination with everolimus or pembrolizumab versus sunitinib as first-line 
treatment in subjects with advanced RCC.  
Approximately 1050 eligible subjects will be randomized to 1 of the following 3 treatment arms in 
a 1:1:1 ratio, with approximately 350 subjects in each arm:

Arm A: lenvatinib 18 mg (orally, once daily) plus everolimus 5 mg (orally, once daily)

Arm B: lenvatinib 20 mg (orally, once daily) plus pembrolizumab 200 mg (intravenously [IV], 
every 3 weeks [Q3W]) 

Arm C: sunitinib 50 mg (orally, once daily) on a schedule of 4 weeks on treatment followed by 
2 weeks off (Schedule 4/2) 
Randomization will follow a predefined randomization scheme based on the following 
stratification factors: geographic region (Region 1: Western Europe and North America or Region 
2: rest of the world) and Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic groups 
(favorable, intermediate and poor risk).
Eisai will closely monitor patient dropout, including refusal of assignment.  In the event that the 
dropout rate exceeds 5%, Eisai, in collaboration with the principal investigator(s), will consider 
capping the enrollment in the respective site(s) and/or region.  The dropout plan will be detailed in 
a separate document.
The study will be conducted in 3 Phases: a Pre-randomization Phase, a Randomization Phase, and 
an Extension Phase.  
The Pre-randomization Phase will consist of 2 periods: Screening and Baseline.  The 
Pre-randomization Phase will last no longer than 28 days and will include the Screening Period to 
establish protocol eligibility and the 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.

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The Randomization Phase will consist of 2 periods: Treatment Period and Follow-up Period.  The 
Randomization Phase will begin at the time of randomization of the first subject and will end on 
the data cutoff date for the planned final PFS analysis.  
The Treatment Period for each subject will begin at the time of randomization and will end with 
the completion of the Off-Treatment Visit which will occur within 30 days after the final dose of 
study treatment.  
Subjects will receive study treatment as continuous 21-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.  Archival tumor tissue from the 
most recent surgery or biopsy will be collected (if available) from all enrolled subjects.  Subjects 
will continue to receive study treatment until confirmed disease progression (PD) by independent 
review, development of unacceptable toxicity, subject request, withdrawal of consent, completion 
of 35 treatments with pembrolizumab (approximately 2 years), or study termination by the sponsor.  
Discontinuation of treatment may be considered for those subjects who fulfill all of the following 
criteria:  attain a confirmed CR, have been treated for at least 8 cycles (at least 24 weeks) with 
pembrolizumab, and have received at least 2 treatments with pembrolizumab beyond the date when 
the initial CR is declared.  In the presence of clinical benefit, subjects who complete treatment with 
pembrolizumab may continue to receive lenvatinib alone after this time point.
Subjects will be permitted to continue study treatment beyond RECIST 1.1-defined disease 
progression as long as the treating investigator considers that there is clinical benefit and the 
subject is tolerating study treatment.  The assessment of clinical benefit should take into account 
whether the subject is clinically deteriorating and unlikely to receive further benefit from continued 
treatment.  All decisions to continue treatment beyond initial progression must be discussed with 
the Eisai Medical Monitor. Subjects will discontinue study treatment upon evidence of further 
progression and/or loss of clinical benefit, as judged by the Investigator. 
Disease progression must be confirmed by IIR by the imaging core laboratory (ICL) prior to the 
investigator discontinuing study treatment for a subject. In situations where the investigator judges 
that alternative treatments must be instituted immediately for a subject`s safety, study drug may be 
discontinued without waiting for independent review confirmation of radiographic evidence of 
disease progression.  If possible, before discontinuation of the subject from the study, the 
investigator should consult with the sponsor.
The Follow-up Period will begin the day after the Off-Treatment Visit and will continue as long as 
the subject is alive, unless the subject withdraws consent, is lost to follow-up, or the sponsor 
terminates the study.  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.
During the follow-up period, subjects will be treated by the investigator according to the prevailing 
local standard of care.  Subjects will be followed every 12 weeks (±1 week) for PFS2, survival, and 
all subsequent anticancer treatments received.  This information will be recorded unless this 
information is not allowed to be provided due to confidentiality.  The sponsor may choose to 
discontinue survival follow-up following completion of the PFS analysis when appropriate, eg, 
when only a minimal number of subjects remain in follow up.
All subjects who discontinue study drug treatment prior to disease progression will continue to 
undergo tumor assessments every 8 weeks and a bone scan every 24 weeks in the Follow-up 
Period, until disease progression is documented and confirmed by independent review or a new 
anticancer therapy is initiated, unless the subject withdraws consent. 
The end of the Randomization Phase of the study will be the data cutoff date for the planned final
PFS analysis, which will occur when the target number of events (approximately 388 PFS events 

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as determined by the IIR) for each comparison has been observed.  All subjects who are still on 
study treatment at that time will enter the Extension Phase.
The Extension Phase will consist of 2 periods: Treatment Period and Follow-up Period.  In the 
Treatment Period, subjects still on study treatment following the data cutoff date of the planned 
final PFS analysis (ie, at the end of the Randomization Phase) will continue to receive study 
treatment in 21-day cycles.  Tumor assessments will be performed according to the local standard 
of care, and scans will no longer be required to be sent to the ICL.  The Off-Treatment Visit will 
occur within 30 days after the final dose of study treatment. 
The Follow-up Period, which will begin the day after the Off-Treatment Visit and will continue as 
long as the study subject is alive, unless the subject withdraws consent, is lost to follow-up, or the 
sponsor terminates the study.  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. 
Subjects will be treated by the investigator according to the prevailing local standard of care. 
Subjects will be followed every 12 weeks (±1 week) for PFS2, survival, and all subsequent 
anticancer treatments received.  This information will be recorded unless this information is not 
allowed to be provided due to confidentiality.  The sponsor may decide to terminate survival 
follow-up after the completion of the primary study analysis.  All AEs will be captured for up to 30 
days after last dose of study drug.  SAEs must be collected through 120 days after the subject’s last 
dose, or 30 days following the last dose if the subject initiates new anticancer therapy, whichever is 
earlier.  Any pregnancy in which the estimated date of conception is either before the last visit or 
within 120 days of the last study treatment or 30 days following last study treatment if the subject 
initiates new anticancer therapy, whichever is earlier, must be reported.  Also, any exposure to 
study drug through breastfeeding during study treatment or within 120 days of the last study 
treatment, or 30 days following the last study treatment if the subject initiates a new anticancer 
therapy, whichever is earlier, must be reported.
The definition of the end of the study is the date of the data cutoff for the final overall survival 
analysis or last subject/last visit, including discontinuation from the study for any reason, 
whichever occurs later.
Number of Subjects
Approximately 1050 subjects will be randomized (350 subjects in each treatment arm).
Inclusion Criteria
1.
Histological or cytological confirmation of RCC with a clear-cell component (original tissue 
diagnosis of RCC is acceptable).
2.
Documented evidence of advanced RCC.
3.
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.
4.
Male or female subjects age ≥18 years (or any age greater than 18 years of age if that age is 
considered to be an adult per the local jurisdiction) at the time of informed consent 
5.
Karnofsky Performance Status (KPS) of ≥70. 

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6.
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.
7.
Adequate renal function defined as creatinine ≤1.5× upper limit of normal (ULN); or for 
subjects with creatinine >1.5×ULN, the calculated creatinine clearance ≥30 mL/min (per the 
Cockcroft-Gault formula) is acceptable.
8.
Adequate bone marrow function defined by:

Absolute neutrophil count (ANC) ≥1500/mm3

Platelets ≥100,000/mm3

Hemoglobin ≥9 g/dL
NOTE: Criteria must be met without erythropoietin dependency and without packed red 
blood cell (pRBC) transfusion within the previous 2 weeks.
9.
Adequate blood coagulation function defined by International Normalized ratio (INR) ≤1.5
unless participant is receiving anticoagulant therapy, as long as INR is within therapeutic range 
of intended use of anticoagulants. 
10. Adequate liver function defined by:

Total bilirubin ≤1.5×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), unless there 
are bone metastases. Subjects with ALP values >3×ULN and known to have bone 
metastases can be included. 
11. Provide written informed consent. 
12. Willing and able to comply with all aspects of the protocol.
Exclusion Criteria
1.
Subjects who have received any systemic anticancer therapy for RCC, including anti-VEGF 
therapy, or any systemic investigational anticancer agent. Prior adjuvant treatment with an 
investigational anticancer agent is not allowed unless the investigator can provide evidence of 
subject’s randomization to placebo arm.
2.
Subjects with CNS metastases are not eligible unless they have completed local therapy (eg,
whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use 
of corticosteroids for this indication for at least 4 weeks before starting treatment in this study.  
Any signs (eg, radiologic) or symptoms of CNS metastases must be stable for at least 4 weeks 
before starting study treatment.
3.
Active malignancy (except for RCC, definitively treated basal or squamous cell carcinoma of 
the skin, and carcinoma in-situ of the cervix or bladder) within the past 24 months.  Subjects 
with history of localized & low risk prostate cancer are allowed in the study if they were 
treated with curative intent and there is no PSA recurrence within the past 5 years.
4.
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.
5.
Subjects who are using other investigational agents or who had received investigational drugs 
≤4 weeks prior to study treatment start.

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6.
Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/Day 1). 
Examples of live vaccines include, but are not limited to, measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines 
and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.
7.
Subjects with proteinuria >1+ on urine dipstick testing 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×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×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, everolimus, and/or sunitinib.
13. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.  The degree of 
tumor invasion/infiltration of major blood vessels 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 12 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, cerebrovascular accident (CVA), or cardiac arrhythmia 
associated with hemodynamic instability.
The following is also excluded:
Left ventricular ejection fraction (LVEF) below the institutional normal range as determined 
by MUGA or echocardiogram. 
16. Active infection (any infection requiring systemic treatment). 
17. Subjects known to be positive for Human Immunodeficiency Virus (HIV).
18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is 
detected).
19. Known history of, or any evidence of, interstitial lung disease 
20. Has a history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
21. Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study.
22. Subjects with a diagnosis of immunodeficiency or who are receiving chronic systemic steroid 
therapy (at doses exceeding 10 mg/day of prednisone or equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study treatment.  
Physiologic doses of corticosteroids (up to 10 mg/day of prednisone or equivalent) may be
used during the study.

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23. Active autoimmune disease (with the exception of psoriasis) that has required systemic 
treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a 
form of systemic treatment.
24. 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.
25. Females of childbearing potential* who:

Do not agree to use a highly effective method of contraception for the entire study period 
and for 120 days after study 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.
26. Males who have not had a successful vasectomy (confirmed azoospermia) and do not agree to 
use condom + spermicide OR have a female partner who does not meet the criteria above (ie, is 
of childbearing potential and not practicing highly effective contraception throughout the study 
period), starting with the first dose of study therapy through 120 days after the last dose of 
study therapy, unless sexually abstinent. Note: Abstinence is acceptable if this is the usual 
lifestyle and preferred contraception for the subject.
27. Known intolerance to any of the study drugs (or any of the excipients).
28. Subject has had an allogenic tissue/solid organ transplant.
Study Treatments
Test Arm (Arm A): Lenvatinib is provided as 4-mg and 10-mg capsules.  Everolimus is provided 
as 5-mg tablets.  Lenvatinib 18 mg (one 10-mg plus two 4-mg capsules) plus everolimus 5 mg will 
be taken orally once daily in each 21-day cycle. 
Test Arm (Arm B): Lenvatinib is provided as 4-mg and 10-mg capsules.  Lenvatinib 20 mg (two 
10-mg capsules) once daily will be taken orally in each 21-day cycle.  

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Pembrolizumab is provided as a sterile, preservative-free, clear to slightly opalescent, colorless to 
slightly yellow solution that requires dilution for intravenous infusion.  Each vial contains 100 mg 
of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of pembrolizumab. 
Pembrolizumab will be administered at a dose of 200 mg IV over 30 minutes on Day 1 of each 
21-day cycle. 
Comparator Arm (Arm C): Sunitinib malate will be provided as 12.5-mg and 25-mg capsules.  
Sunitinib 50 mg once daily will be administered orally for 4 weeks on treatment followed by 
2 weeks off (Schedule 4/2) in each 21-day cycle. 
Dose Modifications
Adverse events will be graded using Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03.
Lenvatinib-Everolimus Combination 
Dose reduction and interruptions for subjects who experience lenvatinib-everolimus combination 
therapy-related toxicity will be managed as described in the table below.  Investigators 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.
The starting dose of lenvatinib is 18 mg/day for subjects enrolled in Arm A.  Lenvatinib dose 
reductions occur in succession based on the previous dose level (14, 10, and 8 mg/day). Any dose 
reduction below 8 mg/day must be discussed with the sponsor.
Once the study drug dose has been reduced, it 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.
Refer to the subsections below for management of hypertension, proteinuria, diarrhea, non-
infectious pneumonitis, infections, blood glucose/ lipids, hepatotoxicity, thromboembolic events 
and posterior reversible encephalopathy syndrome/reversible posterior leukoencephalopathy 
syndrome (PRES/RPLS), hypocalcemia, and  hemorrhage, as appropriate, before 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 to 
14 mg once a day (1-level 
reduction) and resume 
everolimus at the same 
dose as prior to dose 
interruption
Dose Modification Guidelines for Lenvatinib-Everolimus Combination Treatment-Related 
Toxicity
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib and 
everolimus until resolved 
to Grade 0-1, or tolerable 
Grade 2
Reduce lenvatinib dose to 
10 mg once a day (1-level 
reduction). Dose reduction 
of everolimus to 5 mg 

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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 to 
8 mg orally once a day 
(1-level reduction).  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
Discuss with sponsor
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 and/or diarrhea 
prior to any study treatment interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to 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 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 1 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-Pembrolizumab Combination 
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-pembrolizumab 
combination therapy-related toxicity will be in accordance with the dose modification guidelines 
described in the table below.  Investigators will decide the probability of the event being related to 
one of both drugs as to whether dose modification of one or both drugs is required.
The starting dose of lenvatinib is 20 mg/day for subjects enrolled in Arm B.  Dose reductions of 
lenvatinib occur in succession based on the previous dose level (14, 10, and 8 mg/day).  Any dose 
reduction below 8 mg/day must be discussed with the sponsor.  Once the study drug dose has been 

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reduced, it may not be increased at a later date, unless the dose has been mistakenly decreased; in 
this situation, the sponsor’s approval is required to increase the dose.
Refer to the subsections below for management of hypertension, proteinuria, diarrhea, 
hepatotoxicity, thromboembolic events, PRES/RPLS, hypocalcemia, and hemorrhage, as 
appropriate, before consulting the dose modification table below.
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly after 
the first dose or several months after the last dose of treatment and may affect more than 1 body 
system simultaneously.  Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs are reversible and can be 
managed with interruptions of pembrolizumab, administration of corticosteroids, and/or other 
supportive care.  For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude 
other causes.  Additional procedures or tests such as bronchoscopy, endoscopy, or skin biopsy may 
be included as part of the evaluation.  Dose modification and toxicity management guidelines for 
irAEs associated with pembrolizumab are provided in the Dose Modification Guidelines for 
Pembrolizumab-Related Adverse Events table below.  See Table 4, Infusion Reaction Treatment 
Guidelines, for supportive care guidelines, including premedications.
Dose Modification Guidelines for Lenvatinib-Related Adverse Events (for the Lenvatinib-
Pembrolizumab Combination Arm)
Treatment-Related Toxicitya,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
14 mg once a day (1-level 
reduction)
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
10 mg once a day (1-level 
reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 
8 mg orally once a day 
(1-level reduction)
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib 
Discuss with sponsor
Grade 4f: 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 and/or diarrhea 
prior to any lenvatinib interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to 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 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 

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as the new baseline for further dose reductions. 
e: 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.
f:  Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as 
Grade 3.
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse 
Events Associated with Pembrolizumab
Immune-
related 
Adverse 
Event
Toxicity 
Grade
or Conditions
(CTCAEv4.0)
Action Taken 
with 
Pembrolizumab
irAE Management 
with Corticosteroids 
and Other 
Therapies
Monitor and 
Follow-up
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 0 or 1 and continue to 
taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after 
AE has improved to Grade 0 or 1 and corticosteroid has been tapered.  Pembrolizumab should 
be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed 
by oral steroid.  Other immunosuppressive treatment should be initiated if irAEs cannot 
be controlled by corticosteroids.
Pneumonitis
Grade 2
Withhold
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone or 
equivalent) followed 
by taper
Add prophylactic 
antibiotics for 
opportunistic 
infections
Monitor subjects 
for signs and 
symptoms of 
pneumonitis
Evaluate 
subjects with 
suspected 
pneumonitis 
with 
radiographic 
imaging 
Grade 3 or 4,
or recurrent 
Grade 2
Permanently 
discontinue
Diarrhea / 
Colitis
Grade 2 or 3
Withhold
Administer 
corticosteroids 
(initial dose of 
1-2 mg/kg 
prednisone or 
equivalent) 
followed by taper
Subjects with 
diarrhea/
colitis should be 
advised to drink 
Monitor subjects 
for signs and 
symptoms of 
enterocolitis (ie, 
diarrhea, 
abdominal pain, 
blood or mucus 
in stool with or 
without fever) 
and of bowel 
perforation (ie, 
Grade 4
Permanently 
discontinue

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liberal quantities of 
clear fluids.  If 
sufficient oral fluid 
intake is not 
feasible, fluid and 
electrolytes should 
be substituted via 
IV infusion.
peritoneal signs 
and ileus)
Subjects with 
Grade ≥2 
diarrhea 
suspecting 
colitis should 
consider GI 
consultation and 
performing 
endoscopy to 
rule out colitis
ASTa / ALTa
elevation or 
Increased 
bilirubin
Grade 2
Withhold
Administer 
corticosteroids 
(initial dose of 0.5 -
1 mg/kg prednisone 
or equivalent) 
followed by taper
Monitor with 
liver function 
tests (consider 
weekly or 
more 
frequently 
until liver 
enzyme value 
returned to 
baseline or is 
stable)
Grade 3 or 4
Permanently 
discontinue
Type 1 diabetes 
mellitus 
(T1DM) or
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withhold
Initiate insulin 
replacement 
therapy for subjects 
with T1DM .
Administer anti-
hyperglycemic in 
subjects with 
hyperglycemia. 
Monitor 
subjects for 
hyperglycemia 
or other signs 
and symptoms 
of diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids and 
initiate hormonal 
replacements as 
clinically indicated
Monitor for 
signs and 
symptoms of 
hypophysitis 
(including 
hypopituitarism 
and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue
Hyperthyroidism
Grade 2
Continue
Treat with 
nonselective beta-
blockers (eg, 
propranolol) or 
thionamides as 
appropriate 
Monitor for signs 
and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue

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Hypothyroidism
Grade 2-4
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyroinine) per 
standard of care
Monitor for signs 
and symptoms of 
thyroid disorders
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold
Administer 
corticosteroids 
(prednisone 1-2 
mg/kg or 
equivalent) 
followed by taper
Monitor changes 
of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity 
of AE administer 
corticosteroids
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes
Grade 3 or 4
Permanently 
discontinue
All other irAEs
Intolerable/ 
persistent 
Grade 2
Withhold
Grade 3
Withhold or 
discontinue 
based on the 
type of event.  
Events that 
require 
discontinuation 
include but are 
not limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Based on type and 
severity of AE 
administer 
corticosteroids
Ensure adequate 
evaluation to 
confirm etiology 
and/or exclude 
other causes
Grade 4 or 
recurrent 
Grade 3
Permanently 
discontinue
Withholding or permanently discontinuing pembrolizumab is at the discretion of the 
investigator or treating physician.  
For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of 
pembrolizumab is required, pembrolizumab may be resumed when the AE improves to Grade 
≤2 and is controlled with hormonal replacement therapy or metabolic control is achieved (in the 
case of T1DM).
GI = gastrointestinal; irAE = immune-related adverse event; IV = intravenous; T1DM = Type 1 
diabetes mellitus.
a:  If a subject with liver metastasis has Grade 2 AST or ALT at the start of study treatment, 
and the AST or ALT value increases by ≥50% relative to Baseline and lasts for ≥1 week, 
then the subject should permanently discontinue study treatment.

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Sunitinib
The starting dose of sunitinib is 50 mg/day on a Schedule 4/2 for subjects enrolled in Arm C.  See 
drug-drug interactions section in protocol for dose recommendations if sunitinib must be 
co-administered with a strong CYP3A4 inhibitor or inducer.
Dose reduction and interruptions for subjects who experience sunitinib therapy-related toxicity will 
be managed as described in the table below. Sunitinib dose reductions occur in succession based 
on the previous dose level (37.5, 25 mg/day schedule 4/2). Any dose reduction below 25 mg/day 
must be discussed with the sponsor. Once the study drug dose has been reduced, it may not be 
increased at a later date, unless the dose has been mistakenly decreased; in this situation, the 
sponsor’s approval is required to increase the dose.
Refer to the subsections below for management of hypertension, proteinuria, diarrhea, 
hepatotoxicity, thromboembolic events, PRES/RPLS, and hemorrhage, as appropriate, before 
consulting the dose modification table below.
Dose Modification Guidelines for Sunitinib-related Toxicity 
Treatment-Related Toxicitya,b
During Therapy
Adjusted Dose
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
First occurrence
Interrupt sunitinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
37.5 mg daily for 4 
weeks followed by 2 
weeks off (1-level 
reduction) 
Second occurrence
(same toxicity or new toxicity)
Interrupt sunitinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
25 mg daily for 4 weeks 
followed by 2 weeks off
(1-level reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt sunitinib 
Discuss with sponsor
Grade 4f: 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 and/or diarrhea 
prior to any study treatment interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be 
intolerable.
d: Obese subjects with weight loss do not need to return to 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 
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 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.
f:  Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage 
as Grade 3.

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MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib/sunitinib have BP of ≤150/90 mm Hg 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/sunitinib dose interruptions and reductions.
Regular assessment of BP should be conducted as detailed in the Schedule of Procedures/
Assessments.  Hypertension will be graded using CTCAE v4.03, based on BP measurements only 
(and not on the number of antihypertensive medications).
If the subject’s initial BP measurement is elevated (systolic BP ≥140 mm Hg or diastolic BP 
≥90 mm Hg), the BP measurement should be repeated at least 5 minutes later. The mean value of 
2 measurements at least 5 minutes apart is defined as one BP assessment. If the BP assessment (ie, 
the mean of the 2 BP measurements obtained at least 5 minutes apart) is elevated (systolic BP 
≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 
30 minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes apart. One BP 
assessment is defined as the mean value of 2 measurements at least 5 minutes apart. The choice of 
antihypertensive treatment should be individualized to the subject’s clinical circumstances and 
follow standard medical practice. For previously normotensive subjects, appropriate 
antihypertensive therapy should be started when systolic BP ≥140 mm Hg or diastolic BP ≥90 mm 
Hg is first observed on 2 assessments at least 30 minutes apart. For those subjects already on 
antihypertensive medication, treatment modification may be necessary if hypertension persists.
Lenvatinib/sunitinib 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 mm Hg, significant risk factors for cardiac disease, 
intracerebral hemorrhage, or other significant co-morbidities). Once the subject has been on the 
same antihypertensive medications for at least 48 hours and the BP is controlled, 
lenvatinib/sunitinib should be resumed as described below.
Subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP monitored 
on Day 15 (or more frequently as clinically indicated) until systolic BP has been ≤150 mm Hg and 
diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles. If a repeat event of systolic 
BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the subject must resume the Day 15 
evaluation until systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2
consecutive treatment cycles.
A diary will be provided to the subject to capture the blood pressure evaluations between study 
visits.
The following guidelines should be followed for the management of systolic BP ≥160 mmHg or 
diastolic BP ≥100 mmHg confirmed on repeat measurements after at least 30 minutes:
1.
Continue study drug 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 1 or more agents of a different class of antihypertensive should be 
added.

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3.
If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib/sunitinib administration should be interrupted and 
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/sunitinib administration should be interrupted and restarted at an additional dose 
reduction only when systolic BP ≤150 mmHg and diastolic BP ≤95 mmHg and the subject 
has been on a stable dose of antihypertensive medication for at least 48 hours. 

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive medications 
(either by dose increase or the addition of a different class of antihypertensive), then 
lenvatinib/sunitinib administration should be interrupted and 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 drug
MANAGEMENT OF PROTEINURIA
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria:
Grading of Proteinuria

Grading of proteinuria according to CTCAE v4.03 will be based on the 24-hour urinary protein 
result if available.  
Management of Proteinuria

Management of lenvatinib/sunitinib administration will be based on the grade of proteinuria 
according to the respective treatment arm’s Dose Modification Guidelines.

In the event of nephrotic syndrome, lenvatinib/sunitinib must be discontinued
Detection and Confirmation
1.
Perform urine dipstick testing per the Schedule of Assessments (Table 7 and Table 8)
2.
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) or an 
immediate spot urine protein-to-creatinine ratio (UPCR) test is required in the following 
situations:

The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug

A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib/sunitinib dose level

When there has been a lenvatinib/sunitinib dose reduction and at the new dose level the 
urine protein dipstick result is ≥2+

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3.
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to verify 
the grade of proteinuria is required when UPCR is ≥2.4.
Monitoring

Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 (or 
more frequently as clinically indicated) until the results have been 1+ or negative for 
2 consecutive treatment cycles.  
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 respective treatment arm’s Dose 
Modification Guidelines 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, 2016).  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.
1.
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).  
2.
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).  
3.
If symptoms are life-threatening (CTCAE Grade 4):

Study medications should be discontinued.
MANAGEMENT OF INFECTIONS
Everolimus has immunosuppressive properties and may predispose subjects to infections.  It is 
important therefore 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

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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 (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) 
should be conducted as detailed in the Schedule of Procedures/Assessments and as clinically 
indicated.  If signs/symptoms indicating liver injury occur, instructions contained in the respective 
treatment arm’s Dose Modification Guidelines 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, 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 respective treatment arm’s Dose Modification Guidelines 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)
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, the respective treatment arm’s Dose Modification Guidelines 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. 

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Hypocalcemia should be treated per institutional guidelines (eg, using appropriate calcium, 
magnesium, and Vitamin D supplementation) until resolution.
MANAGEMENT OF HEMORRHAGE
Dose modification guidelines for lenvatinib- (Arms A and B) and sunitinib- (Arm C) related 
adverse events should be followed for the management of hemorrhage. Either resume 
lenvatinib/sunitinib at a reduced dose or discontinue lenvatinib/sunitinib, depending on the severity 
and persistence of hemorrhage.
For subjects receiving treatment with sunitinib (Arm C) who experience hemorrhage associated 
with thrombocytopenia, treatment interruption is recommended; following resolution, treatment 
may be resumed at the discretion of the investigator.
Duration of Treatment
A subject will remain on study treatment until 1 or more of the following events occur(s):

Progressive Disease (PD) (as confirmed by independent review)
Note: Subjects will be permitted to continue treatment beyond initial RECIST 1.1-defined 
progression as long as investigator-assessed clinical benefit is observed and the subject is 
tolerating study drug. Subjects will discontinue study treatment upon evidence of further 
progression and/or loss of clinical benefit as judged by the Investigator. 

