Clinical trial NCT02915783
Conditions: Non Clear Cell Renal Cell Carcinoma (nccRCC)
Keywords: unresectable advanced metastatic
Sponsor: Eisai Inc.
Start date: 2017-02-20; Completion date: 2021-11-02
Enrollment: 41 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single-arm, multicenter, Phase 2 study of lenvatinib in combination with everolimus in participants with unresectable advanced or metastatic non clear cell renal cell carcinoma (nccRCC) who have not received any chemotherapy for advanced disease. The primary objective of the study is to evaluate the objective response rate (ORR). This study consists of three phases: a Pretreatment Phase (Screening and Baseline Periods), a Treatment Phase (starting Cycle 1, Day 1), and a Posttreatment Phase (End of Treatment Visit and survival Follow-up).

Detailed description:

Arms: arm 1: Participants will receive initial doses of lenvatinib 18 milligrams per day (mg/day) (one 10-mg capsule and two 4-mg capsules) and everolimus 5 mg/day (5-mg tablets). Capsules and tablets are to be taken orally in immediate succession once a day (QD), and dosing is recommended to occur at approximately the same time each morning (consistently either with or without food).
Interventions: intervention 1: lenvatinib intervention 2: everolimus
Intervention descriptions: intervention 1: 4 mg and 10 mg capsules intervention 2: 5 mg tablets

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol  
Amendment 01 
E7080-M001-221 
 
 
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FINAL: 01 May 2019 
Confidential 
Page 1 of 103  
 
REVISION HISTORY 
The table below describes revisions in Amendment 01 presented in the new protocol 
template (November 2016).    
Revisions Per Amendment 01 
Date: 01 May 2019 
Change 
Rationale 
Affected Protocol Sections 
Updated formal name of the 
International Council for 
Harmonisation of Technical 
Requirements for Pharmaceuticals 
for Human Use (ICH). 
The ICH changed its formal title in 
2018.  
 
Title page (GCP statement) 
 
Investigator signature page 
 
Section 5.2 
Clarified that the primary objective 
and endpoint is to evaluate ORR 
per investigator assessment.  
Clarified that evaluation of ORR 
for the primary objective and 
endpoint will be per investigator 
assessment. 
 
Synopsis 
 
8.1 
 
9.7.1.1.1 
 
9.7.1.6.1 
Clarified that the secondary 
objective and endpoint is to 
evaluate PFS per investigator 
assessment.   
Evaluation of PFS for the 
secondary objective and endpoint 
will remain as per investigator 
assessment.   
 
Synopsis 
 
8.2 
 
9.7.1.1.2 
 
9.7.1.6.2 
Added exploratory objectives and 
endpoints:  
To explore ORR based on IIR 
assessment. 
To explore PFS based on IIR 
assessment.  
Added supportive exploratory 
endpoints per IIR to support the 
investigator assessed endpoints.  
 
Synopsis 
 
8.3 
 
9.5.1.2 
 
9.7.1.1.3 
 
9.7.1.6.3 
Added that the clinical benefit rate 
(CBR), disease control rate (DCR), 
and duration of response (DOR) 
endpoints will be explored per IIR 
assessment as well as per 
investigator.  
Clarified that these exploratory 
endpoints will be determined based 
on both investigator and IIR 
assessments. 
 
Synopsis 
 
8.3 
 
9.5.1.2 
 
9.7.1.1.3 
 
9.7.1.6.3 
Added independent imaging review 
(IIR) for tumor assessment scans. 
To strengthen data collection for 
potential regulatory submission of 
results from this open-label, single 
arm study. 
 
Synopsis 
 
Section 9.5.1.2.1 
Updated when to perform formal 
analyses of ORR, PFS, and OS.  
Last patient in (LPI) plus 6 months 
will provide enough time to collect 
information for the primary and 
secondary endpoints and for 
efficacy and safety evaluation. 
 
Synopsis 
 
Section 9.7.1.6.4 
 
 


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1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7080-M001-221 
Study Protocol 
Title: 
A single-arm, multicenter, Phase 2 trial to evaluate efficacy and 
safety of lenvatinib in combination with everolimus in subjects with 
unresectable advanced or metastatic non clear cell renal cell 
carcinoma (nccRCC) who have not received any chemotherapy for 
advanced disease 
Sponsor:  
Eisai Inc. 
155 Tice Boulevard 
Woodcliff Lake,  
New Jersey 07677 
USA 
Investigational 
Product Name: 
Lenvatinib (E7080) and everolimus    
 
Indication: 
Non clear cell renal cell carcinoma 
Phase: 
Phase 2 
Approval Date:  
V1.0 
13 May 2016 (Original Protocol) 
 
V2.0 
01 May 2019 (Amendment 01) 
IND Number: 
124564 
GCP Statement: 
This study is to be performed in full compliance with International 
Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) and all applicable local 
Good Clinical Practice (GCP) and regulations.  All required study 
documentation will be archived as required by regulatory 
authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 


Clinical Study Protocol  
Amendment 01 
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Confidential 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E7080 
Name of Active Ingredients:  Lenvatinib and Everolimus 
Study Protocol Title 
A single-arm, multicenter, Phase 2 study to evaluate efficacy and safety of lenvatinib in combination 
with everolimus in subjects with unresectable advanced or metastatic non clear cell renal cell 
carcinoma (nccRCC) who have not received any chemotherapy for advanced disease 
Investigators 
To be determined 
Site(s) 
Approximately 8 centers in the United States 
Study Period and Phase of Development 
Approximately 24 months, which include 18 months of enrollment and estimated 6 months of 
treatment 
Phase 2 
Objectives 
Primary Objective 
 
To evaluate objective response rate (ORR), as assessed by the investigator, of lenvatinib in 
combination with everolimus in subjects with unresectable advanced or metastatic non clear 
cell renal cell carcinoma (nccRCC) who have not received any chemotherapy for advanced 
disease 
Secondary Objectives 
The secondary objectives of the study are: 
 
To assess safety and tolerability of lenvatinib in combination with everolimus 
 
To evaluate progression-free survival (PFS) as assessed by the investigator 
 
To evaluate overall survival (OS)  
 
To assess the pharmacokinetic (PK) profiles of lenvatinib and everolimus during combination 
therapy in subjects with nccRCC 
Exploratory Objectives 
 
 
To explore ORR as assessed by independent imaging review (IIR) 
 
To explore PFS as assessed by IIR 
 
To explore clinical benefit rate (CBR) as assessed by the investigator and by IIR 
 
To explore disease control rate (DCR) as assessed by the investigator and by IIR 
 
To explore duration of response (DOR) as assessed by the investigator and by IIR 
 
To identify and explore tumor and blood biomarkers that correlate with clinical outcomes, 
including efficacy 
 
To explore the relationship of population PK derived exposure parameters to biomarker, 
safety, and efficacy data using a model-based approach 


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Confidential 
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Study Design 
This is a single-arm, multicenter, Phase 2 study of lenvatinib in combination with everolimus 
(lenvatinib 18 mg/day + everolimus 5 mg/day) in subjects with unresectable advanced or metastatic 
nccRCC who have not received any chemotherapy for advanced disease.  A Simon’s Two-Stage 
Design will be implemented in approximately 31 enrolled subjects.  Sixteen subjects will be enrolled 
in Stage 1.  If there are at least 2 responders as assessed by ORR, the study will proceed to Stage 2 in 
which 15 more subjects may be enrolled.  Otherwise, the study will stop early for futility.  In the final 
analysis of 31 subjects, at least 6 responders are required to show a statistically significant 
improvement of ORR over historical control in the same patient population.  
This study consists of 3 Phases:  a Pretreatment Phase (Screening and Baseline Periods), a Treatment 
Phase (starting Cycle 1, Day 1), and a Posttreatment Phase (End of Treatment Visit and survival 
Follow-up). 
The Pretreatment Phase will last no longer than 21 days and will include a Screening Period to 
establish protocol eligibility and a Baseline Period to confirm eligibility and establish disease 
characteristics prior to treatment.  
The Treatment Phase will begin at the time of study drug administration on Day 1 of Cycle 1  
and continue in 28-day (4-week) cycles until completion of the off-treatment assessments (within 
30 days after the last study drug administration).  Lenvatinib 18 mg/day and everolimus 5 mg/day 
will be administered orally. Subjects will undergo safety and efficacy assessments.  Toxicity will be 
managed by treatment interruption, dose reduction and/or treatment discontinuation.  Subjects who 
discontinue one of the study drugs due to its toxicities may continue to receive the other study drug as 
long as they demonstrate clinical benefit.  Subjects will discontinue both study drugs at the time of 
confirmed disease progression, development of unacceptable toxicity, withdrawal of consent, or study 
termination by the sponsor.  
The Posttreatment Phase will start at the End of Treatment Visit and will continue as long as the 
subject is alive or until the study subject withdraws consent.  Subjects who discontinue study 
treatment before disease progression will continue to undergo tumor assessment every 8 weeks 
±1 week until documentation of disease progression or start of another anticancer therapy.  Follow-up 
assessment for survival will be performed every 12 weeks ±1 week. 
Number of Subjects 
A total of approximately 31 subjects will be enrolled. 
Inclusion Criteria 
1. Males or females age ≥ 18 years at the time of informed consent form (ICF). 
2. Histologically confirmed nccRCC who have not received any chemotherapy for advanced 
disease. Subjects must have one of the following subtypes of nccRCC: papillary, chromophobe, 
collecting duct carcinoma (CDC), renal medullary carcinoma (RMC), or unclassified.   
3. Radiologically measurable disease meeting the following criteria: 
a. At least 1 lesion of ≥ 10 mm in the longest diameter for a nonlymph node or ≥ 15 mm in the 
short axis diameter for a lymph node which is serially measurable according to Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Appendix 1) using computerized 
tomography (CT) or magnetic resonance imaging (MRI). 
b. Lesions that have had external beam radiotherapy (EBRT) or locoregional therapies such as 
radiofrequency (RF) ablation must show evidence of subsequent progressive disease 
(substantial size increase of ≥20%) to be deemed a target lesion.   
4. Eastern Cooperative Oncology Group (ECOG) (Appendix 2) performance status of 0 to 1. 


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5. Blood pressure (BP) ≤ 140/90 mmHg at Screening with or without antihypertensive medications 
and no change in antihypertensive medications within 1 week prior to Cycle 1/Day 1. 
6. Adequate renal function as evidenced by calculated creatinine clearance ≥ 30 mL/minute 
according to the Cockcroft and Gault formula (Appendix 3). 
7. Adequate bone marrow function: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L and 
b. Hemoglobin ≥ 10.0 g/dL (can be corrected by growth factor or transfusion prior to first 
dose of study drug) and 
c. Platelet count ≥ 100 × 109/L  
8. Adequate liver function: 
a. Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia or Gilbert’s syndrome 
b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver metastases).  If ALP 
is > 3 × ULN (in the absence of liver metastases) or > 5 × ULN (in the presence of liver 
metastases) AND subjects are also known to have bone metastases, the liver-specific 
ALP must be separated from the total and used to assess the liver function instead of the 
total ALP. 
9. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol. 
Exclusion Criteria 
1. Predominant clear cell renal cell carcinoma (RCC) 
2. Prior anticancer chemotherapy or targeted therapy for advanced nccRCC. 
3. Prior exposure to lenvatinib or mammalian target of rapamycin (mTOR) inhibitor. 
4. Known intolerance to lenvatinib, everolimus (or other rapamycin derivatives), or any of the 
excipients. 
5. Major surgery performed within 3 weeks prior to the first dose of study drugs or scheduled for 
major surgery during the study. 
6. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might 
affect the absorption of lenvatinib or everolimus. 
7. Subjects having > 1 + proteinuria on urine dipstick testing will undergo 24 hour urine collection 
for quantitative assessment of proteinuria.  Subjects with urine protein ≥ 1 g/24 hours will be 
ineligible. 
8. Fasting total cholesterol ˃300 mg/dL (or ˃7.75 mmol/L) 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 times the ULN.  NOTE: In case this 
threshold is exceeded, these subjects can only be included after initiation or adjustment of 
glucose-lowering medication. 
10. Known history of, or any evidence of, interstitial lung disease or active noninfectious 
pneumonitis. 
11. Significant cardiovascular impairment: History of (a) congestive heart failure greater than New 
York Heart Association (NYHA) (Appendix 4) Class II, (b) unstable angina, (c) myocardial 
infarction (d) stroke, or (e) cardiac arrhythmia associated with hemodynamic instability within 6 


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months of the first dose of study drugs. 
12. Prolongation of QTcF interval to >480 msec.  
13. Known history of human immunodeficiency virus (HIV) positive. 
14. Known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (eg, 
hepatitis C virus [HCV] RNA detected). 
15. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study 
drug. 
16. Subjects with central nervous system (CNS) (eg, brain or leptomeningeal) metastases. 
17. Other active malignancy (except definitively treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) within past 24 months. 
18. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive 
beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin [hCG] test with a 
minimum sensitivity of 25 IU/L or equivalent units of ß-hCG or hCG).  A separate baseline 
assessment is required if a negative screening pregnancy test was obtained more than 72 hours 
before the first dose of study drug. 
19. Females of childbearing potential who: 
 
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (eg, total abstinence, an 
intrauterine device, a double-barrier method [such as a condom plus diaphragm with 
spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized 
partner with confirmed azoospermia) throughout the entire study period and for 28 days 
after study drug discontinuation.  
 
Are currently abstinent, and do not agree to use a double-barrier method (as described 
above) or refrain from being sexually active during the study period or for 28 days after 
study drug discontinuation. 
 
Are using hormonal contraceptives but are not on a stable dose of the same hormonal 
contraceptive product for at least 4 weeks before dosing and who do not agree to use the 
same contraceptive during the study or for 28 days after study drug discontinuation.  
 
Are using oral hormonal contraceptives and who do not agree to add a barrier method. 
 
(NOTE:  All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically [ie, 
bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at 
least 1 month before dosing]). 
20. Males who have not had a successful vasectomy (confirmed azoospermia) or they and their 
female partners do not meet the criteria above (ie, not of childbearing potential or practicing 
highly effective contraception throughout the study period or for 28 days after study drug 
discontinuation).  No sperm donation is allowed during the study period and for 28 days after 
study drug discontinuation. 
21. Evidence of clinically significant disease (eg, cardiovascular, respiratory, gastrointestinal, renal, 
or infectious disease) that in the opinion of the investigator(s) could affect the subject’s safety or 
interfere with the study assessments. 
22. Any medical or other condition that in the opinion of the investigator(s) would preclude the 
subject’s participation in a clinical study. 
23. Active and current use of illegal recreational drugs. 


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24. Currently enrolled in another interventional clinical study or used any investigational drug or 
device within the past 28 days preceding informed consent. 
Study Treatments 
Lenvatinib will be provided as 4 mg and 10 mg capsules and everolimus will be provided as 5 mg 
tablets.  
Initial doses of lenvatinib 18 mg/day (one 10-mg capsule and two 4-mg capsules) and everolimus 
5 mg/day are to be taken orally in immediate succession once a day (QD), recommended 
approximately at the same time each morning (consistently either with or without food). 
If a subject cannot tolerate lenvatinib due to its toxicities, the lenvatinib dose may be reduced, 
interrupted or discontinued according to the guidelines provided in Table 1 and Table 2.  Lenvatinib 
dose reductions occur in succession based on the previous dose level, ie, one level at a time from 
18 mg/day to 14, 10, and 8 mg/day.  Any dose reduction below 8 mg/day must be discussed with the 
sponsor.  
If a subject cannot tolerate everolimus due to its toxicities, the everolimus dose may be reduced, 
interrupted or discontinued.  Everolimus dose may be reduced from 5 mg/day to 5 mg every other 
day. 
Dose adjustments for both study drugs will be made according to the guidelines provided in Table 2 
for management of intolerable toxicities. 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. Once 
the dose has been reduced, it cannot be increased at a later date.  
Subjects who are discontinued from one of the study drugs due to intolerance to that drug may 
continue to receive the other study drug as long as they demonstrate clinical benefit. 
Refer to appropriate protocol section for management of hypertension (Section 9.4.1.1.1), proteinuria 
(Section 9.4.1.1.2), hepatic injury (Section 9.4.1.1.3), thromboembolic events (Section 9.4.1.1.4), 
posterior reversible encephalopathy syndrome (PRES) (Section 9.4.1.1.5), hypocalcemia (Section 
9.4.1.1.6), noninfectious pneumonitis (Section 9.4.1.1.7), infections (Section 9.4.1.1.8), and blood 
glucose/lipids (Section 9.4.1.1.9) before consulting the table below, as appropriate.  
 
Table 1  Dose Reduction Recommendations for Lenvatinib in Combination With 
Everolimus 
Initial  
Lenvatinib Dose 
(mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
 
Reduction 1 
Reduction 2 
Reduction 3 
Reduction 4 
18 
14 
10 
8 
a 
QD = once daily. 
a:  Consult Sponsor for further dose reduction recommendations. 
 
 
 
Table 2  Lenvatinib-Everolimus Combination Therapy Dose Reduction and Interruption 
Instructionsa 
Lenvatinib/Everolimus 
Treatment-Related 
Toxicityb,c Including 
Hepatic Injury and 
Thromboembolic Events 
During Therapy  
Adjusted Dose  
Grade 1 Tolerable Grade 2 


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Continue treatment 
No change 
Intolerable Grade 2c 
First occurrence 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 1 above) and, if 
combination dosing, resume everolimus 
at the same dose as prior to dose 
interruption. 
Second occurrence  
(same toxicity or new 
toxicity) 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 1 above) and, if 
combination dosing, resume everolimus 
at the same dose as prior to dose 
interruption. 
Third occurrence 
(same toxicity or new 
toxicity) 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 1 above) and, if 
combination dosing, resume everolimus 
at the same dose as prior to dose 
interruption. 
Fourth occurrence 
(same toxicity or new 
toxicity) 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Discuss with sponsor 
Grade 3d,e 
First occurrence 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1f 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 1 above) and, if 
combination dosing, resume everolimus 
at the same dose as prior to dose 
interruption. 
Second occurrence 
(same toxicity or new 
toxicity)  
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 of 
Investigator to decide the probability of 
the event being related to 1 or both drugs 
as to whether dose modification of 1 or 
both drugs was required.  Dose reduction 
of lenvatinib (one dose reduction level, 
see Table 1 above) and/or reduce 
everolimus to 5 mg every other day.  
Third occurrence 
(same toxicity or new 
toxicity)  
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1f 
Investigator to decide the probability of 
the event being related to 1 or both drugs 
as to whether dose modification of 1 or 
both drugs was required.  Dose reduction 
of lenvatinib (one dose reduction level, 
see Table 1 above) and/or adjust 
everolimus as follows: 
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 
Interrupt lenvatinib and everolimus 
Discuss with sponsor 
Grade 4g:  Discontinue lenvatinib and everolimus 
Note:  For grading see Common Terminology Criteria (CTC) for Adverse Events (AE) version 4.03 (Appendix 5). 
Collect all CTC grades of AEs, decreasing and increasing grade. 
a: 
A delay of lenvatinib/everolimus treatment for more than 28 days (due to lenvatinib/ everolimus-related toxicities) 
requires a discussion with the sponsor before treatment may be resumed. 
b: 
Excluding alopecia.  Drug interruption and dose reduction may be initiated for intolerable Grade 2 and Grade 3 


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related symptoms such as anemia, lymphocytopenia, asymptomatic neutropenia if there are no other treatment 
options available and the investigator considers that dose interruption or reduction of study medication is the only 
remaining alternative.  Optimal medical management for nausea, vomiting, and/or diarrhea have to be initiated 
prior to any lenvatinib/ everolimus interruption or dose reduction. 
c: 
Applicable only to Grade 2 toxicities judged by the subject and physician to be intolerable. If Grade 2 toxicity is 
determined to be intolerable, the dose of study drug will be reduced with or without dose interruption.  Interruption 
for Grade 3 toxicities is mandatory. 
d: 
Obese subjects with weight loss requiring dose interruption and reduction do not need to return to Baseline or 
Grade 1 weight loss to restart lenvatinib.  Based on the judgment of the investigator, subjects may be restarted at 
the lower dose of lenvatinib once the weight has been stable for at least 1 week. Normal body mass index (BMI) 
should be used as the new baseline for future dose reductions. 
e: 
Not applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of the 
investigator (eg, alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma glutamyl 
transpeptidase [ γ-GTP] values < 10 × upper limit of normal [ULN], and Na). 
f: 
For hematology toxicities, restart treatment after toxicity resolves to Grade 2. 
g: 
Excluding laboratory abnormalities judged to be nonlife-threatening, in which case have to be managed as Grade 3. 
Management of Hypertension 
Lenvatinib-everolimus combination therapy 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 significantly ≥ 160/100 mmHg, significant risk factors for 
cardiac disease, intracerebral hemorrhage, or other significant comorbidities).  Once the BP is 
controlled, lenvatinib-everolimus combination therapy should be resumed as described below. 
The following guidelines should be followed for the management of systolic BP ≥ 140 mmHg up to 
< 160 mmHg or diastolic BP ≥ 90 mmHg up to < 100 mmHg confirmed on repeat measurements 
after an hour, for subjects receiving lenvatinib-everolimus combination therapy: 
 
Continue lenvatinib-everolimus combination therapy and institute antihypertensive therapy 
for subjects not already receiving this. 
 
For subjects already on antihypertensive medication, the dose of the current agent may be 
increased, if appropriate, or one or more agents of a different class of antihypertensive should 
be added. 
The following guidelines should be followed for the management of systolic BP ≥ 160 mmHg or 
diastolic BP ≥ 100 mmHg confirmed on repeat measurements after an hour, for subjects receiving 
lenvatinib-everolimus combination therapy: 
 
If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib-everolimus combination therapy administration 
should be interrupted and restarted when BP ≤ 150/95 mmHg at a dose of:  one level of dose 
reduction (ie, 14-mg once daily) per Table 2 of lenvatinib.  Resume everolimus at the same 
dose as prior to dose interruption.   
○ If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the first reduced dose 
(ie, 14-mg once daily) despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different class 
of antihypertensive), then lenvatinib-everolimus combination therapy administration 
should be interrupted and restarted when BP ≤ 150/95 mmHg at a dose of:  one level of 
dose reduction (ie, 10-mg once daily) per Table 1 and Table 2 of lenvatinib.  Resume 
everolimus at the same dose as prior to dose interruption. 
○ If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the next reduced dose 
(ie, 10-mg once daily) despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different class 
of antihypertensive), then lenvatinib-everolimus combination therapy administration 


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should be interrupted and restarted when BP ≤ 150/95 mmHg at a dose of:  one level of 
dose reduction (ie, 8-mg once daily) per Table 1 and Table 2 of lenvatinib.  Resume 
everolimus at the same dose as prior to dose interruption.  
○ Additional dose reduction should be discussed with the sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences): 
 
Institute appropriate medical management. 
 
Discontinue lenvatinib-everolimus combination therapy. 
Management of Proteinuria 
Regular assessment of proteinuria should be conducted as detailed in the Schedule of Visits and 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria are summarized 
as follows for subjects receiving lenvatinib-everolimus combination therapy: 
 Initial episode of proteinuria: if proteinuria ≥ 2+ is detected on urine dipstick testing, lenvatinib-
everolimus combination therapy will be continued and a 24-hour urine collection for total protein 
will be obtained as soon as possible within 72 hours to verify the grade of proteinuria.  Grading 
according to the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE v4.03) will be based on the 24-hour urinary protein result.  Management of 
lenvatinib-everolimus combination therapy will be based on the grade of proteinuria according to 
the Dose Reduction and Interruption Instructions (Table 2).  Where lenvatinib-everolimus 
combination therapy is interrupted and restarted, everolimus should resume at the same dose as 
prior to dose interruption and not as instructed in Table 2. 
 Urine dipstick testing for subjects with proteinuria ≥ 2+ should be performed every 2 weeks (or 
more frequently as clinically indicated) until the results have been 1+, trace, or negative for 
3 consecutive months.  Any subsequent increases in the level of proteinuria ≥2+ on urine dipstick 
testing must be confirmed with a 24-hour urinary protein test, which will be assessed and graded, 
and continued management of lenvatinib-everolimus combination therapy administration will be 
based on the Dose Reduction and Interruption Instructions (Table 2).  Where lenvatinib-
everolimus combination therapy is interrupted and restarted, everolimus should resume at the 
same dose as prior to dose interruption and not as instructed in Table 2.  If a new event of 
proteinuria ≥ 2+ occurs, the subject must resume urine dipstick testing for evaluation of 
proteinuria every 2 weeks until results are 1+, trace, or negative for 3 consecutive months. 
Management of Hepatotoxicity 
Regular monitoring of liver function tests (ALT, AST, bilirubin levels) should be conducted as 
clinically indicated.  If signs/symptoms indicating liver injury occur, instructions contained in the 
Dose Reduction and Interruption Instructions (Table 2) should be followed.  Appropriate supportive 
care should be provided along with close monitoring.  If hepatic failure occurs the lenvatinib-
everolimus combination therapy must be discontinued. 
Management of Thromboembolic Events  
Subjects should be advised to pay attention to symptoms suggestive of venous thromboembolic 
events, which include acute onset of shortness of breath, dyspnea, chest pain, cough, hemoptysis, 
tachypnea, tachycardia, cyanosis, signs of deep vein thrombosis (DVT) 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 Dose Reduction and Interruption Instructions (Table 2) should 
be followed.  Appropriate supportive care should be provided together with close monitoring.  If a 
subject experiences life-threatening (Grade 4) thromboembolic reactions, lenvatinib-everolimus 
combination therapy must be discontinued.  


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Management of Posterior Reversible Encephalopathy Syndrome  
In clinical studies with lenvatinib, events of PRES were reported in less than 1% of lenvatinib-treated 
subjects.  PRES is a neurological disorder, which can present with headache, seizure, lethargy, 
confusion, altered mental function, blindness, and other visual or neurological disturbances.  Mild to 
severe hypertension may be present.  An MRI is necessary to confirm the diagnosis of PRES.  
Appropriate measures should be taken to control BP. If subject develops PRES, contact study 
sponsor. 
Management of Hypocalcemia 
Serum calcium should be monitored at least monthly and replace calcium as necessary during 
lenvatinib treatment.  Interrupt and adjust lenvatinib dosing as necessary depending on severity, 
presence of electrocardiogram (ECG) changes, and persistence of hypocalcemia.   
Management of Noninfectious Pneumonitis 
Noninfectious pneumonitis is a recognized class effect of rapamycin derivatives, including 
everolimus. Noninfectious pneumonitis (including interstitial lung disease) was described in 12% of 
subjects taking everolimus. Some cases were severe and on rare occasions, a fatal outcome was 
observed. Investigators should therefore consider a diagnosis of noninfectious pneumonitis in 
subjects presenting with nonspecific respiratory signs and symptoms and in whom infectious, 
neoplastic and other nonmedicinal causes have been excluded by means of appropriate investigations. 
Guidelines for assessment and management of noninfectious pneumonitis are summarized as follows 
for subjects receiving lenvatinib-everolimus combination therapy: 
 
Subjects who develop radiological changes suggestive of noninfectious pneumonitis and have 
few or no symptoms (CTCAE grade 1) may continue lenvatinib-everolimus combination 
therapy without dose adjustments. 
 
If symptoms are CTCAE grade 2:  
o Starting dose of lenvatinib combination therapy with 5 mg daily everolimus:  
combination therapy should be interrupted and the use of corticosteroids may be 
indicated until symptoms abate (resolved to CTCAE Grade 0-1 or baseline) and may 
be restarted with 5 mg everolimus daily in combination with lenvatinib (ie, lenvatinib 
reinitiated at the same dose as prior to dose interruption) administered daily.  
Discontinue everolimus if failure to recover within 4 weeks of reinitiating treatment, 
and continue lenvatinib as a single agent therapy depending on individual clinical 
circumstance. 
o If Grade 2 noninfectious 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 or baseline).  Lenvatinib may be reinitiated as a single agent 
therapy depending on individual clinical circumstances. 
 
If symptoms are CTCAE Grade 3:  
o Starting dose of lenvatinib combination therapy with 5 mg daily everolimus:  
combination therapy should be interrupted and the use of corticosteroids may be 
indicated until clinical symptoms resolve. Lenvatinib may be reinitiated as single 
agent therapy depending on the individual clinical circumstances. 
 
If symptoms are CTCAE grade 4: 
o Study medications should be discontinued. 
Management of Infections 
Everolimus has immunosuppressive properties and may predispose subjects to infections. Therefore, 
monitor for signs and symptoms of infection and treat promptly. Dose alterations of everolimus 
(either as single agent or in lenvatinib-everolimus combination therapy) may be required in 


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accordance with prescribing information.  
Management of Blood Glucose and Lipids 
Hyperglycemia, hyperlipidemia and hypertriglyceridemia are recognized class effects of 
rapamycin derivatives, including everolimus. Glycemic control should be optimized before 
starting a subject on this study. 
Blood glucose will be monitored as specified in the Schedule of Visits and Procedures/Assessments. 
For subjects with blood glucose > ULN, a fasting (> 6 hours, water only) blood glucose sample will 
be obtained.  Grading according to CTCAE will be based on the fasting blood glucose result. Insulin 
and/or oral hypoglycemic agents may have to be introduced (or the dose increased) to control blood 
glucose levels. The choice of hypoglycemic agent should be individualized to the subjects’ clinical 
circumstances and follow standard medical practice in addition to consideration of avoiding 
coadministration of everolimus with inhibitors and inducers of cytochrome P450 (CYP) 3A4 and/or 
the multidrug efflux pump P-glycoprotein (PgP). 
Dose alterations of everolimus (either as single agent or in lenvatinib-everolimus combination 
therapy) may be required in accordance with prescribing information. Where lenvatinib-everolimus 
combination therapy is interrupted, lenvatinib should resume at the same dose as prior to dose 
interruption. 
Duration of Treatment 
Subjects will continue to receive study treatment until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or sponsor discontinuation. The duration of treatment 
for each subject is estimated to be approximately 6 months. 
Concomitant Drug/Therapy 
All prior medications (including over-the-counter medications) administered 30 days before the first 
dose of study drug and any concomitant therapy administered to the subject during the course of the 
study (starting at the date of ICF) until 28 days after the final dose of study 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 drugs may be continued during 
the study. 
Treatment of complications or adverse events (AEs), or therapy to ameliorate symptoms (including 
blood products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation of (or 
to interact with) the study drugs. 
Aspirin, nonsteroidal anti-inflammatory drugs, and low-molecular-weight heparin are permissible but 
should be used with caution.  Granulocyte colony-stimulating factor or equivalent may be used in 
accordance with American Society of Clinical Oncology (ASCO), institutional, or national 
guidelines.  Erythropoietin may be used according to ASCO, institutional, or national guidelines, but 
the subject should be carefully monitored for increases in red blood cell (RBC) counts. 
If concomitant medication/therapy is administered for an AE, investigators will record that AE on the 
Adverse Events Case Report Form (CRF).  
Subjects should not receive other antitumor therapies while on study.  If subjects receive additional 
antitumor therapies during the study, such as radiotherapy, other chemotherapy, or immunotherapy, 
this will be judged to represent evidence of disease progression, and continuation of study medication 
should be discussed with the sponsor.  Following this discussion, if the joint decision is made to 
discontinue study treatment, then such subjects will complete all End of Treatment assessments and 
continue to be followed for survival in the Follow-Up Period. 


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Assessments 
Efficacy Assessments 
The primary endpoint (ORR), secondary endpoint (PFS), and exploratory endpoints (CBR, DCR, and 
DOR) will be evaluated by the investigator.  In addition, ORR, PFS, CBR, DCR, and DOR will be 
assessed by IIR.  The OS status will be assessed throughout the study. 
Tumor assessments will be performed using RECIST v1.1.  Investigator-determined response 
assessments are to be performed at the site by appropriately qualified personnel at each time point 
and recorded on the appropriate CRFs.  All tumor assessment scans will be sent to an imaging core 
laboratory specified by the sponsor for quality assessment and independent imaging review.  Tumor 
assessments will be carried out following the guidelines provided by the imaging core laboratory.  
Historical scans performed within the Screening period that do not follow the guidelines completely 
may be used to demonstrate eligibility, as long as they meet minimum standards as separately defined 
by the imaging core laboratory.   
Tumor assessments including a CT chest and CT or MRI of the abdomen and pelvis, and other areas 
of known or newly suspected disease should be performed prior to Baseline (between Day –28 to 
Day -2) and every 8 weeks (within the 8th week) from the date of first dose during the Treatment 
Phase.  A brain scan will be performed at Screening, and thereafter if clinically indicated.  A bone 
scan will be performed during the pretreatment phase to establish a baseline (a historical bone scan 
performed within 6 weeks before first dose is acceptable), every 24 weeks, and as clinically indicated. 
Lesions identified on bone scans should be followed with cross-sectional imaging. 
In subjects with complete response (CR) based on body CT/MRI scans, bone scan and brain scan, 
assessment will be required at response confirmation.  All objective responses must be confirmed at 
least 28 days following the initial achievement of response.  Subjects going off study treatments 
without disease progression in the Treatment Phase will continue to undergo tumor assessments 
according to the above schedule until disease progression is documented or another anticancer 
therapy is initiated.  
Pharmacokinetic Assessments 
Sparse PK samples will be collected from all subjects and will be analyzed using the population 
approach.  A total of 12 samples (6 plasma samples for lenvatinib and 6 whole blood samples for 
everolimus) per subject will be obtained at the following time points: 2 to 8 hours postdose on 
Cycle 1 Day 1 (C1D1), prior to dose on Cycle 1 Day 15 (C1D15), prior to dose and 2 to 8 hours 
postdose on Day 1 of Cycles 2 and 3.   
Pharmacodynamic, Pharmacogenomics, and Other Biomarker Assessments  
Blood and Tissue Biomarkers: 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.  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. 
A blood sample for pharmacodynamic and exploratory biomarker analysis will be collected predose 
on Day -1 or C1D1, on C1D15, and on Day 1 of subsequent cycles (during Treatment Phase), and at 
the End of Treatment assessment.  Blood samples from all consented subjects may undergo analyses 
including, but not limited to, global proteomic and/or enzyme-linked immunosorbent assay (ELISA)-
based analyses or multiplex bead-based immunoassay in an effort to assess pharmacodynamic 
biomarkers.  
Pharmacogenomic (PG) Assessments:  Archived, fixed tumor tissue will be collected (if available) 


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from all subjects for potential assessment of mutations and other genetic alterations or genes and/or 
proteins that may be important in the development and progression of cancer as well as in response to 
study drug treatment for potential use in diagnostic development.  Appropriate 
technology/methodologies will be used based on the amount of tumor tissue available. 
A blood sample for peripheral blood mononuclear cells (PBMC) and plasma isolation will be 
collected from consented subjects for potential analysis of cell free nucleic acid (cf-nucleic acid) 
analysis and exploratory immune cell analysis.  Cell free nucleic acid isolated from plasma samples 
may be used to obtain circulating tumor DNA (ctDNA) and explore tumor genetic alterations such as 
mutations observed in archival tumor samples as well as those which develop during drug treatment.  
PBMCs may be used for immune cell profiling (eg. tumor infiltrating lymphocytes, T-cell repertoire, 
and immune cell types). 
A blood sample will be collected for pharmacogenomics (PG) analysis (except where prohibited by 
regional or local laws). Variation in lenvatinib exposure or the occurrence of AEs observed in the 
study population may be evaluated by correlating single–nucleotide polymorphisms with PK, safety, 
or pharmacodynamic data.  Genomic deoxyribonucleic acid (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 for potential profiling of immune cells. 
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 lenvatinib, 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 
General safety will be assessed by the monitoring and recording of all AEs and serious adverse events 
(SAEs), regular monitoring of hematology and blood chemistry, regular measurement of vital signs, 
ECG, and the performance of physical examinations (PE) and other safety assessments in line with 
local regulations governing a study of this nature.  
Progression of nccRCC and signs and symptoms clearly related to the disease progression should not 
be captured as an AE.  Disease progression is a study endpoint and should be captured in the CRF as 
per the guidelines for reporting disease progression. 
In case of life-threatening bleeding, the investigator should discuss the case with the Eisai Medical 
Monitor, in addition to discontinuing lenvatinib per Synopsis Table 1 for Grade 4 toxicity and treat 
the subject based on the institution’s standard practice.  Clinically significant bleeding will be 
considered as study-specific events and should always be considered as serious important medical 
events, which will be entered on the adverse event CRF and reported using the procedures for 
reporting SAEs, even if the study-specific event does not meet other serious criteria. 
Bioanalytical Methods 
Lenvatinib in plasma and everolimus in blood will be quantified using validated high pressure liquid 
chromatography (HPLC)-tandem mass spectroscopy methods. 
Statistical Methods 
Study Endpoints 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is ORR based on investigator assessment, defined as the 


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proportion of subjects who have a best overall response (BOR) of CR or PR.  
Secondary Efficacy Endpoints   
 
Progression-free survival (PFS) based on investigator assessment – defined as the time from 
date of first dose of study drug to date of first documentation of disease progression or death, 
whichever occurs first. 
 
Overall survival (OS) – defined as the time from the date of first dose of study drug until date 
of death from any cause. 
Exploratory Endpoints 
 
ORR based on IIR assessment 
 
PFS based on IIR assessment 
 
Clinical benefit rate (CBR) is the proportion of subjects who have a BOR of CR or PR or 
durable stable disease (SD).  Stable disease must be achieved at ≥ 23 weeks after first 
lenvatinib administration to be considered durable SD.  The CBR will be determined based 
on both investigator and IIR assessment. 
 
Disease control rate (DCR) is the proportion of subjects who have a BOR of CR, PR or SD.  
The DCR will be determined based on both investigator and IIR assessment. 
 
Duration of response (DOR) is defined as the time from the date that the criteria are met for 
CR or PR (whichever is recorded first) to the date that progressive disease (PD) is objectively 
documented or death, whichever occurs first.  The DOR will be determined based on both 
investigator and IIR assessment. 
Analysis Sets 
The Full Analysis Set (FAS) includes subjects who received at least 1 dose of the study drugs. This 
will be the analysis set for all efficacy and safety evaluations. 
The Evaluable Analysis Set (EAS, a subset of the FAS) includes all subjects who have both an 
evaluable baseline tumor assessment and an evaluable postbaseline tumor assessment, unless the 
subjects are discontinued because of disease progression or toxicity. This will be used for the 
sensitivity analyses of efficacy. 
The Pharmacokinetic Analysis Set will include all subjects who received at least one dose of study 
drug and have evaluable lenvatinib plasma and/or everolimus whole blood concentration data. 
The Pharmacodynamic Analysis Set will include all subjects who received at least one dose of study 
drug and have evaluable pharmacodynamics data. 
Efficacy Analyses 
Primary efficacy analyses 
Primary endpoint ORR assessed by investigator review will be analyzed using the FAS.  Subjects 
who did not have a tumor assessment for any reason will be considered as nonresponders and 
included in the denominator when calculating response rate. 
In this population, ORR in the historical control is assumed to be 8% (Hudes, et al., 2007).  The ORR 
in this study is estimated as 25%, which is deemed a clinical meaningful improvement.  Hence, the 
null and alternative hypotheses are set as follows: 
                                                     H0: ORR=8% 
                                                     Ha: ORR ≥25% 
Simon’s Two-Stage Design (Simon, 1989) is used in hypothesis testing for the primary endpoints.  
The interim futility analysis after Stage 1 allows for an early evaluation of efficacy results in order to 
stop the study early in the case of low anticancer activity.  A minimum of 2 responders as assessed by 


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ORR in the Stage 1 subjects (n1=16) is required in the interim analysis for the study to proceed to 
Stage 2 in which 15 more subjects may be enrolled.  In the final analysis of ORR, a minimum of 6 
responders is required in Stages 1 and 2 subjects combined (n=31) to claim the superiority of study 
treatment over historical controls. 
Simon’s Two-Stage Design for Interim Futility and Final Analyses of ORR 
 
Threshold 
Interim Analysis 
Continue if ≥2 responders when n1=16 
Final Analysis 
Reject H0 if ≥6 responders when n=31 
Secondary efficacy analyses 
PFS assessed by the investigator and OS will be analyzed using Kaplan–Meier product-limit 
estimates.  Median PFS and OS and the cumulative probability of PFS at 3, 6, and 12 months and 
cumulative probability of OS at 6, 12, and 18 months will be presented with two-sided 95% 
confidence interval (CI) if estimable.  PFS censoring rules will follow Food and Drug Administration 
(FDA) Guidance for Industry, Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics (2018).   
The cumulative PFS and OS will be plotted over time.  The median, first, and third quartiles from 
Kaplan–Meier estimation for PFS and OS will be provided with 95% CI if estimable. 
Exploratory efficacy analyses 
The ORR based on IIR assessment will be evaluated using the same method described in the primary 
analysis. 
A 2-sided Clopper–Pearson 95% CI will be constructed for CBR and DCR.  The DOR and PFS based 
on IIR assessment will be analyzed using time to event methods described above. 
Formal analyses of ORR, PFS and OS 
A formal analysis will be carried out after all subjects have been enrolled and on study treatment for 
at least 6 months or have discontinued due to disease progression, death or toxicity.  Since the 
primary endpoint ORR data are expected to be observed sooner than the secondary endpoints, the 
timing of the formal analysis is chosen such that the secondary endpoints, PFS and OS, will be 
adequately described.  The primary population for efficacy and safety analyses is the FAS. 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Pharmacokinetic Analyses 
A population PK approach will be used to characterize the PK of lenvatinib and everolimus and 
the final PK model will be used to derive lenvatinib and everolimus exposure parameters to be 
used in the subsequent pharmacokinetic (PK)/pharmacodynamic analyses. The analyses will be 
detailed in a separate analysis plan.  Concentrations of each analyte will be graphed by time 
within each nominal collection interval.  Average dose at each collection interval will also be 
displayed. 
Pharmacokinetic/Pharmacodynamic Analyses 
Lenvatinib and everolimus exposure parameters derived from the population PK analysis will be 
related to biomarker, safety, and efficacy data using a model-based approach.  For some PK/ 
pharmacodynamic analyses, data from this study may be pooled with data from other clinical 
studies of study drug. 
For efficacy, a tumor growth inhibition model based on longitudinal tumor size measurements of 


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target lesions will be included.  We plan to explore exposure to both lenvatinib and everolimus 
exposure and/or selected biomarkers, identified in other studies of study drug, as predictors 
and/or correlations with tumor burden changes in the tumor growth inhibition model. Other 
analyses will include logistic regression analysis for ORR24W.   
For the exposure-response relationship of safety, data will be analyzed using a longitudinal 
categorical logistic regression analysis for AEs leading to dosing reduction or interruption.  
For the exposure-response relationship for selected biomarkers, identified in other clinical 
studies of study drug, data may be analyzed using a model-based approach.  
Population PK and PK/pharmacodynamic analyses will be detailed in a separate analysis plan. 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Soluble, tissue, genetic and/or imaging biomarkers (Baseline and/or posttreatment) may be 
summarized using descriptive statistics and correlated with clinical outcomes-related endpoints for 
safety and/or efficacy as appropriate.  Details will be included in a separate analysis plan. 
Safety Analyses 
Safety, using the FAS, will be assessed by monitoring and recording of all AEs including all 
CTCAE grades, regular monitoring of hematology and clinical chemistry, urinalysis, regular 
measurement of vital signs, 12-lead ECGs, and performance of PEs.  
Adverse events and other clinical safety data will be summarized descriptively in the FAS.  The 
incidence of treatment-emergent adverse events (TEAEs), SAEs, drug-related AEs and AEs leading 
to discontinuation will be summarized in tabulation.  Hematology, serum chemistry, vital sign 
variables and ECG will be summarized descriptively for observed values, by grade and by change 
from Baseline by cycle.  All AEs and lab parameters will be listed. 
Interim Analyses 
An interim analysis may be performed by the sponsor after 16 subjects in Stage 1 have completed at 
least 2 tumor assessments (eg, Week 16 tumor assessments), unless discontinued due to disease 
progression, death or toxicity.  If one or no responders are observed in the interim analysis, the study 
will be stopped early for futility and subjects on study at that time will continue treatment under the 
discretion of the investigator.  If 2 or more responders are confirmed before the planned interim 
analysis and the safety profiles of both drugs are acceptable, the study will continue to Stage 2 and a 
formal interim analysis may be waived.  There will be no enrollment gap for the interim analysis 
Sample Size Rationale 
Approximately 31 subjects, including 16 in the first stage, will be enrolled in the study.  The actual 
one-sided type I error is 0.0319 and the power is 0.8053 in the proposed Simon’s Two-Stage design.  
At interim analysis, the probabilities of early futility stopping are 0.6299 under H0: ORR=8% and 
0.0635 under Ha: ORR≥25%, respectively. 
 