Unacceptable toxicity

Subject request

Withdrawal of consent

Completion of 35 treatments (approximately 2 years) with pembrolizumab

Termination of the study by the Sponsor
The duration of treatment for each subject is estimated to be approximately 15 months.
Concomitant Drug/Therapy
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.  
The following concomitant therapies are also allowed: 

Thyroid hormone suppressive therapy 

Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer 

Anticoagulants including low molecular weight heparin (LMWH), warfarin, anti-Xa agents 

Antiinflammatory agents 

Bisphosphonates or denosumab

Antihypertensive therapy (including additional antihypertensive treatment as appropriate if BP 
increases once the subject is enrolled)

Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases will be 
permitted without being considered PD
If the subject is receiving treatment with lenvatinib and requires surgery during the study, the stop 
time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib 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. 

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
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 
investigator and the sponsor.  
The following therapies are prohibited during the Screening and Treatment Phase of this study: 

Concurrent anticancer therapies such as chemotherapy, TKIs, radiotherapy (with the exception 
of palliative radiotherapy as specified above), antitumor interventions (surgical resection, 
surgical debulking of tumors, etc.), or cancer immunotherapy 

Concurrent other investigational drugs

For subjects in Arms A and B, live vaccines while participating in the study.  Examples of live 
vaccines include, but are not limited to 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,
FluMist®) are live attenuated vaccines, and are not allowed.
For subjects in the lenvatinib plus pembrolizumab arm (Arm B), systemic glucocorticoids for 
any purpose other than to modulate symptoms from an AE that is suspected to have an 
immunologic etiology.  Physiologic doses of corticosteroids (up to 10 mg/day of prednisone or 
equivalent) may be used during the study. Note: Use of prophylactic corticosteroids to 
prevent allergic reactions (eg, intravenous [IV] contrast dye or transfusions) is permitted.
Inhaled steroids are allowed for management of asthma or seasonal allergies.
For further information on the prohibited concomitant therapies for everolimus, pembrolizumab, 
and sunitinib please refer to the respective Prescribing Information.
Assessments
Efficacy Assessments
Tumor assessments will be performed using RECIST 1.1 (for all subjects). 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 efficacy assessment.  Tumor assessments will be carried out following the guidelines 
provided by the ICL.  Historical CT or MRI scans performed within 28 days before randomization, 
but before the signing of informed consent, may be used as screening scans to demonstrate 
eligibility, provided they meet minimum standards as separately defined by the ICL.  
Tumor assessments will be performed during the Prerandomization Phase and then every 8 weeks 
from the date of randomization during treatment cycles in the Randomization Phase and as 
determined by the treating physician in the Extension Phase.  A bone scan will be performed within 
6 weeks prior to randomization (historical is acceptable), every 24 weeks after randomization and 
during Follow-up, and within a target of 1 week but no more than 2 weeks following a CR as 
assessed by the investigator. 
A brain scan (CT of the brain with contrast or MRI of the brain pre- and post-gadolinium) 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 CR. For subjects with a history of protocol-eligible 
treated brain metastases, a brain scan will be required at all tumor assessment time points (eg, 
every 8 weeks).
All subjects will be permitted to continue treatment beyond initial RECIST 1.1-defined progression 
as long as the investigator believes that the subject is still receiving clinical benefit and is tolerating 
study drug treatment. 

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Clinical benefit is defined as: 

Absence of signs and symptoms of PD (including labs)

No decline in performance status

Absence of rapid progression of disease

Absence of progressive tumor(s) at critical sites requiring urgent intervention (eg, spinal cord 
compression).
These subjects must continue tumor assessments at the same interval and have copies of all tumor 
assessments sent to the ICL until further progression and/or loss of clinical benefit, as judged by 
the investigator.  The assessment of clinical benefit should take into account the potential efficacy 
benefit versus the safety risk of continuation of treatment.  All decisions to continue treatment 
beyond initial progression determined by the investigator will need to be discussed with the Eisai 
Medical Monitor.  
During the Randomization Phase, disease progression (per RECIST 1.1) must be confirmed by 
independent review by the ICL prior to the investigator discontinuing study treatment for a subject.  
In situations where the investigator judges that alternative treatments must be instituted 
immediately for management of urgent medical complications of disease progression, study drug 
may be discontinued without waiting for independent confirmation of radiographic evidence of 
disease progression. Subjects who discontinue study treatment without disease progression in the 
Randomization Phase will continue to undergo tumor assessments every 8 weeks and a bone scan 
every 24 weeks in the Follow-up Period, until disease progression is documented or another 
anticancer therapy is initiated.  Subjects who have discontinued study treatment without tumor 
progression in the Extension Phase will have tumor assessments performed as clinically indicated 
using the investigator’s discretion, following the prevailing local standard of care, but not less 
frequently than every 12 weeks. Copies of tumor assessment scans will no longer be sent to ICL 
and independent review will not be carried out during the Extension Phase.
Pharmacokinetic Assessments
Blood samples will be collected from all subjects in Arms A and B. Plasma concentrations of 
lenvatinib (for subjects in Arms A and B), whole blood concentrations of everolimus (for subjects 
in Arm A only), and serum concentrations of pembrolizumab (for subjects in Arm B only) will be 
measured.  Data for lenvatinib and everolimus will be analyzed using a population PK approach, 
while pembrolizumab data will be compared with historical data. Serum antidrug antibodies 
(ADA) and neutralizing antibodies (NAb) to pembrolizumab will be measured for subjects in Arm 
B.
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Assessments
Blood and Tissue Biomarkers:  Blood samples for the development of exploratory predictive 
biomarkers will be collected before the first dose of study drug, on Cycle 1 Day 15, and on Day 1 
of subsequent cycles (during Treatment / Randomization Phase), and at the off-treatment 
assessment from all enrolled subjects across the three treatment arms.  Biomarker discovery and/or 
validation may be performed to identify blood or tumor biomarkers that may be useful to predict 
subject response to study drug, evaluation of response-related and/or safety-related outcomes as 
well as for potential use in diagnostic development.  Blood samples may undergo global proteomic 
and/or enzyme-linked immunosorbent assay (ELISA)-based analyses or multiplex bead-based 
immunoassay, but not limited to, in an effort to identify protein biomarkers.  Potential target 
engagement and pharmacodynamic markers include VEGF, FGF23 and other relevant FGF 
ligands, Ang-2/Tie-2, and other relevant circulating markers.  In addition, biomarkers identified in 
other clinical studies of study drug may also be assessed in samples collected from subjects 

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enrolled in this study. The decision to perform exploratory biomarker analysis may be based on the 
clinical outcome of this study and/or the signals observed in other clinical studies or other 
information available at that time.
Pharmacokinetic-Pharmacodynamic
Data from Arms A and B of the study will be used to explore PK/pharmacodynamic relationships 
for effects of lenvatinib in combination with pembrolizumab or everolimus on PFS, other efficacy-
related parameters including ORR and OS, AEs/dose reductions, and blood and tissue biomarkers.  
Exploratory/graphical analyses will be conducted for PK/pharmacodynamic evaluations and, if 
possible, will be followed by model-based analyses. 
Pharmacogenetic/Pharmacogenomic (PG) Assessments
Archived, fixed tumor tissue from the most recent surgery or biopsy will be collected (if available) 
from all enrolled subjects across the three treatment arms for potential assessment of mutations and 
other genetic alterations or genes and/or proteins that may be important in the development and 
progression of cancer as well as in response to study drug treatment for potential use in diagnostic 
development. Genetic alterations in selected molecular targets may be explored based on their 
potential involvement in renal cell tumor biology (eg, VHL, PI3K-mTOR signaling pathway genes, 
FGF/FGFR signaling pathway genes, HGF/cMET axis, and/or any known epigenetic 
modifications).  Immune cell profiling and molecular targets and factors involved in immune 
check-point axis, such as PD1 or PD-L1 levels, markers of Th1/Th2 phenotype, and inflammatory 
status, may also be explored. Appropriate technology/methodologies will be used based on the 
amount of tumor tissue available.
A blood plasma sample to isolate circulating cell free nucleic acids and a whole blood sample for 
immune response profiling will be collected before the first dose of study drug, on Cycle 1 Day 15, 
and on Day 1 of subsequent cycles (during Treatment / Randomization Phase), and at the off-
treatment assessment from all enrolled subjects across the three treatment arms.  Cell free nucleic 
acid isolated from plasma samples may be used to explore tumor genetic alterations such as 
mutations observed in archival tumor samples as well as those which develop during drug 
treatment.  Genomic DNA extracted from blood samples may be used to confirm whether the DNA 
sequence variants observed in DNA extracted from tumor material are limited to the tumor and to 
assess the immune response.
A blood sample will be collected for potential PG analysis from all enrolled subjects in treatment 
arms A and B (in accordance with regional or local laws). Variation in lenvatinib exposure or the 
occurrence of AEs observed in the study population may be evaluated by correlating single–
nucleotide polymorphisms with PK, safety, or pharmacodynamic data.  
Data obtained will be used for research, to assist in developing safer and more effective treatments 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject.  The 
DNA will not be used to determine or predict risks for diseases that an individual subject does not 
currently have.  Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 
15 years to assist in any research scientific questions related to study treatment, cancer and/or for 
potential diagnostic development.
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Manual.
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs and serious adverse events 
(SAEs) using CTCAE v4.03; regular laboratory evaluation for hematology, blood chemistry, and 
urine values; regular performance of physical examinations, periodic measurement of vital signs, 
ECGs and MUGA or echocardiogram. 

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Other Assessments
HRQoL will be assessed at Baseline (prior to first dose of study drug), on Day 1 of each 
subsequent cycle, at time of withdrawal, 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 FKSI-DRS, the EORTC QLQ-C30, and 
the EuroQOL EQ-5D-3L 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 three 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.
Bioanalytical Methods
Lenvatinib and everolimus will be quantified by use of validated High Performance Liquid 
Chromatography-tandem mass spectroscopy methods.  Serum concentrations of pembrolizumab 
will be measured using validated methods.
Statistical Methods
Primary Endpoint

Progression-free survival (PFS) by independent review is defined as the time from the date of 
randomization to the date of the first documentation of disease progression or death (whichever 
occurs first) as determined by IIR using RECIST 1.1.  PFS censoring rules will follow the FDA 
guidance of 2007; specifics of this will be detailed in the Statistical Analysis Plan.
Secondary Endpoints

Objective response rate (ORR) is defined as the proportion of subjects who have best overall 
response of CR or PR as determined by IIR using RECIST 1.1.

Overall survival (OS) is defined as the time from the date of randomization to the date of 
death from any cause. Subjects who are lost to follow-up and those who are alive at the date of 
data cut-off will be censored at the date the subject was last known alive, or date of data cut-
off, whichever occurs first.

Safety will be assessed summarizing the incidence of treatment-emergent adverse events 
(TEAEs) and SAEs together with all other safety parameters.

Proportion of subjects who discontinued treatment due to toxicity is defined as the 
proportion of subjects who discontinue study treatment due to treatment-emergent adverse 
events (TEAEs).

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
Time to treatment failure due to toxicity is defined as the time from the date of first dose to 
the date that a subject discontinues study treatment due to TEAEs. 

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.  

PFS on next-line of therapy (PFS2) is defined as the time from randomization to disease 
progression on next-line of treatment, or death from any cause, (whichever occurs first).

Progression-free survival (PFS) by investigator assessment is defined as the time from the 
date of randomization to the date of first documentation of disease progression based on the 
investigator assessment per RECIST v.1.1 or death (whichever occurs first).

Model-predicted clearance and AUC for lenvatinib in Arms A and B. 

Model-predicted clearance and AUC for everolimus in Arm A.  
Exploratory Endpoints

Duration of response (DOR) is defined as the time from the date a response was first 
documented until the date of the first documentation of disease progression or date of death 
from any case.

Disease control rate is the proportion of subjects who have best overall response of CR or PR 
or SD. Stable disease must be achieved at ≥7 weeks after randomization to be considered best 
overall response.

Clinical benefit rate is the proportion of subjects who have best overall response of CR or PR 
or durable SD (duration of SD ≥ 23 weeks after randomization).

Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints.
Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT] Population) is the group of all 
randomized subjects regardless the treatment actually received. This is the primary analysis 
population used for all efficacy analyses which will be based on the intent-to-treat principle.
The Per Protocol Analysis Set is the group of those 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 
assessments. Subjects for whom death occurred prior to the first post-baseline tumor assessment 
will also be included.  The per protocol analysis set will be the secondary analysis set for efficacy 
endpoints.
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug. This is 
the analyses population used for all safety analyses which will be based on as-treated principle.
Population Pharmacokinetic (PK) Analysis Set: All subjects who have received at least 1 dose 
of study treatment with documented dosing history in the lenvatinib plus everolimus arm (Arm A) 
or the lenvatinib plus pembrolizumab arm (Arm B), and have measurable plasma levels of 
lenvatinib or whole blood levels of everolimus.
Pembrolizumab Pharmacokinetic (PK) Analysis Set: All the subjects who have received at least 
1 dose of study treatment with documented dosing history in the lenvatinib plus pembrolizumab 
arm (Arm B) and have measurable serum concentrations of pembrolizumab.
The Pharmacodynamic Analysis Set is the group of subjects who received at least 1 dose of 
study drug and had sufficient pharmacodynamic data to derive at least 1 pharmacodynamic
measurement and with documented dosing history.

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The QOL Analysis Set will consist of all subjects who have any QOL data. 
Efficacy Analyses
Efficacy analyses will be based on the Full Analysis Set.
Primary Analysis
The primary analysis of PFS will be based upon data provided by IIR of tumor assessments.  PFS 
will be evaluated using Kaplan-Meier (K-M) estimates and statistical significance of difference in 
PFS comparing lenvatinib + everolimus (Arm A) vs. sunitinib alone (Arm C) and lenvatinib + 
pembrolizumab (Arm B) vs. sunitinib alone (Arm C) will be tested by stratified logrank test with 
geographic region (Western Europe and North America vs. Other) and MSKCC prognostic groups 
(favorable, intermediate and poor risk) as strata.  Median PFS and 2-sided 95% CIs will be 
presented and the K-M estimates of PFS will be plotted over time.  Cox regression model with 
Efron’s method for handling tied results will be used to estimate the hazard ratio and its 95% CI 
stratified by the stratification factors as specified above.
An interim and a final analysis of PFS are planned to be performed.  Lan-DeMets spending 
function with O’Brien-Fleming boundary will be used to control alpha levels between the interim 
and final analysis of PFS. The interim analysis of PFS will be performed when it is approximately 
4 months after the last subject is randomized and an approximately 80% information fraction of 
PFS events (as determined by the IIR) in Arm B and Arm C.  The final analysis of PFS will be 
performed when approximately 388 PFS events, as determined by the IIR, are observed between 
each comparison.  A graphical approach will be used to control the family wise error rate (FWER) 
at the two-sided 0.0499 for multiple comparisons, including both PFS comparisons of Arm B vs 
Arm C and Arm A vs Arm C.  For each comparison, a statistical significance can be claimed based 
on either interim or final analysis of PFS at specified alpha levels.
Secondary Analyses
The primary endpoint PFS and key secondary endpoints, ORR and OS, will be tested using a 
graphical approach to control the overall FWER. 
Overall Survival (OS) will be compared between lenvatinib + everolimus (Arm A) vs. sunitinib 
alone (Arm C) and lenvatinib + pembrolizumab (Arm B) vs. sunitinib alone (Arm C) using the 
stratified logrank test with geographic region (Western Europe and North America vs. Other) and 
Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic groups (favorable, intermediate 
and poor risk) as strata. The hazard ratio and its 95% CI comparing lenvatinib + everolimus (Arm 
A) versus sunitinib alone (Arm C) and lenvatinib + pembrolizumab (Arm B) versus sunitinib alone 
(Arm C) will be estimated by a stratified Cox proportional hazards model with Efron’s method for 
handling tied results stratified by geographic region and MSKCC prognostic groups. Median OS 
with 2-sided 95% CIs will be calculated using K-M product-limit estimates for each treatment arm 
and K-M estimates of OS will be plotted over time. 
Three interim and a final analyses of OS are planned to be performed (Section 9.7.3). Lan-DeMets 
spending function with Pocock boundary will be used to control alpha levels among the interim 
and final analysis of OS. The first two OS interim analyses will be performed at the time of PFS 
interim and final analysis, corresponding to approximately 45% and 60% of information fractions 
of OS events. The third OS interim analysis will be performed at approximately 80% information 
fraction of OS events. The final analysis of OS will be performed when 304 OS events are 
observed for each comparison.
Objective Response Rate (ORR) will be calculated with exact 95% confidence intervals using the 
method of Clopper and Pearson.  The difference between treatment arms will be tested using the 
Cochran-Mantel-Haenszel (CMH) test, stratified by geographic region and MSKCC prognostic 
groups.  The p-value for hypothesis testing of ORR will be based on the ORR data at the time of 

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the PFS interim analysis.  The ORR data available at the subsequent analysis time points will be 
provided for supportive purposes.
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 EMA 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.  
PFS2 will be calculated using the Kaplan-Meier (KM) product-limit estimates for each treatment 
group and presented with two-sided 95% CIs. The KM estimate of PFS2 will also be plotted over 
time for each treatment group. 
PFS by investigator assessment per RECIST v1.1 will be analyzed similarly as for the primary 
endpoint of PFS by IIR per RECIST v1.1.
Pharmacokinetic Analyses
Plasma concentrations of lenvatinib and whole blood concentrations of everolimus versus time data 
will be analyzed using a population PK approach to estimate population PK parameters for each 
respective drug, while pembrolizumab concentrations will be compared graphically with historical 
data.  For lenvatinib, data from this study will be pooled with historical data from other Phase 1 
and 2 studies. For everolimus, data from this study will be pooled with data from Study E7080-
G000-205.  
Pharmacokinetic-Pharmacodynamic Analyses 
The effect of lenvatinib in combination with everolimus or pembrolizumab on soluble, tissue, 
genetic and/or imaging biomarkers will be summarized using descriptive statistics using the 
PK/pharmacodynamic analysis set.  PK/pharmacodynamic relationships (ie, exposure-efficacy, 
exposure-safety, and exposure-biomarker relationships) will be modeled, if possible, using a 
mechanistic approach, for effects of study treatment. Efficacy endpoints will include primary 
endpoint of PFS and other efficacy-related metrics including but not limited to ORR (based on 
RECIST 1.1) and OS. Safety endpoint will be most frequent AEs of special interest and dose 
reductions.  Exploratory/graphical analyses will be conducted for PK/pharmacodynamic
evaluations, and, if possible, will be followed by model-based analyses.  
The PK and PK/PD analyses will be detailed in a separate analysis plan and the results will be 
provided in a stand-alone report.
Exploratory Analyses
Disease Control Rate and CBR will be calculated with exact 95% confidence intervals using the 
method of Clopper and Pearson. The differences and odds ratios of the above rates between 
treatment arms and corresponding two-sided 95% CIs will be calculated respectively. Median 
DOR among responders for each treatment arm will be presented along with its corresponding 2-
sided 95% CIs. The difference in PFS between lenvatinib in combination with everolimus versus 
lenvatinib in combination with pembrolizumab will be analyzed using the method used for analysis 
of the primary endpoint.  
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Soluble, tissue, genetic and/or imaging biomarkers (baseline and/or post-treatment) may be 
summarized using descriptive statistics and correlated with clinical outcomes-related endpoints for 
safety and/or efficacy (including best overall response, PFS and OS) as appropriate. Details may
be included in a separate analysis plan. 

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Safety Analyses
Safety analyses will be based on the Safety Analysis Set. All safety analyses will be summarized 
by treatment arm. Adverse events and serious adverse events, laboratory test results, vital signs, 
and echocardiogram results (including LVEF) will be summarized. Safety data will be summarized 
using descriptive statistics. Categorical variables will be summarized by number and percentage. 
Continuous variables will be summarized using n (number of subjects with available data), mean, 
standard deviation, median, Q1, Q3, and range (minimum and maximum) unless otherwise 
specified.
The proportion of subjects who discontinue treatment due to toxicity will be summarized by 
frequency counts and percentages. Median, upper and lower quartiles of time to treatment failure 
due to toxicity will be summarized for subjects who discontinue study treatment due to TEAEs.
Multiplicity Adjustment
The primary endpoint, PFS, and key secondary endpoints, ORR and OS, will be tested using a 
graphical approach (Maurer and Bretz, 2013) to control the overall FWER.  
No multiplicity adjustment will be made for testing other secondary and exploratory endpoints.
Figure: Graphical Approach to Control FWER for Testing Primary and Key Seconday Endpoints
EP = endpoint; ORR = objective response rate; OS = overall survival; PFS = progression-free 
survival
Hypothesis (H1): The PFS of lenvatinib + pembrolizumab arm is superior to that of sunitinib arm.
Hypothesis (H2): The PFS of lenvatinib + everolimus arm is superior to that of sunitinib arm.
Hypothesis (H3): The OS of lenvatinib + pembrolizumab arm is superior to that of sunitinib arm.
Hypothesis (H4): The OS of lenvatinib + everolimus is superior to that of sunitinib arm.
Hypothesis (H5): The ORR of lenvatinib + pembrolizumab arm is superior to that of sunitinib arm.
Hypothesis (H6): The ORR of lenvatinib + everolimus is superior to that of sunitinib arm. 
Interim Analyses

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An interim analysis of ORR for the first 88 subjects from the lenvatinib + pembrolizumab arm 
(Arm B) of this study will be performed.  No comparative analysis will be conducted for the 
interim analysis of ORR; however, an α of 0.0001 will be allocated.  This interim analysis of ORR 
will occur after the first 88 subjects treated in Arm B have completed a median follow-up of 12 
months and a minimum duration of response follow-up of 6 months.
An interim analysis of PFS is planned to be performed. The interim analysis of PFS will be 
performed when it is approximately 4 months after the last subject is randomized and 
approximately 80% information fraction of PFS events (as determined by the IIR) in Arm B and 
Arm C.  Lan-DeMets spending function with O’Brien-Fleming boundary will be used to control 
alpha levels between the interim and final analysis of PFS.
Three interim analyses of OS are planned to be performed. The first two OS interim analyses will 
be performed at the time of PFS interim and final analysis, corresponding to approximately 45% 
and 60% of information fractions of OS events. The third OS interim analysis will be performed at 
approximately 80% information fraction of OS events. Lan-DeMets spending function with 
Pocock boundary will be used to control alpha levels among the interim and final analysis of OS.
The interim efficacy analyses will be conducted by an independent statistical group that has no 
other responsibilities for the study.  
The safety monitoring will be conducted by the independent data monitoring committee (DMC) 
and only the DMC will have access to data with treatment information.  The frequency of the 
safety reviews will be defined in the DMC charter.  Minutes from the open meetings of the DMC 
will be provided if requested by regulatory agencies.  The recommendation whether to stop the trial 
for safety will be reached by the DMC based on their review of safety data with treatment 
information.  The function and membership of the DMC will be described in the DMC charter.
Sample Size Rationale
The sample size is estimated based on the primary endpoint PFS.  Approximately 1050 subjects 
will be randomized in a 1:1:1 ratio into 1 of 3 treatment arms: lenvatinib + everolimus, lenvatinib + 
pembrolizumab, or sunitinib alone.  The randomization scheme will be stratified by geographic 
region (Western Europe and North America vs. Other) and MSKCC prognostic groups (favorable, 
intermediate and poor risk).  
The same treatment effect is assumed for the primary comparisons of lenvatinib + everolimus 
(Arm A) and lenvatinib + pembrolizumab (Arm B) each compared to sunitinib alone (Arm C). 
Assuming the median PFS in sunitinib alone (Arm C) to be 12.3 months and a hazard ratio of 
0.714 for the primary comparisons, this corresponds to 40% improvement (4.9 months) in median 
PFS from 12.3 months to 17.2 months from Arm A versus Arm C and for Arm B versus Arm C.  
The yearly loss to PFS event rate of 22% is assumed in the sample size calculation.  
Since the study is testing more than one comparison for the primary and secondary endpoints, 
respectively, the graphical approach (Section 9.7.4) will be used for testing multiple hypotheses.  
For the two PFS comparisons (one for each test arm), the sponsor chooses to split the total alpha of 
0.0499 (2-sided), as initial allocations, into α = 0.045 for the comparison between Arm B and Arm 
C, and α = 0.0049 for the comparison between Arm A and Arm C. 
The study is designed to achieve 90% power at α = 0.045 to detect a statistically significant 
difference in PFS in the comparison between Arm B and Arm C.  Therefore, a total of 388 PFS 
events are required between Arms B and C in the final PFS analysis.  Since the same number of 
PFS events are expected to be observed in Arms A and C, a total of 388 PFS events is expected in 
the final PFS analysis for the comparison between Arms A and C. The power to detect a 
statistically significant difference in PFS between Arm A and Arm C is approximately 70% at the 
initial assigned α = 0.0049, and will be at least 90% when the hypothesis tests of PFS and OS in the 

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comparison of Arm B and Arm C are statistically significant. In the power calculation for PFS 
analysis, it is assumed that one interim analysis of PFS is to be performed at the 80% information 
fraction and a Lan-DeMets spending function with O’Brien-Fleming boundary is used between the 
interim and final analysis of PFS. 
Assuming an average enrollment rate of 31 subjects per month, the interim and final analysis of 
PFS will occur approximately 38 and 45 months (34 month enrollment period) after the first 
subject is randomized.  A total of 582 PFS events are expected in 3 arms by the time of the planned 
final PFS analysis.
For the key secondary endpoint of OS, a total of 304 deaths for each comparison (456 death events 
among the 3 arms) are expected in the final OS analysis.  For OS testing, when the corresponding 
PFS testing is statistically significant at the initial assigned alpha, the study will provide 80% 
power to detect a statistically significant difference at an α level of 0.045 for the comparison 
between Arms B and C, and 50% power at an α level of 0.0049 for the comparison between Arm A 
and C.  By using the graphical approach, the power for the OS comparison between Arms A and C 
will increase to at least 80% when the OS testing between Arms B and C is significant and both 
PFS tests are significant.  The assumptions that are used for the OS power calculations are: 1) the 
hazard ratio is 0.70 (median OS is 54.1 months in Arm A or Arm B and 37.9 months in Arm C), 2) 
interim analyses are performed at approximately 45%, 60%, and 80% information fraction of death 
events, 3) a Lan-DeMets spending function with Pocock boundary is used, and 4) the yearly rate 
for loss to follow-up is 3%.  With the planned sample size and the assumptions for enrollment, the 
final analysis of OS is expected to occur approximately 69 months after the first subject is 
randomly assigned to treatment.