 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .................................................................................................................. 2 
2 
CLINICAL PROTOCOL SYNOPSIS .......................................................................... 3 
3 
Table Of Contents ......................................................................................................... 18 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ........................... 23 
5 
ETHICS ......................................................................................................................... 27 
5.1 
Institutional Review Boards/Independent Ethics Committees ........................... 27 
5.2 
Ethical Conduct of the Study ................................................................................. 27 
5.3 
Subject Information and Informed Consent ........................................................ 28 
6 
INVESTIGATORS AND STUDY PERSONNEL ..................................................... 29 
7 
INTRODUCTION......................................................................................................... 29 
7.1 
Indication ................................................................................................................. 29 
7.1.1 Current Therapeutic Options ................................................................................ 29 
7.1.2 Lenvatinib ............................................................................................................ 30 
7.1.2.1 Mechanism of Action .................................................................................... 30 
7.1.3 Everolimus ........................................................................................................... 30 
7.1.3.1 Mechanism of Action .................................................................................... 30 
7.1.4 Preclinical and Clinical Experience with the Combination of Lenvatinib and 
Everolimus ...................................................................................................................... 31 
7.1.4.1 Preclinical Experience with the Combination of Lenvatinib and Everolimus
 
31 
7.1.4.2 Clinical Experience with Combination Lenvatinib Plus Everolimus 
Treatment in Renal Cell Carcinoma ........................................................................... 32 
7.2 
Study Rationale ....................................................................................................... 33 
8 
STUDY OBJECTIVES ................................................................................................. 33 
8.1 
Primary Objective .................................................................................................. 33 
8.2 
Secondary Objectives ............................................................................................. 33 
8.3 
Exploratory Objectives .......................................................................................... 34 
9 
INVESTIGATIONAL PLAN ...................................................................................... 34 
9.1 
Overall Study Design and Plan .............................................................................. 34 
9.1.1 Pretreatment Phase ............................................................................................... 35 
9.1.1.1 Screening Period ........................................................................................... 35 
9.1.1.2 Baseline Period ............................................................................................. 35 
9.1.2 Treatment Phase ................................................................................................... 35 
9.1.3 Posttreatment Phase ............................................................................................. 36 
9.2 
Discussion of Study Design, Including Choice of Control Groups ..................... 36 
9.3 
Selection of Study Population ................................................................................ 36 
9.3.1 Inclusion Criteria.................................................................................................. 36 
9.3.2 Exclusion Criteria ................................................................................................ 38 
9.3.3 Removal of Subjects From Therapy or Assessment ............................................ 39 
9.4 
Treatments ............................................................................................................... 40 


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9.4.1 Treatments Administered ..................................................................................... 40 
9.4.1.1 Criteria for Interruption of Treatment, Dose Reduction, and Resumption of 
Treatment .................................................................................................................... 41 
9.4.1.1.1 Management of Hypertension ................................................................. 43 
9.4.1.1.2 Management of Proteinuria ..................................................................... 44 
9.4.1.1.3 Management of Hepatotoxicity............................................................... 45 
9.4.1.1.4 Management of Thromboembolic Events ............................................... 45 
9.4.1.1.5 Management of Posterior Reversible Encephalopathy Syndrome .......... 45 
9.4.1.1.6 Management of Hypocalcemia ............................................................... 46 
9.4.1.1.7 Management of Noninfectious Pneumonitis ........................................... 46 
9.4.1.1.8 Management of Infections ...................................................................... 47 
9.4.1.1.9 Management of Blood Glucose and Lipids ............................................ 47 
9.4.2 Identity of Investigational Products ..................................................................... 47 
9.4.2.1 Chemical Name, Structural Formula of Lenvatinib ...................................... 47 
9.4.2.2 Chemical Name, Structural Formula of Everolimus..................................... 48 
9.4.2.3 Comparator Drug .......................................................................................... 48 
9.4.2.4 Labeling for Study Drug ............................................................................... 48 
9.4.2.5 Storage Conditions ........................................................................................ 48 
9.4.3 Method of Assigning Subjects to Treatment Groups ........................................... 49 
9.4.4 Selection of Doses in the Study ........................................................................... 49 
9.4.5 Selection and Timing of Dose for Each Subject .................................................. 49 
9.4.6 Blinding ................................................................................................................ 49 
9.4.7 Prior and Concomitant Therapy ........................................................................... 50 
9.4.7.1 Drug-Drug Interactions ................................................................................. 50 
9.4.7.2 Prohibited Concomitant Therapies and Drugs .............................................. 51 
9.4.8 Treatment Compliance ......................................................................................... 51 
9.4.9 Drug Supplies and Accountability ....................................................................... 51 
9.5 
Study Assessments .................................................................................................. 53 
9.5.1 Assessments ......................................................................................................... 53 
9.5.1.1 Demography .................................................................................................. 53 
9.5.1.1.1 Medical History and Physical Examinations .......................................... 53 
9.5.1.2 Efficacy Assessments.................................................................................... 54 
9.5.1.2.1 Tumor Assessments ................................................................................ 54 
9.5.1.3 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments .............................................................................................. 54 
9.5.1.3.1 Pharmacokinetic Assessments ................................................................ 54 
9.5.1.3.2 Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ............................................................................................................ 55 
9.5.1.4 Safety Assessments ....................................................................................... 56 
9.5.1.4.1 Adverse Events and Events Associated with Special Situations ............ 56 
9.5.1.4.2 Serious Adverse Events and Events Associated with Special Situations 58 
9.5.1.4.3 Laboratory Measurements ...................................................................... 59 
9.5.1.4.4 Vital Signs and Weight Measurements ................................................... 60 
9.5.1.4.5 Physical Examinations ............................................................................ 61 
9.5.1.4.6 Electrocardiograms ................................................................................. 61 


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9.5.1.4.7 Other Safety Assessments ....................................................................... 61 
9.5.2 Schedule of Procedures/Assessments .................................................................. 62 
9.5.2.1 Schedule of Procedures/Assessments ........................................................... 62 
9.5.2.2 Description of Procedures/Assessments Schedule ........................................ 68 
9.5.3 Appropriateness of Measurements ....................................................................... 68 
9.5.4 Reporting of Serious Adverse Events, Pregnancy, and Events Associated with 
Special Situations ............................................................................................................ 68 
9.5.4.1 Reporting of Serious Adverse Events ........................................................... 68 
9.5.4.2 Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
 
69 
9.5.4.3 Reporting of Events Associated with Special Situations .............................. 69 
9.5.4.3.1 Reporting of Adverse Events Associated With Study Drug Overdose, 
Misuse, Abuse, or Medication Error ....................................................................... 69 
9.5.4.3.2 Reporting of Study-Specific Events........................................................ 70 
9.5.4.4 Expedited Reporting ..................................................................................... 70 
9.5.4.5 Breaking the Blind ........................................................................................ 70 
9.5.4.6 Regulatory Reporting of Adverse Events ..................................................... 70 
9.5.5 Completion/Discontinuation of Subjects ............................................................. 70 
9.5.6 Abuse or Diversion of Study Drug ...................................................................... 71 
9.5.7 Confirmation of Medical Care by Another Physician ......................................... 71 
9.6 
Data Quality Assurance ......................................................................................... 71 
9.6.1 Data Collection .................................................................................................... 71 
9.6.2 Clinical Data Management................................................................................... 72 
9.7 
Statistical Methods .................................................................................................. 72 
9.7.1 Statistical and Analytical Plans ............................................................................ 72 
9.7.1.1 Study Endpoints ............................................................................................ 72 
9.7.1.1.1 Primary Endpoint .................................................................................... 72 
9.7.1.1.2 Secondary Endpoints .............................................................................. 72 
9.7.1.1.3 Exploratory Endpoints ............................................................................ 72 
9.7.1.2 Definitions of Analysis Sets.......................................................................... 73 
9.7.1.3 Subject Disposition ....................................................................................... 73 
9.7.1.4 Demographic and Other Baseline Characteristics ........................................ 73 
9.7.1.5 Prior and Concomitant Therapy .................................................................... 73 
9.7.1.6 Efficacy Analyses ......................................................................................... 74 
9.7.1.6.1 Primary Efficacy Analysis ...................................................................... 74 
9.7.1.6.2 Secondary Efficacy Analyses ................................................................. 75 
9.7.1.6.3 Exploratory Efficacy Analyses ............................................................... 75 
9.7.1.6.4 Formal Analyses of ORR, PFS, and OS ................................................. 75 
9.7.1.6.5 Sensitivity Analyses ................................................................................ 75 
9.7.1.7 Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses .................................................................................................... 75 
9.7.1.7.1 Pharmacokinetic Analyses ...................................................................... 75 
9.7.1.7.2 Pharmacokinetic/Pharmacodynamic Analyses ....................................... 75 
9.7.1.7.3 Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 76 
9.7.1.8 Safety Analyses ............................................................................................. 76 


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9.7.1.8.1 Extent of Exposure .................................................................................. 76 
9.7.1.8.2 Adverse Events ....................................................................................... 76 
9.7.1.8.3 Laboratory Values ................................................................................... 77 
9.7.1.8.4 Vital Signs ............................................................................................... 77 
9.7.1.8.5 Electrocardiograms ................................................................................. 78 
9.7.1.8.6 Other Safety Analyses............................................................................. 78 
9.7.1.9 Other Analyses .............................................................................................. 78 
9.7.2 Determination of Sample Size ............................................................................. 78 
9.7.3 Interim Analysis ................................................................................................... 78 
9.7.4 Other Statistical/Analytical Issues ....................................................................... 78 
9.7.5 Procedure for Revising the Statistical Analysis Plan ........................................... 79 
10 REFERENCE LIST ...................................................................................................... 80 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) 83 
11.1 Changes to the Protocol .......................................................................................... 83 
11.2 Adherence to the Protocol ...................................................................................... 83 
11.3 Monitoring Procedures .......................................................................................... 83 
11.4 Recording of Data ................................................................................................... 84 
11.5 Identification of Source Data ................................................................................. 84 
11.6 Retention of Records .............................................................................................. 84 
11.7 Auditing Procedures and Inspection ..................................................................... 85 
11.8 Handling of Study Drug ......................................................................................... 85 
11.9 Publication of Results ............................................................................................. 85 
11.10 Disclosure and Confidentiality .............................................................................. 86 
11.11 Discontinuation of Study ........................................................................................ 86 
11.12 Subject Insurance and Indemnity ......................................................................... 86 
12 APPENDICES ............................................................................................................... 87 
 
LIST OF IN-TEXT TABLES 
Table 1 
Treatment Administered ............................................................................41 
Table 2 
Dose Reduction Recommendations for Lenvatinib in Combination 
With Everolimus ........................................................................................41 
Table 3 
Lenvatinib-Everolimus Combination Therapy Dose Reduction and 
Interruption Instructionsa ...........................................................................42 
Table 4 
Clinical Laboratory Tests ...........................................................................60 
Table 5 
Schedule of Procedures/Assessments for Study E7080-M001-221...........63 
Table 6 
Simon’s Two-Stage Design for Interim Futility and Final Analyses of 
ORR ...........................................................................................................74 
 


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LIST OF IN-TEXT FIGURES 
Figure 1 
Progression-Free Survival of Lenvatinib + Everolimus Versus Single 
Agent ..........................................................................................................32 
 
LIST OF APPENDICES 
Appendix 1 
Overview of RECIST v1.1 for Evaluation of Tumors Response...............88 
Appendix 2 
Eastern Cooperative Oncology Group Performance Status .......................94 
Appendix 3 
Estimated Glomerular Filtration Rate (eGFR) Using Cockcroft and 
Gault Formula ............................................................................................95 
Appendix 4 
New York Heart Association Cardiac Disease Classification ...................96 
Appendix 5 
Common Terminology Criteria for Adverse Events (v4.03) .....................97 
Appendix 6 
 Stage Information for Renal Cell Cancer ..................................................98 
Appendix 7 
Sponsor’s Grading for Laboratory Values ...............................................100 
 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event  
ADL 
activities of daily living 
ATC  
Anatomical Therapeutic Chemical  
AKT 
protein kinase B 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic chemical 
ß-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BCRP 
breast cancer resistance protein 
BOR 
best overall response 
BP 
blood pressure 
CA 
Competent Authority 
CBR 
clinical benefit rate 
C1D1 
Cycle 1 Day 1 
C1D15 
Cycle 1 Day 15 
ccRCC 
clear cell renal cell carcinoma 
CDC 
collecting duct carcinoma 
CI 
confidence interval 
CNS 
central nervous system 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 


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Abbreviation 
Term 
CV 
curriculum vitae 
CYP 
cytochrome P450 
DCR 
disease control rate 
DNA 
deoxyribonucleic acid 
DOR 
duration of response 
DVT 
deep vein thrombosis 
EAS 
Evaluable Analysis Set 
EBRT 
external beam radiotherapy 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ESMO 
European Society for Medical Oncology 
EAS 
Evaluable Analysis Set 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
fluorodeoxyglucose positron emission tomography 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
FKBP-12 
FK506 binding protein-12 
GCP 
Good Clinical Practice 
ß-hCG 
beta-human chorionic gonadotropin 
HBsAg 
hepatitis B surface antigen  
HCV 
hepatitis C virus 
HDL-C 
high density lipoprotein-C 
HER2 
human epidermal growth factor receptor 
HIV 
human immunodeficiency virus 
HPLC 
high pressure liquid chromatography 
HR 
heart rate 
HUVEC 
human umbilical vein endothelial cell 
ICF 
informed consent form 


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Abbreviation 
Term 
ICH 
International Council on Harmonisation 
IEC 
Independent Ethics Committee 
IIR 
independent imaging review 
IND 
investigational new drug 
IRB 
Institutional Review Board 
KIT 
C-kit receptor CD 117 
LD 
longest diameter 
LDL-C 
low-density lipoprotein cholesterol 
LLT 
lower level terms 
LMWH 
Low-molecular-weight heparin 
MDP 
methylene diphosphonate 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
mTOR 
Mammalian target of rapamycin 
nccRCC 
non clear cell renal cell carcinoma 
NCI 
National Cancer Institute 
NCCN 
National Comprehensive Cancer Network 
NSAID 
nonsteroidal anti-inflammatory 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD 
progressive disease 
PDGFR 
platelet-derived growth factor receptor 
PE 
physical examination 
PET 
proton-emission tomography 
PFS 
progression-free survival 
PG 
pharmacogenomics 
PgP 
P-glycoprotein 
PI 
principal investigator 
PK 
pharmacokinetic 


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Abbreviation 
Term 
P13K 
phosphoinositide 3-kinase 
PRES 
posterior reversible encephalopathy syndrome 
PT 
preferred term 
PVC 
polyvinyl chloride 
QD 
once a day 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RET 
rearranged during transfection 
RF 
radiofrequency 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RMC 
renal medullary carcinoma 
RNA 
ribonucleic acid 
RP2D 
recommended Phase 2 dose 
RTK 
receptor tyrosine kinase 
S6K1 
S6 ribosomal protein kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reactions 
TC 
total cholesterol 
TEAE 
Treatment Emergent Adverse Even 
TG 
triglycerides 
TNM 
tumor-node-metastasis 
TSH 
thyroid stimulation hormone 
T4 
thyroxine 
ULN 
upper limit of normal 
US 21 CFR 
Title 21 of the United States Code of Federal Regulations 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
WBC 
white blood cell 
WHO DD 
World Health Organization Drug Dictionary 
99m-Tc 
99m-technetium 


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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 International Council on 
Harmonisation (ICH) E6 (Good Clinical Practice [GCP]), Section 3, and any local 
regulations.  Any protocol amendment or revision to the ICF will be resubmitted to the 
IRB/IEC for review and approval, except for changes involving only logistical or 
administrative aspects of the study (eg, change in clinical research associates [CRAs], change 
of telephone number[s]).  Documentation of IRB/IEC compliance with the ICH E6 and any 
local regulations regarding constitution and review conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB/IEC chairman must be sent to the principal 
investigator (PI) with a copy to the sponsor before study start and the release of any study 
drug to the site by the sponsor or its designee (ICH E6, Section 4.4).  If the IRB/IEC decides 
to suspend or terminate the study, the investigator will immediately send the notice of study 
suspension or termination by the IRB/IEC to the sponsor. 
Study progress is to be reported to IRB/IECs annually (or as required) by the investigator or 
sponsor, depending on local regulatory obligations.  If the investigator is required to report to 
the IRB/IEC, he/she will forward a copy to the sponsor at the time of each periodic report.  
The investigator(s) or the sponsor will submit, depending on local regulations, periodic 
reports and inform the IRB/IEC of any reportable adverse events (AEs) per ICH guidelines 
and local IRB/IEC standards of practice.  Upon completion of the study, the investigator will 
provide the IRB/IEC with a brief report of the outcome of the study, if required. 
At the end of the study, the sponsor should notify the IRB/IEC and Competent Authority 
(CA) within 90 days.  The end of the study will be the date of the last study visit for the last 
subject in the study.  Upon completion of the study, the investigator or sponsor will provide 
the IRB/IEC with a brief report of the outcome of the study, if required. 
In the case of early termination/temporary halt of the study, the investigator should notify the 
IRB/IEC and CA within 15 calendar days, and a detailed written explanation of the reasons 
for the termination/halt should be given. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to GCP guidelines as required 
by the following: 
 
Principles of the World Medical Association Declaration of Helsinki  


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 
ICH E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the 
Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, 
International Council for Harmonisation of 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 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator must explain to 
each subject or guardian/legally authorized representative the nature of the study, its purpose, 
the procedures involved, the expected duration, the potential risks and benefits involved, any 
potential discomfort, potential alternative procedure(s) or course(s) of treatment available to 
the subject, and the extent of maintaining confidentiality of the subject’s records.  Each 
subject must be informed that participation in the study is voluntary, that he/she may 
withdraw from the study at any time, and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject or the subject’s legally acceptable representative should 
understand the statement before signing and dating it and will be given a copy of the signed 
document.  If a subject is unable to read or if a legally acceptable representative is unable to 
read, an impartial witness should be present during the entire informed consent discussion.  
After the ICF and any other written information to be provided to subjects is read and 
explained to the subject or the subject’s legally acceptable representative, and after the 
subject or the subject’s legally acceptable representative has orally consented to the subject’s 
participation in the study and, if capable of doing so, has signed and personally dated the 
ICF, the witness should sign and personally date the consent form.  The subject will be asked 
to sign an ICF before any study-specific procedures are performed.  No subject can enter the 
study before his/her informed consent has been obtained. 
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.  Subjects will be asked to either sign a separate ICF 
for pharmacokinetic (PK) assessments or provide consent for PK assessments within the 
main ICF.  For biomarker assessments, subjects will be asked to either sign a separate ICF or 
provide consent within the main ICF (see Section 9.5.1.3.2). Subjects may also be asked to 
either sign a separate ICF or provide consent within the main ICF to allow the sponsor to 
request scans of their tumor assessments for central review. 
The subject or the subject’s legally authorized representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 


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willingness to continue participation in the study.  The communication of this information 
should be documented. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at approximately 8 investigational sites in the United States. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in the Regulatory Binder provided to each site. 
7 
INTRODUCTION 
7.1 
Indication  
This is a single-arm, multicenter, Phase 2 study of lenvatinib in combination with everolimus 
in subjects with unresectable advanced or metastatic non clear cell renal cell carcinoma 
(nccRCC) who have not received any chemotherapy for advanced disease. 
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 62,700 new cases of 
kidney (renal) cancer are expected to be diagnosed and an estimated 14,240 deaths from 
kidney cancer are expected to occur in 2016 (American Cancer Society, 2016). 
RCC is broadly classified as clear cell renal cell carcinoma (ccRCC), which constitutes 
approximately 75 to 80% of RCC and non clear cell renal carcinoma (nccRCC), which 
constitute approximately 20% to 25% of the total RCC disease burden.  Non clear cell renal 
carcinoma (nccRCC) is a group of heterogeneous diseases, which are grouped together due to 
their low incidence rather than due to their underlying pathology or clinical outcomes. The 
most common type of nccRCC is papillary and constitutes approximately 15% of kidney 
cancers, followed by chromophobe (5%), collecting duct (1%), and translocation associated 
RCC (<1%).  The objective response rate (ORR) for nccRCC with targeted agents is 
approximately 8.3% with a median overall survival (OS) approximately 11.6 months 
(Hudes, et al., 2007).  
Non clear cell RCC has shown an increased expression of vascular endothelial growth factor 
(VEGF) and its receptors (Ljungberg, et al., 2006).  Also, the pathway of 
mammalian target of rapamycin (mTOR), a key regulatory kinase, has been shown to be 
deregulated in a significant number of patients with nccRCC (Davis, et al., 2014). 
7.1.1 
Current Therapeutic Options 
The current treatment approach for patients with metastatic nccRCC mirror that of clear cell 
RCC due to lack of randomized data and consists of sequential administration of single agent 
therapies that target either the VEGF/VEGF receptor (VEGFR) or mTOR pathways 
(Escudier, et al., 2014).   