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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
REVSION HISTORY ...........................................................................................................3
2
CLINICAL PROTOCOL SYNOPSIS..........................................................................14
3
TABLE OF CONTENTS.............................................................................................43
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................49
5
ETHICS.......................................................................................................................53
5.1
Institutional Review Boards/Independent Ethics Committees.............................53
5.2
Ethical Conduct of the Study..............................................................................54
5.3
Subject Information and Informed Consent ........................................................54
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................55
7
INTRODUCTION.......................................................................................................55
7.1
Renal Cell Carcinoma: Epidemiology and Current Therapeutic Options.............55
7.1.1
Preclinical Experience with the Combination of Lenvatinib with 
Everolimus ...............................................................................................56
7.1.2
Clinical Results Obtained with Combination Lenvatinib plus 
Everolimus ...............................................................................................57
7.1.3
Preclinical Experience with the Combination of Lenvatinib plus PD-
1/L1 inhibitors..........................................................................................58
7.1.4
Preliminary Clinical Results Obtained with Combination Treatment 
with Lenvatinib plus Pembrolizumab........................................................58
7.2
Study Rationale and Benefit/Risk Assessment....................................................60
8
STUDY OBJECTIVES................................................................................................61
8.1
Primary Objective ..............................................................................................61
8.2
Secondary Objectives.........................................................................................61
8.3
Exploratory Objectives.......................................................................................62
9
INVESTIGATIONAL PLAN ......................................................................................62
9.1
Overall Study Design and Plan...........................................................................62
9.1.1
Prerandomization/Pretreatment Phase.......................................................64
9.1.1.1
Screening Period...............................................................................64
9.1.1.2
Baseline Period.................................................................................64
9.1.2
Randomization/Treatment Phase ..............................................................64
9.1.2.1
Treatment Period ..............................................................................64
9.1.2.2
Follow-Up Period .............................................................................65
9.1.3
Extension Phase .......................................................................................66
9.1.3.1
Treatment Period ..............................................................................66
9.1.3.2
Follow-up Period..............................................................................67
9.2
Discussion of Study Design, Including Choice of Control Groups......................67

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9.3
Selection of Study Population ............................................................................68
9.3.1
Inclusion Criteria......................................................................................68
9.3.2
Exclusion Criteria.....................................................................................69
9.3.3
Removal of Subjects From Therapy or Assessment ..................................71
9.4
Treatments.........................................................................................................72
9.4.1
Treatments Administered..........................................................................72
9.4.2
Dose Interruption and Dose Reduction for Combination Lenvatinib plus 
Everolimus Treatment ..............................................................................72
9.4.2.1
Management of Hypertension ...........................................................74
9.4.2.2
Management of Proteinuria...............................................................75
9.4.2.3
Management of Diarrhea ..................................................................76
9.4.2.4
Management of Non-Infectious Pneumonitis ....................................76
9.4.2.5
Management of Infections ................................................................77
9.4.2.6
Management of Blood Glucose and Lipids........................................77
9.4.2.7
Management of Hepatotoxicity.........................................................77
9.4.2.8
Management of Thromboembolic Events..........................................78
9.4.2.9
Management of Posterior Reversible Encephalopathy 
Syndrome/Reversible Posterior Leukoencephalopathy Syndrome 
(PRES/RPLS)...................................................................................78
9.4.2.10
Management of Hypocalcemia..........................................................78
9.4.2.11
Management of Hemorrhage.............................................................79
9.4.3
Dose Interruption and Dose Reduction for Combination Lenvatinib plus 
Pembrolizumab Treatment........................................................................79
9.4.4
Dose Interruption and Reduction for Sunitinib..........................................85
9.4.5
Identity of Investigational Products ..........................................................86
9.4.5.1
Chemical Name, Structural Formula of Lenvatinib ...........................87
9.4.5.2
Chemical Name, Structural Formula of Everolimus ..........................87
9.4.5.3
Information on Pembrolizumab.........................................................87
9.4.5.4
Chemical Name, Molecular Formula of Sunitinib .............................87
9.4.5.5
Labeling for Study Drug ...................................................................88
9.4.5.6
Storage Conditions ...........................................................................88
9.4.6
Method of Assigning Subjects to Treatment Arms....................................88
9.4.7
Selection of Doses in the Study ................................................................88
9.4.8
Selection and Timing of Dose for Each Subject........................................89
9.4.9
Blinding ...................................................................................................89
9.4.10
Prior and Concomitant Therapy................................................................90
9.4.10.1
Drug-Drug Interactions.....................................................................91
9.4.10.2
Prohibited Concomitant Therapies and Drugs ...................................91

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9.4.11
Treatment Compliance .............................................................................92
9.4.12
Drug Supplies and Accountability ............................................................92
9.5
Study Assessments.............................................................................................94
9.5.1
Assessments .............................................................................................94
9.5.1.1
Demography.....................................................................................94
9.5.1.2
Efficacy Assessments .......................................................................95
9.5.1.2.1
Tumor Assessments during Study Treatment...............................95
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................96
9.5.1.3.1
Pharmacokinetic Assessments.....................................................96
9.5.1.3.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker, 
Assessments................................................................................97
9.5.1.4
Safety Assessments...........................................................................98
9.5.1.4.1
Adverse Events and Events Associated with Special Situations...99
9.5.1.4.2
Serious Adverse Events and Events Associated with Special 
Situations..................................................................................100
9.5.1.4.3
Laboratory Measurements.........................................................101
9.5.1.4.4
Vital Signs and Weight Measurements......................................103
9.5.1.4.5
Physical Examinations ..............................................................103
9.5.1.4.6
Electrocardiograms ...................................................................103
9.5.1.4.7
Echocardiogram or Multiple-gated Acquisition Scan.................104
9.5.1.5
Other Assessments..........................................................................104
9.5.2
Schedule of Procedures/Assessments......................................................105
9.5.2.1
Description of Procedures/Assessments Schedule ...........................115
9.5.3
Appropriateness of Measurements..........................................................115
9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations .........................................................115
9.5.4.1
Reporting of Serious Adverse Events..............................................115
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding..................................................................................116
9.5.4.3
Reporting of Events Associated with Special Situations..................116
9.5.4.3.1
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error.........................116
9.5.4.4
Expedited Reporting .......................................................................117
9.5.4.5
Breaking the Blind..........................................................................117
9.5.4.6
Regulatory Reporting of Adverse Events ........................................117
9.5.5
Completion/Discontinuation of Subjects.................................................117
9.5.6
Abuse or Diversion of Study Drug..........................................................118
9.5.7
Confirmation of Medical Care by Another Physician..............................118

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9.6
Data Quality Assurance....................................................................................118
9.6.1
Data Collection.......................................................................................118
9.6.2
Clinical Data Management .....................................................................119
9.7
Statistical Methods...........................................................................................119
9.7.1
Statistical and Analytical Plans...............................................................119
9.7.1.1
Study Endpoints..............................................................................119
9.7.1.1.1
Primary Endpoint......................................................................119
9.7.1.1.2
Secondary Endpoints.................................................................119
9.7.1.1.3
Exploratory Endpoints ..............................................................120
9.7.1.2
Definitions of Analysis Sets............................................................120
9.7.1.3
Subject Disposition.........................................................................121
9.7.1.4
Demographic and Other Baseline Characteristics............................121
9.7.1.5
Prior and Concomitant Therapy ......................................................121
9.7.1.6
Efficacy Analyses...........................................................................122
9.7.1.6.1
Primary Efficacy Analysis.........................................................122
9.7.1.6.2
Secondary Efficacy Analyses....................................................122
9.7.1.6.3
Exploratory Efficacy Analyses..................................................123
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses..............................................................123
9.7.1.7.1
Pharmacokinetic Analyses ........................................................123
9.7.1.7.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ...................................................................................124
9.7.1.7.3
Pharmacokinetic-Pharmacodynamic Analyses...........................124
9.7.1.8
Safety Analyses ..............................................................................124
9.7.1.8.1
Extent of Exposure....................................................................124
9.7.1.8.2
Adverse Events.........................................................................124
9.7.1.8.3
Laboratory Values.....................................................................125
9.7.1.8.4
Vital Signs ................................................................................126
9.7.1.8.5
Electrocardiograms ...................................................................126
9.7.1.8.6
Other Safety Analyses...............................................................126
9.7.2
Determination of Sample Size ................................................................126
9.7.3
Interim Analysis.....................................................................................127
9.7.4
Multiplicity ............................................................................................128
9.7.5
Other Statistical/Analytical Issues ..........................................................131
9.7.6
Procedure for Revising the Statistical Analysis Plan...............................131
10
REFERENCE LIST...................................................................................................132
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).....135
11.1
Changes to the Protocol....................................................................................135

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11.2
Adherence to the Protocol................................................................................135
11.3
Monitoring Procedures.....................................................................................135
11.4
Recording of Data............................................................................................136
11.5
Identification of Source Data............................................................................136
11.6
Retention of Records........................................................................................137
11.7
Auditing Procedures and Inspection .................................................................137
11.8
Handling of Study Drug ...................................................................................137
11.9
Publication of Results ......................................................................................138
11.10 Disclosure and Confidentiality .........................................................................138
11.11 Discontinuation of Study..................................................................................138
11.12 Subject Insurance and Indemnity......................................................................139
12
APPENDICES...........................................................................................................140
LIST OF IN-TEXT TABLES
Table 1
Dose Modification Guidelines for Lenvatinib-Everolimus 
Combination Treatment-Related Toxicity...............................................73
Table 2
Dose Modification Guidelines for Lenvatinib-Related Adverse Events 
(for the Lenvatinib-Pembrolizumab Combination Arm)..........................80
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab ........................81
Table 4
Infusion Reaction Treatment Guidelines.................................................84
Table 5
Dose Modification Guidelines for Sunitinib-related Toxicity..................85
Table 6
Clinical Laboratory Tests......................................................................102
Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: 
Prerandomization and Randomization Phases .......................................106
Table 8
Schedule of Visits and Procedures in E7080-G000-307 Extension 
Phase....................................................................................................112
Table 9
Summary of Interim and Final Efficacy Analyses.................................128
Table 10
Efficacy Boundaries and Properties for PFS H1 and PFS H2 (LDOF 
spending function) Based on Initial Assigned Alpha.............................130
Table 11
Efficacy Boundaries and Properties for OS H3 and OS H4 (LD-Pocock 
Spending function) when PFS Tests Are Significant.............................130

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LIST OF IN-TEXT FIGURES
Figure 1
Kaplan-Meier Plot of Progression-free Survival – Full Analysis Set 
(Phase 2) – Study E7080-G000-205........................................................57
Figure 2
Study Design for Study E7080-G000-307...............................................63
Figure 3
Structural Formula of Lenvatinib Mesilate..............................................87
Figure 4
Graphical Approach to Control Familywise Error Rate for Testing 
Primary and Key Secondary Endpoints.................................................129
LIST OF APPENDICES
Appendix 1
Clinical Studies Evaluating Drug-Drug Interactions with Lenvatinib ....141
Appendix 2
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03.........................................................................................142
Appendix 3
Karnofsky Performance Status Scale ....................................................143
Appendix 4
New York Heart Association (NYHA) Cardiac Disease Classification..144
Appendix 5
Tumor, Node, and Metastasis Staging of Renal Cell Carcinoma ...........145
Appendix 6
Response Evaluation Criteria in Solid Tumors (RECIST).....................147
Appendix 7
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 148
Appendix 8
Health-Related Quality of Life Questionnaire FKSI-DRS.....................151
Appendix 9
Health-Related Quality of Life Questionnaire EORTC QLQ-C30.........152
Appendix 10
Health-Related Quality of Life Questionnaire EQ-5D-3L .....................154
Appendix 11
MSKCC Risk Model Criteria................................................................157
Appendix 12
Cockcroft-Gault Formula......................................................................158

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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AEs
adverse events
AJCC
American Joint Committee on Cancer 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
CBR
clinical benefit rate (CR + PR + durable SD ≥ 23 weeks)
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CPK
creatine phosphokinase
CR
complete response
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
curriculum vitae 
CVA
cerebrovascular accident
CYP
cytochrome P
DCR
disease control rate
DLT
dose-limiting toxicity
DMC
data monitoring committee
DOR
duration of response
durable SD
durable stable disease 
ECG
electrocardiogram
EORTC
European Organization for the Research and Treatment of 
Cancer

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Abbreviation
Term
EuroQOL
European Quality of Life
18F-NaF
18F-sodium fluoride
FDA
Food and Drug Administration
FGF
fibroblast growth factor
FKSI-DRS
Functional Assessment of Cancer Therapy Kidney Symptom
Index-Disease-Related Symptoms
FWER
familywise error rate
GCP
Good Clinical Practice
GI
gastrointestinal
HR
hazard ratio; heart rate
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
IIR
independent imaging review
INR
international normalized ratio 
IRB
Institutional Review Board
ITT
intent-to-treat data set
IV
intravenous
IxRS
interactive voice and web response system
K-M
Kaplan-Meier
KPS
Karnofsky Performance Status
LLN
lower limit of normal
LLT
lower level term
LMWH
low molecular-weight heparin
LVEF
left ventricular ejection fraction
mAbs
monoclonal antibodies
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging

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Abbreviation
Term
MSKCC
Memorial Sloan-Kettering Cancer Center
MTD
maximum tolerated dose
mTOR
mammalian target of rapamycin 
MUGA
multiple-gated acquisition 
NAb
neutralizing antibody(ies)
NCCN
National Comprehensive Cancer Network
NSAID
non-steroidal antiinflammatory drug
NYHA
New York Heart Association
ORR
objective response rate
P-gp
CYP3A4/P-glycoprotein
PR
partial response
pRBC
packed red blood cells
PRES/RPLS
posterior reversible encephalopathy syndrome/reversible 
posterior leukoencephalopathy syndrome
OS
overall survival
PD
progressive disease; pharmacodynamics
PFS
progression-free survival
PFS2
progression-free survival during next-line therapy
PG
Pharmacogenomics
PI
principal investigator
PR
partial response
PK
pharmacokinetics
PT
preferred term
Q1
first quartile
Q3
third quartile
Q3W
every 3 weeks
QD
once daily
RBC
red blood cell
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RTK
receptor tyrosine kinase

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Abbreviation
Term
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SI
Système International
SOC
system organ class
SOPs
standard operating procedures
TAM
tumor associated macrophage
TEAEs
treatment-emergent adverse events
TEMAV
treatment-emergent markedly abnormal laboratory values 
ULN
upper limit of normal
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBRT
whole brain radiation therapy
WHO DD
World Health Organization Drug Dictionary

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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 CRA[s], 
change of telephone number[s]).  Documentation of IRB/IEC compliance with the ICH E6 
and any local regulations regarding constitution and review conduct will be provided to the 
sponsor.
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (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.
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  The definition of the end of the study is the date of the data cutoff for 
the final analysis of overall survival or last subject/last visit, including discontinuation from 
the study for any reason, whichever occurs later.  The sponsor should also provide the 
IRB/IEC with a summary of the study’s outcome.
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given.

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5.2
Ethical Conduct of the Study
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following:

Principles of the World Medical Association Declaration of Helsinki 2013

ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of 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 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 Pharmaceuticals, Medical devices and 
Other Therapeutic Products Act (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 
Screening Visit before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained.

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An unsigned copy of an IRB/IEC-approved ICF must be prepared in accordance with ICH 
E6, Section 4, and all applicable local regulations.  Each subject must sign an approved ICF 
before study participation.  The form must be signed and dated by the appropriate parties.  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.  
The subject 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.
With regard to the pharmacogenomic (PG) assessments described in Section 9.5.1.3.2, an 
informed consent for collection of samples during the study for gene analysis will be 
prepared separately.  Subjects may still participate in the study if they do not give informed 
consent for gene analysis.
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the
sponsor) at approximately 200 investigational sites 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 Investigator 
Study File provided to each site.
7
INTRODUCTION
7.1
Renal Cell Carcinoma: Epidemiology and Current Therapeutic 
Options
Renal cell carcinoma (RCC), which originates within the renal cortex from the proximal 
renal tubular epithelium, is the most common kidney cancer, constituting 80 to 85 percent of 
primary renal neoplasms (Wahal and Mardi, 2014).  An estimated 365,943 new cases of 
kidney (renal) cancer are expected to be diagnosed in 2015, and an estimated 155,520 deaths
from kidney cancer are expected to occur in 2015 (GLOBOCAN 2012).
Nephrectomy is the mainstay of treatment for RCC.  Surgical resection can be curative for 
patients presenting with localized disease, however, approximately 20-30% of RCC patients 
present with metastasis at the time of initial diagnosis and less than 5% of these will present 
with solitary metastases.  Additionally, about 40% of those with clinically localized disease 
may develop metastatic disease following nephrectomy.  Median time to relapse following 
nephrectomy is 15-18 months (Athar and Gentile, 2008).  Once RCC has metastasized, the 5 
year survival rate ranges from 5-10% (Gupta, et al., 2008).  In general, the median survival 
for these patients is only 12 months. 
The current treatment approach for patients with metastatic RCC consists of sequential 
administration of single-agent therapies that target either the vascular endothelial growth 

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factor (VEGF)/VEGF receptor (VEGFR) or mammalian target of rapamycin (mTOR) 
pathways (National Comprehensive Cancer Network [NCCN] Clinical Practice Guidelines in 
Oncology, 2016; Escudier, et al., 2014).  First-line therapy consists of treatment with anti-
VEGF agents, typically sunitinib or pazopanib (Motzer, et al., 2015a; Escudier, et al., 2014), 
however, all patients ultimately progress after therapy (Sosman, et al., 2007) and will need 
further treatment.
Current strategies for first-line treatment of metastatic RCC have focused on the development 
of new therapeutic agents, optimal sequencing, and combinations of these agents to 
maximize their impact on clinical outcomes.  To date, however, results of combination-
therapy studies (ie, temsirolimus plus bevacizumab, temsirolimus plus sunitinib, erlotinib 
plus bevacizumab, everolimus plus bevacizumab) have shown no advantage in progression 
free survival (PFS) over monotherapy with approved single agents and, in some cases, an 
unacceptably high degree of toxicity (Bukowski, et al., 2007; Dorff, et al., 2014; 
Feldman, et al., 2009; Graves, et al., 2013; Hainsworth, et al., 2010; Kanesvaran, et al., 2015;
Negrier, et al., 2011; Powles, et al., 2014; Ravaud, et al., 2013).  Therefore, there remains a 
significant unmet medical need for more effective treatment options, including possible 
combination therapies, with a manageable safety profile in patients with advanced RCC.
7.1.1
Preclinical Experience with the Combination of Lenvatinib with Everolimus
Angiogenesis has been identified as a key factor in the development of RCC.  A major 
component of the angiogenic process in RCC is VEGF (Posadas, et al., 2013).  An alternative 
pathway is mediated by mTOR which is downstream of phosphoinositide 3-kinase and 
protein kinase B and is regulated by the phosphatase and tensin homolog tumor suppressor 
gene.  Inhibition of the mTOR pathway can inhibit both angiogenesis and tumor cell 
proliferation (Faivre, et al, 2006). It is hypothesized that combinations of anti-angiogenic 
agents with mTOR inhibitors may overcome the resistance which develops with single-agent 
therapy. With this combination, blockade could take place at two levels of the pathways 
activated in RCC (at hypoxia-inducible factor and at VEGF) and this may overcome an 
aspect of resistance that may develop through feedback mechanisms.  
Lenvatinib is a potent multiple-receptor tyrosine kinase (RTK) inhibitor that selectively 
inhibits VEGF receptors (VEGFR1 [FLT1], VEGFR2 [KDR], VEGFR3 [FLT4]) in addition 
to other pro-angiogenic and oncogenic pathway-related RTKs, including fibroblast growth 
factor (FGF) receptors FGFR1-4, platelet-derived growth factor (PDGF) receptor α, KIT, and 
RET.  Lenvatinib inhibited VEGF-driven VEGFR2 phosphorylation and suppressed 
proliferation and tube formation in human umbilical vein endothelial cell (HUVEC) models.  
Antitumor activity of lenvatinib in vivo has been shown in numerous xenograft animals.  
These results suggest that lenvatinib may be a novel anticancer therapy through inhibition of 
angiogenesis and may be useful as either monotherapy or in combination with other 
anticancer drugs.
In preclinical models (A498 and Caki-1), the lenvatinib plus everolimus combination 
demonstrated superior antiangiogenesis as well as antitumor activity compared to each single 
agent alone (M14026). The mechanism of action of the combination of lenvatinib and 

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everolimus was further investigated in cell-based nonclinical models, and it is hypothesized 
that the dual inhibition of the VEGF- and FGF-driven MAPK and mTOR pathways by the 
combination of lenvatinib plus everolimus in endothelial cells may contribute to the 
enhanced antiangiogenic activity of the combination treatment.  In addition, the dual 
targeting of the mTOR-S6K-S6 pathway by the lenvatinib plus everolimus combination may 
contribute towards the superior antitumor activity of the combination (W-20110629).
7.1.2
Clinical Results Obtained with Combination Lenvatinib plus Everolimus
The safety and efficacy of lenvatinib and everolimus combination treatment was investigated 
in the randomized, controlled, open-label trial, E7080-G000-205 (hereafter referred to as 
“Study 205”) in subjects with unresectable, advanced or metastatic RCC. Study 205 
consisted of a Phase 1b portion and a Phase 2 portion.  The recommended Phase 2 dose 
(RP2D) for the lenvatinib/everolimus combination was lenvatinib 18 mg plus everolimus 5 
mg administered daily. 
The Phase 2 portion of Study 205 enrolled 153 patients with advanced or metastatic, clear-
cell, RCC who had a history of receiving 1 prior VEGF agent. A total of 153 patients were 
randomized in a 1:1:1 ratio to receive treatment with lenvatinib plus everolimus, lenvatinib 
(24 mg once daily [QD]), or everolimus (10 mg QD).
The combination significantly prolonged progression-free survival (PFS) compared with 
either single-agent as shown in the Kaplan-Meier curve in Figure 1:
Figure 1
Kaplan-Meier Plot of Progression-free Survival – Full Analysis Set 
(Phase 2) – Study E7080-G000-205
CI = confidence interval; EVE = everolimus; HR = hazard ratio; LEN = lenvatinib.
Source: Study 205 CSR, Figure 4.

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The safety profile for lenvatinib plus everolimus was consistent with the known toxic effects 
of each individual agent, with no unexpected treatment-emergent adverse events (TEAEs)
observed.  The most common TEAEs of any grade in the lenvatinib plus everolimus arm 
were diarrhea and fatigue or asthenia. Grade 3 and 4 events occurred in fewer patients 
allocated single-agent everolimus (25 [50%]) compared with those assigned lenvatinib alone 
(41 [79%]) or lenvatinib plus everolimus (36 [71%]).  The most common Grade 3 or 4 
TEAEs in patients allocated lenvatinib plus everolimus was diarrhea (10 [20%]), in those 
assigned single-agent lenvatinib it was proteinuria (10 [19%]), and in those assigned single-
agent everolimus it was anemia (6 [12%]). Two deaths were deemed related to study drug, 
1 cerebral hemorrhage in the lenvatinib plus everolimus group and 1 myocardial infarction 
with single-agent lenvatinib (Motzer, et al., 2015a).
7.1.3
Preclinical Experience with the Combination of Lenvatinib plus PD-1/L1 
inhibitors
Pembrolizumab is an anti-PD-1 monoclonal antibody that releases the natural break on the 
immune system by blocking the interaction between the PD-1 receptor expressed on T cells 
and its 2 ligands, PD-L1 and PD-L2. Blockade of PD-1 or PD-L1, using monoclonal 
antibodies (mAbs), has demonstrated substantial clinical activity in patients with metastatic 
renal cell carcinoma (Brahmer, et al., 2012; Hamid and Carvajal, 2013; Philips and Atkins, 
2015; Motzer, et al., 2015b).
In preclinical models, lenvatinib decreased the tumor associated macrophage (TAM) 
population which is known as an immune-regulator in the tumor microenvironment. By 
decreasing TAM, expression levels of cytokines and immune-regulating receptors were 
changed to increase immune activation. The immune-modulating effect of lenvatinib may 
result in a potent combination effect with PD-1/L1 signal inhibitors. The effect of combining 
lenvatinib with PD-1/L1 (programmed death, ligand 1) mAbs has been investigated in the 
CT26 colorectal cancer syngeneic model (PD-L1 mAb) as well as the LL/2 lung cancer 
syngeneic model (PD-1 mAb). Combination treatment with lenvatinib and PD-1/L1 mAb 
showed significant and superior antitumor effects compared with either compound alone in 
two syngeneic models (Kato et al, 2015).
7.1.4
Preliminary Clinical Results Obtained with Combination Treatment with 
Lenvatinib plus Pembrolizumab
An open-label, Phase 1b/2 study (E7080-A001-111; hereafter referred to as “Study 111”) of 
the combination of lenvatinib plus pembrolizumab in subjects with select metastatic tumor 
types, including metastatic RCC is being conducted to assess the safety and efficacy of the 
combination of lenvatinib plus pembrolizumab.  During the Phase 1b portion of the study, the 
recommended Phase 2 dose was determined to be 20 mg lenvatinib daily in combination with 
a fixed dose of pembrolizumab 200 mg given every 3 weeks, and is being used in the Phase 2 
portion of the study.
As of 31 May 2017, 13 subjects (3 treated with lenvatinib 24 mg plus 200 mg 
pembrolizumab and 10 treated with lenvatinib 20 mg plus 200 mg pembrolizumab) were 

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enrolled in the Phase 1b portion of this study and 22 subjects with RCC were among those 
enrolled in the Phase 2 portion of this study.  In Phase 1b, 8 of the 13 enrolled subjects had 
RCC, 2 had non-small-cell lung cancer (NSCLC), 2 had endometrial cancer, and 1 had 
melanoma.  A total of 22 subjects were enrolled in the RCC cohort in Phase 2 of the study.  
Dose-limiting toxicity (DLT) reported in Phase 1b was Grade 3 arthralgia in 1 subject and 
Grade 3 fatigue in 1 subject, both in the 24 mg lenvatinib plus 200 mg pembrolizumab 
cohort.  No DLT was reported in the lenvatinib 20 mg plus pembrolizumab 200 mg cohort, 
and this was the recommended Phase 2 dose.  
Twelve of the 30 subjects (40.0%) with RCC had no prior anticancer therapy for their 
advanced RCC, 10 subjects (33.3%) had received 1 prior anticancer therapy, and 8 subjects 
(26.7%) had received 2 or more prior anticancer therapies. Of the 18 subjects (60.0%) with 
RCC who received prior anticancer therapy, 16 subjects received at least 1 prior VEGF-
targeted therapy and 7 subjects received 2 or more prior VEGF-targeted therapies.
As of 31 May 2017, based on interim data for Phases 1b/2 combined, the best overall 
response for the 30 subjects with RCC at Week 24 was:

Partial response (PR) in 19 subjects (63%)

Stable disease (SD) in 10 subjects (33%)

Progressive disease (PD) in 1 subject (3.3%)
The ORR (CR + PR) as determined by the investigator using immune-related RECIST
(irRECIST) was 70% (95% CI: 50.6, 85.3), comprising 21 subjects with a confirmed PR. 
Two subjects had a confirmed PR after Week 24: 1 at Week 60 and 1 at Week 51.  As of the 
data cutoff date (31 May 2017), the median follow-up time was 11.8 months (95% CI, 11.5, 
13.7), and the median duration of objective response had not been reached.
Among the 12 subjects who were treatment-naïve, the confirmed ORR was 83.3% (95% CI: 
51.6, 97.9). For the 18 subjects who received previous anticancer treatment, the ORR was 
61.1% (95% CI: 35.7, 82.7).
Responses were seen in both subjects with PD-L1-positive and PD-L1 negative disease.  
Among the 12 subjects whose tumors expressed the PD-L1 protein, ORR was 66.7% 
(95% CI: 34.9, 90.1); among the 14 subjects whose tumors did not express the PD-L1
protein, ORR was 78.6% (95% CI: 49.2, 95.3). 
The most frequently reported TEAEs in subjects with RCC (occurring in ≥30% of treated 
subjects, in descending order of frequency) were: diarrhea (n=25; 83%), fatigue (21, 70%), 
hypothyroidism (20, 67%), nausea (18, 60%), stomatitis (18, 60%), hypertension (16, 53%), 
cough (15, 50%), dysphonia (14, 47%), proteinuria (12, 40%), arthralgia (11, 37%), 
decreased appetite (11, 37%), epistaxis (10, 33%), vomiting (10, 33%), constipation 
(9, 30%), Palmar-plantar erythrodysesthesia syndrome (9, 30%), and weight decreased 
(9, 30%).  Grade 3 TEAEs that occurred in 2 or more subjects included lipase increased (n=4, 
13%), hypertension (3, 10%), proteinuria (3, 10%), amylase increased (2, 7%), dehydration 
(2, 7%), fatigue (2, 7%), and renal failure (2, 7%).  Grade 4 TEAEs were reported for 

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2 subjects with RCC: lipase increased and clostridial sepsis in 1 subject each.  Two subjects 
with RCC had a Grade 5 TEAE (malignant neoplasm progression, cerebral hemorrhage); 
both were considered by the investigator to be related to disease progression (PD).  Serious 
AEs were reported for 13 subjects (43%) with RCC.  Dehydration was reported as serious in 
2 subjects (7%); all other SAEs occurred in 1 subject each.  Treatment-emergent AEs were 
managed with supportive care and dose modification (treatment interruptions and dose 
reductions).  A total of 28 subjects (93%) with RCC had a dose adjustment due to a TEAE, 
most commonly diarrhea (n=11, 37%) and fatigue (4, 11%).  Three subjects (10%) with RCC 
discontinued treatment with either lenvatinib or pembrolizumab for a TEAE as the primary 
reason.
7.2
Study Rationale and Benefit/Risk Assessment
The currently available first-line therapies for RCC are unsatisfactory.  These treatments do 
not induce durable tumor responses and virtually all patients experience progression of 
disease requiring initiation of another therapy.
Clinical evaluation of lenvatinib in combination with everolimus as a first-line therapy is 
warranted based on the following:

Clinical experience with the combination of lenvatinib plus everolimus in Study 205 
shows that this combination therapy results in significant prolongation of PFS compared 
with lenvatinib and everolimus as single agents in patients with metastatic RCC.