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Hence, the European Society for Medical Oncology (ESMO) and National Comprehensive 
Cancer Network (NCCN) guidelines list clinical trials as the preferred option. Temsirolimus 
is the only Food and Drug Administration (FDA) approved agent (Hudes, et al., 2007).  Other 
agents that are available include sorafenib, sunitinib, pazopanib, axitinib, everolimus, 
bevacizumab, and erlotinib.  Of these, everolimus inhibits mTOR, resulting in downstream 
inhibition of protein synthesis and cell proliferation (AFINITOR® US Package Insert). 
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. 
7.1.2 
Lenvatinib 
Lenvatinib (LENVIMA®) is a kinase inhibitor that was approved by the US FDA on 
13 Feb 2015 and by the European Medicines Agency (EMA) on 28 May 2015, and indicated 
for the treatment of patients with locally recurrent or metastatic, progressive, radioactive 
iodine-refractory differentiated thyroid cancer (LENVIMA® US Package Insert/EU SmPC). 
7.1.2.1 
Mechanism of Action 
Lenvatinib is an oral, multiple receptor tyrosine kinase inhibitor (TKI).  By inhibiting the 
kinase activities of various receptors (eg, VEGFR 1-3, fibroblast growth factor receptor 
[FGFR] 1-4, platelet-derived growth factor receptor [PDGFR] alpha, c-kit receptor CD117 
[KIT] and Rearranged during Transfection [RET] protein), lenvatinib impedes pathogenic 
angiogenesis (development of new blood vessels), tumor growth, and cancer progression 
(LENVIMA® US Package Insert/EU SmPC).  
7.1.3 
Everolimus 
Everolimus (AFINITOR®) is an inhibitor of mTOR that is indicated for the treatment of adult 
patients with advanced RCC after failure of treatment with sunitinib or sorafenib 
(AFINITOR® US Package Insert).  It is also indicated for other conditions including: 
advanced hormone receptor-positive, human epidermal growth factor receptor (HER2)-
negative breast cancer; advanced neuroendocrine tumors of pancreatic origin; renal 
angiomyolipoma with tuberous sclerosis complex; and subependymal giant cell astrocytoma 
with tuberous sclerosis complex. 
7.1.3.1 
Mechanism of Action 
The mTOR, a serine-threonine kinase, acts as a signal transducing protein in the 
phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT)/ mTOR pathway, which is known 
to be involved in numerous human cancers. mTOR regulates protein synthesis, cellular 
metabolic state, cell proliferation, cell survival and also has some control over the angiogenic 
pathway through the hypoxia-inducible factor 1 (HIF1α) and VEGF and is linked to 
endothelial proliferation.  Inhibition of the mTOR signaling pathway interferes with protein 
translation and synthesis by reducing the activity of S6 ribosomal protein kinase (S6K1) and 
eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in 
the cell cycle, angiogenesis and glycolysis. 


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Everolimus is an mTOR inhibitor.  Everolimus binds the intracellular protein FK506 binding 
protein-12 (FKBP-12), forming a complex which then inhibits mTOR complex-1 (mTORC1) 
activity.  Everolimus reduces levels of VEGF and is a potent inhibitor of the growth and 
proliferation of tumor cells, endothelial cells, fibroblasts and blood vessel-associated smooth 
muscle cells and has been shown to reduce glycolysis in solid tumors in vitro and in vivo. 
7.1.4 
Preclinical and Clinical Experience with the Combination of Lenvatinib and 
Everolimus 
7.1.4.1 
Preclinical Experience with the Combination of Lenvatinib and 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 antiangiogenic 
agents with mTOR inhibitors may overcome the resistance that 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 vascular endothelial growth factor (VEGF) receptors (VEGFR1, VEGFR2, 
VEGFR3) in addition to other proangiogenic and oncogenic pathway-related RTKs, 
including fibroblast growth factor (FGF) receptors FGFR1-4, 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 (data on file). The mechanism of action of the combination of lenvatinib and 
everolimus was further investigated in cell-based nonclinical models, and it is hypothesized 
that the dual inhibition of the VEGF- and FGF-driven mitogen-activated protein kinase 
(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 (ribosomal s6 kinase)-S6 
pathway by the lenvatinib plus everolimus combination may contribute towards the superior 
antitumor activity of the combination (data on file). 


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7.1.4.2 
Clinical Experience with Combination Lenvatinib Plus Everolimus Treatment 
in Renal Cell Carcinoma 
The safety and efficacy of lenvatinib and everolimus combination treatment was investigated 
in the randomized, controlled, open-label study, 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 (Motzer, et al., 2015).  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, renal cell carcinoma who had a history of receiving one 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 (KM) curve below (Figure 1).  In addition, 
an objective response was achieved by 43% of subjects treated with the combination 
compared with 6% for single agent everolimus (p<0.0001) and 27% for single agent 
lenvatinib (p=0.10). 
 
Source: Study 205 CSR, Figure 4. 
Figure 1 
Progression-Free Survival of Lenvatinib + Everolimus Versus 
Single Agent 
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 


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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 TEAE 
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., 2015). 
7.2 
Study Rationale 
Clinical evaluation of lenvatinib in combination with everolimus in subjects who have not 
received any chemotherapy for advanced disease is warranted based on the following:   
 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. 
 the importance of VEGF, FGF, and mTOR signaling in RCC 
 the clinical experience with lenvatinib in metastatic clear cell RCC 
 The lack of availability of data to demonstrate that combination therapy in treatment 
of metastatic nccRCC provides significant advantage over single agent therapy.   
It is hypothesized that combinations of targeted agents may overcome the resistance to 
treatments with single agent therapy.  By using an mTOR inhibitor (everolimus) in 
combination with a VEGFR inhibitor (lenvatinib), blockade could take place at two levels of 
the pathways activated in RCC and this may overcome an aspect of resistance that may 
develop through feedback mechanisms.  
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
The primary objective of the study is to evaluate ORR, as assessed by the investigator, of 
lenvatinib in combination with everolimus in subjects with unresectable advanced or 
metastatic nccRCC who have not received any chemotherapy for advanced disease. 
8.2 
Secondary Objectives 
The secondary objectives of the study are: 
 To assess safety and tolerability of lenvatinib in combination with everolimus 
 To evaluate PFS as assessed by the investigator 


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 To evaluate OS  
 To assess the PK profiles of lenvatinib and everolimus during combination therapy in 
subjects with nccRCC 
8.3 
Exploratory Objectives 
The exploratory objectives of the study are: 
 To explore ORR as assessed by independent imaging review (IIR) 
 To explore PFS as assessed by IIR 
 To explore clinical benefit rate (CBR) as assessed by the investigator and by IIR 
 To explore disease control rate (DCR) as assessed by the investigator and by IIR 
 To explore duration of response (DOR) as assessed by the investigator and by IIR 
 To identify and explore tumor and blood biomarkers that correlate with clinical 
outcomes, including efficacy 
 To explore the relationship of population PK derived exposure parameters to 
biomarker, safety, and efficacy data using a model-based approach 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
E7080-M001-221 is a single-arm, multicenter, Phase 2 study of lenvatinib in combination 
with everolimus (lenvatinib 18 mg/day + everolimus 5 mg/day) in subjects with unresectable 
advanced or metastatic nccRCC who have not received any chemotherapy for advanced 
disease.  A Simon’s Two-Stage Design will be implemented in approximately 31 enrolled 
subjects.  Sixteen subjects will be enrolled in Stage 1.  If there are at least 2 responders as 
assessed by ORR, the study will proceed to Stage 2, in which 15 more subjects may be 
enrolled.  Otherwise, the study will stop early for futility.  In the final analysis of 31 subjects, 
at least 6 responders are required to show a statistically significant improvement of ORR 
over historical control in the same patient population.  
This study consists of three Phases: a Pretreatment Phase (Screening and Baseline Periods), a 
Treatment Phase (starting Cycle 1, Day 1), and a Posttreatment Phase (End of Treatment 
Visit and survival Follow-up).   


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9.1.1 
Pretreatment Phase 
The Pretreatment Phase will last no longer than 21 days and will include a Screening Period 
to establish protocol eligibility and a Baseline Period to confirm eligibility and establish 
disease characteristics prior to treatment. 
9.1.1.1 
Screening Period 
Screening will occur between Day –21 and Day –2.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3. 
Subjects must have a histologically-confirmed diagnosis of nccRCC. 
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable. 
9.1.1.2 
Baseline Period 
The purpose of the Baseline Period is to establish disease characteristics prior to starting 
treatment, and to confirm protocol eligibility as specified in the inclusion/exclusion criteria.  
Results of baseline assessments must be obtained and reviewed by the investigator prior to 
the first dose of study drug, ie, Cycle 1 Day 1 (C1D1), to confirm eligibility.  Baseline 
assessments will be performed on Day -1 or on C1D1 prior to treatment. 
Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase. 
9.1.2 
Treatment Phase 
The Treatment Phase will begin at the time of study drug administration on C1D1 and 
continue in 28-day (4-week) cycles until completion of the off-treatment assessments (within 
30 days after the last study drug administration).  Lenvatinib 18 mg/day and everolimus 
5 mg/day will be administered orally.  Subjects will undergo safety and efficacy assessments.  
Toxicity will be managed by treatment interruption, dose reduction and/or treatment 
discontinuation.  Subjects who discontinue one of the study drugs due to its toxicities may 
continue to receive the other study drug as long as they demonstrate clinical benefit.  
Subjects will discontinue both study drugs at the time of confirmed disease progression, 
development of unacceptable toxicity, withdrawal of consent, or study termination by the 
sponsor. 


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9.1.3 
Posttreatment Phase 
The Posttreatment Phase will start at the End of Treatment Visit and will continue as long as 
the subject is alive or until the study subject withdraws consent.  Subjects who discontinue 
study treatment before disease progression will continue to undergo tumor assessment every 
8 weeks ± 1 week until documentation of disease progression or start of another anticancer 
therapy.  Follow-up assessment for survival will be performed every 12 weeks ±1 week. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is a single-arm, multicenter, Phase 2 study of lenvatinib in combination with everolimus 
(lenvatinib 18 mg/day + everolimus 5 mg/day) in subjects with unresectable advanced or 
metastatic nccRCC who have not received any chemotherapy for advanced disease.  The 
current treatment approach for patients with metastatic nccRCC mirror that of clear cell RCC 
due to lack of randomized data and consists of sequential administration of single agent 
therapies that target either the vascular endothelial growth factor (VEGF)/VEGF receptor 
(VEGFR) or mammalian target of rapamycin (mTOR) pathways.  As discussed in 
Section 7.1.4, combining everolimus (an mTOR inhibitor) with lenvatinib (a VEGFR 
inhibitor) could block the pathways activated in RCC at 2 levels and may overcome an aspect 
of resistance, which develops with single agent therapy.  The combination of lenvatinib and 
everolimus is chosen based on robust results from Study 205. 
The current study is designed to provide efficacy and safety data for lenvatinib in 
combination with everolimus in this patient population.  A recently reported Phase 1b/2 study 
in RCC showed a response rate of 43.1% and median PFS of 14.6 months (95% CI 5.9-20.1).  
The primary objective of the study is to evaluate ORR.  The efficacy and safety parameters 
being evaluated are commonly used in oncology trials. 
9.3 
Selection of Study Population 
Approximately 31 subjects will be enrolled at approximately 8 sites in regions that include 
the United States.  Subjects who do not meet all of the inclusion criteria or who meet any of 
the exclusion criteria will not be eligible to receive study drug. 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to be included in this study: 
1. Males or females age ≥ 18 years at the time of informed consent form. 
2. Histologically confirmed nccRCC who have not received any chemotherapy for 
advanced disease.  Subjects must have one of the following subtypes of nccRCC: 
papillary, chromophobe, collecting duct carcinoma (CDC), renal medullary 
carcinoma (RMC), or unclassified.   
3. Radiologically measurable disease meeting the following criteria: 


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a. At least 1 lesion of ≥ 10 mm in the longest diameter for a nonlymph node or 
≥ 15 mm in the short axis diameter for a lymph node which is serially measurable 
according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) 
(Appendix 1) using computerized tomography (CT) or magnetic resonance 
imaging (MRI). 
b. Lesions that have had external beam radiotherapy (EBRT) or locoregional 
therapies such as radiofrequency (RF) ablation must show evidence of subsequent 
progressive disease (PD) (substantial size increase of ≥20%) to be deemed a target 
lesion.   
4. Eastern Cooperative Oncology Group (ECOG) (Appendix 2) performance status of 
0 to 1. 
5. Blood pressure (BP) ≤ 140/90 mmHg at Screening with or without antihypertensive 
medications and no change in antihypertensive medications within 1 week prior to 
C1D1. 
6. Adequate renal function as evidenced by calculated creatinine clearance ≥ 30 mL/min 
according to the Cockcroft and Gault formula (Appendix 3). 
7. Adequate bone marrow function: 
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L and 
b. Hemoglobin ≥ 10.0 g/dL (can be corrected by growth factor or transfusion 
prior to first dose of study drug) and 
c. Platelet count ≥ 100 × 109/L  
8. Adequate liver function: 
a. Bilirubin ≤ 1.5 × upper limit of normal (ULN) except for unconjugated 
hyperbilirubinemia or Gilbert’s syndrome 
b. Alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate 
aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if subject has liver 
metastases).  If ALP is > 3 × ULN (in the absence of liver metastases) or 
> 5 × ULN (in the presence of liver metastases) AND subjects are also known 
to have bone metastases, the liver-specific ALP must be separated from the 
total and used to assess the liver function instead of the total ALP. 
9. Voluntary agreement to provide written informed consent and the willingness and 
ability to comply with all aspects of the protocol. 


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9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Predominant clear cell RCC. 
2. Prior anticancer chemotherapy or targeted therapy for advanced nccRCC. 
3. Prior exposure to lenvatinib or mTOR inhibitor. 
4. Known intolerance to lenvatinib, everolimus (or other rapamycin derivatives), or any 
of the excipients. 
5. Major surgery performed within 3 weeks prior to the first dose of study drugs or 
scheduled for major surgery during the study. 
6. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition 
that might affect the absorption of lenvatinib or everolimus. 
7. Subjects having > 1 + proteinuria on urine dipstick testing will undergo 24 hour urine 
collection for quantitative assessment of proteinuria.  Subjects with urine protein 
≥ 1 g/24 hours will be ineligible. 
8. Fasting total cholesterol >300 mg/dL (or >7.75 mmol/L) 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 times the ULN.  NOTE: In 
case this threshold is exceeded, these subjects can only be included after initiation or 
adjustment of glucose-lowering medication. 
10. Known history of, or any evidence of, interstitial lung disease or active noninfectious 
pneumonitis. 
11. Significant cardiovascular impairment: History of (a) congestive heart failure greater 
than New York Heart association (NYHA) (Appendix 4) Class II, (b) unstable angina, 
(c) myocardial infarction (d) stroke, or (e) cardiac arrhythmia associated with 
hemodynamic instability within 6 months of the first dose of study drugs. 
12. Prolongation of QTcF interval to >480 msec.  
13. Known history of human immunodeficiency virus (HIV) positive. 
14. Known active hepatitis B (eg, hepatitis B surface antigen [HBsAg] reactive) or 
hepatitis C (eg, hepatitis C virus [HCV] RNA detected). 
15. Clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first 
dose of study drug. 
16. Subjects with central nervous system (CNS) (eg, brain or leptomeningeal) metastases. 
17. Other active malignancy (except definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix or bladder) 
within past 24 months. 
18. Females who are breastfeeding or pregnant at Screening or Baseline (as documented 
by a positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic 
gonadotropin [hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of 


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ß-hCG or hCG).  A separate baseline assessment is required if a negative screening 
pregnancy test was obtained more than 72 hours before the first dose of study drug. 
19. Females of childbearing potential who: 
o Had unprotected sexual intercourse within 30 days before study entry and who 
do not agree to use a highly effective method of contraception (eg, total 
abstinence, an intrauterine device, a double-barrier method [such as condom 
plus diaphragm with spermicide], a contraceptive implant, an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) 
throughout the entire study period or for 28 days after study drug 
discontinuation. 
o Are currently abstinent, and do not agree to use a double-barrier method (as 
described above) or refrain from sexually active during the study period or for 
28 days after study drug discontinuation. 
o Are using hormonal contraceptives but are not on a stable dose of the same 
hormonal contraceptive product for at least 4 weeks before dosing and who do 
not agree to use the same contraceptive during the study or for 28 days after 
study drug discontinuation.  
o Are using oral hormonal contraceptives and who do not agree to add a barrier 
method. 
o (NOTE:  All females will be considered to be of childbearing potential unless 
they are postmenopausal [amenorrheic for at least 12 consecutive months, in 
the appropriate age group, and without other known or suspected cause] or 
have been sterilized surgically [ie, bilateral tubal ligation, total hysterectomy, 
or bilateral oophorectomy, all with surgery at least 1 month before dosing]). 
20. Males who have not had a successful vasectomy (confirmed azoospermia) or they and 
their female partners do not meet the criteria above (ie, not of childbearing potential 
or practicing highly effective contraception throughout the study period or for 28 days 
after study drug discontinuation).  No sperm donation is allowed during the study 
period or for 28 days after study drug discontinuation. 
21. Evidence of clinically significant disease (eg, cardiovascular, respiratory, 
gastrointestinal, renal, or infectious disease) that in the opinion of the investigator(s) 
could affect the subject’s safety or interfere with the study assessments. 
22. Any medical or other condition that in the opinion of the investigator(s) would 
preclude the subject’s participation in a clinical study. 
23. Active and current use of illegal recreational drugs. 
24. Currently enrolled in another interventional clinical study or used any investigational 
drug or device within the past 28 days preceding informed consent. 
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.  


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The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-Up Period and complete protocol-specified off-
treatment visits, procedures, and survival follow-up unless the subject withdraws consent.  
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, the 
date will be documented in the source documents.  The Subject Discontinuation From 
Treatment Phase CRF page will be completed indicating the reason for discontinuation.  In 
addition, the date of last dose of study drug(s) will be recorded on the Study Drug Dosing 
CRF page. 
During the Follow-Up Period, subjects who have discontinued study treatment before disease 
progression will continue to undergo tumor assessment every 8 weeks ±1 week until disease 
progression is documented or another anticancer therapy is initiated. 
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.  Subjects will be followed for survival every 12 weeks ±1 week after the 
End of Treatment Visit.  If a clinic visit is not feasible, follow-up information may be 
obtained via telephone or email. 
A subject who discontinues study treatment should be followed for subsequent protocol-
specified visits and procedures.  If a subject discontinues study drug(s) but remains in the 
study, the set of End of Treatment procedures will be administered, and protocol-specified 
information will be collected.  The reason for discontinuation from study drug(s) should be 
collected on the Subject Disposition From Treatment Phase CRF page.  In addition, the date 
of last dose of study drug(s) will be recorded on the Study Drug Dosing CRF page.  If a 
subject discontinues study treatment and the study at the same time, the end-of-study 
procedures (Final Visit) will be followed (see Section 9.5.5). 
9.4 
Treatments 
The study drugs under evaluation are lenvatinib in combination with everolimus. 
9.4.1 
Treatments Administered 
Lenvatinib will be provided as 4-mg and 10-mg capsules and everolimus will be provided as 
5 mg tablets.  
Initial doses of lenvatinib 18 mg/day (one 10-mg capsule and two 4-mg capsules) and 
everolimus 5 mg/day are to be taken orally in immediate succession once a day (QD), 
recommended approximately at the same time each morning (consistently either with or 
without food). 
The following treatments will be administered to subjects in this study (Table 1). 


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Table 1 
Treatment Administered  
Drug Name 
Strength 
Oral Dose Form 
Number Dispensed and Frequency 
Durationa 
Lenvatinib 
10 mg 
Capsule 
1 × 10 mg capsule, once a day, 
recommended at approximately same 
time each morning 
Daily 
Lenvatinib 
4 mg 
Capsule 
2 × 4 mg capsule, once a day, 
recommended at approximately same 
time each morning 
Daily 
Everolimus 
5 mg 
Tablet 
1 × 5 mg tablet, once a day, 
recommended at approximately same 
time each morning 
Daily 
a. Subjects will continue to receive study treatment until disease progression, development of 
unacceptable toxicity, withdrawal of consent, or sponsor discontinuation.  
9.4.1.1 
Criteria for Interruption of Treatment, Dose Reduction, and Resumption of 
Treatment 
If a subject cannot tolerate lenvatinib due to its toxicities, the lenvatinib dose may be 
reduced, interrupted or discontinued according to the guidelines provided in Table 2 and 
Table 3.  Lenvatinib dose reductions occur in succession based on the previous dose level, ie, 
one level at a time from 18 mg/day to 14, 10, and 8 mg/day.  Any dose reduction below 
8 mg/day must be discussed with the sponsor.  
If a subject cannot tolerate everolimus due to its toxicities, the everolimus dose may be 
reduced, interrupted or discontinued.  Everolimus dose may be reduced from 5 mg/day to 
5 mg every other day. 
Dose adjustments for both study drugs will be made according to the guidelines provided in 
Table 3 for management of intolerable toxicities. 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. Once the dose has been reduced, it cannot be increased at a later date.  
Table 2 
Dose Reduction Recommendations for Lenvatinib in 
Combination With Everolimus 
Initial  
Lenvatinib Dose 
(mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
 
Reduction 1 
Reduction 2 
Reduction 3 
Reduction 4 
18 
14 
10 
8 
a 
QD = once daily. 
a:  Consult Sponsor for further dose reduction recommendations. 
Refer to appropriate section for management of hypertension (Section 9.4.1.1.1), proteinuria 
(Section 9.4.1.1.2), hepatic injury (Section 9.4.1.1.3), thromboembolic events (Section 
9.4.1.1.4), posterior reversible encephalopathy syndrome (PRES) (Section 9.4.1.1.5), 
hypocalcemia (Section 9.4.1.1.6), noninfectious pneumonitis (Section 9.4.1.1.7), infections 
(Section 9.4.1.1.8), and blood glucose / lipids (Section 9.4.1.1.9) before consulting the table 
below, as appropriate. 


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Table 3 
Lenvatinib-Everolimus Combination Therapy Dose Reduction 
and Interruption Instructionsa 
Lenvatinib/Everolimus 
Treatment-Related 
Toxicityb,c Including 
Hepatic Injury and 
Thromboembolic Events 
During Therapy  
Adjusted Dose  
Grade 1 Tolerable Grade 2 
 
Continue treatment 
No change 
Intolerable Grade 2c 
First occurrence 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 2 above) and, if 
combination dosing, resume everolimus at 
the same dose as prior to dose 
interruption. 
Second occurrence  
(same toxicity or new 
toxicity) 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 2 above) and, if 
combination dosing, resume everolimus at 
the same dose as prior to dose 
interruption. 
Third occurrence 
(same toxicity or new 
toxicity) 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 2 above) and, if 
combination dosing, resume everolimus at 
the same dose as prior to dose 
interruption. 
Fourth occurrence 
(same toxicity or new 
toxicity) 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 
Discuss with sponsor 
Grade 3d,e 
First occurrence 
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1f 
Dose reduction of lenvatinib (one dose 
reduction level, see Table 2 above) and, if 
combination dosing, resume everolimus at 
the same dose as prior to dose 
interruption. 
Second occurrence 
(same toxicity or new 
toxicity)  
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1 of 
Investigator to decide the probability of 
the event being related to 1 or both drugs 
as to whether dose modification of 1 or 
both drugs was required.  Dose reduction 
of lenvatinib (one dose reduction level, see 
Table 2 above) and/or reduce everolimus 
to 5 mg every other day.  
Third occurrence 
(same toxicity or new 
toxicity)  
Interrupt lenvatinib and, if combination 
dosing, interrupt everolimus until resolved 
to tolerable Grade 2 or Grade 0-1f 
Investigator to decide the probability of 
the event being related to 1 or both drugs 
as to whether dose modification of 1 or 
both drugs was required.  Dose reduction 
of lenvatinib (one dose reduction level, see 
Table 2 above) and/or adjust everolimus 
as follows: 
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 


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Table 3 
Lenvatinib-Everolimus Combination Therapy Dose Reduction 
and Interruption Instructionsa 
Lenvatinib/Everolimus 
Treatment-Related 
Toxicityb,c Including 
Hepatic Injury and 
Thromboembolic Events 
During Therapy  
Adjusted Dose  
event onset, discontinue. 
Fourth occurrence 
Interrupt lenvatinib and everolimus 
Discuss with sponsor 
Grade 4g:  Discontinue lenvatinib and everolimus 
Note:  For grading see Common Terminology Criteria (CTC) for Adverse Events (AE) version 4.03. Collect all CTC 
grades of AEs, decreasing and increasing grade. 
a: 
A delay of lenvatinib/ everolimus treatment for more than 28 days (due to lenvatinib/ everolimus-related toxicities) 
requires a discussion with the sponsor before treatment may be resumed. 
b: 
Excluding alopecia.  Drug interruption and dose reduction may be initiated for intolerable Grade 2 and Grade 3 
related symptoms such as anemia, lymphocytopenia, asymptomatic neutropenia if there are no other treatment 
options available and the investigator considers that dose interruption or reduction of study medication is the only 
remaining alternative.  Optimal medical management for nausea, vomiting, and/or diarrhea have to be initiated prior 
to any lenvatinib/ everolimus interruption or dose reduction. 
c: 
Applicable only to Grade 2 toxicities judged by the subject and physician to be intolerable. If Grade 2 toxicity is 
determined to be intolerable, the dose of study drug will be reduced with or without dose interruption.  Interruption 
for Grade 3 toxicities is mandatory. 
d: 
Obese subjects with weight loss requiring dose interruption and reduction do not need to return to baseline or Grade 1 
weight loss to restart lenvatinib.  Based on the judgment of the investigator, subjects may be restarted at the lower 
dose of lenvatinib once the weight has been stable for at least 1 week. Normal body mass index (BMI) should be used 
as the new baseline for future dose reductions. 
e: 
Not applicable to abnormal clinical laboratory values that are not clinically relevant based on the judgment of the 
investigator (eg, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transpeptidase 
(γ-GTP) values < 10 × upper limit of normal (ULN), and Na). 
f: 
For hematology toxicities, restart treatment after toxicity resolves to Grade 2. 
g: 
Excluding laboratory abnormalities judged to be nonlife-threatening, in which case have to be managed as Grade 3. 
9.4.1.1.1 
MANAGEMENT OF HYPERTENSION 
Lenvatinib-everolimus combination therapy should be withheld in any instances 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 significantly ≥ 160/100 mmHg, 
significant risk factors for cardiac disease, intracerebral hemorrhage, or other significant 
comorbidities).  Once the BP is controlled, lenvatinib-everolimus combination therapy 
should be resumed as described below. 
The following guidelines should be followed for the management of systolic BP 
≥ 140 mmHg up to < 160 mmHg or diastolic BP ≥ 90 mmHg up to < 100 mmHg confirmed 
on repeat measurements after an hour, for subjects receiving lenvatinib-everolimus 
combination therapy: 
 Continue lenvatinib-everolimus combination therapy and institute antihypertensive 
therapy for subjects not already receiving this. 


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 For subjects already on antihypertensive medication, the dose of the current agent 
may be increased, if appropriate, or one or more agents of a different class of 
antihypertensive should be added. 
The following guidelines should be followed for the management of systolic BP ≥ 
160 mmHg or diastolic BP ≥ 100 mmHg confirmed on  repeat measurements after an hour, 
for subjects receiving lenvatinib-everolimus combination therapy: 
 If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib-everolimus combination therapy 
administration should be interrupted and restarted when BP ≤ 150/95 mmHg at a dose 
of:  one level of dose reduction (ie, 14-mg once daily) per Table 3 of lenvatinib.  
Resume everolimus at the same dose as prior to dose interruption.   
○ If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the first 
reduced dose (ie, 14-mg once daily) despite optimal management of hypertension 
with antihypertensive medications (either by dose increase or the addition of a 
different class of antihypertensive), then lenvatinib-everolimus combination 
therapy administration should be interrupted and restarted when BP 
≤ 150/95 mmHg at a dose of :  one level of dose reduction (ie, 10 mg once daily) 
per Table 2 and Table 3 of lenvatinib.  Resume everolimus at the same dose as 
prior to dose interruption. 
○ If systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg recurs on the next 
reduced dose (ie, 10 mg once daily) despite optimal management of hypertension 
with antihypertensive medications (either by dose increase or the addition of a 
different class of antihypertensive), then lenvatinib-everolimus combination 
therapy administration should be interrupted and restarted when BP 
≤ 150/95 mmHg at a dose of:  one level of dose reduction (ie, 8 mg once daily) 
per Table 2 and Table 3 of lenvatinib.  Resume everolimus at the same dose as 
prior to dose interruption.  
○ Additional dose reduction should be discussed with the sponsor. 
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences): 
 
Institute appropriate medical management. 
 
Discontinue lenvatinib-everolimus combination therapy. 
9.4.1.1.2 
MANAGEMENT OF PROTEINURIA 
Regular assessment of proteinuria should be conducted as detailed in the Schedule of Visits 
and Procedures/Assessments.  Guidelines for assessment and management of proteinuria are 
summarized as follows for subjects receiving lenvatinib-everolimus combination therapy: 
 Initial episode of proteinuria: if proteinuria ≥ 2+ is detected on urine dipstick testing, 
lenvatinib-everolimus combination therapy will be continued and a 24-hour urine 
collection for total protein will be obtained as soon as possible within 72 hours to verify 
the grade of proteinuria.  Grading according to the National Cancer Institute’s (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE v4.03) (Appendix 5) will be 
based on the 24-hour urinary protein result.  Management of lenvatinib-everolimus 


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combination therapy will be based on the grade of proteinuria according to the Dose 
Reduction and Interruption Instructions (Table 3).  Where lenvatinib-everolimus 
combination therapy is interrupted and restarted, everolimus should resume at the same 
dose as prior to dose interruption and not as instructed in Table 3. 
 Urine dipstick testing for subjects with proteinuria ≥ 2+ should be performed every 
2 weeks (or more frequently as clinically indicated) until the results have been 1+, trace, 
or negative for 3 consecutive months.  Any subsequent increases in the level of 
proteinuria ≥2+ on urine dipstick testing must be confirmed with a 24-hour urinary 
protein test, which will be assessed and graded, and continued management of lenvatinib-
everolimus combination therapy administration will be based on the Dose Reduction and 
Interruption Instructions (Table 3).  Where lenvatinib-everolimus combination therapy is 
interrupted and restarted, everolimus should resume at the same dose as prior to dose 
interruption and not as instructed in Table 3.  If a new event of proteinuria ≥ 2+ occurs, 
the subject must resume urine dipstick testing for evaluation of proteinuria every 2 weeks 
until results are 1+, trace, or negative for 3 consecutive months. 
9.4.1.1.3 
MANAGEMENT OF HEPATOTOXICITY 
Regular monitoring of liver function tests (ALT, AST, and bilirubin levels) should be 
conducted as clinically indicated.  If signs/symptoms indicating liver injury occur, 
instructions contained in the Dose Reduction and Interruption Instructions (Table 3) should 
be followed.  Appropriate supportive care should be provided along with close monitoring.  
If hepatic failure occurs the lenvatinib-everolimus combination therapy must be 
discontinued. 
9.4.1.1.4 
MANAGEMENT OF THROMBOEMBOLIC EVENTS  
Subjects should be advised to pay attention to symptoms suggestive of venous 
thromboembolic events, which include acute onset of shortness of breath, dyspnea, chest 
pain, cough, hemoptysis, tachypnea, tachycardia, cyanosis, signs of deep vein thrombosis 
(DVT) 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 
Dose Reduction and Interruption Instructions (Table 3) should be followed.  Appropriate 
supportive care should be provided together with close monitoring. If a subject experiences 
life-threatening (Grade 4) thromboembolic reactions, lenvatinib-everolimus combination 
therapy must be discontinued.  
9.4.1.1.5 
MANAGEMENT OF POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME  
In clinical studies with lenvatinib, events of posterior reversible encephalopathy syndrome 
(PRES) were reported in less than 1% of lenvatinib-treated subjects.  PRES is a neurological 
disorder, which can present with headache, seizure, lethargy, confusion, altered mental 
function, blindness, and other visual or neurological disturbances.  Mild to severe 
hypertension may be present.  MRI is necessary to confirm the diagnosis of PRES.  


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Appropriate measures should be taken to control BP.  If subject develops PRES, contact 
study sponsor. 
9.4.1.1.6 
MANAGEMENT OF HYPOCALCEMIA 
Serum calcium should be monitored at least monthly and replace calcium as necessary during 
lenvatinib treatment.  Interrupt and adjust lenvatinib dosing as necessary depending on 
severity, presence of electrocardiogram (ECG) changes, and persistence of hypocalcemia.   
9.4.1.1.7 
MANAGEMENT OF NONINFECTIOUS PNEUMONITIS 
Noninfectious pneumonitis is a recognized class effect of rapamycin derivatives, including 
everolimus.  Noninfectious pneumonitis (including interstitial lung disease) was described in 
12% of subjects taking everolimus.  Some cases were severe and on rare occasions, a fatal 
outcome was observed.  Investigators should therefore consider a diagnosis of noninfectious 
pneumonitis in subjects presenting with nonspecific respiratory signs and symptoms and in 
whom infectious, neoplastic and other nonmedicinal causes have been excluded by means of 
appropriate investigations. 
Guidelines for assessment and management of noninfectious pneumonitis are summarized as 
follows for subjects receiving lenvatinib-everolimus combination therapy: 
 Subjects who develop radiological changes suggestive of noninfectious pneumonitis 
and have few or no symptoms (CTCAE Grade 1) may continue lenvatinib-everolimus 
combination therapy without dose adjustments. 
 If symptoms are CTCAE Grade 2:  
o Starting dose of lenvatinib combination therapy with 5 mg daily everolimus:  
combination therapy should be interrupted and the use of corticosteroids may 
be indicated until symptoms abate (resolved to CTCAE Grade 0-1 or baseline) 
and may be restarted with 5 mg everolimus daily in combination with 
lenvatinib (ie, lenvatinib reinitiated at the same dose as prior to dose 
interruption) administered daily.  Discontinue everolimus if failure to recover 
within 4 weeks of reinitiating treatment, and continue lenvatinib as a single 
agent therapy depending on individual clinical circumstance. 
o If Grade 2 noninfectious 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 or baseline).  Lenvatinib may be 
reinitiated as a single agent therapy depending on individual clinical 
circumstances. 
 If symptoms are CTCAE Grade 3:  
o Starting dose of lenvatinib combination therapy with 5 mg daily everolimus:  
combination therapy should be interrupted and the use of corticosteroids may 
be indicated until clinical symptoms resolve.  Lenvatinib may be reinitiated as 
single agent therapy depending on the individual clinical circumstances. 
 If symptoms are CTCAE Grade 4: 
o Study medications should be discontinued. 


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9.4.1.1.8 
MANAGEMENT OF INFECTIONS 
Everolimus has immunosuppressive properties and may predispose subjects to infections. 
Therefore, monitor for signs and symptoms of infection and treat promptly.  Dose alterations 
of everolimus (either as single agent or in lenvatinib-everolimus combination therapy) may 
be required in accordance with prescribing information.  
9.4.1.1.9 
MANAGEMENT OF BLOOD GLUCOSE AND LIPIDS 
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia are recognized class effects of 
rapamycin derivatives, including everolimus.  Glycemic control should be optimized before 
starting a subject on this study. 
Blood glucose will be monitored as specified in the Schedule of Visits and 
Procedures/Assessments. For subjects with blood glucose > ULN, a fasting (> 6h, water 
only) blood glucose sample will be obtained.  Grading according to CTCAE will be based on 
the fasting blood glucose result. Insulin and/or oral hypoglycemic agents may have to be 
introduced (or the dose increased) to control blood glucose levels. The choice of 
hypoglycemic agent should be individualized to the subjects’ clinical circumstances and 
follow standard medical practice in addition to consideration of avoiding coadministration of 
everolimus with inhibitors and inducers of cytochrome P450 (CYP)3A4 and/or the multidrug 
efflux pump P-glycoprotein (PgP). 
Dose alterations of everolimus (either as single agent or in lenvatinib-everolimus 
combination therapy) may be required in accordance with prescribing information.  Where 
lenvatinib-everolimus combination therapy is interrupted, lenvatinib should resume at the 
same dose as prior to dose interruption. 
Subjects who are discontinued from one of the study drugs due to intolerance to that drug 
may continue to receive the other study drug as long as they demonstrate clinical benefit.  
9.4.2 
Identity of Investigational Products  
The sponsor will provide the study drugs as open-label supplies.   
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib 
 
Test drug code:  E7080 
 
Generic name:  lenvatinib 
 
Chemical name:  4-[3-Chloro-4-(N’-cyclopropylureido) phenoxy]-7-methoxyquinoline-6-
carboxamide methanesulfonate 
 
Molecular formula:  C21H19ClN4O4•CH3SO3H 
 
Molecular weight:  522.96 
 
Structural formula:   


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9.4.2.2 
Chemical Name, Structural Formula of Everolimus 
 
Trade name:  Afinitor®    
 
Test drug code:  NA 
 
Generic name:  everolimus 
 
Chemical name:  40-O-(2-hydroxyethyl)-rapamycin    
 
Other names:  RAD001, Certican, SDZ RAD 
 
Molecular formula:  C53H83NO14 
9.4.2.3 
Comparator Drug 
Not applicable. 
9.4.2.4 
Labeling for Study Drug 
 Lenvatinib and everolimus will be labeled in accordance with text that is in full regulatory 
compliance with each participating country and is translated into the required language(s) for 
each of those countries. 
The following information will be included in the label (but not limited to): 
 
Protocol Number 
 
Name and address of the sponsor 
 
Pharmaceutical dosage form, route of administration, quantity of dosage units, identifier, 
and potency 
 
Lot number/batch number 
 
Storage conditions, expiration date if necessary 
 
CAUTION: New Drug-Limited by the United States law to investigational use. 
9.4.2.5 
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 


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calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, single-arm study.  There is no randomization in this study. 
9.4.4 
Selection of Doses in the Study 
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 
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.   
9.4.5 
Selection and Timing of Dose for Each Subject 
Lenvatinib capsules and everolimus tablets are to be taken orally QD at approximately the 
same time in the morning without regard to food intake from C1D1 onward.  A cycle is 
considered 28 days.  The two drugs should be administered in immediate succession.  If a 
subject misses a dose, it may be taken within the 12 hours following the usual time of the 
morning dose.  If more than 12 hours have elapsed from the time of the usual daily dose, 
study drugs should be taken the next day at the usual time in the morning.  In the event a 
subject vomits after study drug administration, the subject should not take another dose until 
the next scheduled dose. Subjects should not take a double dose (two doses at the same time) 
to make up for a forgotten dose. 
Lenvatinib capsules should be swallowed whole with water each morning.  Caregivers 
should avoid exposure to the contents of the capsule.  Lenvatinib is supplied in high density 
polyethylene (HDPE) bottles and the capsules should only be removed at the time of the 
administration because the drug is hygroscopic.   
Everolimus tablets should be swallowed whole with a glass of water.  The tablet should not 
be chewed or crushed.  Everolimus is supplied in aluminium/polyamide/aluminium/polyvinyl 
chloride (PVC) blisters.  Each tablet should be opened only at the time of administration 
because the drug is hygroscopic and light-sensitive.    
9.4.6 
Blinding 
The study will not be blinded. 