The median PFS of 14.6 months for the combination of lenvatinib and everolimus is 
clinically relevant and longer than the PFS duration for any other agents approved for 
treatment of RCC.

The combination of lenvatinib plus everolimus is associated with acceptable and 
manageable toxicity, with no overlapping or unexpected TEAEs.
Clinical evaluation of combination therapy with lenvatinib plus pembrolizumab as a first-line 
therapy for RCC is warranted based on the following:

Preliminary efficacy data obtained with lenvatinib in combination with pembrolizumab in 
Study 111 revealed that 29 (97%) of 30 subjects with RCC showed a best overall 
response of either PR or SD and 1 subject had PD while receiving this treatment, as 
described in Section 7.1.4.  These efficacy data are compelling, showing significant 
tumor reduction with durable responses in treatment-naïve and previously treated 
subjects.

Patients treated in Study 111 with the combination of lenvatinib and pembrolizumab 
experienced toxicities manageable with dose interruptions and dose reductions.
Therefore, based on the definitive results of Study 205 (Section 7.1.2) and the preliminary 
results obtained in Study 111 (Section 7.1.4), Eisai is conducting a multicenter, open-label, 
randomized, Phase 3 trial (Study E7080-G000-307, hereafter referred to as Study 307) to 
compare the efficacy and safety of lenvatinib in combination with everolimus or 

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pembrolizumab versus sunitinib alone in first-line treatment of subjects with advanced renal 
cell carcinoma.
Based on the available data to date for the two investigational treatment arms (ie, Arms A 
and B), the benefit/risk profile for subjects who participate in Study 307 is positive. With the 
measures contained within the protocol, the safety will continue to be assessed moving 
forward.
8
STUDY OBJECTIVES
8.1
Primary Objective
The primary objective of the study is to demonstrate that lenvatinib in combination with 
everolimus (Arm A) or pembrolizumab (Arm B) is superior compared to sunitinib alone 
(Arm C) in improving PFS (by independent imaging review [IIR] using Response Evaluation 
Criteria in Solid Tumors [RECIST 1.1]) as first-line treatment in subjects with advanced 
renal cell carcinoma.
8.2
Secondary Objectives

To compare objective response rate (ORR) by IIR using RECIST 1.1 of subjects treated 
with lenvatinib in combination with everolimus or pembrolizumab versus sunitinib.

To compare overall survival (OS) of subjects treated with lenvatinib in combination with 
everolimus or pembrolizumab versus sunitinib.

To compare safety and tolerability of treatment with lenvatinib in combination with 
everolimus or pembrolizumab versus sunitinib, including the assessment of the
proportion of subjects who discontinued treatment due to toxicity and time to treatment 
failure due to toxicity.

To compare the impact of treatment on Health-Related Quality of Life (HRQoL) as 
assessed by using the Functional Assessment of Cancer Therapy Kidney Index-Disease-
Related Symptoms (FKSI-DRS), the European Organization for the Research and 
Treatment of Cancer (EORTC) QLQ-30 and the European Quality of Life (EuroQOL) 
EQ-5D-3L instruments, for subjects treated with lenvatinib in combination with 
everolimus or pembrolizumab versus sunitinib.

To assess PFS on next-line of therapy (PFS2) as reported by investigator.

To assess PFS based on investigator assessment per RECIST v.1.1.

To characterize the population pharmacokinetics (PK) of lenvatinib when co-
administered with everolimus or pembrolizumab.

To compare the PK of pembrolizumab from this study to historical data.

To characterize the population PK of everolimus when co-administered with lenvatinib.

To assess the PK/pharmacodynamic relationship between exposure and 
efficacy/biomarkers/safety, if possible, using a mechanistic approach.

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8.3
Exploratory Objectives

To compare objective response rate (ORR) by investigator assessment using RECIST 1.1

To assess the duration of response (DOR) by IIR and investigator assessment using
RECIST 1.1 for subjects in all treatment arms.

To compare the disease control rate (DCR) (complete response [CR] + PR + stable 
disease [SD]) and clinical benefit rate (CBR) (CR, PR + durable SD) by IIR and 
investigator assessment using RECIST 1.1 of subjects treated with lenvatinib in 
combination with everolimus or pembrolizumab versus sunitinib. 

To compare PFS by IIR and investigator assessment using RECIST 1.1 in subjects treated 
with lenvatinib in combination with everolimus (Arm A) versus lenvatinib in 
combination with pembrolizumab (Arm B).

To investigate the relationship between candidate tumor and blood biomarkers and
clinical outcome measures including antitumor activity of study treatment.
9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
This is a multicenter, randomized, open-label, Phase 3 study to compare the efficacy and 
safety of lenvatinib in combination with everolimus or pembrolizumab versus sunitinib as 
first-line treatment in subjects with advanced RCC.  
Approximately 1050 eligible subjects will be randomized to 1 of the following 3 treatment 
arms in a 1:1:1 ratio, with approximately 350 subjects in each arm:

Arm A: lenvatinib 18 mg (orally, once daily) plus everolimus 5 mg (orally, once daily)

Arm B: lenvatinib 20 mg (orally, once daily) plus pembrolizumab 200 mg (intravenously 
[IV], every 3 weeks [Q3W]) 

Arm C: sunitinib 50 mg (orally, once daily) on a schedule of 4 weeks on treatment 
followed by 2 weeks off (Schedule 4/2) 
The study will be conducted in 3 Phases: a Pre-randomization Phase, a Randomization Phase, 
and an Extension Phase.  The Pre-randomization phase will have 2 periods, Screening and 
Baseline.  The Randomization Phase and the Extension Phase will each consist of 2 periods, 
a Treatment Period and a Follow-up Period.
The Randomization Phase of the study will end at the date of the data cutoff for the planned 
final analysis of PFS by independent review, which is estimated to be approximately 45 
months after the first subject is randomized assuming an average enrollment rate of 31
subjects/month.
Subjects who are still on treatment at the time of the data cutoff will continue to receive 
study treatment in the Extension Phase.  Ongoing subjects will be followed for survival and 
all subsequent anticancer treatments received will be recorded on the case report form (CRF).  

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The Sponsor may decide to terminate survival follow-up after the completion of the PFS 
analysis.  
Eisai will closely monitor subject dropout, including refusal of assignment.  In the event that 
the dropout rate exceeds 5%, Eisai, in collaboration with the principal investigator(s), will 
consider capping the enrollment in the respective site(s) and/or region.  The dropout plan will 
be detailed in a separate document.
The definition of the end of the study is the date of the data cutoff for the final analysis of 
overall survival or last subject/last visit, including discontinuation from the study for any 
reason, whichever occurs later.
An overview of the study design is presented in Figure 2.   
Figure 2
Study Design for Study E7080-G000-307
R = Randomization
a:
Extension Phase includes a Treatment and Follow-up Period.  All subjects still on treatment at the end of 
the Randomization Phase will enter the Extension Phase and continue to receive the same study treatment 
they received in the Randomization Phase.
b:
Lenvatinib 18 mg plus everolimus 5 mg given orally once daily.
c:
Lenvatinib 20 mg once daily plus pembrolizumab 200 mg intravenously every 3 weeks.
d:
Sunitinib 50 mg once daily on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).

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9.1.1
Prerandomization/Pretreatment Phase
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.
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. Repeated laboratory evaluation 
to establish eligibility is not allowed unless discussed and agreed upon with the sponsor.  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.
The Screening Disposition 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 assessments can be performed within 72 hours or prior to randomization on 
Cycle 1/Day 1.  Laboratory tests and a pregnancy test (for female subjects of childbearing 
potential) may be performed up to 72 hours before randomization.  Repeated laboratory 
evaluation to establish eligibility is not allowed unless discussed and agreed upon with the 
sponsor.
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Randomization/Treatment Phase.
9.1.2
Randomization/Treatment Phase
The Randomization Phase will begin at the time of randomization of the first subject and will 
end on the data cutoff date for the planned final PFS analysis, at which time all subjects who 
are still on study treatment or in follow-up will enter the Extension Phase.  The 
Randomization Phase will include both a Treatment Period and Follow-up Period.  
9.1.2.1
Treatment Period
The Treatment Period for each subject will begin at the time of randomization and will end 
with the completion of the Off-Treatment Visit, which will occur within 30 days after the 
final dose of study treatment.  All AEs will be captured up to 30 days after last dose of study 
drug.  Serious AEs must be collected for 120 days after the subject’s last dose of study drug, 
or 30 days following the last dose of study drug if the subject initiates new anticancer 
therapy, whichever is earlier.  

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
Subjects will receive study treatment as continuous 21-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.  
Subjects will continue to receive study treatment until confirmed PD by IIR, development 
of unacceptable toxicity, subject request, withdrawal of consent, completion of 
35 treatments (approximately 2 years) with pembrolizumab, or study termination by the 
sponsor.  

Subjects in Arm B who discontinue pembrolizumab after 35 treatments may continue 
treatment with lenvatinib alone unless any other criteria above apply. 

Discontinuation of treatment may be considered for those subjects who fulfill all of the 
following criteria:  attain a confirmed CR, have been treated for at least 8 cycles (at least 
24 weeks) with pembrolizumab, and have received at least 2 treatments with 
pembrolizumab beyond the date when the initial CR is declared. In the presence of 
clinical benefit, subjects who complete treatment with pembrolizumab may continue to 
receive lenvatinib alone after this time point.
Subjects will be permitted to continue study treatment beyond RECIST 1.1-defined disease 
progression as long as the treating investigator considers that there is clinical benefit, and the 
subject is tolerating study drug.  The assessment of clinical benefit should take into account 
whether the subject is clinically deteriorating and unlikely to receive further benefit from 
continued treatment.  All decisions to continue treatment beyond initial progression must be 
discussed with the Eisai Medical Monitor.  Subjects will discontinue study treatment upon 
evidence of further progression and/or loss of clinical benefit as judged by the Investigator. 
Disease progression (per RECIST 1.1) must be confirmed by IIR by the imaging core 
laboratory (ICL) prior to the investigator discontinuing study treatment for a subject. In 
situations where the investigator judges that alternative treatments must be instituted 
immediately for a subject`s safety, study drug may be discontinued without waiting for 
independent review confirmation of radiographic evidence of disease progression.  If 
possible, before discontinuation of the subject from the study, the investigator should consult 
with the sponsor.
9.1.2.2
Follow-Up Period
The Follow-up Period will begin the day after the Off-Treatment Visit and will continue as 
long as the subject is alive, unless the subject withdraws consent, is lost to follow-up, or the 
sponsor terminates the study.  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. 
During the follow-up period, subjects will be treated by the investigator according to the 
prevailing local standard of care. Subjects will be followed every 12 weeks (± 1 week) for 
PFS2, survival, and all subsequent anticancer treatments received.  This information will be 
recorded unless this information is not allowed to be provided due to confidentiality.  The 

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sponsor may choose to discontinue survival follow-up following completion of the primary 
study analysis when appropriate, eg, when only a minimal number of subjects remain in 
follow up.
If a subject becomes unavailable for follow-up (eg, misses scheduled assessment, telephone 
contact), the investigator or designee will make every attempt to contact the subject to 
determine his or her status.  All attempts at contact will be recorded in the subject’s medical 
notes.  Subjects will only be deemed lost to follow-up:

After a minimum of 3 attempted contacts (eg, telephone, letter) with the subject, the 
subject’s family, or the primary care (family) physician, at least 4 weeks apart.  The last 
attempt at contact must occur no earlier than 3 months after the subject’s last successful 
contact.

If the last attempt at contact is unsuccessful, the site should write a letter with certified 
proof of posting to the subject, subject’s family, or the primary care (family) physician to 
request information on the subject's status, if regionally required.
All subjects who discontinue study treatment prior to disease progression will continue to 
undergo tumor assessments every 8 weeks and a bone scan every 24 weeks in the Follow-up 
Period, until disease progression is documented and confirmed by IIR or a new anticancer 
therapy is initiated, unless the subject withdraws consent or is lost to follow-up.
To ensure current and complete survival data are available at the time of analysis, updated 
survival status may be requested during the course of the study by the sponsor (eg, 
independent Data Monitoring Committee [DMC] reviews, interim analysis, final analysis).  
Upon notification by the sponsor, all subjects who do not or will not have a scheduled study 
visit or study contact during the sponsor-defined time period will be contacted by the 
investigator or designee for their survival status.
9.1.3
Extension Phase
9.1.3.1
Treatment Period
All subjects who are still on study treatment following the data cut-off date of the planned 
final PFS analysis (ie, at the end of the Randomization Phase) will continue to receive the 
same study treatment in 21-day cycles.  Tumor assessments will be performed according to 
the local standard of care, but not less frequently than every 12 weeks, and scans will no 
longer be required to be sent to the ICL.  Subjects will continue to receive study treatment 
until disease progression, development of unacceptable toxicity, subject request, withdrawal 
of consent, loss of clinical benefit, completion of 35 treatments (approximately 2 years) with 
pembrolizumab, or sponsor termination of the study.  In the presence of clinical benefit, 
subjects in Arm B who discontinue pembrolizumab may continue treatment with lenvatinib 
alone unless any of the other discontinuation criteria apply.
The Off-Treatment Visit will occur within 30 days after the final dose of study treatment. 
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collected for 120 days after the subject’s last dose of study drug or 30 days following the last 
dose of study drug if the subject initiates new anticancer therapy, whichever is earlier.
9.1.3.2
Follow-up Period
The Follow-up Period, which will begin the day after the Off-Treatment Visit and will 
continue as long as the study subject is alive, unless the subject withdraws consent, is lost to 
follow-up, or the sponsor terminates the study.  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.  See Section 9.1.2.2 for information pertaining to the
circumstances under which a subject is considered “lost to follow-up.”
Subjects will be treated by the investigator according to the prevailing local standard of care.  
Subjects will be followed every 12 weeks (±1 week) for PFS2, survival, and all subsequent 
anticancer treatments received.  This information will be recorded unless this information is 
not allowed to be provided due to confidentiality.  The sponsor may decide to terminate 
survival follow-up after the completion of the primary study analysis.  
To ensure current and complete survival data are available at the time of analysis, updated 
survival status may be requested during the course of the study by the sponsor (eg,
independent DMC reviews, interim analysis, final analysis).  Upon notification by the 
sponsor, all subjects who do not or will not have a scheduled study visit or study contact 
during the sponsor-defined time period will be contacted by the investigator or designee for 
their survival status.
9.2
Discussion of Study Design, Including Choice of Control Groups
This multicenter, randomized, open-label, Phase 3 study was designed to compare the 
efficacy and safety of lenvatinib in combination with everolimus or pembrolizumab versus 
sunitinib as first-line treatment in subjects with advanced RCC.  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 arms, and to ensure the validity of statistical 
comparisons across treatment arms.  Treatments will be open-labeled, since the dosage and 
administration is different between lenvatinib, everolimus, pembrolizumab and sunitinib.  
Sunitinib will be used as a comparator since it is a recognized standard-of-care for first-line 
treatment of patients with advanced RCC.
The study sample size is based on the required target events to detect a difference in at least 
one of the primary comparisons of PFS (combination lenvatinib plus everolimus versus 
sunitinib, or combination lenvatinib plus pembrolizumab versus sunitinib) in a reasonable 
time frame.

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9.3
Selection of Study Population
Approximately 1050 subjects will be randomized at approximately 200 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
1.
Histological or cytological confirmation of RCC with a clear-cell component (original 
tissue diagnosis of RCC is acceptable).
2.
Documented evidence of advanced RCC.
3.
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 computed 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.
4.
Male or female subjects age ≥18 years (or any age >18 years of age (if that age is 
considered to be an adult per the local jurisdiction) at the time of informed consent 
5.
Karnofsky Performance Status (KPS) of ≥70. 
6.
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.
7.
Adequate renal function defined as creatinine ≤1.5× upper limit of normal (ULN); or for 
subjects with creatinine >1.5×ULN, the calculated creatinine clearance ≥30 mL/min (per 
the Cockcroft-Gault formula) is acceptable (Appendix 12). 
8.
Adequate bone marrow function defined by:

Absolute neutrophil count (ANC) ≥1500/mm3

Platelets ≥100,000/mm3

Hemoglobin ≥9 g/dL
NOTE: Criteria must be met without erythropoietin dependency and without packed red 
blood cell (pRBC) transfusion within the previous 2 weeks.
9.
Adequate blood coagulation function defined by International Normalized ratio (INR 
≤1.5 unless participant is receiving anticoagulant therapy, as long as INR is within 
therapeutic range of intended use of anticoagulants. 
10. Adequate liver function defined by:

Total bilirubin ≤1.5×ULN except for unconjugated hyperbilirubinemia of Gilbert’s 
syndrome.

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
Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤3×ULN (in the case of liver metastases ≤5×ULN), unless 
there are bone metastases. Subjects with ALP values >3×ULN and known to have 
bone metastases can be included. 
11. Provide written informed consent. 
12. Willing and able to comply with all aspects of the protocol.
9.3.2
Exclusion Criteria
1.
Subjects who have received any systemic anticancer therapy for RCC, including anti-
VEGF therapy, or any systemic investigational anticancer agent. Prior adjuvant 
treatment with an investigational anticancer agent is not allowed unless the investigator 
can provide evidence of subject’s randomization to placebo arm.
2.
Subjects with central nervous system (CNS) metastases are not eligible, unless they have 
completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or 
radiosurgery) and have discontinued the use of corticosteroids for this indication for at 
least 4 weeks before starting treatment in this study.  Any signs (eg, radiologic) or 
symptoms of CNS metastases must be stable for at least 4 weeks before starting study 
treatment.
3.
Active malignancy (except for RCC, definitively treated basal or squamous cell 
carcinoma of the skin, and carcinoma in-situ of the cervix or bladder) within the past 
24 months.  Subjects with history of localized & low risk prostate cancer are allowed in 
the study if they were treated with curative intent and there is no PSA recurrence within 
the past 5 years.
4.
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.
5.
Subjects who are using other investigational agents or who had received investigational 
drugs ≤4 weeks prior to study treatment start.
6.
Received a live vaccine within 30 days of planned start of study treatment (Cycle 1/
Day 1). Examples of live vaccines include, but are not limited to, measles, mumps, 
rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin 
(BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally
killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.
7.
Subjects with proteinuria >1+ on urine dipstick testing 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×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×ULN.  NOTE: these subjects 
can be included after initiation or adjustment of glucose-lowering medication.

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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, everolimus, and sunitinib.
13. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage. The degree of 
tumor invasion/infiltration of major blood vessels 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 12 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, cerebral vascular accident, or cardiac 
arrhythmia associated with hemodynamic instability. The following is also excluded:

Left ventricular ejection fraction (LVEF) below the institutional normal range as 
determined by MUGA or echocardiogram. 
16. Active infection (any infection requiring systemic treatment). 
17. Subjects known to be positive for Human Immunodeficiency Virus (HIV).
18. Known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected).
19. Known history of, or any evidence of, interstitial lung disease. 
20. Has a history of (non-infectious) pneumonitis that required steroids, or current 
pneumonitis. 
21. Any medical or other condition that in the opinion of the investigator(s) would preclude 
the subject’s participation in a clinical study.
22. Subjects with a diagnosis of immunodeficiency or who are receiving chronic systemic 
steroid therapy (doses exceeding 10 mg/day of prednisone equivalent) or any other form 
of immunosuppressive therapy within 7 days prior to the first dose of study treatment.  
Physiologic doses of corticosteroids (up to 10 mg/day of prednisone or equivalent) may 
be used during the study.
23. Active autoimmune disease (with the exception of psoriasis) that has required systemic 
treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic 
corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not 
considered a form of systemic treatment.
24. 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.

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25. Females of childbearing potential* who:

do not agree to use a highly effective method of contraception for the entire study 
period and for 120 days after study 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.
26. Males who have not had a successful vasectomy (confirmed azoospermia) and do not 
agree to use condom + spermicide OR have a female partner who does not meet the 
criteria above (ie, is of childbearing potential and not practicing highly effective 
contraception throughout the study period), starting with the first dose of study therapy 
through 120 days after the last dose of study therapy, unless sexually abstinent.  
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
27. Known intolerance to any of the study drugs (or any of the excipients). 
28. Subject has had an allogenic tissue/solid organ transplant.
9.3.3
Removal of Subjects From Therapy or Assessment
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete protocol-specified off 
treatment visits, procedures, and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, the 

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date will be documented in the source documents.  The Subject Disposition CRF page will be 
completed indicating the primary reason for discontinuation.  In addition, the date of last 
dose of study drug(s) will be recorded on the Study Drug Dosing CRF page.
All subjects who discontinue study drug treatment prior to disease progression will continue 
to undergo tumor assessments every 8 weeks and a bone scan every 24 weeks in the 
Follow-up Period, until disease progression is documented and confirmed by independent 
review or a new anticancer therapy is initiated, unless the subject withdraws consent or is lost 
to follow-up. 
All subjects will be followed for survival until death, except where a subject withdraws 
consent or the sponsor chooses to halt survival follow-up after completion of the primary 
study analysis.
9.4
Treatments
9.4.1
Treatments Administered
Combination lenvatinib plus everolimus arm (Arm A): Lenvatinib 18 mg QD plus 
everolimus 5 mg QD will be taken orally in each 21-day cycle. 
Combination lenvatinib plus pembrolizumab arm (Arm B): Lenvatinib 20 mg QD will be 
taken orally in each 21-day cycle.  Pembrolizumab will be administered at a dose of 200 mg 
IV over 30 minutes on Day 1 of each 21-day cycle.
Sunitinib arm (Arm C): Sunitinib 50 mg once daily will be administered orally for 4 weeks 
on treatment followed by 2 weeks off (Schedule 4/2) in each 21-day cycle.
9.4.2
Dose Interruption and Dose Reduction for Combination Lenvatinib plus 
Everolimus Treatment
Dose reduction and interruptions for subjects who experience lenvatinib everolimus 
combination therapy-related toxicity will be managed as described in Table 1. Investigators 
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.
The starting dose of lenvatinib is 18 mg/day for subjects enrolled in the combination 
lenvatinib plus everolimus arm.  Lenvatinib dose reductions occur in succession based on the 
previous dose level (14, 10, and 8 mg/day).  Any dose reduction below 8 mg/day must be 
discussed with the sponsor.  Once the study drug dose has been reduced, it 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.
Refer to the following subsections for management of hypertension (Section 9.4.2.1), 
proteinuria (Section 9.4.2.2), diarrhea (Section 9.4.2.3), non-infectious pneumonitis 
(Section 9.4.2.4), infections (Section 9.4.2.5), blood glucose/ lipids (Section 9.4.2.6), 
hepatotoxicity (Section 9.4.2.7), thromboembolic events (Section 9.4.2.8), posterior 

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reversible encephalopathy syndrome/reversible posterior leukoencephalopathy syndrome 
(PRES/RPLS) (Section 9.4.2.9), hypocalcemia (Section 9.4.2.10), and hemorrhage 
(Section 9.4.2.11), as appropriate, before consulting the dose modification table (Table 1).  
Table 1
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 to 14 mg once a 
day (1-level reduction) 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 to 10 mg once a 
day (1-level reduction). 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 to 8 mg orally 
once a day (1-level reduction).
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
Discuss with sponsor
Grade 4g: Discontinue Study Treatment
Note: For grading see CTCAE version 4.03 (Appendix 2). Collect all CTC grades of adverse events, 
decreasing and increasing grade. 
BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse Events.
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 and/or diarrhea prior to any 
study treatment interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to 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 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 1 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.