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9.4.7 
Prior and Concomitant Therapy 
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 28 days after the final 
dose of study drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures relating to malignancy should be recorded.  Any medication that is considered 
necessary for the subject’s health and that is not expected to interfere with the study drugs 
may be continued during the study. 
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) the study drugs. 
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Granulocyte colony-stimulating 
factor or equivalent may be used in accordance with American Society of Clinical Oncology 
(ASCO), institutional, or national guidelines.  Erythropoietin may be used according to 
ASCO, institutional, or national guidelines, but the subject should be carefully monitored for 
increases in red blood cell (RBC) counts.  Both systemic and inhalant forms of 
corticosteroids are permissible. 
If the subject is receiving treatment with lenvatinib and requires surgery during the study, the 
stop time and restart time of lenvatinib should be as follows: 
 For minor procedures: stop lenvatinib for 2 days before the procedure and restart it 2 
days after, once there is clear evidence of wound healing and no risk of bleeding, but 
at least 2 days after the procedure. 
 For major procedures: hold lenvatinib for 1 week (5 half-lives) prior to surgery and 
then restart when there is clear evidence of wound healing and no risk of bleeding, 
but at least 1 week after the procedure.  
If the subject is receiving treatment with everolimus and requires surgery during the study, 
refer to the AFINITOR® US Package Insert. 
If concomitant medication/therapy is administered for an AE, investigators will record that 
AE on the Adverse Events CRF.  
9.4.7.1 
Drug-Drug Interactions 
No dose adjustment of lenvatinib is recommended when coadministered with CYP3A, PgP, 
and breast cancer resistance protein (BCRP) inhibitors, and with CYP3A and PgP inducers 
(LENVIMA® US Package Insert).  Similarly, lenvatinib at the proposed dose for clinical use 
is not expected to inhibit the cytochrome P450-mediated metabolism of other drugs 


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administered concomitantly (CPMS-E7080-007R-v1, RDMPKA2013-156 REVISION NO. 
1). 
A population PK analysis also indicated that agents that raise gastric pH (eg, H2-blockers, 
proton pump inhibitors, antacids) do not have a significant effect on the absorption and 
bioavailability of lenvatinib (CPMS-E7080-007R-v1).   
Everolimus is a substrate of CYP3A4 and also a substrate and moderate inhibitor of PgP. In 
vitro results indicate that everolimus inhibition of PgP and CYP3A4 is unlikely.  However, 
everolimus may affect the bioavailability of coadministered drugs that are CYP3A4 and/or 
PgP substrates since inhibition of CYP3A4 and PgP in the gut cannot be excluded.  
Drugs metabolized by CYP3A4 or drugs that are inhibitors or inducers of CYP3A4 
(including herbal supplements or grapefruit) could affect the metabolism of everolimus.  
Please refer to Flockhart DA, 2007 for the most current information regarding inhibitors and 
inducers of CYP3A4. 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs 
Subjects should not receive other antitumor therapies while on study.  If subjects receive 
additional antitumor therapies during the study, such as radiotherapy, other chemotherapy, or 
immunotherapy, this will be judged to represent evidence of disease progression, and 
continuation of study medication should be discussed with the sponsor.  Following this 
discussion, if the joint decision is made to discontinue study treatment, then such subjects 
will complete all End of Treatment assessments and continue to be followed for survival in 
the Follow-Up Period. 
9.4.8 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study. 
9.4.9 
Drug Supplies and Accountability 
In compliance with local regulatory requirements, drug supplies will not be sent to the 
investigator until the following documentation has been received by the sponsor: 
 
A signed and dated confidentiality agreement 
 
A copy of the final protocol signature page, signed and dated by both the sponsor and 
investigator 
 
Written proof of approval of the protocol, the ICFs, and any other information provided 
to the subjects by the IRB/IEC for the institution where the study is to be conducted 
 
A copy of the IRB/IEC-approved ICF and any other documentation provided to the 
subjects to be used in this study 
 
The IRB/IEC membership list and statutes or Health and Human Services Assurance 
number 


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 
A copy of the certification and a table of the normal laboratory ranges for the reference 
laboratory conducting the clinical laboratory tests required by this protocol 
 
An investigator-signed and dated FDA Form FDA 1572, where applicable 
 
Financial Disclosure form(s) for the 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 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, including any other required country-specific documentation and the 
Importation License 
The investigator and the study staff 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/study supplies to be used 
other than as directed by this protocol.  Study drugs/study supplies will not be dispensed to 
any individual who is not enrolled in the study.   
The site must maintain an accurate and timely record of the following:  receipt of all study 
drugs/study supplies, dispensing of study drugs/study supplies to the subject, collection and 
reconciliation of unused study drugs/study supplies that are either returned by the subjects or 
shipped to site but not dispensed to subjects, and return of reconciled study drugs/study 
supplies to the sponsor or (where applicable) destruction of reconciled study drugs/study 
supplies at the site.  This includes, but may not be limited to: (a) documentation of receipt of 
study drugs/study supplies, (b) study drugs/study supplies dispensing/return reconciliation 
log, (c) study drugs/study supplies 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/study supplies 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/study supplies and inventory records must be made available, upon request, 
for inspection by a designated representative of the sponsor or a representative of a health 
authority (eg, FDA, Medicines and Healthcare Products Regulatory Agency [MHRA]).  As 
applicable, all unused study drugs/study supplies and empty and partially empty containers 
from used study drugs/study supplies are to be returned to the investigator by the subject and, 
together with unused study drugs/study supplies 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/study supplies 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/study supplies to the central or local depot(s).  Approval for destruction to occur 
at the site must be provided by the sponsor in advance.  Upon completion of drug 
accountability and reconciliation procedures by the site’s personnel and documentation 


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procedures by the sponsor’s personnel, study drugs/study supplies 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/study supplies may be removed from the site and hand delivered to the central or 
local depot by sponsor representatives.  Where study drugs/study supplies 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 (record in accordance with 
prevailing regulations).  Baseline characteristics will include ECOG performance status and 
NYHA cardiac disease classification (see Appendix 2 and Appendix 4, respectively).  
9.5.1.1.1 
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS 
Significant medical and surgical history and current medical conditions will be obtained 
during the Pretreatment Phase (Screen and Baseline).   
Physical examinations (comprehensive [including neurological examination] or symptom 
directed) will be performed as designated in the Schedule of Procedures/Assessments (Table 
5).  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 site.  Significant findings at the Screening Visit 
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 v1.1 (Appendix 1) as defined 
in Inclusion Criterion #3.  Tumor-node-metastasis (TNM) staging at diagnosis should follow 
the guidelines provided in 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. 


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9.5.1.2 
Efficacy Assessments 
The primary endpoint (ORR), secondary endpoint (PFS), and exploratory endpoints (CBR, 
DCR, and DOR) will be evaluated by the investigator.  In addition, ORR, PFS, CBR, DCR 
and DOR will be assessed by IIR.  The OS status will be assessed throughout the study. 
9.5.1.2.1 
TUMOR ASSESSMENTS 
Tumor assessments will be performed using RECIST v1.1.  Investigator-determined response 
assessments are to be performed at the site by appropriately qualified personnel at each time 
point and recorded on the appropriate CRFs.  Copies of all tumor assessment scans will be 
sent to an imaging core laboratory specified by the sponsor for quality assessment and 
independent imaging review.  Tumor assessments will be carried out following the guidelines 
provided by the imaging core laboratory.  Historical scans performed within the Screening 
period that do not follow the guidelines completely may be used to demonstrate eligibility, as 
long as they meet minimum standards as separately defined by the imaging core laboratory.   
Tumor assessments including a CT chest and CT or MRI of the abdomen and pelvis, and 
other areas of known or newly suspected disease should be performed prior to Baseline 
(between Day –28 to Day -2) and every 8 weeks (within the 8th week) from the date of first 
dose during the Treatment Phase.  The same imaging modality and image-acquisition 
protocol (including use or nonuse of contrast, oral and IV) should be used consistently across 
all time points. A brain scan will be performed at Screening, and thereafter if clinically 
indicated.  Bone scans using whole body bone MRI, 99m-technetium (99m-Tc)  based bone 
scans, or 18F sodium fluoride positron-emission tomography (Na-F PET) will be performed 
during the pretreatment phase to establish a baseline (a historical bone scan performed within 
6 weeks before first dose is acceptable), every 24 weeks, and as clinically indicated.  Lesions 
identified on bone scans should be followed with cross-sectional imaging. 
In subjects with complete response (CR) based on body CT/MRI scans, bone scan and brain 
scan, assessment will be required at response confirmation.  All objective responses must be 
confirmed at least 28 days following the initial achievement of response. Subjects going off 
study treatments without disease progression in the Treatment Phase will continue to undergo 
tumor assessments according to the above schedule until disease progression is documented 
or another anticancer therapy is initiated.  
9.5.1.3 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Assessments 
9.5.1.3.1 
PHARMACOKINETIC ASSESSMENTS 
Sparse PK samples will be collected from all subjects and will be analyzed using the 
population approach.  A total of 12 samples (6 plasma samples for lenvatinib and 6 whole 
blood samples for everolimus) per subject will be obtained at the following time points: 2 to 
8 hours postdose on C1D1, prior to dose on Cycle 1 Day 15 (C1D15), prior to dose and 2 to 8 
hours postdose on Day 1 of Cycles 2 and 3.  Actual time and date of PK blood collection as 
well as time of drug administration will be recorded on the appropriate page of the CRF. 


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Refer to the Laboratory Manual for the total blood volume to be collected along with 
instructions for processing, shipping and handling of the samples. 
Lenvatinib in plasma and everolimus in blood will be quantified using validated high 
pressure liquid chromatography (HPLC)-tandem mass spectroscopy methods. 
9.5.1.3.2 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Blood and Tissue Biomarkers 
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.  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. 
A blood sample for pharmacodynamic and exploratory biomarker analysis will be collected 
predose on Day -1 or C1D1, on C1D15, and on Day 1 of subsequent cycles (during 
Treatment Phase), and at the End of Treatment assessment.  Blood samples from all 
consented subjects may undergo analyses including, but not limited to, global proteomic 
and/or enzyme-linked immunosorbent assay (ELISA)-based analyses or multiplex bead-
based immunoassay in an effort to assess pharmacodynamic biomarkers.  
Pharmacogenomic (PG) Assessments 
Archived, fixed tumor tissue will be collected (if available) from all subjects for potential 
assessment of mutations and other genetic alterations or genes and/or proteins that may be 
important in the development and progression of cancer as well as in response to study drug 
treatment for potential use in diagnostic development. Appropriate 
technology/methodologies will be used based on the amount of tumor tissue available. 
A blood sample for peripheral blood mononuclear cells (PBMC) and plasma isolation will be 
collected from consented subjects for potential analysis of cell free nucleic acid (cf-nucleic 
acid) analysis and exploratory immune cell analysis.  Cell free nucleic acid isolated from 
plasma samples may be used to obtain circulating tumor DNA (ctDNA) and explore tumor 
genetic alterations such as mutations observed in archival tumor samples as well as those 
which develop during drug treatment. PBMCs may be used for immune cell profiling (eg. 
tumor infiltrating lymphocytes, T-cell repertoire, and immune cell types). 
A blood sample will be collected for pharmacogenomics (PG) analysis (except where 
prohibited by regional or local laws).  Variation in lenvatinib exposure or the occurrence of 
AEs observed in the study population may be evaluated by correlating single–nucleotide 
polymorphisms with PK, safety, or pharmacodynamic data.  Genomic DNA extracted from 
blood samples may be used to confirm whether the DNA sequence variants observed in DNA 


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extracted from tumor material are limited to the tumor and for potential profiling of immune 
cells. 
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 lenvatinib, cancer and/or for potential diagnostic development. 
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual. 
9.5.1.4 
Safety Assessments 
General safety will be assessed by the monitoring and recording of all AEs and serious 
adverse events (SAEs), regular monitoring of hematology and blood chemistry, regular 
measurement of vital signs, ECG, and the performance of physical examinations (PE) and 
other safety assessments in line with local regulations governing a study of this nature.  
Progression of nccRCC and signs and symptoms clearly related to the disease progression 
should not be captured as an AE.  Disease progression is a study endpoint and should be 
captured in the CRF as per the guidelines for reporting disease progression. 
In case of life-threatening bleeding, the investigator should discuss the case with the Eisai 
Medical Monitor, in addition to discontinuing lenvatinib per Table 2 for Grade 4 toxicity and 
treat the subject based on the institution’s standard practice.  Clinically significant bleeding 
will be considered as study-specific events and should always be considered as serious 
important medical events, which will be entered on the adverse event CRF and reported 
using the procedures for reporting SAEs, even if the study-specific event does not meet other 
serious criteria. 
Safety assessments will consist of monitoring and recording all AEs, including all 
CTCAE v4.03 grades (for both increasing and decreasing severity) (Appendix 5), and SAEs; 
regular monitoring of hematology, blood chemistry, and urine values; periodic measurement 
of vital signs and ECGs; and performance of physical examinations as detailed in Table 5. 
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 and everolimus.  
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, 


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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 
 
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 and for 28 days after the last dose of study 
treatment.  Subjects who fail screening primarily due to AE(s) must have the AE(s) leading 
to screen failure reported on the Screening Disposition CRF.  SAEs will be collected for 28 
days after the last dose of study treatment. 
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 (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 
450 ms and there is an increase of more than 60 ms from baseline.  Any ECG abnormality 
that the investigator considers as an AE should be reported as such.  
All AEs must be followed for 28 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization. 
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment. 


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Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to Common Terminology Criteria 
for Adverse Event (CTCAE v4.03).  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 
 
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) 


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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.  
For this study, the following events should always be considered serious and reported as an 
important medical event if it does not meet other serious criteria:  clinically significant 
bleeding. 
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 
9.5.1.4.3 
LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 4.  Subjects should be in a seated or supine position during blood 
collection.  The Schedule of Procedures/Assessments (Table 5) shows the visits and time 
points at which blood for clinical laboratory tests and urine for urinalysis will be collected in 
the study. 
Efforts should be made to conduct study visits on the day scheduled.  If necessary, study 
visits may be held up to 3 days sooner or later than the scheduled day that clinical laboratory 
assessments may be conducted according to (Table 5). 


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Table 4 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
Hematocrit, hemoglobin, platelets, RBC count, WBC count with 
differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), and ANC 
Chemistry 
 
 Electrolytes 
Bicarbonate, chloride, magnesium, potassium, sodium 
 Liver function tests 
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin 
 Renal function tests 
Blood urea/blood urea nitrogen, creatinine 
 Thyroid function testsa 
TSH and free T4  
 Pregnancy test 
Serum β-hCG (if urine not tested) 
Fasting blood tests 
Glucose, lipids (total cholesterol, LDL-C, HDL-C, triglycerides) 
 Other 
Albumin, amylase, calcium, lactate dehydrogenase, lipase, 
phosphorus, total protein, uric acid 
Urinalysis 
glucose, ketones, pH, protein, RBCs, specific gravity 
Pregnancy test 
Urine β-hCG (if serum not tested) 
ANC= absolute neutrophil count, β hCG = beta-human chorionic gonadotropin, HDL-C= high density 
lipoprotein-C, LDL-C=low density lipoprotein-C, RBC = red blood cells, T4 = thyroxine, TSH = thyroid 
stimulating hormone, WBC = white blood cells. 
a:  Thyroid function will be assessed at the Screening Visit, at Baseline/C1D1, Day 1 of every cycle (starting at 
C2) throughout the study, and at the End of Treatment Visit.  
 
Clinical laboratory tests during the study will be performed by trained staff at the study sites. 
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. 
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to study drug administration and results reviewed prior to 
administration/dispensing of study drug at the beginning of each treatment cycle.  Refer to 
Table 3 for the management of clinically significant laboratory abnormalities. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.4.1) 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 blood pressure [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 5) by a validated method.  Height will be measured at the 


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Screening Visit only.  Blood pressure and heart rate will be measured after the subject has 
been sitting for 5 minutes.  All BP measurements should be performed on the same arm, 
preferably by the same person, if feasible.  For subjects with an elevated BP (systolic BP 
≥140 mmHg or diastolic BP ≥ 90 mmHg), confirmation should be obtained by performing 
repeat measurements after 1 hour to obtain a mean value. 
Subjects with systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg must have their BP 
monitored every 2 weeks (on Day 15 or more frequently as clinically indicated) until systolic 
BP has been ≤ 150 mmHg and diastolic BP has been ≤ 95 mmHg for 3 consecutive months.  
If a new event of systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg occurs, the subject 
must resume the Day 15 evaluation until systolic BP has been ≤ 150 mmHg and diastolic BP 
has been ≤ 95 mmHg for 3 consecutive months.   
9.5.1.4.5 
PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 5).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF. 
9.5.1.4.6 
ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 5).  Complete, standardized, 12-lead ECG recordings that 
permit all 12 leads to be displayed on a single page with an accompanying lead II rhythm 
strip below the customary 3 × 4 lead format are to be used.  In addition to a rhythm strip, a 
minimum of 3 full complexes should be recorded from each lead simultaneously.  Subjects 
must be in the recumbent position for a period of 5 minutes prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.4.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF. 
9.5.1.4.7 
OTHER SAFETY ASSESSMENTS 
Eastern Cooperative Oncology Group Performance Status 
Eastern Cooperative Oncology Group performance status will be assessed at the Screening 
Visit, Baseline/C1D1, Day 1 of each treatment cycle starting at Cycle 2, and at End of 
Treatment Visits.  The table in Appendix 2 will be used to assess performance status. 
Pregnancy Test 
A serum or urine β-hCG test will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months.  A 6-mL 


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sample of blood will be taken at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 5). 
9.5.2 
Schedule of Procedures/Assessments  
9.5.2.1 
Schedule of Procedures/Assessments 
Table 5 presents the schedule of procedures/assessments for the study. 
 


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Table 5 
Schedule of Procedures/Assessments for Study E7080-M001-221 
Phase 
Pretreatmenta, 
Treatmentb  
All cycles are 28 days in duration 
 
Posttreatmentc  
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2  
Cycle 3 – 
Last 
Cycle 
End of Treatment 
Follow-
Up 
Period  
Day 
-21 to -2 
-1 
Day 
1a 
Day 8 
Day 15 
Day 1 
Day 15 
Day 1 
Within 30 days of last 
dose 
Every 12 
weeksd 
Visit 
1 
2 
3 
4 
5 
6 
7 
8, 9, 10, 
etc. 
 
 
Informed consent 
X 
 
  
 
 
 
 
 
 
 
Inclusion/Exclusione  
X 
X 
 
 
 
 
 
 
 
 
Demographic dataf  
X 
 
 
 
 
 
 
 
 
 
Archival tumor block or 
slidesg 
X 
 
 
 
 
 
 
 
 
 
Pharmacogenomic 
blood sample 
 
X 
 
 
 
 
 
 
 
 
Biomarker blood 
serum/PBMC/plasma 
sampleh 
 
X 
 
 
X 
X 
 
X 
X 
 
ECOGi  
X 
X 
 
 
 
X 
 
X 
X 
 
TNM staging at 
diagnosis 
X 
 
 
 
 
 
 
 
 
 
Medical/surgical history 
X 
X 
 
 
 
 
 
 
 
 
Vital signsj,k 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
Physical examinationl 
X 
X 
 
 
X 
X 
 
X 
X 
 
12-Lead ECGm 
X 
 
 
 
X 
X 
 
X 
X 
 
Clinical chemistry and 
hematologyn  
X 
X 
 
 
X 
X 
Xo 
X 
X 
 
Fasting blood glucosep 
X 
X 
 
 
 
X 
 
X 
X 
 


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Table 5 
Schedule of Procedures/Assessments for Study E7080-M001-221 
Phase 
Pretreatmenta, 
Treatmentb  
All cycles are 28 days in duration 
 
Posttreatmentc  
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2  
Cycle 3 – 
Last 
Cycle 
End of Treatment 
Follow-
Up 
Period  
Day 
-21 to -2 
-1 
Day 
1a 
Day 8 
Day 15 
Day 1 
Day 15 
Day 1 
Within 30 days of last 
dose 
Every 12 
weeksd 
Visit 
1 
2 
3 
4 
5 
6 
7 
8, 9, 10, 
etc. 
 
 
Amylase and Lipase 
X 
X 
 
 
 
X 
 
X 
X 
 
Fasting lipidsq 
X 
X 
 
 
 
 
 
X 
X 
 
TSH and free T4 levelsr 
X 
X 
 
 
 
X 
 
X 
X 
 
Urine dipstick testings  
X 
X 
 
 
X 
X 
X 
X 
X 
 
Pregnancy testt 
X 
 
 
 
 
 
 
 
 
 
PKu 
 
 
X 
 
X 
X 
 
X 
 
 
Telephone contact 
 
 
 
 
 
 
 
 
 
Xd 
Lenvatinib treatment 
 
 
Once Daily 
 
 
Everolimus treatment 
 
 
Once Daily 
 
 
Tumor assessments: 
CT/MRIv 
X 
 
Performed every 8 weeks after C1D1, or sooner if clinically indicated, until documentation of disease 
progression or beginning another anticancer therapy. 
Bone  Scanw 
X 
 
Every 24 weeks ± 1 week after C1D1, or as clinically indicated. In subjects with CR based on body CT/MRI 
scans, a bone scan assessment will be required at response confirmation. 
Brain Scanx 
X 
 
If clinically indicated.  In subjects with CR based on body CT/MRI scans, a brain scan will be required at 
response confirmation. 
Survival 
 
Throughout 
Concomitant 
medicationsy 
Throughout 
AEs/SAEsz 
Throughout 


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Table 5 
Schedule of Procedures/Assessments for Study E7080-M001-221 
Phase 
Pretreatmenta, 
Treatmentb  
All cycles are 28 days in duration 
 
Posttreatmentc  
Period 
Screening 
Baseline 
Cycle 1 
Cycle 2  
Cycle 3 – 
Last 
Cycle 
End of Treatment 
Follow-
Up 
Period  
Day 
-21 to -2 
-1 
Day 
1a 
Day 8 
Day 15 
Day 1 
Day 15 
Day 1 
Within 30 days of last 
dose 
Every 12 
weeksd 
Visit 
1 
2 
3 
4 
5 
6 
7 
8, 9, 10, 
etc. 
 
 
 
AEs = adverse events, BP = blood pressure, C1D1 = Cycle 1/Day 1, C1D15 = Cycle 1/Day 15, CR = complete response, CT = computerized tomography, ECG = 
electrocardiogram, ECOG = Eastern Cooperative Oncology Group, h = hour, HR = heart rate, med = medical/medication(s), MRI = magnetic resonance imaging, , PK = 
pharmacokinetics, PBMC= peripheral blood mononuclear cells, PR = partial response, RR = respiratory rate, SAEs = serious adverse events, T4 = thyroxine, TNM = tumor-mode-
metastasis, TSH = thyroid stimulating hormone, Tx = treatment, w/in = within. 
a. 
The results of all screening assessments and evaluations must be completed and reviewed by the investigator prior to the Baseline Visit.  Baseline assessments can be 
performed on Day -1 or on C1D1 prior to initiation of lenvatinib and everolimus treatment.  Informed consent must be obtained up to 21 days prior to C1D1. 
b. 
Efforts should be made to conduct study visits on the day scheduled ( 3 day).  Clinical laboratory assessments may be conducted anytime within 72 hours prior to the 
scheduled visit, unless otherwise specified. 
c. 
The Posttreatment Phase will start at the End of Treatment visit and will continue as long as the subject is alive or until the subject withdraws consent or is lost to follow-
up.  Subjects who discontinue study treatment before disease progression will continue to undergo tumor assessment every 8 weeks ± 1 week until documentation of 
disease progression or start of another anticancer therapy.  Follow-up assessment for survival will be performed every 12 weeks ± 1 week. 
d. 
Subjects will be followed for survival every 12 weeks ± 1 week after the End of Treatment Visit.  If a clinic visit is not feasible, follow-up information may be obtained 
via telephone or email. 
e. 
New York Heart Association (NYHA) cardiac disease classification should be performed at Screening only, if needed. 
f. 
Demographic information includes date of birth (or age), sex, and race/ethnicity. 
g. 
Archived, fixed tumor tissue will be collected (if available) and may be used in the future for potential assessment of genetic biomarkers.  The decision to perform other 
biomarker assessments may be based on the clinical outcome of this study and/or the signals observed in other studies or  other information available at that time. 
h. 
Collection of blood samples to obtain serum, peripheral blood mononuclear cells, and/or plasma to be used for cell-free nucleic acid, immune cell, and biomarker studies 
from subjects.  Samples will be obtained predose on Day -1 or C1D1, C1D15, Day 1 of all subsequent cycles, and at the End of Treatment Visit. 
i. 
ECOG will be performed at the Screening and Baseline Visits, on C 2/D1, on Day 1 of every subsequent cycle thereafter, and at the End of Treatment Visit. 
j. 
Assessments will include vital signs (resting BP, HR, RR, and body temperature), weight, and height.  Height will be measured at the Screening Visit only.   Vital signs 
will be performed at Screening, Baseline, C1D8, C1D15, C2D1, C2D15, Day 1 of every cycle thereafter, all unscheduled visits, and at the End of Treatment Visit. 
Elevated BP (systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) should be confirmed by repeat measurements after 1 hour to obtain a mean value. 


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k. 
Subjects with systolic BP ≥ 160 mmHg or diastolic BP ≥ 100 mmHg must have their BP monitored every 2 weeks (on Day 15 or more frequently as clinically indicated) 
until systolic BP has been ≤ 150 mmHg and diastolic BP has been ≤ 95 mmHg for 3 consecutive months.  If a new event of systolic BP ≥ 160 mmHg or diastolic BP ≥ 
100 mmHg occurs, the subject must resume the Day 15 evaluation until systolic BP has been ≤ 150 mmHg and diastolic BP has been ≤ 95 mmHg for 3 consecutive 
months.   
l. 
A comprehensive physical examination (including a neurological examination) will be performed at the Screening Visit, on Cycle 1/Day 15, on Day 1 of each subsequent 
cycle, and at the End of Treatment assessment.  A symptom-directed physical examination will be performed on Baseline (Day -1) or on C1D1 prior to treatment, and at 
any time during the study, as clinically indicated. 
m. Single 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  
n. 
Clinical chemistry and hematology results must be reviewed prior to administration of lenvatinib and everolimus on C1D1 and all subsequent cycles.  Scheduled 
assessments (Screening Visit, Baseline/C1D1, Cycle 1/Day 15, Day 1 of each subsequent cycle starting with Cycle 2 and at the End of Treatment Visit) may be 
performed within 72 hours prior to the visit.  If there is a clinically relevant hematologic or chemistry toxicity of ≥ Grade 3, additional laboratory tests and AE 
assessments are required until the toxicity improved to < Grade 3.  
o. 
On C2D15, only liver function (ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin) should be performed.  Note: liver function should be assessed at 
the Screening Visit, then every 2 weeks for the first two months (Baseline/C1D1, C1D15, C2D1, and C2D15), and then monthly thereafter (Day 1 of each subsequent 
cycle) and at the End of Treatment Visit. 
p. 
Assessments of fasting blood glucose are to be performed at the Screening Visit, Baseline/C1D1, monthly thereafter on Day 1 of each subsequent cycle starting at Cycle 
2, and at the End of Treatment Visit.   
q. 
Assessment of fasting lipids (including total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], and 
triglycerides [TG]) are to be performed at the Screening Visit, Baseline/C1D1, on Day 1 of every 3rd cycle thereafter (Cycles 4, 7, etc.), and at the End of Treatment Visit.  
r. 
Assessment of TSH and free T4 levels are to be performed at the Screening Visit, Baseline/C1D1, Day 1 of each subsequent cycle starting at Cycle 2, and at the End of 
Treatment Visit. 
s. 
Urinalysis will be performed at Screening, Baseline, Cycle 1/Day 15, Cycle 2/Day 1, Cycle 2/Day 15, Day 1 of every cycle thereafter, all unscheduled visits, and at the 
End of Treatment Visit. Urinalysis will include glucose (fasting at Baseline only), ketones, pH, protein, RBCs, and specific gravity.  If urine protein ≥ 2+ on urinalysis, 
lenvatinib will be continued and a 24-hour urine collection for total protein will be obtained as soon as possible within 72 hours to verify the grade of proteinuria.  Urine 
dipstick testing for subjects with proteinuria ≥ 2+ should be performed every 2 weeks (on Day 1 and Day 15 of each cycle or more frequently as clinically indicated) until 
the results have been 1+ or negative for 3 consecutive months. If a new event of proteinuria ≥ 2+ occurs, the subject must resume urine dipstick testing for evaluation of 
proteinuria every 2 weeks until results are 1+ or negative for 3 consecutive months. 
t. 
A serum or urine pregnancy test will be performed in women of childbearing potential (ie, premenopausal and perimenopausal women who have been amenorrheic for 
less than 12 months) at the Screening Visit. If a negative screening pregnancy test is obtained more than 72 hours before the planned first dose of lenvatinib and 
everolimus, a separate serum or urine sample must be obtained and tested at the Baseline Visit. 
u. 
Sparse PK samples will be collected from all subjects at the following time points: 2-8 hours postdose on C1D1, prior to dose on C1D15, prior to dose and 2-8 hours 
postdose on Day 1 of Cycles 2 and 3.   
v. 
Screening: Screening tumor assessments using CT of the brain, chest, abdomen and pelvis, and other areas of known or newly suspected disease should be performed 
between Day –28 to Day -2.  Detailed imaging guidelines will be provided by the imaging core laboratory.  Scans that were performed within this window but before 
informed consent may be used if they were acquired consistent with the guidelines provided by the imaging core laboratory.  
Treatment Phase:  Tumor assessments of the chest/abdomen/pelvis and other areas of known disease at Screening plus any areas of newly suspected disease should be 
performed every 8 weeks (within the 8th week), or sooner if clinically indicated, until documentation of disease progression and should utilize the same methodology and 
scan acquisition techniques used at Screening to ensure comparability. All objective responses must be confirmed at least 28 days following the initial achievement of the 
response. The same methodology and acquisition techniques used at Screening should be used throughout the study to ensure comparability. 
Follow-up Period: Subjects who discontinue treatment without disease progression should continue tumor assessments every 8 weeks ± 1 week, until disease 
progression or beginning another anticancer therapy. 


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w. Bone scans using whole body bone MRI, 99m-technetium based bone scans, or 18F sodium fluoride positron-emission tomography (Na-F PET) will be performed during 
the pre-treatment phase to establish a baseline (a historical bone scan performed within 6 weeks before first dose is acceptable), every 24 weeks, and as clinically 
indicated. Lesions identified on bone scans should be followed with cross-sectional imaging. 
x. 
A brain scan will be performed at Screening and thereafter if clinically indicated.  In subjects with CR based on body CT/MRI scans, a brain scan assessment will be 
required at response confirmation.        
y. 
Concomitant medications will be recorded throughout and for 28 days after last dose of lenvatinib and/or everolimus.  All anticancer therapy will be recorded until time 
of death or termination of survival follow-up. 
z. 
Throughout the study from the signature of Informed Consent.  SAE irrespective of relationship to study treatment must be reported as soon as possible but not later than 
24 h.  AEs will be recorded for 28 days after last dose of lenvatinib and/or everolimus. During treatment interruption due to AEs, repeat AE assessments at least every 
7 days (until restarting lenvatinib and/or everolimus administration).  
 
 


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9.5.2.2 
Description of Procedures/Assessments Schedule 
Refer to Table 5 for a description and timing of each procedure and assessment in the 
Pretreatment, Treatment, and Posttreatment phases. 
9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of nccRCC. 
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, radiologic studies, and assessment of AEs, are standard 
evaluations to ensure subject safety. 
9.5.4 
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 1 business day from when the investigator becomes aware of the event. 
Serious adverse events, regardless of causality assessment, must be collected through the last 
visit and for up to 28 days after the subject’s last dose of study treatment.  All SAEs must be 
followed to resolution or, if resolution is unlikely, to stabilization.  Any SAE judged by the 
investigator to be related to the study treatment or any protocol-required procedure should be 
reported to the sponsor regardless of the length of time that has passed since study 
completion. 
The detailed contact information for reporting of SAEs is provided in the Investigator Study 
File. 
For urgent safety issues, please ensure all appropriate medical care is administered to the 
subject and contact the appropriate study team member listed in the Investigator Study File. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 


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The investigator must notify his/her IRB/IEC of the occurrence of the SAE in writing, if 
required by their institution.  A copy of this communication must be forwarded to the sponsor 
to be filed in the sponsor’s Trial Master File. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which either the estimated date of conception is before the last visit or 
within 28 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 28 days of last study treatment, must be reported.  
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]). 
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Investigator Study File.  
The Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study.   
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose.  
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol.  
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects. 


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Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.   
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF. 
9.5.4.3.2 
REPORTING OF STUDY-SPECIFIC EVENTS 
Study-specific events, consisting of clinically significant bleeding, should always be 
considered as serious important medical events and be entered on the Adverse Event CRF 
and reported using the procedures detailed in Reporting of Serious Adverse Events 
(Section 9.5.4.1), even if the study-specific event does not meet other serious criteria.   
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators 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. 
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 5). 
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 


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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 reasons: 
AE(s), lost to follow-up, subject choice, (ie, subject chooses to discontinue from the 
treatment but is willing to participate in the Follow-Up portion of the study), progression of 
disease, withdrawal of consent (ie, subject no longer wishes to participate in the study and be 
contacted), pregnancy, sponsor discontinuation of the study, or other.  Study disposition 
information will be collected on the Subject Disposition From Treatment Phase CRF page. 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s or the CRO’s qualified compliance auditing team, 
which is an independent function from the study team responsible for conduct of the study.   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by ICH 
guidelines, the CRF is a printed, optical, or electronic document designed to record all of the 
protocol-required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator or designee as identified on Form FDA 
1572 must sign the completed CRF to attest to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 


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9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
All statistical analyses will be performed by the sponsor or designee after the study is 
completed and the database is locked and released and a snapshot of the database is obtained 
and released.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP). 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock. 
9.7.1.1 
Study Endpoints 
9.7.1.1.1 
PRIMARY ENDPOINT 
The primary efficacy endpoint is ORR based on investigator assessment, defined as the 
proportion of subjects who have a BOR of CR or PR.  
9.7.1.1.2 
SECONDARY ENDPOINTS 
The secondary efficacy endpoints are: 
 PFS based on investigator assessment – defined as the time from date of first dose of 
study drug to date of first documentation of disease progression or death, whichever 
occurs first. 
 OS – defined as the time from the date of first dose of study drug until date of death 
from any cause. 
9.7.1.1.3 
EXPLORATORY ENDPOINTS  
The exploratory endpoints are: 
 ORR based on IIR assessment. 
 PFS based on IIR assessment. 
 CBR is the proportion of subjects who have a BOR of CR or PR or durable SD. 
Stable disease must be achieved at ≥ 23 weeks after first lenvatinib administration to 


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be considered durable SD.  The CBR will be determined based on both investigator 
and IIR assessments. 
 DCR is the proportion of subjects who have a BOR of CR, PR, or SD.  The DCR will 
be determined based on both investigator and IIR assessments. 
 DOR is defined as the time from the date that the criteria are met for CR or PR 
(whichever is recorded first) to the date that PD is objectively documented or death, 
whichever occurs first.  The DOR will be determined based on both investigator and 
IIR assessments. 
9.7.1.2 
Definitions of Analysis Sets 
The Full Analysis Set (FAS) includes subjects who received at least 1 dose of the study 
drugs. This will be the analysis set for all efficacy and safety evaluations.   
The Evaluable Analysis Set (EAS, a subset of the Full Analysis Set) includes all subjects 
who have both an evaluable baseline tumor assessment and an evaluable postbaseline tumor 
assessment, unless the subjects are discontinued because of disease progression or toxicity. 
This will be used for the sensitivity analyses of efficacy. 
The PK Analysis Set will include all subjects who received at least one dose of study drug 
and have evaluable lenvatinib plasma and/or everolimus whole blood concentration data. 
The Pharmacodynamic Analysis Set  will include all subjects who received at least one dose 
of study drug and have evaluable pharmacodynamics data. 
9.7.1.3 
Subject Disposition 
The number of subjects enrolled, prematurely discontinued from study treatment (defined as 
those who discontinued study treatment due to any reason except for progressive disease) and 
those with major protocol deviations will be counted.  The reason for study drug 
discontinued will be summarized according to the categories in the CRF.  The end of study 
status (alive, death, withdrew consent or lost to follow-up) at the data cutoff date will be 
summarized using the data from the survival follow-ups. 
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the FAS will be summarized using 
descriptive statistics.  Continuous demographic and baseline variables include age, weight, 
and vital signs; categorical variables include sex, age group, ECOG performance status, race, 
and subtypes of nccRCC.   
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).  The number 


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(percentage) of subjects who took prior and concomitant medications will be summarized on 
the FAS by Anatomical Therapeutic Chemical (ATC) class and WHO DD preferred term 
(PT).  Prior medications will be defined as medications that stopped before the first dose of 
study drug.  Concomitant medications will be defined as medications that (1) started before 
the first dose of study drug and were continuing at the time of the first dose of study drug, or 
(2) started on or after the date of the first dose of study drug up to 28 days after the subject’s 
last dose.  All medications will be presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
9.7.1.6.1 
PRIMARY EFFICACY ANALYSIS 
Primary endpoint ORR assessed by investigator review will be analyzed using the Full 
Analysis Set. Subjects who did not have a tumor assessment for any reason will be 
considered as nonresponders and included in the denominator when calculating response rate. 
In this population, ORR in the historical control is assumed to be 8% (Hudes et al.,2007). 
The ORR in this study is estimated as 25%, which is deemed a clinical meaningful 
improvement. Hence, the null and alternative hypotheses are set as follows: 
                                                     H0: ORR=8% 
                                                     Ha: ORR ≥25% 
Simon’s Two-Stage Design (Simon, 1989) is used in hypothesis testing for the primary 
endpoints.  The interim futility analysis after Stage 1 allows for an early evaluation of 
efficacy results in order to stop the study early in the case of low anticancer activity.  A 
minimum of 2 responders as assessed by ORR in the Stage 1 subjects (n1=16) is required in 
the interim analysis for the study to proceed to Stage 2, in which 15 more subjects may be 
enrolled.  In the final analysis of ORR, a minimum of 6 responders is required in Stages 1 
and 2 subjects combined (n=31) to claim the superiority of study treatment over historical 
controls.  
The ORR based on investigator assessment in the final analysis will be calculated and a 
2-sided Clopper–Pearson 95% confidence interval (CI) will be constructed.  
Table 6 
Simon’s Two-Stage Design for Interim Futility and Final 
Analyses of ORR 
 
Threshold 
Interim Analysis 
Continue if  ≥2 responders when n1=16 
Final Analysis 
Reject H0 if ≥6 responders when n=31 
H0 = null hypothesis,  n = sample size for Stages 1 and 2 subjects combined, n1 = sample size for 
Stage 1 subjects, ORR = objective response rate  


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9.7.1.6.2 
SECONDARY EFFICACY ANALYSES 
The PFS assessed by the investigator and OS will be analyzed using Kaplan–Meier product-
limit estimates.  Median PFS and OS and the cumulative probability of PFS at 3, 6, and 12 
months and cumulative probability of OS at 6, 12, and 18 months will be presented with two-
sided 95% CI if estimable.  PFS censoring rules will follow FDA Guidance for Industry, 
Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2018).   
The cumulative PFS and OS will be plotted over time.  The median, first, and third quartiles 
from Kaplan–Meier estimation for PFS and OS will be provided with 95% CI if estimable. 
9.7.1.6.3 
EXPLORATORY EFFICACY ANALYSES 
The ORR based on IIR assessment will be evaluated using the same method described in the 
primary analysis.  
A 2-sided Clopper–Pearson 95% CI will be constructed for CBR and DCR.  The DOR and 
PFS per IIR assessment will be analyzed using time to event methods described above. 
9.7.1.6.4 
FORMAL ANALYSES OF ORR, PFS, AND OS 
A formal analysis will be carried out after all subjects have been enrolled and on study 
treatment for at least 6 months or have discontinued due to disease progression, death, or 
toxicity.  Since the primary endpoint ORR data are expected to be observed sooner than the 
secondary endpoints, the timing of the formal analysis is chosen such that the secondary 
endpoints, PFS and OS, will be adequately described.  The primary population for efficacy 
and safety analyses is the FAS. 
9.7.1.6.5 
SENSITIVITY ANALYSES 
The above efficacy analyses will be conducted in the EAS as sensitivity analyses. 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
9.7.1.7.1 
PHARMACOKINETIC ANALYSES 
A population PK approach will be used to characterize the PK of lenvatinib and everolimus 
and the final PK model will be used to derive lenvatinib and everolimus exposure parameters 
to be used in the subsequent pharmacokinetic (PK)/pharmacodynamic analyses. The analyses 
will be detailed in a separate analysis plan.  Concentrations of each analyte will be graphed 
by time within each nominal collection interval.  Average dose at each collection interval 
will also be displayed. 
9.7.1.7.2 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
Lenvatinib and everolimus exposure parameters derived from the population PK analysis will 
be related to biomarker, safety, and efficacy data using a model-based approach.  For some 


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PK/pharmacodynamic analyses, data from this study may be pooled with data from other 
clinical studies of study drug. 
For efficacy, a tumor growth inhibition model based on longitudinal tumor size 
measurements of target lesions will be included.  We plan to explore exposure to both 
lenvatinib and everolimus exposure and/or selected biomarkers, identified in other studies of 
study drug, as predictors and/or correlations with tumor burden changes in the tumor growth 
inhibition model. Other analyses will include logistic regression analysis for ORR24W.   
For the exposure-response relationship of safety, data will be analyzed using a longitudinal 
categorical logistic regression analysis for AEs leading to dosing reduction or interruption.  
For the exposure-response relationship for selected biomarkers, identified in other clinical 
studies of study drug, data may be analyzed using a model-based approach.  
Population PK and PK/pharmacodynamic analyses will be detailed in a separate analysis 
plan. 
9.7.1.7.3 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Soluble, tissue, genetic and/or imaging biomarkers (Baseline and/or posttreatment) may be 
summarized using descriptive statistics and correlated with clinical outcomes-related 
endpoints for safety and/or efficacy as appropriate.  Details will be included in a separate 
analysis plan. 
9.7.1.8 
Safety Analyses 
Safety, using the FAS, will be assessed by monitoring and recording of all AEs including all 
CTCAE grades, regular monitoring of hematology and clinical chemistry, urinalysis, regular 
measurement of vital signs, 12-lead ECGs, and performance of physical examinations.  
Adverse events and other clinical safety data will be summarized descriptively in the FAS. 
The incidence of TEAEs, SAEs, drug-related AEs, and AEs leading to discontinuation will 
be summarized in tabulation. Hematology, serum chemistry, vital sign variables and ECG 
will be summarized descriptively for observed values, by grade and by change from Baseline 
by cycle. All AEs and lab parameters will be listed. 
9.7.1.8.1 
EXTENT OF EXPOSURE 
The number of cycles/days on treatment, quantity of study treatment administered, and the 
number of subjects requiring dose reductions, treatment interruption, treatment delay, and 
treatment discontinuation due to adverse events will be summarized for each study drug. 
9.7.1.8.2 
ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 


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(MedDRA).  Adverse events will be coded to the MedDRA (Version 17 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, 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.  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 (mild, moderate, or severe by highest CTCAE grade). 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
each study drug and combined (Yes [related] and No [not related]). 
9.7.1.8.3 
LABORATORY VALUES 
Clinical laboratory (ie, hematology, serum chemistry, and qualitative urinalysis) values will 
be evaluated for each laboratory parameter.  Abnormal laboratory values will be flagged and 
identified as those outside (above or below) the normal range.  Reference (normal) ranges for 
laboratory parameters will be included in the clinical study report for this protocol.  
Descriptive summary statistics (eg, n, mean, standard deviation, median, minimum, 
maximum for continuous variables; n[%] for categorical variables) for laboratory parameters 
and their changes from baseline will be calculated.  Laboratory values will be summarized by 
visit and by worst postbaseline visit. 
Laboratory parameters that are graded in CTCAE (v4.03) will be summarized by CTCAE 
grade.  In the summary of laboratory parameters by CTCAE grade, parameters with CTCAE 
grading in both high and low directions (eg, calcium, glucose, magnesium, potassium, 
sodium) will be summarized separately. 
Please see Appendix 7 for sponsor’s grading of laboratory values. 
9.7.1.8.4 
VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit for all visits.  Vital signs will be listed by subject and visit. 