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9.4.2.1
Management of Hypertension
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling. 
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib/sunitinib have BP of ≤150/90 mm Hg 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/sunitinib dose interruptions and reductions.
Regular assessment of BP should be conducted as detailed in the Schedule of Procedures/
Assessments (Table 7 and Table 8). Hypertension will be graded using CTCAE v4.03, based 
on BP measurements only (and not on the number of antihypertensive medications).  
If the subject’s initial BP measurement is elevated (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg), the BP measurement should be repeated at least 5 minutes later.  The mean 
value of 2 measurements at least 5 minutes apart is defined as one BP assessment. If the BP 
assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is 
elevated (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg), a confirmatory assessment 
should be obtained at least 30 minutes later by performing 2 measurements (at least 
5 minutes apart) to yield a mean value.
Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥140 mm Hg 
or diastolic BP ≥90 mm Hg) is confirmed on 2 assessments at least 30 minutes later. 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 mm Hg or 
diastolic BP ≥90 mm Hg is first observed on 2 assessments at least 30 minutes apart.  For 
those subjects already on antihypertensive medication, treatment modification may be 
necessary if hypertension persists.  
Lenvatinib/sunitinib 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 mm Hg, significant risk factors for cardiac 
disease, intracerebral hemorrhage, or other significant co-morbidities).  Once the subject has 
been on the same antihypertensive medications for at least 48 hours and the BP is controlled, 
lenvatinib/sunitinib should be resumed as described below.
Subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP 
monitored on Day 15 (or more frequently as clinically indicated) until systolic BP has been 
≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles.  If a 
repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg occurs, the subject 
must resume the Day 15 evaluation until systolic BP has been ≤150 mm Hg and diastolic BP 
has been ≤95 mm Hg for 2 consecutive treatment cycles. A diary will be provided to the 
subject to capture the blood pressure evaluations between study visits.

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The following guidelines should be followed for the management of systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg confirmed on repeat measurements after at least 30 minutes:
1.
Continue study drug 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 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/sunitinib administration should be interrupted 
and 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/sunitinib administration should be interrupted and 
restarted at an additional dose reduction only when systolic BP ≤150 mmHg and 
diastolic BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours. 

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs on the second dose 
reduction despite optimal management of hypertension with antihypertensive 
medications (either by dose increase or the addition of a different class of 
antihypertensive), then lenvatinib/sunitinib administration should be interrupted and 
restarted at a third dose reduction dose only when systolic BP ≤150 mmHg and 
diastolic BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.

Additional dose reduction should be discussed with the sponsor.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life threatening consequences):
1.
Institute appropriate medical management
2.
Discontinue study drug.
9.4.2.2
Management of Proteinuria
Regular assessment of proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria are as 
follows:
Grading of Proteinuria

Grading according to CTCAE v4.03 will be based on the 24-hour urinary protein 
result if available.  

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Management of Proteinuria

Management of lenvatinib/sunitinib administration will be based on the grade of 
proteinuria according to the respective treatment arm’s Dose Modification 
Guidelines.

In the event of nephrotic syndrome, lenvatinib/sunitinib must be discontinued.
Detection and Confirmation
1.
Perform urine dipstick testing per the Schedule of Assessments (Table 7 and Table 8)
2.
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) or 
an immediate spot urine protein-to-creatinine ratio (UPCR) test is required in the 
following situations:

The first (initial) occurrence of ≥2+ proteinuria on urine dipstick while on study drug

A subsequent increase in severity of urine dipstick proteinuria occurring on the same 
lenvatinib/sunitinib dose level

When there has been a lenvatinib/sunitinib dose reduction and at the new dose level 
the urine protein dipstick result is ≥2+
3.
A 24-hour urine collection (initiated as soon as possible and at least within 72 hours) to 
verify the grade of proteinuria is required when UPCR is ≥2.4.
Monitoring

Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on 
Day 15 (or more frequently as clinically indicated) until the results have been 1+ or 
negative for 2 consecutive treatment cycles.  
9.4.2.3
Management of 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 respective treatment arm’s Dose Modification Guidelines should be 
followed.
9.4.2.4
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 2016). 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.

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Subjects who develop radiological changes suggestive of non-infectious pneumonitis and 
have few or no symptoms (Common Terminology Criteria for Adverse Events [CTCAE]
Grade 1) may continue study dosing without dose adjustments.
1.
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).  
2.
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).  
3.
If symptoms are life-threatening (CTCAE Grade 4):
-
Study medications should be discontinued.
9.4.2.5
Management of Infections
Everolimus has immunosuppressive properties and may predispose subjects to infections.  It 
is important therefore to monitor for signs and symptoms of infection, and treat promptly.  
Dose alterations of everolimus may be required in accordance with prescribing information.
9.4.2.6
Management of Blood Glucose and Lipids
Hyperglycemia, hyperlipidemia and hypertriglyceridemia are recognized class effects of 
rapamycin derivatives, including everolimus. Glycemic and lipid 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 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.
9.4.2.7
Management of Hepatotoxicity
Liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin 
levels) should be conducted as detailed in the Schedule of Procedures/Assessments and as 
clinically indicated.  If signs/symptoms indicating liver injury occur, instructions contained 
in the respective treatment arm’s Dose Modification Guidelines should be followed.  

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Appropriate supportive care should be provided together with close monitoring.  If hepatic 
failure occurs the study drug must be discontinued.
9.4.2.8
Management of Thromboembolic Events
Subjects should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events which include acute onset of shortness of breath, dyspnea, chest pain, 
cough, hemoptysis, tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity 
swelling, and warmth to touch or tenderness. In case any of these symptoms appear, subjects 
should be instructed to report such symptoms promptly to the treating physician.  If a 
thromboembolic event is confirmed, instructions contained in the respective treatment arm’s 
Dose Modification Guidelines 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.
9.4.2.9
Management of Posterior Reversible Encephalopathy Syndrome/Reversible 
Posterior Leukoencephalopathy Syndrome (PRES/RPLS)
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, the respective treatment arm’s Dose Modification Guidelines 
should be followed.
9.4.2.10
Management of Hypocalcemia
Serum calcium should be monitored per the Schedule of Procedures/Assessments (Table 7
and Table 8).  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.

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9.4.2.11
Management of Hemorrhage
Dose modification guidelines for lenvatinib- (Arm A, Arm B) and sunitinib- (Arm C) related 
adverse events should be followed for the management of hemorrhage (see Table 1, Table 2, 
and Table 5). Either resume study drug at a reduced dose or discontinue lenvatinib/sunitinib,
depending on the severity and persistence of hemorrhage.
For subjects receiving treatment with sunitinib (Arm C) who experience hemorrhage 
associated with thrombocytopenia, treatment interruption is recommended; following 
resolution, treatment may be resumed at the discretion of the investigator.
9.4.3
Dose Interruption and Dose Reduction for Combination Lenvatinib plus 
Pembrolizumab Treatment
Lenvatinib
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib 
pembrolizumab combination therapy-related toxicity will be in accordance with the dose 
modification guidelines described in Table 2.  The 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.
The starting dose of lenvatinib is 20 mg/day for subjects enrolled in the combination 
lenvatinib plus pembrolizumab arm.  Dose reductions of lenvatinib occur in succession based 
on the previous dose level (14, 10, and 8 mg/day).  Any dose reduction below 8 mg/day must 
be discussed with the sponsor.  Once the study drug dose has been reduced, it 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.
Refer to the following sections for management of hypertension (Section 9.4.2.1), proteinuria 
(Section 9.4.2.2), diarrhea (Section 9.4.2.3), hepatotoxicity (Section 9.4.2.7), 
thromboembolic events (Section 9.4.2.8), PRES/RPLS (Section 9.4.2.9), hypocalcemia 
(Section 9.4.2.10), and hemorrhage (Section 9.4.2.11), as appropriate, before consulting dose 
modification table (Table 2).

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Table 2
Dose Modification Guidelines for Lenvatinib-Related Adverse 
Events (for the Lenvatinib-Pembrolizumab Combination Arm)
Treatment-Related Toxicity a,b
Management
Dose Adjustment
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
First occurrence
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 14 mg 
once a day (1-level reduction) 
Second occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 10 mg 
once a day (1-level reduction)
Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
Reduce lenvatinib dose to 8 mg 
orally once a day (1-level 
reduction)
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib 
Discuss with sponsor
Grade 4f: 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 and/or diarrhea prior to any 
lenvatinib interruption or dose reduction. 
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable.
d: Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (i.e. 
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 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 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.
f: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
Pembrolizumab
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These immune-related AEs (irAEs) may occur shortly 
after the first dose or several months after the last dose of treatment and may affect more than 
1 body system simultaneously.  Therefore, early recognition and initiation of treatment is 
critical to reduce complications.  Based on existing clinical study data, most irAEs are
reversible and can be managed with interruptions of pembrolizumab, administration of 
corticosteroids and/or other supportive care.  For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes.  Additional procedures or tests such 
as bronchoscopy, endoscopy, or skin biopsy may be included as part of the evaluation.
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 3.

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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events 
Associated with Pembrolizumab
Immune-related 
Adverse Event
Toxicity Grade
or Conditions
(CTCAEv4.0)
Action Taken with
Pembrolizumab
irAE Management with 
Corticosteroids and Other 
Therapies
Monitor and Follow-up
General instructions:
Corticosteroid taper should be initiated upon AE improving to Grade 0 or 1 and continue to taper over at least 4 weeks.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has improved to Grade 0 or 1 and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks. 
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids.
Pneumonitis
Grade 2
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Add prophylactic antibiotics for 
opportunistic infections
Monitor subjects for signs and symptoms of 
pneumonitis
Evaluate subjects with suspected pneumonitis 
with radiographic imaging 
Grade 3 or 4,
or recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis
Grade 2 or 3
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper.
Subjects with diarrhea/colitis should 
be advised to drink liberal quantities 
of clear fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be substituted via 
IV infusion.
Monitor subjects for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
Subjects with Grade ≥2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
Grade 4
Permanently 
discontinue
ASTa / ALTa
elevation or 
Increased bilirubin
Grade 2
Withhold
Administer corticosteroids (initial
dose of 0.5 - 1 mg/kg prednisone or 
equivalent) followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4
Permanently 
discontinue

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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events 
Associated with Pembrolizumab
Immune-related 
Adverse Event
Toxicity Grade
or Conditions
(CTCAEv4.0)
Action Taken with
Pembrolizumab
irAE Management with 
Corticosteroids and Other 
Therapies
Monitor and Follow-up
Type 1 diabetes 
mellitus (T1DM) or 
Hyperglycemia
Newly onset T1DM 
or Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold
Initiate insulin replacement therapy 
for subjects with T1DM .
Administer anti-hyperglycemic in 
subjects with hyperglycemia.
Monitor subjects for hyperglycemia or other 
signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 
Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue
Hypothyroidism
Grade 2-4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis and Renal 
dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or equivalent) 
followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue

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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events 
Associated with Pembrolizumab
Immune-related 
Adverse Event
Toxicity Grade
or Conditions
(CTCAEv4.0)
Action Taken with
Pembrolizumab
irAE Management with 
Corticosteroids and Other 
Therapies
Monitor and Follow-up
All other immune-
related AEs
Intolerable/ 
persistent Grade 2
Withhold
Grade 3
Withhold or 
discontinue based on 
the type of event.  
Events that require 
discontinuation 
include but are not 
limited to:  Guillain-
Barre Syndrome, 
encephalitis
Based on type and severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
Withholding or permanently discontinuing pembrolizumab is at the discretion of the investigator or treating physician.  
For subjects with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab is required, pembrolizumab may be resumed when the AE 
improves to Grade ≤2 and is controlled with hormonal replacement therapy or metabolic control is achieved (in the case of T1DM).
AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CTCAE = Common Terminology Criteria for Adverse Events: 
GI = gastrointestinal; irAE = immune-related adverse event; IV = intravenous; T1DM = Type 1 diabetes mellitus.
a:  If a subject with liver metastasis has Grade 2 AST or ALT at the start of study treatment, and the AST or ALT value increases by ≥50% relative to Baseline 
and lasts for ≥1 week, then the subject should permanently discontinue study treatment.

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Table 4 shows treatment guidelines for subjects who experience an infusion reaction 
associated with the administration of pembrolizumab, including premedications.
Table 4
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/h to 50 mL/h).  Otherwise 
dosing will be held until symptoms resolve 
and the subject should be premedicated for 
the next scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study treatment administration.
Subject may be 
premedicated 1.5 h 
(±30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg 
orally (or equivalent dose 
of antihistamine).
Acetaminophen 500-
1000 mg orally (or 
equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
No subsequent dosing

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Table 4
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further study treatment administration.
Appropriate resuscitation equipment should be available in the room and a physician readily available 
during the period of drug administration.
CTCAE = Common Terminology Criteria for Adverse Events, version 4.03, IV = intravenous, NCI = 
National Cancer Institute, NSAID = nonsteroidal antiinflammatory drug.
9.4.4
Dose Interruption and Reduction for Sunitinib
The starting dose of sunitinib is 50 mg/day on a Schedule 4/2 for subjects enrolled in Arm C.  
See Section 9.4.10.1 for dose recommendations if sunitinib must be co-administered with a 
strong CYP3A4 inhibitor or inducer.  
Dose reduction and interruptions for subjects who experience sunitinib therapy-related 
toxicity will be managed as described in Table 5.  Sunitinib dose reductions occur in 
succession based on the previous dose level (37.5, 25 mg/day schedule 4/2). Any dose 
reduction below 25 mg/day must be discussed with the sponsor. Dose modification of 
sunitinib to a schedule of 2 weeks on treatment followed by 1 week off (Schedule 2/1) is not 
permitted. Once the study drug dose has been reduced, it may not be increased at a later 
date, unless the dose has been mistakenly decreased; in this situation, the Sponsor’s approval 
is required to increase the dose.
Refer to the following sections for management of hypertension (Section 9.4.2.1), proteinuria 
(Section 9.4.2.2), diarrhea (Section 9.4.2.3), hepatotoxicity (Section 9.4.2.7), 
thromboembolic events (Section 9.4.2.8), PRES/RPLS (Section 9.4.2.9), and hemorrhage 
(Section 9.4.2.11), as appropriate, before consulting the dose modification table (Table 5).
Table 5
Dose Modification Guidelines for Sunitinib-related Toxicity 
Treatment-Related Toxicity a,b
During Therapy
Adjusted Dose
Grade 1 or Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c, d or Grade 3e
First occurrence
Interrupt sunitinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
37.5 mg daily for 4 weeks 
followed by 2 weeks off
(1-level reduction) 
Second occurrence
(same toxicity or new toxicity)
Interrupt sunitinib until 
resolved to Grade 0-1, or 
tolerable Grade 2
25 mg daily for 4 weeks 
followed by 2 weeks off
(1-level reduction)

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Table 5
Dose Modification Guidelines for Sunitinib-related Toxicity 
Treatment-Related Toxicity a,b
During Therapy
Adjusted Dose
Third occurrence
(same toxicity or new toxicity)
Interrupt sunitinib 
Discuss with sponsor
Grade 4f: Discontinue Study Treatment
Note: For grading see CTCAE version 4.03. Collect all CTC grades of adverse events, decreasing and 
increasing grade. 
BMI = body mass index; CTCAE = Common Terminology Criteria for Adverse Events.
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 and/or diarrhea prior to 
any study treatment interruption or dose reduction.
c: Applicable only to Grade 2 toxicities judged by the subject and/or physician to be intolerable
d: Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight 
(i.e. 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 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 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.
f: Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 
3.
9.4.5
Identity of Investigational Products
The study drugs under evaluation in this study are 1) lenvatinib in combination with 
everolimus (Arm A), 2) lenvatinib in combination with pembrolizumab (Arm B), and 
3) sunitinib (Arm C).  All study drugs will be provided to sites as open-label supplies by the 
Sponsor. 
Lenvatinib will be supplied as 4-mg and 10-mg hard capsules by the sponsor.  Lenvatinib is 
formulated with calcium carbonate, mannitol, microcrystalline cellulose, 
hydroxypropylcellulose, low-substituted hydroxypropylcellulose, and talc.  The capsule shell 
contains hypromellose, titanium dioxide (E171), yellow iron oxide (E172), and red iron 
oxide (E172).
Everolimus will be supplied as 5-mg tablets by the sponsor. Note that everolimus tablets 
contain lactose.  
Pembrolizumab concentrate for solution for infusion will be supplied by the sponsor.  
Pembrolizumab is provided as a sterile, preservative-free, clear to slightly opalescent, 
colorless to slightly yellow solution that requires dilution for intravenous infusion.  Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution.  Each 1 mL of solution contains 
25 mg of pembrolizumab and is formulated in L-histidine (1.55 mg), polysorbate 80 
(0.2 mg), sucrose (70 mg), and Water for Injection, USP.  

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Sunitinib will be provided by the sponsor as 12.5-mg and 25-mg hard capsules containing 
sunitinib malate equivalent to 12.5-mg and 25-mg of sunitinib, respectively.
9.4.5.1
Chemical Name, Structural Formula of Lenvatinib

Test drug code:  E7080 

Generic name:  lenvatinib, lenvatinib mesilate, lenvatinib mesylate

Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido) phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate

Molecular formula:  C21H19ClN4O4·CH4O3S

Molecular weight:  522.96

Structural formula:  (see Figure 3)
Figure 3
Structural Formula of Lenvatinib Mesilate
9.4.5.2
Chemical Name, Structural Formula of Everolimus

Generic name:  everolimus

Chemical name:  -O-(2-hydroxyethyl)-rapamycin

Molecular formula:  C53H83NO14
Refer to the latest AFINITOR® package insert.
9.4.5.3
Information on Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-
1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with 
an approximate molecular weight of 149 kDa.
Refer to the latest KEYTRUDA® package insert.
9.4.5.4
Chemical Name, Molecular Formula of Sunitinib
Sunitinib is an oral multi-kinase inhibitor.  

Generic name:  sunitinib malate

Molecular formula:  is C22H27FN4O2 • C4H6O5

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Refer to the latest SUTENT® package insert.
9.4.5.5
Labeling for Study Drug
Lenvatinib, everolimus, pembrolizumab, and sunitinib will be provided by Eisai. The 
everolimus, and sunitinib will be supplied in commercial packaging, which includes the 
package insert or patient information leaflet. All study drugs will be labeled in accordance 
with text that is in full compliance with each participating country and is translated into the 
required language(s) for each of those countries.  
9.4.5.6
Storage Conditions
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required.
9.4.6
Method of Assigning Subjects to Treatment Arms
Subjects will be assigned to treatments based on a computer-generated randomization 
scheme that will be reviewed and approved by an independent statistician.  The 
randomization scheme and identification for each subject will be included in the final clinical 
study report for this study.
After the Baseline Period, subjects will be randomized to 1 of 3 treatment arms.  Each 
treatment arm will receive 1 of the following treatments: combination lenvatinib plus 
everolimus, combination lenvatinib plus pembrolizumab, or sunitinib.  
Randomization will be performed centrally by an interactive voice and web response system 
(IxRS) based on the following stratification factors:
-
Geographic region: Region 1(Western Europe and North America); Region 2 (rest of 
the world)
-
Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic groups: favorable, 
intermediate, and poor risk (Appendix 11).
9.4.7
Selection of Doses in the Study
Clinical experience with the combination of lenvatinib 18 mg QD plus everolimus 5 mg QD 
in Study 205 shows that combination therapy results in significant prolongation of PFS 
compared with lenvatinib and everolimus as single agents in patients with metastatic RCC.  
The median PFS of 14.6 months for the combination of lenvatinib and everolimus is 
clinically relevant and longer than the PFS duration for any other agents approved for 

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treatment of RCC.  The combination of lenvatinib plus everolimus is associated with 
acceptable and manageable toxicity, with no overlapping or unexpected treatment-emergent 
adverse events.  
The dosage of lenvatinib 20 mg QD plus pembrolizumab 200 mg IV is based on the 
MTD/RP2D established in Study 111, and the available interim safety and activity results of 
the Phase 1b/2 portions of Study 111.  All but 1 subject with RCC had a best overall response 
of either partial response or stable disease, and 1 had PD while receiving this treatment.  No 
DLT has been reported thus far in the lenvatinib 20 mg plus pembrolizumab 200 mg cohort.  
Treatment-emergent AEs reported by ≥30% of subjects in the RCC cohort (in descending 
order of frequency) were: diarrhea, fatigue, hypothyroidism, nausea, stomatitis, hypertension, 
cough, dysphonia, proteinuria, arthralgia, decreased appetite, epistaxis, vomiting, 
constipation, Palmar-plantar erythrodysesthesia syndrome, and weight decreased. Adverse 
events were managed with supportive care, dose interruptions, and dose reductions.  
Sunitinib will be administered at a dosage of 50 mg QD, 4 weeks on, 2 weeks off in 
accordance with the sunitinib prescribing information in each country/region.
9.4.8
Selection and Timing of Dose for Each Subject
Lenvatinib capsules are to be taken with water orally once a day at approximately the same 
time each day for 21 days in each cycle from Cycle 1 onward. 
If a subject misses a dose of lenvatinib or everolimus, it may be taken within 12 hours 
following the usual time of the dose.  If more than 12 hours have elapsed from the time of the 
usual daily dose, lenvatinib and/or everolimus should be taken the next day at the usual time.  
In the event a subject vomits after study drug administration, the subject should not take 
another dose until the next scheduled dose.
For subjects receiving combination lenvatinib plus everolimus, the 2 drugs should be 
administered in immediate succession. 
For subjects receiving combination lenvatinib plus pembrolizumab, pembrolizumab will be 
administered at a dose of 200 mg as a 30-minute IV infusion, Q3W (infusion durations of 
25 minutes to 40 minutes are acceptable) on Day 1 of each 21-day cycle.  The Pharmacy 
Manual contains specific instructions for the preparation of the pembrolizumab infusion and 
its administration.  Subjects should maintain a normal diet unless modifications are required 
to manage an AE such as diarrhea, nausea or vomiting.  Study treatment of pembrolizumab 
may be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons.  On Day 1 (D1) of Cycles 1 and 2, lenvatinib will be administered 
approximately within 4 hours after completion of pembrolizumab administration. 
Sunitinib will be administered orally in accordance with the prescribing information.
9.4.9
Blinding
The study will not be blinded.

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9.4.10
Prior and Concomitant Therapy
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent will be recorded on the 
Prior & Concomitant Medication CRF or Non-Pharmacological Procedures CRF.  The 
investigator will record on the Adverse Event CRF any AE for which the concomitant 
medication/therapy was administered.  If the concomitant medication/therapy is being 
administered for a medical condition present at the time of entry into the study, the 
investigator will record the medical condition on the Medical History and Current Medical 
Condition CRF.
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 30 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 the study medication may be continued during the study.
Treatment (including blood products, blood transfusions, fluid transfusions, antibiotics, 
antidiarrheal drugs, etc.) of complications or AEs, or therapy to ameliorate symptoms (may 
be given at the discretion of the investigator, unless it is expected to interfere with the 
evaluation of (or to interact with) the study medication.
The following concomitant medications are also allowed:

Thyroid hormone suppressive therapy

Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer

Anticoagulants including low molecular-weight heparin (LMWH), warfarin, anti-Xa 
agents.

Antiinflammatory agents 

Bisphosphonates or denosumab

Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the subject is enrolled)

Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases will be 
permitted without being considered PD.
If the subject is receiving treatment with lenvatinib and requires surgery during the study, the 
stop time and restart time of lenvatinib should be as follows:

For minor procedures: stop lenvatinib 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. 

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Any additional procedural or patient specific particularities should be discussed with the 
sponsor.
9.4.10.1
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 which are co-administered in usual 
clinic practice.  Nonclinical studies identify CYP3A4 as the important CYP isozyme 
responsible for human hepatic metabolism of lenvatinib. However, clinical studies 
conducted showed that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp) 
inhibitors or inducers is not of clinical concern.  The main metabolic pathways for lenvatinib 
in humans were identified as enzymatic (CYP3A and aldehyde oxidase) and non-enzymatic 
processes.  Please refer to Appendix 1 and http://medicine.iupui.edu/clinpharm/ddis/ for the 
most current information.
For subjects receiving everolimus, drugs or substances (including herbal supplements or 
grapefruit juice) known to be potent inhibitors of CYP3A4/P-gp should not be used.  Potent 
inducers of CYP3A4/P-gp should not be used unless there is no alternative treatment 
available.  Moderate/ weak inhibitors or inducers or substrates of CYP3A4 and/or P-gp 
should be used with caution.  Dose reduction of everolimus may be considered when co-
administering moderate CYP3A4 or P-gp inhibitors.  For further information please refer to 
the prescribing information.
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab.  Pembrolizumab is a monoclonal antibody; pharmacokinetic interactions 
with lenvatinib (and vice-versa) are not expected. 
Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma 
concentrations.  CYP3A4 inducers such as rifampin may decrease sunitinib plasma 
concentrations.  Selection of an alternate concomitant medication with no or minimal enzyme 
inhibition or induction is recommended.  A dose reduction for sunitinib to a minimum of 
37.5 mg daily should be considered if sunitinib must be co-administered with a strong 
CYP3A4 inhibitor.  A dose increase for sunitinib to a maximum of 87.5 mg daily should be 
considered if sunitinib must be co-administered with a CYP3A4 inducer.  If dose is 
increased, the patient should be monitored carefully for toxicity. For further information 
please refer to the prescribing information.
9.4.10.2
Prohibited Concomitant Therapies and Drugs
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase of this study:

Concurrent anticancer therapies such as chemotherapy, TKIs, radiotherapy (with the 
exception of palliative radiotherapy as specified in Section 9.4.10.1), antitumor 
interventions (surgical resection, surgical debulking of tumor, etc.), or cancer
immunotherapy

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
Concurrent other investigational drugs

For subjects receiving combination treatment with lenvatinib plus everolimus or 
pembrolizumab, live vaccines are prohibited while participating in the study.  Examples 
of live vaccines include, but are not limited to 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, FluMist®) are live attenuated vaccines, and are not allowed.

For subjects in the lenvatinib plus pembrolizumab arm (Arm B), systemic glucocorticoids 
for any purpose other than to modulate symptoms from an AE that is suspected to have 
an immunologic etiology.  Physiologic doses of corticosteroids (up to 10 mg/day of 
prednisone or equivalent may be used during the study.
Note: The use of prophylactic corticosteroids to prevent allergic reactions (eg, IV 
contrast dye or transfusions) is permitted. Inhaled steroids are allowed for management 
of asthma or seasonal allergies.  
For subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with the sponsor.
If subjects receive additional anticancer therapies, this will be judged to represent evidence of 
disease progression, and study medication will be discontinued.  These subjects should 
complete all off-treatment assessments and continue to be followed for survival in the 
Follow-Up Period unless they withdraw consent or are lost to follow-up.
For further information on the prohibited concomitant therapies for everolimus, 
pembrolizumab, and sunitinib please refer to the drug’s Prescribing Information.
9.4.11
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during site visits and at the 
completion of the study.
9.4.12
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

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
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number

A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol

An investigator-signed and dated Food and Drug Administration (FDA) Form FDA 1572, 
where applicable

Financial Disclosure form(s) for the principal investigator (PI) and all subinvestigators 
listed on Form FDA 1572, where applicable

A signed and dated curriculum vitae (CV) of the PI including a copy of the PI’s current 
medical license (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/study supplies (dispensing, inventory, and record keeping) following the sponsor’s 
instructions and adherence to GCP guidelines as well as local or regional requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs, dispensing of study drugs to the subject, collection and reconciliation of unused study 
drugs that are either returned by the subjects or shipped to site but not dispensed to subjects, 
and return of reconciled study drugs to the sponsor or (where applicable) destruction of 
reconciled study drugs at the site.  This includes, but may not be limited to:  
(a) documentation of receipt of study drugs, (b) study drugs dispensing/return reconciliation 
log, (c) study drugs accountability log, (d) all shipping service receipts, (e) documentation of 
returns to the sponsor, and (f) certificates of destruction for any destruction of study 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, MHRA).  As applicable, all unused study drugs and empty and partially empty 
containers from used study drugs are to be returned to the investigator (or if regionally 
required, the head of the medical institution or the designated pharmacist) by the subject and, 
together with unused study drugs that were shipped to the site but not dispensed to subjects, 
are to be returned to the sponsor’s designated central or local depot(s) during the study or at 
the conclusion of the study, unless provision is made by the sponsor for destruction of study 
drugs and containers at the site.  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 

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advance.  Upon completion of drug accountability and reconciliation procedures by the site’s 
personnel and documentation procedures by the sponsor’s personnel, study drugs that are to 
be returned to the sponsor’s designated central or local depot(s) must be boxed, sealed, and 
shipped back to the central or local depot(s) following all local regulatory requirements.  In 
some regions, study drugs may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs are approved for destruction at 
the site, destruction will occur following the site’s standard procedures and certificates of 
destruction will be provided to the sponsor.
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race/ethnicity 
Baseline characteristics will include KPS (Appendix 3), NYHA cardiac disease classification 
(Appendix 4), and RCC AJCC staging (Appendix 5) at the time of initial diagnosis.  
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 7 and Table 8). 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 subject informed 
consent 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 Eligibility 
Criteria (Appendix 6). Subjects must also fulfill the medical and physical characteristics 
identified in the inclusion criteria and not otherwise meet any of the exclusion criteria.
See the Schedule of Assessments (Table 7) for a complete list of baseline assessments.

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9.5.1.2
Efficacy Assessments
9.5.1.2.1
TUMOR ASSESSMENTS DURING STUDY TREATMENT
Tumor assessments will be performed using RECIST 1.1 (for all subjects).  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 efficacy assessment.  Tumor assessments will be carried 
out following the guidelines provided by the ICL.
Historical CT or MRI scans performed within 28 days before randomization, but before the 
signing of informed consent, may be used as screening scans, provided they meet minimum 
standards as separately defined 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 
every 8 weeks from the date of randomization during treatment cycles in the Randomization 
Phase and as determined by the treating physician in the Extension Phase.  The same imaging 
modality and image-acquisition protocol should be used consistently across all time points. 
A bone scan (99m-technetium-based scintigraphy, whole-body bone MRI, or 18F-sodium 
fluoride positron emission tomography [NaF PET]) will be performed within 6 weeks prior 
to randomization (historical is acceptable), every 24 weeks after randomization, and within a 
target of 1 week but no more than 2 weeks following a CR as assessed by the investigator. 
Lesions identified on bone scans should be followed with cross-sectional imaging. 
A brain scan (CT of the brain with contrast or MRI of the brain pre- and post-gadolinium) 
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 CR. For subjects with a 
history of protocol-eligible treated brain metastases, a brain scan will be required at all tumor 
assessment time points (eg, every 8 weeks).
All subjects will be permitted to continue treatment beyond initial RECIST 1.1-defined 
progression as long as the investigator believes that the subject is still receiving clinical 
benefit and is tolerating study drug treatment.  
Clinical benefit is defined as: 

Absence of signs and symptoms of PD (including labs)

No decline in performance status

Absence of rapid progression of disease

Absence of progressive tumor(s) at critical sites requiring urgent intervention (eg, spinal 
cord compression)
The investigator’s reason for assessing that a subject is still deriving clinical benefit must be 
entered into the eCRF. These subjects must continue tumor assessments at the same interval 
and have copies of all tumor assessments sent to the ICL until further progression and/or loss 
of clinical benefit, as judged by the investigator.  The assessment of clinical benefit should 

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take into account the potential efficacy benefit versus the safety risk of continuation of 
treatment.  All decisions to continue treatment beyond initial progression determined by the 
investigator will need to be discussed with the Eisai Medical Monitor and documented in the 
study records.
To minimize informative censoring, if, at any time during the Randomization Phase, an 
investigator intends to discontinue a subject from study treatment for disease progression, the 
ICL must be notified and must confirm (rapid turnaround read within 3-5 working days) that 
they have assessed PD per RECIST 1.1, before a subject may be discontinued.  (However, in 
situations where the investigator judges that alternative treatments must be instituted 
immediately for management of urgent medical complications of disease progression, study 
drug may be discontinued without waiting for independent confirmation of radiographic 
evidence of disease progression).
In addition, if both independent reviewers assess that a subject has PD during the standard 
rolling read (timepoints will be read on a rolling basis after they have been reconciled with 
Eisai’s clinical trial database for subject, timepoint, date, anatomy and modality), the 
investigator will be notified of this finding to assist in their decision as to whether to continue 
the subject on study treatment.
Subjects who discontinue study treatment without disease progression in the Randomization 
Phase will continue to undergo tumor assessments every 8 weeks and a bone scan every 
24 weeks in the Follow-up Period, until disease progression is documented or another 
anticancer therapy is initiated.  Subjects who have discontinued study treatment without 
tumor progression in the Extension Phase will have tumor assessments performed as 
clinically indicated using the investigator’s discretion, following the prevailing local standard 
of care. Copies of tumor assessment scans will no longer be sent to the ICL and independent 
review will not be carried out during the Extension Phase.
9.5.1.3
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
9.5.1.3.1
PHARMACOKINETIC ASSESSMENTS
Plasma concentrations of lenvatinib (for subjects in the combination lenvatinib plus 
everolimus or lenvatinib plus pembrolizumab arms), whole blood concentrations of 
everolimus (for subjects in the lenvatinib plus everolimus arm only), and serum 
concentrations of pembrolizumab (for subjects in the lenvatinib plus pembrolizumab arm 
only) will be measured in all subjects.  Lenvatinib and everolimus concentrations will be 
analyzed using a population PK approach. Data for lenvatinib from this study will be pooled 
with historical data from other Phase 1 and 2 studies.  Data for everolimus from this study 
will be pooled with data from Study E7080-G000-205.  Pembrolizumab concentrations will 
be compared with historical data. Serum antidrug antibodies (ADA) and neutralizing 
antibodies (NAb) to pembrolizumab will also be measured for subjects in the lenvatinib plus 
pembrolizumab arm (Arm B).

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Blood samples will be collected as specified in Table 7.  Study sites must have appropriately 
trained staff and adequate equipment for procuring and processing specimens.  Instructions 
for the collection, handling, and shipping procedures of PK samples will be provided in the 
laboratory manual.  
Samples from all subjects receiving lenvatinib plus everolimus (Arm A) or lenvatinib plus 
pembrolizumab (Arm B) will be analyzed.  Plasma levels of lenvatinib and whole blood 
levels of everolimus will be quantified by liquid chromatography with tandem mass 
spectrometry (LC/MS/MS) methodology using previously validated assays.  Serum 
concentrations of pembrolizumab will be measured using validated methods.
9.5.1.3.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
Blood and Tissue Biomarkers:  Blood samples for the development of exploratory 
predictive biomarkers will be collected before the first dose of study drug, on Cycle 1 
Day 15, and on Day 1 of subsequent cycles (during Treatment / Randomization Phase), and 
at the off-treatment assessment from all enrolled subjects across the three treatment arms.  
Biomarker discovery and/or validation may be performed to identify blood or tumor 
biomarkers that may be useful to predict subject response to study drug, evaluation of 
response-related and/or safety-related outcomes as well as for potential use in diagnostic 
development.  Blood samples may undergo global proteomic and/or enzyme-linked 
immunosorbent assay (ELISA)-based analyses or multiplex bead-based immunoassay, but 
not limited to, in an effort to identify protein biomarkers. Potential target engagement and 
pharmacodynamic markers include VEGF, FGF23 and other relevant FGF ligands, 
Ang-2/Tie-2, and other relevant circulating markers.  In addition, biomarkers identified in 
other clinical studies of study drug may also be assessed in samples collected from subjects 
enrolled in this study.  The decision to perform exploratory biomarker analysis may be based 
on the clinical outcome of this study and/or the signals observed in other clinical studies or 
other information available at that time.
The biomarker analysis plan is provided in a separate analysis plan (TSBM-E7080-307-
ANA-1P) and the results will be provided in a stand-alone report.
Pharmacokinetic/Pharmacodynamic:
Plasma concentration data for lenvatinib from the combination lenvatinib plus everolimus 
arm and the combination lenvatinib plus pembrolizumab arm of the study will be used to 
explore PK/pharmacodynamic relationships for effects of lenvatinib in combination with 
pembrolizumab or everolimus on PFS, other efficacy-related parameters including ORR and 
OS, AEs/dose reductions, and blood and tissue biomarkers.  Exploratory/graphical analyses 
will be conducted for PK/pharmacodynamic evaluations and, if possible, will be followed by 
model-based analyses. Pharmacodynamic data for pembrolizumab (Arm B) will not be 
measured.
The pharmacodynamic analyses will be detailed in a separate analysis plan (CPMS-E7080-
008ADD10 v1.0) and the results will be provided in a stand-alone report.

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Pharmacogenetic/Pharmacogenomic (PG) Assessments
Archived, fixed tumor tissue from the most recent surgery or biopsy will be collected (if 
available) from all enrolled subjects across the three treatment arms for potential assessment 
of mutations and other genetic alterations or genes and/or proteins that may be important in 
the development and progression of cancer as well as in response to study drug treatment for 
potential use in diagnostic development. Genetic alterations in selected molecular targets 
may be explored based on their potential involvement in renal cell tumor biology (eg, VHL, 
P I3K-mTOR signaling pathway genes, FGF/FGFR signaling pathway genes, HGF/cMET 
axis, and/or any known epigenetic modifications). Immune cell profiling and molecular 
targets and factors involved in immune check-point axis, such as PD1 or PD-L1 levels, 
markers of Th1/Th2 phenotype, and inflammatory status, may also be explored. Appropriate 
technology/methodologies will be used based on the amount of tumor tissue available.
A blood plasma sample to isolate circulating cell free nucleic acids and a whole blood sample 
for immune response profiling will be collected before the first dose of study drug, on 
Cycle 1 Day 15, and on Day 1 of subsequent cycles (during Treatment/Randomization 
Phase), and at the off-treatment assessment from all enrolled subjects across the three 
treatment arms.  Cell-free nucleic acid isolated from plasma samples may be used to explore 
tumor genetic alterations such as mutations observed in archival tumor samples as well as 
those which develop during drug treatment.  Genomic DNA extracted from blood samples 
may be used to confirm whether the DNA sequence variants observed in DNA extracted 
from tumor material are limited to the tumor and to assess the immune response.
A blood sample will be collected for potential PG analysis from all enrolled subjects in 
treatment arms A and B (in accordance with regional or local laws). Variation in lenvatinib 
exposure or the occurrence of AEs observed in the study population may be evaluated by 
correlating single–nucleotide polymorphisms with PK, safety, or pharmacodynamic data.  
Data obtained will be used for research, to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject.  The DNA will not be used to determine or predict risks for diseases that an 
individual subject does not currently have.  Any sample or derivatives (DNA, RNA, and 
protein) may be stored for up to 15 years to assist in any research scientific questions related 
to study treatment, cancer and/or for potential diagnostic development.
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual. Refer to Appendix 7 for additional information.
9.5.1.4
Safety Assessments
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs) using Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03 (Appendix 2), regular laboratory evaluation for hematology, blood 
chemistry, and urine values; regular performance of physical examinations, periodic 
measurement of vital signs, ECGs and MUGA or echocardiogram.

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9.5.1.4.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drugs are 
lenvatinib, everolimus, pembrolizumab, and sunitinib. 
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 AEs must have the AEs leading to screen failure reported on the Screening Disposition 
CRF.  Serious AEs must be collected through 120 days after the subject’s last dose of study 
drug, or for 30 days after the last dose of study drug if the subject initiates new anticancer 
therapy, whichever is earlier.
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.

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All AEs must be followed for 30 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.
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 2).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with
the occurrence of the event
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

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
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations. 
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF 
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
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, blood sample(s) for the measurement of lenvatinib plasma concentration should 
be drawn at the first report of an SAE or a severe unexpected AE and at its resolution.
9.5.1.4.3
LABORATORY MEASUREMENTS
Clinical laboratory tests 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 6.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 7 and Table 8) shows the visits 
and time points at which blood for clinical laboratory tests and urine for urinalysis/urine 
dipstick testing will be collected in the study.

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Clinical laboratory tests during the study will be performed by a central laboratory.  All 
blood and urine samples (except urine sample for urine dipstick and microscopy) 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.  
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 6
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils)
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, CPKd, 
Pregnancy test (serum or urine β-hCG)
Urinalysis/Urine Dipstick Testinge
glucose, hemoglobin (or blood), ketones, pH, proteinf, specific
gravity
β-hCG = beta-human chorionic gonadotropin; CPK = creatine phosphokinase; INR = international 
normalized ratio; RBC = red blood cell; WBC = white blood cell.
a. INR should only be performed as part of the screening assessment and when clinically indicated.
b. Thyroid function will be assessed every 2 cycles.
c. For subjects with blood glucose >ULN, a fasting (>6h, water only) blood glucose sample will be obtained.
d. CPK isoenzymes (CK-MM and CK-MB) should be evaluated if CPK is greater than 3 × the upper limit of 
normal.
e. If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory.
f. If urine protein is ≥2+ (first occurrence or a subsequent increase in severity of urine dipstick proteinuria 
occurring on the same lenvatinib/sunitinib dose level), then a 24-hour urine collection or an immediate spot 
urine protein-to-creatinine (UPCR) test should be done to quantify the 24-hour urine protein excretion.

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All hematology, clinical chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of Cycle 1, and within 2 business 
days of receipt of results for all subsequent treatment cycles.
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], heart rate [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 7 and 
Table 8) 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.  
Only 1 BP measurement is needed for subjects with systolic BP <140 mmHg and diastolic 
BP <90 mmHg. If the subject’s initial BP measurement is elevated (systolic BP ≥140 mmHg 
or diastolic BP ≥90 mmHg), the BP measurement should be repeated at least 5 minutes later. 
The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP assessment.  If 
the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) 
is elevated (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg), a confirmatory 
assessment should be obtained at least 30 minutes later by performing 2 measurements (at 
least 5 minutes apart) to yield a mean value.  
9.5.1.4.5
PHYSICAL EXAMINATIONS
Physical examinations (including a neurologic examination) will be performed as designated 
in the Schedule of Procedures/Assessments (Table 7 and Table 8).  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
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 7 and Table 8).  Complete, standardized, 12-lead ECG 
recordings that permit all 12 leads to be displayed on a single page with an accompanying 
lead II rhythm strip below the customary 3 × 4 lead format are to be used.  In addition to a 
rhythm strip, a minimum of 3 full complexes should be recorded from each lead 
simultaneously.  Subjects must be in the recumbent position for a period of 5 minutes prior to 
the ECG.

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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
An echocardiogram or MUGA scan (using technetium-based tracer) will be performed to 
assess left ventricular ejection fraction (LVEF) as designated in the Schedule of 
Procedures/Assessments (Table 7 and Table 8). MUGA scans or echocardiograms should be 
performed locally in accordance with the institution’s standard practice. MUGA scans are the 
preferred modality; however, whichever modality is used for an individual subject at baseline 
should be repeated for all subsequent LVEF assessments for that subject. LVEFs as assessed 
by the institution will be entered onto the CRF. Investigator assessment will be based upon 
institutional reports.
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, at time of withdrawal, 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 FKSI-DRS (Appendix 8), the 
EORTC QLQ-C30 (Appendix 9), and the EuroQOL EQ-5D-3L (Appendix 1) 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 of 9 multiple-item scales and 6 single items.  Multiple-
item scales of QLQ-C30 consisted 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 three 
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.

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9.5.2
Schedule of Procedures/Assessments
Table 7 (Prerandomization and Randomization Phase) and Table 8 (Extension Phase) present 
the schedules of procedures/assessments for the study.  

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Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: Prerandomization and 
Randomization Phases
Phase
Prerandomization
Randomization
All Cycles are 21 Days in Duration
Period
Screeninga
Baselinea
Treatment Period
Follow-up
Period
Visit
1
2
3
4
5
6
7
8, 9, etc.
98
99
Day
–28 to –3
--3 to –1
Cycle 1b
Cycle 2c
Cycle 3 – Lastc
Off-
Treatment 
Visit
1
8
15
1
15
1
15
Procedures/Assessments
Informed consent
X
Inclusion/exclusion criteria
X
X
Randomizationd
X
Demographic data
X
KPSe
X
X
X
X
X
NYHAe
X
RCC AJCC staging (at the 
time of initial diagnosis of 
RCC)e
X
Medical/surgical history
X
X
Phone contact or visitf
X
Vital signs and weightg
X
X
X
X
X
X
X
X
X
Physical Examinationi
X
Xj
X
X
X
X
12-Lead ECGk
X
X
X
X
X
MUGA scan or 
echocardiograml
X
X
Hematology and clinical 
chemistrym
X
X
X
X
X
X
X

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Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: Prerandomization and 
Randomization Phases
Phase
Prerandomization
Randomization
All Cycles are 21 Days in Duration
Period
Screeninga
Baselinea
Treatment Period
Follow-up
Period
Visit
1
2
3
4
5
6
7
8, 9, etc.
98
99
Day
–28 to –3
--3 to –1
Cycle 1b
Cycle 2c
Cycle 3 – Lastc
Off-
Treatment 
Visit
1
8
15
1
15
1
15
Procedures/Assessments
Urine dipstick testingh
X
X
X
X
X
X
X
X
Pregnancy testn
X
X
X
X
X
X
HRQoLo
X
X
X
X
PK blood samplep,q
X
X
X
X
Pembrolizumab PK blood 
samplesr
X
X
X
X
Biomarker (serum) samples
X
X
X
X
X
Biomarker (plasma) samples
X
X
X
X
X
Biomarker (whole blood) 
samples
X
X
X
X
X
Tumor assessments 
(CT/MRI)t
X
Performed every 8 weeks (from the date of randomization), or sooner 
if clinically indicated, until IIR confirmation of disease progression.  
Xt,u
Xt
Bone Scanv
X
Performed every 24 weeks and as clinically indicated.  
Xv
Brain scanw
X
X
Xu,w
Xw
Archival tumor block or 
slidesx
X
Survival and PFS2y
X

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Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: Prerandomization and 
Randomization Phases
Phase
Prerandomization
Randomization
All Cycles are 21 Days in Duration
Period
Screeninga
Baselinea
Treatment Period
Follow-up
Period
Visit
1
2
3
4
5
6
7
8, 9, etc.
98
99
Day
–28 to –3
--3 to –1
Cycle 1b
Cycle 2c
Cycle 3 – Lastc
Off-
Treatment 
Visit
1
8
15
1
15
1
15
Procedures/Assessments
Blood sample for PG 
analysisz
X
Study drug treatment
21 day cycles of lenvatinib daily plus everolimus daily or 21 day cycle of lenvatinib 
daily plus pembrolizumab IV every 21 days or sunitinib daily for 4 weeks plus 
2 weeks off, depending on randomization arm
Concomitant medicationsaa
Throughout
AEs/SAEsbb
Throughout
AAE = adverse event; AJCC = American Joint Committee on Cancer; BP = blood pressure; CR = complete response; CT = computed tomography; BW = body 
weight; C = cycle; D = day; ECG = electrocardiogram; eCRF = electronic case report form; 18F-NaF = 18F-sodium fluoride; HR = heart rate; HRQoL = Health-
related Quality of Life; ICF = informed consent form; ICL = imaging core laboratory; IV = intravenous; KPS = Karnofsky performance status; MRI = magnetic 
resonance imaging; MUGA = multiple-gated acquisition; NAb = neutralizing antibody(ies); NYHA = New York Heart Association; PE = physical examination; 
PFS2 = progression-free survival after start of next-line therapy; PG = pharmacogenomics; PK = pharmacokinetics; RCC = renal cell carcinoma; RR = 
respiration rate; SAE = serious AE.

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Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: Prerandomization and Randomization 
Phases
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.  The baseline assessments can be performed within 72 hours or prior to randomization on C1D1.  An ICF should be signed by the subject before any 
screening procedures are performed.  Informed consent may be obtained up to 4 weeks prior to C1D1.
b:
Efforts should be made to conduct study visits on the day scheduled (± 1 day).  Clinical laboratory assessments may be conducted anytime within 72 hours prior to the 
scheduled visit, unless otherwise specified in the Schedule of Procedures/Assessments.
c:
Efforts should be made to conduct study visits on the day scheduled (± 3 days).  Clinical laboratory assessments may be conducted anytime within 72 hours prior to the 
scheduled visit, unless otherwise specified in the Schedule of Procedures/Assessments.
d:
Subjects will be randomized on C1D1 (-1 day) after confirmation of eligibility at the Baseline Visit.  All procedures and assessments on C1D1 should be performed after 
randomization.
e:
See protocol appendices for KPS assessments, NYHA Cardiac Disease Classification, AJCC Staging.
f:
Telephone contact or visit on C1D8 will assess subjects for development of early toxicity.  An unscheduled visit can occur prior to C1D15 if deemed necessary by the 
investigator.
g:
Assessments will include vital signs (resting BP [including date and time of measurement for the first 6 treatment cycles], HR, RR, and body temperature) and BW. Only 
1 BP measurement is needed for subjects with systolic BP <140 mmHg and diastolic BP <90 mmHg. If the subject’s initial BP measurement is elevated (ie, systolic BP 
≥140 mmHg or diastolic BP ≥90 mmHg), the BP measurement should be repeated at least 5 minutes later. The mean value of 2 measurements at least 5 minutes apart is 
defined as 1 BP assessment. If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is elevated (ie, systolic BP ≥140 mm Hg or 
diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 30 minutes later by performing 2 measurements (at least 5 minutes apart) to yield a mean 
value. Subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg must have their BP monitored on Day 15 or more frequently as clinically indicated) until their 
systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive treatment cycles.  If a repeat event of systolic BP ≥160 mm Hg or diastolic BP 
≥100 mm Hg occurs, the subject must resume the Day 15 evaluation until systolic BP has been ≤ 150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive 
treatment cycles. A diary will be provided to the subject to capture the blood pressure evaluations between study visits. See Section 9.4.2.1, Management of Hypertension, 
for further details.
Note:  During Cycle 3 and subsequent cycles, subjects may return to the clinic for the Day 15 visit if BP monitoring is required as specified above.  The Day 15 visit is 
mandatory in Cycles 1 and 2.
h:
Urine dipstick testing for subjects with proteinuria ≥ 2+ should be performed on Day 15 (or more frequently as clinically indicated) until the results have been 1+ or negative 
for 2 consecutive treatment cycles). Urine dipstick testing should be performed preferably at the investigational site (but may be performed locally by the primary care 
physician or a local laboratory if the subject does not have to come for a visit to the site). If a new event of proteinuria ≥ 2+ occurs, the subject must resume the Day 15 urine 
dipstick testing for evaluation of proteinuria until results are 1+ or negative for 2 consecutive treatment cycles.  For subjects with proteinuria ≥2+, see Section 9.4.2.2, 
Management of Proteinuria, for further details.
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.
i:
A comprehensive PE (including a neurological examination) will be performed at the Screening or Baseline Visit, on C1D15, on Day 1 of each subsequent cycle, and at the 
Off-Treatment Visit.  A symptom-directed PE will be performed on C1D1 and at any time during the study as clinically indicated.  Height will be measured at the Screening 
Visit only.
j:
Required if screening PE is performed >7 days prior to C1D1.

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Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: Prerandomization and Randomization 
Phases
k:
Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.
l:
MUGA scan or echocardiogram will be performed during the Screening Visit and during or within 1 week following the Off-Treatment Visit, or sooner if clinically 
indicated.  Assessment should use the same methodology (MUGA or echocardiogram).
m:
Clinical laboratory tests will be performed at the central laboratory.  Every effort will be made to collect samples for analysis at the central laboratory at the same time.  
Laboratory tests at Baseline may be performed up to 72 hours before randomization.  If central laboratory results are not available within the necessary timeframe to allow 
the subject to be enrolled, local laboratories may be used to perform laboratory test to qualify subjects for entry into the study.  Hematology and clinical chemistry 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 patients before starting treatment.  
Assessments scheduled may be performed within 72 hours prior to the visit.  If ≥ Grade 3 clinically significant hematologic or clinical chemistry toxicities occur, repeat 
laboratory tests and AE assessments at least every 3-7 days until improvement to < Grade 3. For subjects with blood glucose > ULN, a fasting (> 6h, water only) blood 
glucose sample will be obtained.
n:
A serum or urine pregnancy test will be performed in women of childbearing potential (ie, premenopausal women and postmenopausal women who have been amenorrheic 
for less than 12 months) at the Screening and Baseline Visits, on Day 1 of each cycle from Cycle 2 onwards, at the Off-Treatment Visit, and every 30 days up to 120 days 
post last dose of study medication or the start of a new anticancer therapy, whichever comes first.
o:
HRQoL will be assessed at Baseline, on Day 1 of each subsequent cycle, at time of withdrawal 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.
p:
Blood samples for PK profiling of lenvatinib (Arms A and B), and everolimus (Arm A), will be drawn 0.5 – 4 and 6 – 10 h postdose on C1D1, predose and 2 – 12 h postdose 
on C1D15, and predose and 0.5 – 4 and 6 – 10 h postdose on C2D1.  Postdose samplings will be omitted if lenvatinib administration is skipped on C1D15 or C2D1. 
Pharmacokinetic blood samples will be drawn predose only on D1 of Cycles 3, 4, 5, and 6. 
NOTE:  All lenvatinib predose samples should be taken at least 20 h after the previous dose of lenvatinib, and within 4 h prior to administration of the next dose of lenvatinib 
(no predose sample is collected on C1D1).
q:
If an SAE occurs while the subject is taking lenvatinib, blood sample(s) for PK profiling of lenvatinib should be drawn at the first report of an SAE or a severe unexpected 
AE and at its resolution, if possible.
r:
Blood samples for determination of pembrolizumab, antidrug antibodies (ADA), and neutralizing antibodies (NAb) will be collected prior to pembrolizumab administration 
on Day 1 of Cycles 1, 2, 3, 5, and during the off-treatment visit after pembrolizumab discontinuation for subjects in Arm B. Additional pembrolizumab PK and ADA 
samples will be drawn 30 minutes following the end of the pembrolizumab infusion on Day 1 of Cycles 1 and 2 for subjects in Arm B.
s:
Collection of blood samples to be used for biomarker studies will be collected from subjects in all treatment arms.  Samples will be obtained predose on C1D1, C1D15, 
Day 1 of all subsequent cycles, and at the Off-Treatment Visit.  
t:
Screening Period:  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 
plus suspected disease should be performed within 28 days prior to randomization. Historical scans performed within the screening period but before signing informed 
consent may be used if consistent with protocol requirements per imaging core lab.
Treatment Period:  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 plus newly suspected disease should be performed every 8 weeks (starting from date of randomization with a window of ±5 days), or sooner, if clinically 
indicated.  The same methodology (CT or MRI) and scan acquisition techniques that were used for the screening assessments should be followed during the Randomization 
Phase.  Detailed image acquisition guidelines will be provided by the ICL.
All subjects continuing study treatment after initial RECIST 1.1-defined progression must continue tumor assessments at the same interval and have copies of all tumor 

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Table 7
Schedule of Procedures/Assessments in Study E7080-G000-307: Prerandomization and Randomization 
Phases
assessments sent to the ICL until further progression and/or loss of clinical benefit as judged by the investigator.
Follow-up Period:  Subjects who discontinue treatment without disease progression should continue tumor assessments every 8 weeks until disease progression or beginning 
another anticancer therapy unless the subject withdraws consent or is lost to follow-up.  
u:
Tumor assessments at the Off-Treatment Visit (within 1 week of the Off-treatment Visit) are only necessary for subjects who discontinue study drug without disease 
progression if more than 4 weeks have passed since the previous assessment and if the subject will not continue with follow-up scans.  All other subjects will continue tumor 
assessments as scheduled every 8 weeks from the date of randomization.  
v:
A bone scan (99m-technetium-based scintigraphy, whole body bone MRI, or 18F-NaF) to assess bone metastases will be performed within 6 weeks prior to randomization 
(historical scans before signing informed consent are acceptable) and then every 24 weeks (within that 24th week) from randomization or sooner if clinically indicated.  In 
subjects whose body CT/MRI scans indicates 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.  If a non-target lesion is 
being followed by bone scan (not present on CT/MRI), and is not imaged at a follow-up time point because a bone scan is not required at that time point, the time point non-
target lesion response will be based upon the other non-target lesions and will not be considered not evaluable (NE).
For subjects who discontinue treatment without disease progression, a bone scan should continue to be performed every 24 weeks in the Follow-up Period until disease 
progression or beginning another anticancer therapy unless the subject withdraws consent or is lost to follow-up.
w:
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should be performed within 28 days before randomization.  During the Randomization 
Phase, CT/MRI of the brain should be performed if clinically indicated. For subjects with a history of protocol eligible treated brain metastases, a brain scan will be required 
at all tumor assessment time points (e.g., every 8 weeks). The same methodology and scan acquisition techniques used at Screening should be used throughout the study to 
ensure comparability.  A brain scan will be performed within a target of 1 week but no more than 2 weeks following achievement of a CR.
For subjects with a history of protocol-eligible, treated brain metastases who discontinue treatment without disease progression, brain scans should continue to be performed 
every 8 weeks in the Follow-up Period until disease progression or beginning another anticancer therapy, unless the subject withdraws consent or is lost to follow-up.
x:
An archival tumor sample from the most recent surgery or biopsy for identification of predictive biomarkers and pathology review will be collected (if available) from all
enrolled subjects in all treatment arms at any time during the study, with subject and site approval, and in accordance with regional or local laws.
y:
Subjects will be followed for survival and PFS on next-line therapy (PFS2; unless this information is not allowed to be provided due to confidentiality) every 12 weeks 
(±1 week) after the Off-treatment Visit.  If a clinic visit is not feasible, follow-up information may be obtained via telephone or e-mail.
z:
Collection of whole blood to obtain genomic DNA for PG analysis will be obtained on C1D1.  Samples will be collected from all subjects receiving lenvatinib (i.e. Arms A 
and B) only, with subject and site approval, and in accordance with regional or local laws.  If sampling is not performed predose, sampling may occur at any subsequent visit 
in which other blood sampling is scheduled to occur. 
aa:
Concomitant medications will be recorded for 30 days after last dose.  All anticancer therapy will be recorded until time of death or termination of survival follow-up.
bb: All AEs will be captured up to 30 days after last dose of study drug.  SAEs must be collected through 120 days after the subject’s last dose, or 30 days following the last dose 
if the subject initiates new anticancer therapy, whichever is earlier. Any pregnancy in which the estimated date of conception is either before the last visit or within 120 days 
of the last study treatment or 30 days following last study treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported. Also, any exposure 
to study drug through breastfeeding during study treatment or within 120 days of the last study treatment, or 30 days following the last study treatment if the subject initiates a 
new anticancer therapy, whichever is earlier, must be reported.

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Table 8
Schedule of Visits and Procedures in E7080-G000-307 Extension Phase
Phase
Extension
Period
Treatment Period
Follow-Up Period
Visit
100-998
101-997
999p
1000
Cycle X (Last Cycle +1) and Beyonda
Off-Treatment Visit
Day
1
15
Assessments
KPSb
X
X
Vital signs and weightc
X
Xc
X
Physical Examinatione
X
X
12-lead ECGf
X
X
MUGA scan or echocardiogramg
X
Hematology and clinical chemistryh
X
X
Urine dipstick testingd
X
Xd
X
Pregnancy testi
X
X
X
Biomarker (serum) samplej
X
Biomarker (plasma) samplej
X
Biomarker (whole blood) samplej
X
Tumor assessments: CT (MRI)k
Tumor assessments will be performed according to the 
local standard of care.
Bone Scan
Bone scans will be performed if clinically indicated.
Brain Scan
Brain scans will be performed if clinically indicated.
Survival and PFS2l
X
Study drug treatment
21-day cycles of lenvatinib daily plus everolimus daily or 
21-day cycle of lenvatinib daily plus pembrolizumab IV 
every 21 days or sunitinib daily for 4 weeks plus 2 weeks 
off, depending on randomization arm
Concomitant medicationsm
Throughout
X
AEs/SAEsn,o
Throughout
X
X

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Table 8
Schedule of Visits and Procedures in E7080-G000-307 Extension Phase
AEs = adverse events; BP = blood pressure; BW = body weight; CBC = complete blood count; CT = computed tomography; ECG = electrocardiogram; h = 
hour(s); HR = heart rate; IV = intravenous; KPS = Karnofsky performance status; med = medication(s); MRI = magnetic resonance imaging; MUGA = 
multiple-gated acquisition; NYHA = New York Heart Association; PFS2 = progression-free survival during next-line therapy; RR = respiratory rate; SAEs =  
serious adverse events; ULN = upper limit of normal; w/in = within.
a.
Efforts should be made to conduct study visits on the day scheduled (3 days).  Clinical laboratory assessments may be conducted anytime within 
72 hours prior to the scheduled visit, unless otherwise specified in the Schedule of Procedures/Assessments.
b.
For KPS assessment see protocol appendices. 
c.
Assessments will include vital signs (resting BP, HR, RR, and body temperature) and BW. Only 1 BP measurement is needed for subjects with systolic 
BP <140 mmHg and diastolic BP <90 mmHg. If the subject’s initial BP measurement is elevated (ie, systolic BP ≥140 mmHg or diastolic BP ≥90 
mmHg), the BP measurement should be repeated at least 5 minutes later. The mean value of 2 measurements at least 5 minutes apart is defined as 1 BP 
assessment. If the BP assessment (ie, the mean of the 2 BP measurements obtained at least 5 minutes apart) is elevated (ie, systolic BP ≥ 140 mm Hg or 
diastolic BP ≥90 mm Hg), a confirmatory assessment should be obtained at least 30 minutes later by performing 2 measurements (at least 5 minutes 
apart) to yield a mean value.  Subjects with systolic BP ≥160 mm Hg or diastolic BP ≥100 mm Hg assessment must have their BP monitored on Day 15 
(or more frequently as clinically indicated) until their systolic BP has been ≤150 mm Hg and diastolic BP has been ≤95 mm Hg for 2 consecutive 
treatment cycles.  If a repeat event of systolic BP ≥160 mm Hg or diastolic BP ≥ 100 mm Hg occurs, the subject must resume the Day 15 evaluation 
until systolic BP has been ≤ 150 mm Hg and diastolic BP has been ≤ 95 mm Hg for 2 consecutive treatment cycles. A diary will be provided to the 
subject to capture the blood pressure evaluations between study visits. See Section 9.4.2.1, Management of Hypertension, for further details.
Note:  During Cycle 3 and subsequent cycles, subjects may return to the clinic for the Day 15 visit if BP monitoring is required as specified above.  The 
Day 15 visit is mandatory in Cycles 1 and 2.
d.
Urine dipstick testing for subjects with proteinuria ≥ 2+ should be performed on Day 15 or more frequently as clinically indicated until the results have 
been 1+ or negative for 2 consecutive treatment cycles. Urine dipstick testing should be performed preferably at the investigational site (but may be 
performed locally by the primary care physician or a local laboratory if the subject does not have to come for a visit to the site).  If a new event of 
proteinuria ≥2+ occurs, the subject must resume the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 
2 consecutive treatment cycles. For subjects with proteinuria ≥ 2+, see Section 9.4.2.2, Management of Proteinuria, for further details.
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.
e.
A comprehensive physical exam will be performed on Day 1 of each cycle and at the off-treatment assessment.  A physical exam may also be performed 
on Day 15 or sooner if clinically indicated.
f.
Single 12-lead ECG as clinically indicated. Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.
g.
MUGA or echocardiogram will be performed during or within 1 week following the off-treatment assessment, or sooner if clinically indicated. MUGA 
scans or echocardiogram will be performed in accordance with the institution’s standard practice.  Assessment should use the same methodology 
(MUGA or echocardiogram).
h.
Hematology and clinical chemistry results (central or local) must be reviewed within 2 business days of receipt of results for all subsequent cycles.

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Table 8
Schedule of Visits and Procedures in E7080-G000-307 Extension Phase
Assessments scheduled may be performed within 72 hours prior to the visit. If local laboratory results are used, they should be entered on an 
unscheduled eCRF for that visit. If ≥Grade 3 clinically significant hematologic or clinical chemistry toxicities occur, repeat laboratory tests and AE 
assessments at least every 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. 
i.
A serum or urine pregnancy test will be performed in women of childbearing potential (ie, premenopausal women and postmenopausal women who have 
been amenorrheic for less than 12 months) on Day 1 of each cycle from Cycle 2 onwards, at the Off-Treatment Visit and every 30 days up to 120 days 
post last dose of the study medication or the start of a new anticancer therapy, whichever comes first.
j.
Collection of blood samples to be used for biomarker studies will be collected from subjects in all treatment arms at the Off-Treatment visit.
k.
Extension Phase: Tumor Assessments should be performed according to the local standard of care, but not less frequently than every 12 weeks. 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 during the Extension Phase. During the extension phase scans will no longer be sent to the imaging core lab.
l.
Subjects will be followed for survival and PFS on next-line therapy (PFS2; unless this information is not allowed to be provided due to confidentiality) 
every 12 weeks (±1 week) after the Off-Treatment Visit unless they withdraw consent or are lost to follow-up.  If a clinic visit is not feasible, follow up 
information may be obtained via telephone or e-mail.
m. Concomitant medications will be recorded for 30 days after last dose.  All anticancer therapy will be recorded until time of death or termination of 
survival follow up.
n.
All AEs will be captured up to 30 days after last dose of study drug.  SAEs must be collected through 120 days after the subject’s last dose, or 30 days 
following the last dose if the subject initiates new anticancer therapy, whichever is earlier. Any pregnancy in which the estimated date of conception is 
either before the last visit or within 120 days of the last study treatment or 30 days following last study treatment if the subject initiates new anticancer 
therapy, whichever is earlier, must be reported. Also, any exposure to study drug through breastfeeding during study treatment or within 120 days of the 
last study treatment, or 30 days following the last study treatment if the subject initiates a new anticancer therapy, whichever is earlier, must be reported.
o.
If an SAE occurs while the subject is taking lenvatinib, blood sample(s) for PK profiling of lenvatinib should be drawn at the first report of an SAE or a 
severe unexpected AE and at its resolution, if possible.
p.
The off-treatment assessments should occur within 30 days of the final dose of study treatment.

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9.5.2.1
Description of Procedures/Assessments Schedule
Refer to Table 7 and Table 8 for description and timing of each procedure and assessment in 
the Prerandomization and Randomization Phase and the Extension Phase, respectively
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.
SAEs regardless of causality assessment must be collected through the last visit and for 120
days after the subject’s last dose, or 30 days following the last dose if the subject initiates 
new anticancer therapy, whichever is earlier. 
Regardless of treatment arm, all SAEs must be followed to resolution or, if resolution is 
unlikely, to stabilization.  Any SAE judged by the investigator to be related to the study 
treatment or any protocol-required procedure should be reported to the sponsor regardless of 
the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File.
For urgent safety issues, please ensure all appropriate medical care is administered to 
the subject and contact the appropriate study team member listed in the Investigator Study 
File.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 24 hours of its 
receipt.  If the follow-up information changes the investigator’s assessment of causality, this 
should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.

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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 
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 120 days of the last study treatment or 30 days following last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported. Also, any 
exposure to study drug through breastfeeding during study treatment or within 120 days of
the last study treatment, or 30 days following the last study treatment if the subject initiates a 
new anticancer therapy, whichever is earlier, must be reported.
Regardless of treatment arm, if an adverse outcome of a pregnancy is suspected to be related 
to study drug exposure, this should be reported regardless of the length of time that has 
passed since the exposure to study treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events
[Section 9.5.4.1]).
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 the time that the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 24 hours from the time that the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol. 
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with 
the protocol

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Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
Medication error
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
Note: Overdose for pembrolizumab is defined as a dose greater than 5 times the 200 mg 
dose.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators (or as regionally required, the head of the medical 
institution) and regulatory authorities of reportable events, in compliance with applicable 
regulatory requirements, on an expedited basis (ie, within specific time frames).  For this 
reason, it is imperative that sites provide complete SAE information in the manner described 
above.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor or a third party acting on behalf of the 
sponsor to regulatory authorities in compliance with local and regional law and established 
guidance.  The format of these reports will be dictated by the local and regional 
requirements.
All studies that are conducted within any European country will comply with European Good 
Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC.  All 
suspected unexpected serious adverse reactions (SUSARs) will be reported, as required, to 
the competent authorities of all involved European member states.
9.5.5
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 7 and Table 8).

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The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, progression of disease, withdrawal of 
consent, pregnancy, study terminated by sponsor, or other.  Study disposition information 
will be collected on the Subject Disposition CRF.
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 end of the 
Randomization Phase after database lock and randomization codes have been released.  
Statistical analyses will be performed using SAS software or other validated statistical 
software as required.  Details of the statistical analyses will be included in a separate 
statistical analysis plan (SAP), which will be finalized before the database lock.
9.7.1
Statistical and Analytical Plans
The statistical analyses of the primary analysis of the study data are described in this section.  
Further details of the analytical plan will be provided in the SAP, which will be finalized 
before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary endpoint is PFS by independent review defined as the time from the date of 
randomization to the date of the first documentation of disease progression per RECIST 1.1 
or death (whichever occurs first).  PFS censoring rules will follow the FDA guidance of 
2007; specifics of this will be detailed in the Statistical Analysis Plan.
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints are as follows:

Objective response rate (ORR) is defined as the proportion of subjects who have best 
overall response of CR or PR as determined by IIR using RECIST 1.1.

Overall survival (OS) is defined as the time from the date of randomization to the date of 
death from any cause. Subjects who are lost to follow-up and those who are alive at the 
date of data cut-off will be censored at the date the subject was last known alive, or date 
of data cut-off, whichever occurs first.

Safety will be assessed summarizing the incidence of treatment-emergent adverse events 
(TEAEs) and SAEs together with all other safety parameters.  

Proportion of subjects who discontinued treatment due to toxicity is defined as the 
proportion of subjects who discontinue study treatment due to treatment-emergent 
adverse events (TEAEs).

Time to treatment failure due to toxicity is defined as the time from the date of first dose 
to the date that a subject discontinues study treatment due to TEAEs. 

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
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.  

PFS on next-line of therapy (PFS2) is defined as the time from randomization to disease 
progression on next-line of treatment, or death from any cause, (whichever occurs first).

Progression-free survival (PFS) by investigator assessment is defined as the time from the 
date of randomization to the date of first documentation of disease progression based on 
the investigator assessment per RECIST v.1.1 or death (whichever occurs first).

Model-predicted clearance and AUC for lenvatinib in Arms A and B. 

Model-predicted clearance and AUC for everolimus in Arm A.  
9.7.1.1.3
EXPLORATORY ENDPOINTS
The exploratory endpoints are as follows:

Duration of response (DOR) is defined as the time from the date a response was first 
documented until the date of the first documentation of disease progression or date of 
death from any case.

Disease control rate is the proportion of subjects who have best overall response of CR or 
PR or SD. Stable disease must be achieved at ≥ 7 weeks after randomization to be 
considered best overall response.

Clinical benefit rate is the proportion of subjects who have best overall response of CR or 
PR or durable SD (duration of SD ≥ 23 weeks after randomization).

Blood and tumor biomarkers will be assessed for identifying potential correlation with 
clinical outcomes-related endpoints.
9.7.1.2
Definitions of Analysis Sets
The Full Analysis Set (Intent-to-Treat Analysis [ITT] Population) is the group of all 
randomized subjects regardless of the treatment actually received. This is the primary 
analysis population used for all efficacy analyses which will be based on the intent-to-treat 
principle.
The Per Protocol Analysis Set is the group of those subjects who received at least 1 dose of 
study drug, had no major protocol deviations and had both baseline and at least 1 
postbaseline tumor assessments. Subjects for whom death occurred prior to the first 
postbaseline tumor assessment will also be included. The per protocol analysis set will be 
the secondary analysis set for efficacy endpoints.
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug. 
This is the analyses population used for all safety analyses which will be based on as-treated 
principle.

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Population Pharmacokinetic (PK) Analysis Set: All the subjects who have received at least 
1 dose of study treatment with documented dosing history in the lenvatinib plus everolimus 
arm (Arm A) or the lenvatinib plus pembrolizumab arm (Arm B), and have measurable 
plasma levels of lenvatinib, or whole blood levels everolimus.
Pembrolizumab Pharmacokinetic (PK) Analysis Set: All subjects who have received at 
least 1 dose of study treatment with documented dosing history in the lenvatinib plus 
pembrolizumab arm (Arm B) and have measurable serum concentrations of pembrolizumab.
The Pharmacodynamic Analysis Set is the group of subjects who received at least 1 dose 
of study drug and had sufficient pharmacodynamic data to derive at least 
1 pharmacodynamic measurement and with documented dosing history.
The QOL Analysis Set will consist of all subjects who have any QOL data.
9.7.1.3
Subject Disposition
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 for the full analysis set will be summarized 
for each treatment arm and for all treatment arms combined using descriptive statistics.  
Continuous demographic and baseline variables include age, body weight, and height; 
categorical variables include sex, age group, race, region, KPS, NYHA cardiac disease 
classification, MSKCC prognostic group, and AJCC staging at the time of diagnosis.
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes.  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
full analysis set by treatment arm, Anatomical Therapeutic Chemical (ATC) class, and WHO 
DD preferred term.  Prior medications will be defined as medications that started before the 
first dose of study drug.  Concomitant medications will be defined as medications that (1) 
started before the first dose of study drug and were continuing at the time of the first dose of 
study drug, or (2) started on or after the date of the first dose of study drug up to 30 days after 
the subject’s last dose.  All medications will be presented in subject data listings.

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9.7.1.6
Efficacy Analyses
9.7.1.6.1
PRIMARY EFFICACY ANALYSIS
Comparisons of PFS between lenvatinib + everolimus (Arm A) versus sunitinib (Arm C), 
and lenvatinib + pembrolizumab (Arm B) versus sunitinib (Arm C) will be performed.  PFS 
will be evaluated using Kaplan-Meier (K-M) estimates and the statistical significance of the
difference in PFS for the 2 primary comparisons will be tested by stratified logrank test. 
Geographic region and MSKCC prognostic groups will be used as stratification factors for 
randomization.  The hazard ratio (lenvatinib + everolimus relative to sunitinib and lenvatinib 
+ pembrolizumab relative to sunitinib) and the corresponding 95% confidence intervals (CIs) 
will be estimated using the Cox regression model with Efron’s method for handling tied 
results, stratified by the same stratification factors.  
An interim and a final analysis of PFS are planned to be performed (Section 9.7.3).  Lan-
DeMets spending function with O’Brien-Fleming boundary will be used to control alpha 
levels between the interim and final analysis of PFS. The interim analysis of PFS will be 
performed when it is approximately 4 months after the last subject is randomized and an 
approximately 80% information fraction of PFS events (as determined by the IIR) in Arm B 
and Arm C.  The final analysis of PFS will be performed when approximately 388 PFS 
events, as determined by the IIR, are observed between each comparison.  A graphical 
approach (Section 9.7.4) will be used to control the family wise error rate (FWER) at the 
two-sided 0.0499 for multiple comparisons, including both PFS comparisons of Arm B vs 
Arm C and Arm A vs Arm C.  For each comparison, a statistical significance can be claimed 
based on either interim or final analysis of PFS at specified alpha levels. 
9.7.1.6.2
SECONDARY EFFICACY ANALYSES
Overall Survival (OS) will be compared between lenvatinib + everolimus (Arm A) vs. 
sunitinib alone (Arm C) and lenvatinib + pembrolizumab (Arm B) vs. sunitinib alone (Arm 
C) using the stratified logrank test with geographic region (Western Europe and North
America vs. Other) and MSKCC prognostic groups (favorable, intermediate and poor risk) as 
strata.  The hazard ratio and its 95% CI comparing lenvatinib + everolimus (Arm A) vs. 
sunitinib alone (Arm C) and lenvatinib + pembrolizumab (Arm B) vs. sunitinib alone 
(Arm C) will be estimated by a stratified Cox proportional hazards model with Efron’s 
method for handling tied results, stratified by geographic region and MSKCC prognostic 
groups.  Median OS with 2-sided 95% CIs will be calculated using K-M product-limit 
estimates for each treatment arm and K-M estimates of OS will be plotted over time. 
Three interim and final OS analyses are planned to be performed (Section 9.7.3).  Lan-
DeMets spending function with Pocock boundary will be used to control alpha levels among 
the interim and final analysis of OS.  The first two OS interim analyses will be performed at 
the time of PFS interim and final analysis, corresponding to approximately 45% and 60% of 
information fractions of OS events.  The third OS interim analysis will be performed at 
approximately 80% information fraction of OS events.  The final analysis of OS will be 
performed when 304 OS events are observed for each comparison.  Objective Response Rate 
(ORR) will be calculated with exact 95% confidence intervals using the method of Clopper 

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and Pearson.  The difference between treatment arms will be tested using the Cochran-
Mantel-Haenszel (CMH) test, stratified by geographic region and MSKCC prognostic 
groups.  The p-value for hypothesis testing of ORR will be based on the ORR data at the time 
of the PFS interim analysis.  The ORR data available at the subsequent analysis time points 
will be provided for supportive purposes. 
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 EMA 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. 
PFS2 will be calculated using the Kaplan-Meier (KM) product-limit estimates for each 
treatment group and presented with two-sided 95% CIs. The KM estimate of PFS2 will also 
be plotted over time for each treatment group.
PFS by investigator assessment per RECIST v1.1 will be analyzed similarly as for the 
primary endpoint of PFS by IIR per RECIST v1.1. 
The strategy to address multiplicity and control of the overall FWER for the primary and key
secondary efficacy endpoints is described in 9.7.4.
9.7.1.6.3
EXPLORATORY EFFICACY ANALYSES
Disease Control Rate and CBR will be calculated with exact 95% confidence intervals using 
the method of Clopper and Pearson. The differences and odds ratios of the above rates 
between treatment arms and corresponding two-sided 95% CIs will be calculated 
respectively. Median duration of response among responders for each treatment arm will be 
presented along with its corresponding 2-sided 95% CIs. 
The difference in PFS between lenvatinib in combination with everolimus versus lenvatinib 
in combination with pembrolizumab will be analyzed using the methods used for analysis of
the primary endpoint.  
No multiplicity adjustment will be made for testing exploratory endpoints.
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
Plasma concentrations of lenvatinib and whole blood concentrations of everolimus versus 
time data will be analyzed using a population PK approach to estimate population PK 
parameters for each respective drug, while pembrolizumab concentrations will be compared 
with historical data. For lenvatinib, data from this study will be pooled with historical data 

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from other Phase 1 and 2 studies. For everolimus, data from this study will be pooled with 
data from Study E7080-G000-205. 
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
Soluble, tissue, genetic and/or imaging biomarkers (baseline and/or post-treatment) may be 
summarized using descriptive statistics and correlated with clinical outcomes-related 
endpoints for safety and/or efficacy (including best overall response, PFS and OS) as 
appropriate. Details may be included in a separate analysis plan.
9.7.1.7.3
PHARMACOKINETIC-PHARMACODYNAMIC ANALYSES
The effect of lenvatinib in combination with everolimus or pembrolizumab on soluble, tissue, 
genetic and/or imaging biomarkers will be summarized using descriptive statistics using the 
PK/pharmacodynamic analysis set.  PK/pharmacodynamic relationships (ie, exposure-
efficacy, and exposure-safety and exposure-biomarker relationships) will be modeled, if
possible, using a mechanistic approach for effects of study treatment.  Efficacy endpoints 
will include the primary endpoint of PFS and other efficacy-related metrics including but not 
limited to ORR (based on RECIST 1.1) and OS.  Safety endpoints will be most frequent AEs 
of special interest and dose reductions.  Exploratory/graphical analyses will be conducted for 
PK/pharmacodynamic evaluations, and, if possible, will be followed by model-based 
analyses.  
The PK and PK/PD analyses will be detailed in a separate analysis plan that will be provided 
at a later date and the result will be provided in a standalone report. 
9.7.1.8
Safety Analyses
Safety analyses will be based on the Safety Analysis Set. All safety analyses will be 
summarized by treatment arm. Adverse events and serious adverse events, laboratory test 
results, vital signs, and echocardiogram results (including LVEF) will be summarized.
Safety data will be summarized using descriptive statistics. Categorical variables will be 
summarized by number and percentage. Continuous variables will be summarized using n 
(number of subjects with available data), mean, standard deviation, median, Q1, Q3, and 
range (minimum and maximum) unless otherwise specified.
9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drugs 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 

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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.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized by treatment arm.  The incidence of TEAEs will be reported 
as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will be 
counted only once within an SOC and PT, even if the subject experienced more than 1 TEAE 
within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will also be 
summarized by maximum severity (highest CTCAE grade).
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include TEAEs that were considered by the 
Investigator to be possibly or probably related to study drug or TEAEs with a missing 
causality.  The number (percentage) of subjects with treatment-related TEAEs will also be 
summarized by maximum severity (by highest CTCAE grade).
The proportion of subjects who discontinue treatment due to toxicity will be summarized by 
frequency counts and percentages. Median, upper and lower quartiles of time to treatment 
failure due to toxicity will be summarized for subjects who discontinue study treatment due 
to TEAEs. 
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 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.

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9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, resting HR, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit and treatment arm. Blood pressure will also be summarized using a shift table by 
categories defined based on CTCAE Grades. Subjects will be included in the summary if 
they had both a Baseline value and at least 1 postbaseline value for blood pressure.
9.7.1.8.5
ELECTROCARDIOGRAMS
Change from baseline to worst postbaseline result in ECG findings (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) will be summarized 
by treatment arm using a shift tables.  Descriptive statistics for ECG parameters and changes 
from baseline will be presented by visit by treatment arm.
9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive statistics for LVEF assessed on echocardiogram or MUGA scans and changes 
from baseline will be presented by treatment arm. Percent reduction from baseline will also 
be summarized.
9.7.2
Determination of Sample Size
The sample size is estimated based on the primary endpoint of PFS.  Approximately 
1050 subjects will be randomized in a 1:1:1 ratio into 1 of 3 treatment arms: lenvatinib + 
everolimus, lenvatinib + pembrolizumab, or sunitinib alone.  The randomization scheme will 
be stratified by geographic region (Western Europe + North America vs. Other) and MSKCC 
prognostic groups (favorable, intermediate and poor risk).  
The same treatment effect is assumed for the primary comparisons of lenvatinib + everolimus 
(Arm A) and lenvatinib + pembrolizumab (Arm B) each compared to sunitinib alone (Arm 
C).  Assuming the median PFS of sunitinib to be 12.3 months and a targeted HR of 0.714 for 
the primary comparisons, this corresponds to a 40% improvement (4.9 months) in median 
PFS from 12.3 months to 17.2 months for Arm A versus Arm C and for Arm B versus Arm 
C.  A yearly loss of PFS event rate of 22% is assumed in the sample size calculation.
Since the study is testing more than one comparison for the primary and secondary 
endpoints, the graphical approach (Section 9.7.4) will be used for testing multiple 
hypotheses.  For the two PFS comparisons (one for each test arm), the sponsor chooses to 
split the total alpha of 0.0499 (2-sided), as initial allocations, into α = 0.045 for the 
comparison between Arm B and Arm C, and α = 0.0049 for the comparison between Arm A 
and Arm C. 
The study is designed to achieve 90% power at α = 0.045 to detect a statistically significant 
difference in PFS in the comparison between Arm B and Arm C.  Therefore, a total of 388 
PFS events are required between Arms B and C in the final PFS analysis.  Since the same 
number of PFS events are expected to be observed in Arms A and C, a total of 388 PFS 

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events is expected in the final PFS analysis for the comparison between Arms A and C.  The 
power to detect a statistically significant difference in PFS between Arm A and Arm C is 
approximately 70% at the initial assigned α = 0.0049, and will be at least 90% when the 
hypothesis tests of PFS and OS in the comparison of Arm B and Arm C are statistically 
significant, and vice versa.  In the power calculation for PFS analysis, it is assumed that one 
interim analysis of PFS is to be performed at the 80% information fraction and a Lan-DeMets
spending function with O’Brien-Fleming boundary is used between the interim and final 
analysis of PFS.
Assuming an average enrollment rate of 31 subjects per month, the interim and final analysis 
of PFS will occur approximately 38 and 45 months (34-month enrollment period) after the 
first subject is randomized.  A total of 582 PFS events are expected in 3 arms by the time of 
planned final PFS analysis.
For the key secondary endpoint of OS, a total of 304 deaths for each comparison (456 death 
events among the 3 arms) are expected in the final OS analysis.  For OS testing, when the 
corresponding PFS testing is statistically significant at the initial assigned alpha, the study 
will provide 80% power to detect a statistically significant difference at an α level of 0.045
for the comparison between Arms B and C, and 50% power at an α level of 0.0049 for the 
comparison between Arm A and C.  By using the graphical approach, the power for the OS 
comparison between Arms A and C will increase to at least 80% when the OS testing 
between Arms B and C is significant and both PFS testings are significant, and vice versa.  
The assumptions that are used for the OS power calculations are: 1) the hazard ratio is 0.70
(median OS is 54.1 months in Arm A or Arm B and 37.9 months in Arm C), 2) interim 
analyses are performed at approximately 45%, 60%, and 80% information fraction of death 
events, 3) a Lan-DeMets spending function with Pocock boundary is used, and 4) the yearly 
rate for loss to follow-up is 3%.  With the planned sample size and the assumptions for 
enrollment, the final analysis of OS is expected to occur approximately 69 months after the 
first subject is randomly assigned to treatment. 
For the key secondary endpoint of ORR, assuming an ORR of 32% in Arm C and 48% in
Arm A or Arm B, the study will provide at least 95% power to detect a difference when 
testing of PFS and OS are positive for each comparison of Arm B vs Arm C and Arm A vs 
Arm C.
9.7.3
Interim Analysis
The interim efficacy analyses will be conducted by an independent statistical group that has
no other responsibilities for the study. The safety monitoring will be conducted by the 
independent DMC and only the DMC will have access to data with treatment information. 
The frequency of the safety reviews will be defined in the DMC charter.  Minutes from the 
open meetings of the DMC will be provided if requested by regulatory agencies and the 
DMC closed minutes will be provided after the end of the study. The recommendation 
whether to stop the trial for safety reasons will be reached by the DMC based on its review of 
safety data with treatment information.  The function and membership of the DMC will be 
described in the DMC charter.

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Interim analyses of PFS, OS, and ORR are planned in this study.  The timing of each analysis 
are summarized in Table 9. Type I error control for the efficacy analyses as well as efficacy 
boundaries are described in 9.7.4.
Table 9
Summary of Interim and Final Efficacy Analyses
No.
Analysis
Endpoint(s)
Timing
Estimated Time 
after First Subject 
Randomized
1
Interim analysis of ORR 
and DOR (the first 88 
subjects from Arm B) 
ORR
DOR
Median follow-up of 12 months and a 
minimum DOR follow-up of 6 months
~28 months
2
Interim analysis of PFS, 
Interim analysis of OS
PFS
OS
ORR*
Trigger: approximately 4 months after 
the last subject randomized and 
approximately 310 (80% IF) PFS 
events observed in Arms B and C
(estimated to have ~140 (45% IF) 
deaths observed for each comparison)
~38 months
3
Final analysis of 
PFS,Interim analysis of 
OS
PFS
OS
Trigger: ~ 388 PFS events observed for 
each comparison
(estimated to have 182 (60% IF) deaths 
observed for each comaprison)
~45 months
4
Interim analysis of OS
OS
Trigger: ~243 (80% IF) deaths 
observed for each comparison
~57 months
5
Final analysis of OS
OS
Trigger: ~304 deaths observed for each 
comparison
~69 months
DOR = duration of response; ORR = objective response rate; OS = overall survival; PFS = progression-free 
survival; IF=information fraction.
*:  The p-value for hypothesis testing of ORR will be based on the ORR data at the analysis No 2.
An interim analysis of ORR for the first 88 subjects from the lenvatinib + pembrolizumab 
arm (Arm B) of this study will be performed. No comparative analysis will be conducted for 
the interim analysis of ORR; however, an α of 0.0001 will be allocated and deducted from 
the analyses of PFS.  Details outlining how the integrity of study conduct will be maintained 
are described in a separate operational plan. This interim analysis of ORR will occur after 
the first 88 subjects treated in Arm B (lenvatinib + pembrolizumab) have completed a median 
follow-up of 12 months and a minimum DOR follow-up of 6 months.   
In Table 9, another operational plan will be prepared for the analyses specified at Analysis 
No. 2-5 and this plan will include a procedure to conduct an independent statistical review 
for monitoring the number of events specified as triggers.
9.7.4
Multiplicity
To adjust for multiplicity and control the overall FWER, the graphical approach of Maurer 
and Bretz (Maurer et al., 2013) will be used in the primary endpoint of PFS and the key 

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secondary efficacy endpoints (OS and ORR). No multiplicity adjustment will be made for 
other secondary endpoint analyses. An α of 0.0001 will be subtracted from the total α of 0.05 
to account for the interim analysis of ORR from Arm B.  Figure 4 shows the initial α-
allocation (the remaining α of 0.0499) for each hypothesis and the graphical approach for 
multiple analyses of PFS, OS, and ORR. 
If the null hypothesis of PFS is rejected at the initial allocated alpha level 0.045 for H1 (or 
0.0049 for H2), this alpha of 0.045 (or 0.0049) will be reallocated to the tests with the 
corresponding weights as shown in Figure 4.  The initial weights for reallocation from each 
hypothesis to the others are represented by the numbers next to the arrows (eg, if H1 and H3
are positive, 90% alpha will be reallocated to H2, and 10% to H5). An alpha level 0.045 is 
assigned to H1 to increase the successful rate of H1 test so that this alpha can be re-allocated 
to other hypothesis tests. When alpha is re-allocated as planned for all hypotheses, the PFS 
tests H1 and H2 will both have 90% power, OS tests H3 and H4 will both have 80% power, 
and the ORR tests H5 and H6 will both have more than 95% power.
Figure 4
Graphical Approach to Control Familywise Error Rate for Testing 
Primary and Key Secondary Endpoints
EP = endpoint; ORR = objective response rate; OS = overall survival; PFS = progression-free survival. 
Hypothesis (H1): The PFS of lenvatinib + pembrolizumab arm is superior to that of sunitinib arm.
Hypothesis (H2): The PFS of lenvatinib + everolimus arm is superior to that of sunitinib arm.
Hypothesis (H3): The OS of lenvatinib + pembrolizumab arm is superior to that of sunitinib arm.
Hypothesis (H4): The OS of lenvatinib + everolimus is superior to that of sunitinib arm.
Hypothesis (H5): The ORR of lenvatinib + pembrolizumab arm is superior to that of sunitinib arm.
Hypothesis (H6): The ORR of lenvatinib + everolimus is superior to that of sunitinib arm.

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The nominal α level for each PFS comparison at the interim and final analyses will be 
determined by a Lan-DeMets spending function with an O’Brien-Fleming boundary as 
illustrated in Table 10. The nominal α level for each OS comparison at the interim and final 
analyses will be determined by a Lan-DeMets spending function with Pocock boundary as 
illustrated in Table 11.  The actual boundaries will be calculated using the observed number 
of events at the interim and final analyses and α passed from previous tests. 
The study will continue unless the sponsor decides to discontinue survival follow-up 
following completion of the PFS analysis when appropriate, eg, when only a minimal 
number of subjects remain in follow up.
Table 10
Efficacy Boundaries and Properties for PFS H1 and PFS H2 (LDOF
spending function) Based on Initial Assigned Alpha
Analysis (2 arms)
Value
H1 (α=0.045)
H2 (α=0.0049) d
IA: 80%a
N: 700
Events: 310
Month: 38
P (2-sided)b
0.0216
0.0014
HR at boundaryc
0.7705
0.6964
Power
75%
42%
Final: 100%
N: 700
Events: 388
Month: 45
P (2-sided)b
0.0386
0.0046
HR at boundaryc
0.8105
0.7491
Power
90%
69%
HR = hazard ratio, IA = interim analysis, N = number of subjects.
a:
Information fraction, percentage of expected number of events at final analysis.
b:
P-value (2-sided) is the nominal α for testing.
c:
HR at boundary is the approximate HR required to reach an efficacy boundary.
d:   The power of H2 test will be at least 90% if H1 and H3 testings are significant.
Table 11
Efficacy Boundaries and Properties for OS H3 and OS H4 (LD-
Pocock Spending function) when PFS Tests Are Significant
Analysis (2 arms)
Value
H3 (α=0.045)
H4 (α=0.0049) d
IA: 45%a
N: 700
Events: 137
Month: 38
P (2-sided)b
0.0258
0.0028
HR at boundaryc
0.683
0.600
Power
44%
20%
IA: 60%a
N: 700
Events: 182
Month: 45
P (2-sided)b
0.0152
0.0014
HR at boundaryc
0.698
0.622
Power
55%
27%
IA: 80%a
N: 700
Events: 243
Month: 57
P (2-sided)b
0.0158
0.0014
HR at boundaryc
0.734
0.663
Power
69%
41%

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9.7.5
Other Statistical/Analytical Issues
Not applicable.
9.7.6
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.
Final: 
N: 700
Events: 304
Month: 69
P (2-sided)b
0.0158
0.0014
HR at boundaryc
0.758
0.692
Power
80%
51%
HR = hazard ratio, IA = interim analysis, N = number of subjects.
a:
Information fraction, percentage of expected number of events at final analysis.
b:
P-value (2-sided) is the nominal α for testing.
c:
HR at boundary is the approximate HR required to reach an efficacy boundary.
d:    The power of H4 test will be at least 80% if H1, H3 and H2 are significant.

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10 REFERENCE LIST
AFINITOR® Tablets (everolimus) prescribing information. Revised Feb 2016. Available at: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s036lbl.pdf. Accessed 
14 Apr 2016.
Athar U, Gentile TC. Treatment options for metastatic renal cell carcinoma: a review. 
Canadian J Urology 2008;15(2):3954-66.
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity 
of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65.
Bukowski RM, Kabbinavar FF, Figlin RA, Flaherty K, Srinivas S, Vaishampayan U, et al. 
Randomized phase II study of erlotinib combined with bevacizumab compared with 
bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536-41.
Dorff TB, Pal SK, Quinn DI. Novel tyrosine kinase inhibitors for renal cell carcinoma. 
Expert Rev Clin Pharmacol. 2014;7(1):67-73.
Escudier B, Porta C, Schmidinger M, Algaba F, Patard JJ, Khoo V, Eisen T, Horwich A,
et al. (on behalf of the ESMO Guidelines Working Group) Ann Oncol, 2014; 25(Suppl 3): 
ii49-ii56. 
Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer 
agents. Nat Rev Drug Discov. 2006;5(8):671-88.
Feldman DR, Baum MS, Ginsberg MS, Darren R, Hassoun H, Flombaum C, et al. Phase I 
trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell 
carcinoma. J Clin Oncol. 2009;27:1432-9.
GLOBOCAN 2012: Estimated Cancer Incidence, Morality and Prevalence Worldwide in 
2012 (IARC). Available at: http://globocan.iarc.fr/Pages/burden_sel.aspx.
Graves A, Hesssamodin H, Wong G, Lim WH. Metastatic renal cell carcinoma: update on 
epidemiology, genetics, and therapeutic modalities. ImmunoTargets Ther. 2013;2:73-90.
Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C. Epidemiologic and socioeconomic 
burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev.
2008;34(3):193-205.
Hainsworth JD, Spigel DR, Burris HA 3rd, Waterhouse D, Clark BL, Whorf R. Phase II trial 
of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol. 
2010;28(13):2131-6.
Hamid O, Carvajal RD. Anti-programmed death-1 and anti-programmed death-ligand 1 
antibodies in cancer therapy. Expert Opin Biol Ther. 2013;13(6):847-61. 

Clinical Study Protocol
Protocol Amendment 07
E7080-G000-307
Eisai
FINAL: 06 Aug 2020
Confidential
Page 133 of 160
Kanesvaran R, Watt K, Turnbull JD, Armstrong AJ, Wolkowiez MC, George DJ. A single-
arm phase 1b study of everolimus and sunitinib in patients with advanced renal cell 
carcinoma. Clin Genitourin Cancer. 2015;13(4):319-27.
Kato Y, Tabata K, Hori Y, et al. Effects of lenvatinib on tumor-associated macrophages 
enhance antitumor activity of PD-1 signal inhibitors. 2015 AACR-NCI-EORTC Molecular 
Targets and Cancer Therapeutics. Poster A92.
KEYTRUDA® Package Insert. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf.
LENVIMA® Package Insert. Available from:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206947s000lbl.pdf.
Maurer W, Bretz F. Multiple testing in group sequential trials using graphical approaches. 
Stat Biopharm Res. 2013;5:311–20. doi: 10.1080/19466315.2013.807748
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, 
everolimus, and the combination in patients with metastatic renal cell carcinoma: a 
randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015[a];16(15):1473-82.
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. 
Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 
2015[b];373(19):1803-13.
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Kidney
Cancer. 2016. Available at: 
http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Negrier S, Gravis G, Perol D, Chevreau C, Delva R, Bay JO, et al. Temsirolimus and 
bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced 
renal cell carcinoma (TORAVA): a randomized phase 2 trial. Lancet Oncol. 2011:12(7):
673-80.
Philips GK, Atkins M. Therapeutic uses of anti-PD-1 antibodies. Int Immunol. 
2015 Jan;27(1):39-46.
Posadas EM, Limvorasak S, Sharma S, Figlin, RA. Targeting angiogenesis in renal cell 
carcinoma. Expert Opin Pharmacother. 2013;14(16):2221-36.
Powles T, Foreshew SJ, Shamash J, Sarwar N, Crabb S, Sahdev A, et al. A phase Ib study 
investigating the combination of everolimus and dovitinib in vascular endothelial growth 
factor refractory clear cell renal cancer. Eur J Cancer. 2014;50(12):2057-64.

Clinical Study Protocol
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FINAL: 06 Aug 2020
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Page 134 of 160
Ravaud A, Barrios CH, Alekseev BY, Tay MH, Agarwala SS, Yalcin S, et al. Randomized 
phase II study of first-line everolimus plus bevacizumab (E + B) versus interferon α-2a plus 
bevacizumab (I + B) in patients (pts) with metastatic renal cell carcinoma (mRCC): record-2 
final overall survival (OS) and safety results. J Clin Oncol. 2013;31(15):4576.
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;34:651-9.
Shumaker R, Aluri J, Fan J, Martinez G, Thompson GA, Ren M. Effects of ketoconazole on 
the pharmacokinetics of lenvatinib (E7080) in healthy participants. Clin Pharm Drug Dev. 
2015;4(2):155-60.
Sosman JA, Puzanov I, Atkins M. Opportunities and obstacles to combination targeted 
therapy in renal cell cancer. Clin Cancer Res. 2007;15;13(2 Pt 2):764-9s.
SUTENT® Package Insert. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021938s13s17s18lbl.pdf.
Wahal SP, Mardi K. Multilocular cystic renal cell carcinoma: a rare entity with review of 
literature. J Lab Physicians. 2014;6(1):50-2.
CTCAE Reference
Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 [published 28 May 2009 (v4.03: June 14, 2010)].  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
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 (or appropriate 
study team member) and the IRB/IEC for the site must be notified immediately.  The sponsor 
must notify the health or regulatory authority as required per local regulations.
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB/IEC (or if regionally required, the head of the medical institution) should 
be kept informed of such changes as required by local regulations.  In these cases, the 
sponsor may be required to send a letter to the IRB/IEC and the Competent Authorities (or, if 
regionally required, the head of the medical institution) detailing such changes.
11.2
Adherence to the Protocol
The investigator will conduct the study in strict accordance with the protocol (refer to 
ICH E6, Section 4.5).
11.3
Monitoring Procedures
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator (or if 
regionally required, the head of the medical institution) will allow the CRA to inspect the 
clinical, laboratory, and pharmacy facilities to assure compliance with GCP and local 
regulatory requirements.  The CRFs and subject’s corresponding original medical records 
(source documents) are to be fully available for review by the sponsor’s representatives at 
regular intervals.  These reviews verify adherence to study protocol and data accuracy in 
accordance with local regulations.  All records at the site are subject to inspection by the 
local auditing agency and to IRB/IEC review.
In accordance with ICH E6, Section 1.52, source documents include, but are not limited to, 
the following:

Clinic, office, or hospital charts

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

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
Comments and other information on AEs (eg, severity, relationship to study drug, 
outcome)
11.6
Retention of Records
The circumstances of completion or termination of the study notwithstanding, the 
investigator (or if regionally required, the head of the medical institution or the designated 
representative) is responsible for retaining all study documents, including but not limited to 
the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since
the formal discontinuation of clinical development of the investigational product.
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately.
11.8
Handling of Study Drug
All study drugs 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 any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators/institutions and regulatory authorities of the termination or 
suspension and the reason(s) for the termination or suspension.  The IRB/IEC will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB/IEC and provide the 
sponsor and the IRB/IEC with a detailed written explanation of the termination or 
suspension.  Study records must be retained as noted above.

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

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12 APPENDICES

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Appendix 1
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 2
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 the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03 
For further details regarding MedDRA, refer to the MedDRA website at:  
http://www.meddra.org

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Appendix 3
Karnofsky Performance Status Scale
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 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
Oxford Textbook of Palliative Medicine, Oxford University Press 1993;109.

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Appendix 4
New York Heart Association (NYHA) Cardiac Disease 
Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for 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; 1994:253-6.

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Appendix 5
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 node (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
Anatomic stage/prognostic group
Stage
T
N
M

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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: pp 479-89.

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Appendix 6
Response Evaluation Criteria in Solid Tumors 
(RECIST)
Tumor response assessments in this clinical trial will use Response Evaluation Criteria in Solid 
Tumors (mRECIST) based on the 2009 article by Eisenhauer et al entitled New Response 
Evaluation Criteria in Solid Tumors: revised RECIST guideline (version 1.1).
The sole modification to RECIST 1.1 to be implemented in this study is that chest x-rays may 
not be used to follow disease; only CT scans may be used to follow chest disease.  As required 
by RECIST 1.1, the protocol states that the minimum duration of SD is 7 weeks.
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 7
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic, pharmacogenomic (PG), 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.
The PG samples may be used to identify genetic factors that may influence a subject’s 
exposure to the study drug, as well as genetic factors that may have an effect on clinical 
response or potential adverse events related to study treatment, and to explore the role of 
genetic variability in response.  Samples may be analyzed to determine a subject’s genotypes 
or sequence for a number of genes or non-coding regulatory regions.  The research may 
include the investigation of polymorphisms in genes that are likely to influence the study 
drug pharmacokinetics or therapeutic response.
Collection of the pharmacodynamic, PG, and other biomarker samples will be bound by the 
sample principles and processes outlined in the main study protocol.  Sample collection for 
pharmacodynamic, PG, 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.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  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.

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It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy. 
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  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.  Genomic DNA samples used to explore the effects on PK, 
treatment response, and safety will be single coded.  Genomic DNA samples that will be 
stored for long-term use (defined as 15 years after the completion of the study) will be double 
coded.  Double coding involves removing the initial code (subject ID) and replacing with 
another code such that the subject can be re-identified by use of 2 code keys.  The code keys 
are usually held by different parties.  The key linking the sample ID to the subject number 
will be maintained separately from the sample.  At this point, the samples will be double-
coded, the first code being the subject number.  Laboratory personnel performing genetic 
analysis will not have access to the “key.”  Clinical data collected as part of the clinical trial 
will be cleaned of subject identifying information and linked by use of the sample ID “key.”
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.

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Given the research nature of the pharmacodynamic, PG, 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, PG, 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 8
Health-Related Quality of Life Questionnaire FKSI-DRS

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Appendix 9
Health-Related Quality of Life Questionnaire EORTC 
QLQ-C30

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Appendix 10
Health-Related Quality of Life Questionnaire EQ-5D-3L

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Appendix 11
MSKCC Risk Model Criteria
Determination of Prognostic Score in First Line Setting 
Parameter
Criteria Value
Subject 
Value
If subject value meets 
criteria value, enter 1
KPS, %
< 80
Time from initial RCC
diagnosis to treatment 
with systemic therapy, in 
months
< 12
Hemoglobin
< LLN
Lactate Dehydrogenase 
(LDH)
> 1.5 x ULN
*Corrected Calcium, 
mg/dL
> 10.0
Sum total of above= 
MSKCC
Prognostic Score:
Corrected Calcium = ([4 – serum albumin in g/dL] x 0.8 + serum calcium).
KPS = Karnofsky Performance Status; LLN = lower limit of normal; MSKCC = Memorial Sloan-Kettering 
Cancer Center; RCC = renal cell carcinoma; ULN = upper limit of normal.
* 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. 
Risk Group Based on MSKCC Prognostic Score
Risk Group
MSKCC Prognostic Score
Favorable-Risk
0
Intermediate-Risk
1 or 2
Poor-Risk
≥ 3
MSKCC = Memorial Sloan-Kettering Cancer Center.

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Appendix 12
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, et al.  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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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-G000-307
Study Protocol Title:
A Multicenter, Open-label, Randomized, Phase 3 Trial to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Everolimus or Pembrolizumab Versus Sunitinib Alone in 
First-Line Treatment of Subjects with Advanced Renal Cell 
Carcinoma.
Investigational Product
Name:
lenvatinib (E7080), everolimus, pembrolizumab, and sunitinib
IND Number:
124564
EudraCT Number:
2016-000916-14
SIGNATURES
Authors:
h
Oncology Business Group, Eisai Inc.
Date
al 
Oncology Business Group, Eisai Ltd.
Date
g
Oncology Business Group, Eisai Inc.
Date
PPD
PPD
PPD

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INVESTIGATOR SIGNATURE PAGE
Study Protocol Number:
E7080-G000-307
Study Protocol Title:
A Multicenter, Open-label, Randomized, Phase 3 Trial to 
Compare the Efficacy and Safety of Lenvatinib in Combination 
with Everolimus or Pembrolizumab Versus Sunitinib Alone in 
First-Line Treatment of Subjects with Advanced Renal Cell 
Carcinoma.
Investigational Product
Name:
lenvatinib (E7080), everolimus, pembrolizumab, and sunitinib
IND Number:
124564
EudraCT Number:
2016-000916-14
I have read this protocol and agree to conduct this study in accordance with all stipulations of 
the protocol and in accordance with International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) and all applicable local Good 
Clinical Practice (GCP) guidelines, including the Declaration of Helsinki.
Medical Institution
Investigator
Signature
Date
As regionally required
Head
Medicine Development 
Center
Signature
Date