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9.7.1.8.5 
ELECTROCARDIOGRAMS 
ECG assessments will be performed at the Screening Visit and during the Treatment Phase 
according to Table 5.  Descriptive statistics for ECG parameters and changes from baseline 
will be presented by visit. 
9.7.1.8.6 
OTHER SAFETY ANALYSES 
Not applicable. 
9.7.1.9 
Other Analyses 
Any other statistical/ analytical issues will be discussed in the SAP. 
9.7.2 
Determination of Sample Size 
The sample size is calculated using Simon’s Two-Stage Design for the primary endpoint 
ORR assuming an ORR of 25% from this study versus an historical control of 8%.  A total of 
approximately 31 subjects, including 16 in Stage 1, are planned to be enrolled in the study.  
The actual number of subjects accrued will depend on the results from Stage 1.  If ≤1 
responders are observed in the first 16 subjects treated (Stage 1), the enrollment will be 
stopped. The total sample size will be the actual number of subjects enrolled at the time of 
termination of the study.  If ≥2 responders are observed in Stage 1, the study will proceed to 
Stage 2 and a total of 31 subjects will be enrolled.  At least 6 responders in 31 subjects is 
required to claim superiority of the study treatment.  This design yields a one-sided type I 
error of 0.0319 and the power of 0.8053 in Stages 1 and 2 combined. 
9.7.3 
Interim Analysis 
An interim analysis may be performed by the sponsor after 16 subjects in Stage 1 have 
completed at least 2 tumor assessments (eg, Week 16 tumor assessments), unless 
discontinued due to disease progression, death or toxicity.  If one or no responders are 
observed in the interim analysis, the study will be stopped early for futility and subjects on 
study at that time will continue treatment under the discretion of the investigator. If two or 
more responders are confirmed before the planned interim analysis and the safety profiles of 
both drugs are acceptable, the study will continue to Stage 2 and a formal interim analysis 
may be waived. There will be no enrollment gap for the interim analysis. 
At interim analysis, the probabilities of early futility stopping are 0.6299 under H0: ORR=8% 
and 0.0635 under Ha: ORR≥25%, respectively. 
9.7.4 
Other Statistical/Analytical Issues 
None. 


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9.7.5 
Procedure for Revising the Statistical Analysis Plan 
The SAP will be finalized prior to the database lock in this study.  Any deviation from the 
analysis plan described in the protocol will be documented in the SAP. 


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Ljungberg BJ, Jacobsen J, Rudolfsson SH, Lindh G, Grankvist K, Rasmuson T.  Different 
vascular endothelial growth factor (vegf), vegf-receptor 1 and -2 mrna expression profiles 
between clear cell and papillary renal cell carcinoma. BJU Int. 2006;98(3):661-7. 
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 Nov;16(15):1473-82.  
National Comprehensive Cancer Network [NCCN]. Clinical practice guidelines in oncology, 
2015. Available from: https://www.nccn.org/professionals/physician_gls/default.aspx  
Oken MM, Creech RH, Torney DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
Posadas EM, Limvorasak S, Sharma S, Figlin RA. Targeting angiogenesis in renal cell 
carcinoma. Exp Opin Pharmacother. 2013;14(16):2221-36. 
Robson CJ, Churchill BM, Anderson W. The results of radical nephrectomy for renal cell 
carcinoma. J Urol. 1969;101(3):297-301.   
Simon R. Optimal two-stage designs for phase II clinical trials, Control Clin Trials. 
1989;10(1):1-10. 
Wahal SP, Mardi K. Multilocular Cystic Renal Cell Carcinoma: A Rare Entity with Review 
of Literature. J Lab Physicians. 2014 Jan-Jun; 6(1): 50–52. 
Eisai Clinical Study Reports 


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Report Number: CPMS-E7080-007R-v1. Population pharmacokinetic analysis of lenvatinib 
(pooled data) and pharmacokinetic/pharmacodynamic analyses of lenvatinib efficacy, 
biomarker (Study E7080-G000-303) and safety (Studies E7080-G000-201, E7080-G000-303, 
E7080-J081-208) in subjects with Iodine-131 refractory, unresectable differentiated thyroid 
cancer. 20 May 2014. 
Report Number: RDMPKA2013-156 REVISION NO. 1.  Study Report: Simulation of drug-
drug interaction between lenvatinib and CYP3A4 substrate midazolam, and CYP2C8 
substrate repaglinide. 12 Sep 2014. 
 
 
 


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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.  Amendments specifically 
affecting the safety of subjects, the scope of the investigation, or the scientific quality of the 
study require submission to health or regulatory authorities as well as additional approval by 
the applicable IRBs/IECs.  These requirements should in no way prevent any immediate 
action from being taken by the investigator, or by the sponsor, in the interest of preserving 
the safety of all subjects included in the study.  If the investigator determines that an 
immediate change to or deviation from the protocol is necessary for safety reasons to 
eliminate an immediate hazard to the subjects, the sponsor’s medical monitor and the 
IRB/IEC for the site must be notified immediately.  The sponsor must notify the health or 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB/IEC, but the health or regulatory 
authority and IRB 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 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 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 
 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 


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 
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, electroencephalograms [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  
 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs/IECs 
 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source. 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following item(s), the data recorded directly on the CRF are to be considered source data: 
 
Study treatment compliance (eg, the reason for dose reduction). 
 
Discontinuation information. 
 
Sampling date and time for drug concentration. 
 
Sampling date and time for the clinical laboratory test. 
 
Comments and other information on AEs (eg, severity, relationship to study treatment, 
outcome). 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator is responsible for retaining all study documents, including but not limited to the 


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protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency registration 
documents (eg, Form FDA 1572, ICFs, and IRB/IEC correspondence).  The site should plan 
to retain study documents, as directed by the sponsor, for at least 2 years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 3 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. 
It is requested that at the completion of the required retention period, or should the 
investigator retire or relocate, the investigator contact the sponsor, allowing the sponsor the 
option of permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of ICH GCP and all applicable local 
regulations.  If a government regulatory authority requests an inspection during the study or 
after its completion, the investigator must inform the sponsor immediately. 
11.8 Handling of Study Drug 
All study drug will be supplied to the 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, when approval is given by the sponsor, will destroy supplies and 
containers at the site. 
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant to the terms and conditions set forth in the executed Clinical Trial Agreement 
between the sponsor/CRO and the institution/investigator.  The review is aimed at protecting 


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


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


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


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


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


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


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


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Appendix 3 
Estimated Glomerular Filtration Rate (eGFR) Using 
Cockcroft and Gault Formula 
 
 
 
 
 
 
 
 
 
 


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Appendix 4 
New York Heart Association Cardiac Disease 
Classification 
The New York Heart Association Cardiac Disease Classification provides a 
functional and therapeutic classification for the prescription of physical activity for 
cardiac subjects.  Based on NYHA definitions, subjects are to be classified as follows: 
 
 
Class 
NYHA Status 
Class I: 
Subjects with no limitation of activities; they suffer no symptoms 
from ordinary activities. 
Class II: 
Subjects with slight, mild limitation of activity; they are comfortable 
with rest or with mild exertion. 
Class III: 
Subjects with marked limitation of activity; they are comfortable 
only at rest. 
Class IV: 
Subjects who should be at complete rest, confined to bed or chair; 
any physical activity brings on discomfort and symptoms occur at 
rest. 
NYHA = New York Heart Association. 
Adapted from The Criteria Committee of the New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th ed. 1994:253-6. 


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Appendix 5 
Common Terminology Criteria for Adverse Events 
(v4.03) 
The National Cancer Institute's CTCAE v4.0 published 28 May 2009 (v4.03: June 14, 2010) 
provides descriptive terminology to be used for AE reporting in clinical trials.  A brief 
definition is provided to clarify the meaning of each AE term.  To increase the accuracy of 
AE reporting, all AE terms in CTCAE version 4.0 have be correlated with single-concept, 
MedDRA terms. 
 
Grades in CTCAEs v4.03 refer to the severity of the AE.  Grades of 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline: 
 
Grade 
CTCAE Status 
1 
Mild: asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
2 
Moderate: minimal, local, or noninvasive intervention indicated; limiting 
age- appropriate instrumental activities of daily living (ADL).a 
3 
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b 
4 
Life-threatening consequences: urgent intervention indicated. 
5 
Death related to adverse event. 
CTCAE = Common Terminology Criteria for Adverse Events. 
a: Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
b: Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and 
not bedridden. 
Adapted from the Cancer Therapy Evaluation Program, NCI. CTCAE v4.0. Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 02 Oct 2014). 
 
 
For further details regarding MedDRA, refer to the MedDRA website at: 
http://www.meddramsso.com. CTCAE   v4.0 is available online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 02 Oct 2014). 
 


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Appendix 6 
 
Stage Information for Renal Cell Cancer 
 
http://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq 
 
Definitions of TNM 
 
The TNM Staging System (tumor-node-metastasis) is the most widely used system for cancer 
staging in the world.  The staging system for renal cell cancer is based on the degree of tumor 
spread beyond the kidney (Bassil B et al 1985; Golimbu M et al, 1986; Robson CJ et al 
1969).  Involvement of blood vessels may not be a poor prognostic sign if the tumor is 
otherwise confined to the substance of the kidney. Abnormal liver function test results may 
be caused by a paraneoplastic syndrome that is reversible with tumor removal, and these 
types of results do not necessarily represent metastatic disease. Except when computed 
tomography (CT) examination is equivocal or when iodinated contrast material is 
contraindicated, CT scanning is as good as or better than magnetic resonance imaging for 
detecting renal masses (Magnetic Resonance Imaging JAMA 1988) 
Definitions of TNM 
The American Joint Committee on Cancer has designated staging by TNM classification to 
define renal cell cancer (Edge SB et al 2010) 
Table 1. Primary Tumor (T)a 
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 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 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 Gerota fascia (including contiguous extension into the 
ipsilateral adrenal gland). 


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Table 2. Regional Lymph Nodes (N)a 
NX 
Regional lymph nodes cannot be assessed. 
N0 
No regional lymph node metastasis. 
N1 
Metastases in regional lymph node(s). 
 
Table 3. Distant Metastasis (M)a 
M0 
No distant metastasis. 
M1 
Distant metastasis. 
 
Table 4.  Anatomic Stage/Prognostic Groups 
Stage 
T 
N 
M 
I 
T1 
N0 
M0 
II 
T2 
N0 
M0 
III 
T1 or T2 
N1 
M0 
T3 
N0 or N1 
M0 
IV 
T4 
Any N 
M0 
Any T 
Any N 
M1 
aReprinted with permission from AJCC: Kidney. In: Edge SB, Byrd DR, 
Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, 
NY: Springer, 2010, pp 479-89. 


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Appendix 7 
Sponsor’s Grading for Laboratory Values 
 
Sponsor’s Grading for Laboratory Values 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
BLOOD/BONE MARROW 
 
 
 
 
Hemoglobin   
<LLN – 10.0 g/dL 
<LLN – 100 g/L 
<LLN – 6.2 mmol/L 
<10.0 – 8.0 g/dL 
<100 – 80 g/L 
<6.2 – 4.9 mmol/L  
<8.0 g/dL 
<80 g/L 
<4.9 mmol/L; 
transfusion indicated 
life-threatening 
consequences; urgent 
intervention indicated 
Leukocytes (total WBC) 
<LLN – 3.0109/L 
<LLN – 3000/mm3  
<3.0 – 2.0109/L 
<3000 – 2000/mm3  
<2.0 – 1.0109/L 
<2000 – 1000/mm3  
<1.0109/L 
<1000/mm3  
Lymphocytes  
<LLN – 800/mm3  
<LLN – 0.8109/L 
<800 – 500/mm3 
<0.8 – 0.5109/L 
<500 – 200/mm3  
<0.5 – 0.2109/L 
<200/mm3 
<0.2109/L 
Neutrophils  
<LLN – 1.5109/L 
<LLN – 1500/mm3 
<1.5 – 1.0109/L 
<1500 – 1000/mm3 
<1.0 – 0.5109/L 
<1000 – 500/mm3  
<0.5109/L 
<500/mm3  
Platelets 
<LLN – 75.0109/L 
<LLN – 75,000/mm3  
<75.0 – 50.0109/L 
<75,000 – 50,000/mm3 
<50.0 – 25.0109/L 
<50,000 – 25,000/mm3 
<25.0109/L 
<25,000/mm3  
METABOLIC/LABORATORY 
 
 
 
 
Albumin, serum- low 
(hypoalbuminemia)  
<LLN – 3 g/dL 
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L 
<2 g/dL 
<20 g/L 
life-threatening 
consequences; urgent 
intervention indicated 
Alkaline phosphatase  
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
ALT 
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
AST 
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
Bilirubin (hyperbilirubinemia) 
>ULN – 1.5ULN  
>1.5 – 3.0ULN 
>3.0 – 10.0ULN  
>10.0ULN 
Calcium, serum-low (hypocalcemia)  
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Calcium, serum-high (hypercalcemia) 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Cholesterol, serum-high 
(hypercholesterolemia) 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L  
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L  
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L  
>500 mg/dL 
>12.92 mmol/L  
Creatinine 
>ULN – 1.5ULN 
>1.5 – 3.0ULN 
>3.0 – 6.0ULN 
>6.0ULN 
GGT (γ-glutamyl transpeptidase)  
>ULN – 3.0ULN 
>3.0 – 5.0ULN 
>5.0 – 20.0ULN 
>20.0ULN 
Glucose, serum-high (hyperglycemia) 
Fasting glucose value: 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L  
Fasting glucose value: 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L  
>250 – 500 mg/dL; 
>13.9 – 27.8 mmol/L; 
hospitalization indicated 
>500 mg/dL; 
>27.8 mmol/L; 
life-threatening 
consequences  
Glucose, serum-low (hypoglycemia) 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
life-threatening 


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


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PROTOCOL SIGNATURE PAGE 
Study Protocol Number: E7080-M001-221 
Study Protocol Title: 
A single-arm, multicenter, Phase 2 trial to evaluate efficacy and 
safety of lenvatinib in combination with everolimus in subjects 
with unresectable advanced or metastatic non clear cell renal 
cell carcinoma (nccRCC) who have not received any 
chemotherapy for advanced disease 
Investigational Product 
Name: 
Lenvatinib (E7080) and everolimus   
IND Number: 
124564 
 
 
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
Study Protocol Number: 
E7080-M001-221 
Study Protocol Title: 
A single-arm, multicenter, Phase 2 trial to evaluate efficacy and 
safety of lenvatinib in combination with everolimus in subjects 
with unresectable advanced or metastatic non clear cell renal 
cell carcinoma (nccRCC) who have not received any 
chemotherapy for advanced disease 
Investigational Product 
Name: 
Lenvatinib (E7080) and everolimus  
 
IND Number: 
124564 
 
 
 
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. 
<Name of institution> 
Medical Institution 
 
<Name, degree(s)> 
  
  
Investigator 
 Signature 
 Date 
 
As regionally required 
<Name, degree(s)> 
  
  
President of Japan/Asia 
Clinical Research Product 
Creation Unit 
 Signature 
 Date 
 

SAP_001.pdf: 
Statistical Analysis Plan
E7080-M001-221
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STATISTICAL ANALYSIS PLAN
Study Protocol 
Number:
E7080-M001-221
Study Protocol 
Title:
A single-arm, multicenter, Phase 2 trial to evaluate efficacy and safety 
of lenvatinib in combination with everolimus in subjects with 
unresectable advanced or metastatic non clear cell renal cell 
carcinoma (nccRCC) who have not received any chemotherapy for 
advanced disease
Date:
11 Oct 2019
Version:
Final Version 2.0


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E7080-M001-221
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Page 2 of 27
1
TABLE OF CONTENTS
1
TABLE OF CONTENTS...................................................................................................2
2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS....................................4
3
INTRODUCTION .............................................................................................................6
3.1
Study Objectives ......................................................................................................6
3.1.1
Primary Objective..........................................................................................6
3.1.2
Secondary Objectives.....................................................................................6
3.1.3
Exploratory Objectives ..................................................................................6
3.2
Overall Study Design and Plan................................................................................7
4
DETERMINATION OF SAMPLE SIZE..........................................................................7
5
STATISTICAL METHODS..............................................................................................7
5.1
Study Endpoints.......................................................................................................8
5.1.1
Primary Endpoint...........................................................................................8
5.1.2
Secondary Endpoints .....................................................................................8
5.1.3
Exploratory Endpoints ...................................................................................8
5.2
Study Subjects..........................................................................................................9
5.2.1
Definitions of Analysis Sets...........................................................................9
5.2.2
Subject Disposition........................................................................................9
5.2.3
Protocol Deviations........................................................................................9
5.2.4
Demographic and Other Baseline Characteristics .........................................9
5.2.5
Prior and Concomitant Therapy...................................................................10
5.2.6
Treatment Compliance.................................................................................11
5.3
Data Analysis General Considerations ..................................................................11
5.3.1
Pooling of Centers........................................................................................11
5.3.2
Adjustments for Covariates..........................................................................11
5.3.3
Multiple Comparisons/Multiplicity .............................................................11
5.3.4
Examination of Subgroups...........................................................................11
5.3.5
Handling of Missing Data, Dropouts, and Outliers .....................................11
5.3.6
Other Considerations ...................................................................................11
5.4
Efficacy Analyses ..................................................................................................11
5.4.1
Primary Efficacy Analyses ..........................................................................12
5.4.2
Secondary Efficacy Analyses ......................................................................13
5.4.3
Other Efficacy Analyses ..............................................................................13
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses...............................................................................................13
5.5.1
Pharmacokinetic Analyses...........................................................................13


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5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....13
5.6
Safety Analyses......................................................................................................13
5.6.1
Extent of Exposure.......................................................................................14
5.6.2
Adverse Events ............................................................................................14
5.6.3
Laboratory Values........................................................................................15
5.6.4
Vital Signs....................................................................................................17
5.6.5
Electrocardiograms ......................................................................................17
5.6.6
Other Safety Analyses..................................................................................18
5.7 
Other Analyses.......................................................................................................18
5.8 
Exploratory Analyses.............................................................................................18
6 
INTERIM ANALYSES...................................................................................................18
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................18
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................18
8.1
Baseline..................................................................................................................18
8.2
Day to Month to Year ............................................................................................18
8.3
Censoring Rule.......................................................................................................19
8.4
Best Overall Response (BOR) ...............................................................................20
8.5
Missing Date Handling ..........................................................................................20
8.5.1
Adverse Event with Missing Dates..............................................................20
8.5.2
Medication with Date Missing or Partially Missing....................................21
9
PROGRAMMING SPECIFICATIONS ..........................................................................21
10
STATISTICAL SOFTWARE..........................................................................................21
11
MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................21
12
REFERENCES ................................................................................................................21
13
APPENDICES .................................................................................................................22
13.1
Clinically Significant TEAEs per MedDRA Version 22.0....................................22
13.2
Eastern Cooperative Oncology Group Performance Status...................................23
13.3
New York Heart Association Cardiac Disease Classification ...............................24
13.4
Common Terminology Criteria for Adverse Events (v4.03).................................25
13.5
Table 2 for Renal Cell Cancer ...............................................................................26


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2
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ATC
anatomical therapeutic class
BOR
best overall response
BMI
body mass index
CBR
clinical benefit rate
CI
confidence interval
CR
complete response
CRF
case report form
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
disease control rate
DOR
duration of response
EAS
evaluable analysis set
ECG
electrocardiograms
ECOG
Eastern Cooperative Oncology Group
FAS
full analysis set
FDA
Food and Drug Administration
IIR
Independent imaging review
LLT
lower level term
MedDRA
Medical Dictionary for Regulatory Activities
nccRCC
non clear cell renal cell carcinoma
NE
not evaluable
NA
not applicable
NYHA
New York Heart Association
ORR
objective response rate
OS
overall survival
PD
progressive disease
PFS
progression-free survival


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Abbreviation
Term
PK
pharmacokinetic
PR
partial response
PT
preferred term
Q1
25th percentile
Q3
75th percentile
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SI
Système International
SOC
system organ class
TEAE
treatment-emergent adverse event
TLG
tables, listings, and graphs
TNM
tumor-node-metastasis
UNK
unknown
WHO
World Health Organization
WHO DD
World Health Organization Drug Dictionary


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3
INTRODUCTION
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E7080-
M001-221, A single-arm, multicenter, Phase 2 trial to evaluate efficacy and safety of 
lenvatinib in combination with everolimus in subjects with unresectable advanced or 
metastatic non clear cell renal cell carcinoma (nccRCC) who have not received any
chemotherapy for advanced disease.  The focus of this SAP is on the planned primary, 
secondary and exploratory analyses at the final stage of the study.
3.1
Study Objectives
3.1.1
Primary Objective
The primary objective of the study is to evaluate objective response rate (ORR), as assessed 
by the investigator, of lenvatinib in combination with everolimus in subjects with 
unresectable advanced or metastatic nccRCC who have not received any chemotherapy for 
advanced disease. 
3.1.2
Secondary Objectives
The secondary objectives of the study are: 
•
To assess safety and tolerability of lenvatinib in combination with everolimus
•
To evaluate progression-free survival (PFS) as assessed by the investigator
•
To evaluate overall survival (OS)
•
To assess the pharmacokinetic (PK) profiles of lenvatinib and everolimus during 
combination therapy in subjects with nccRCC
3.1.3
Exploratory Objectives
The exploratory objectives of the study are: 
•
To explore ORR as assessed by independent imaging review (IIR)
•
To explore PFS as assessed by IIR
•
To explore clinical benefit rate (CBR) as assessed by the investigator and by IIR
•
To explore disease control rate (DCR) as assessed by the investigator and by IIR
•
To explore duration of response (DOR) as assessed by the investigator and by IIR
•
To identify and explore tumor and blood biomarkers that correlate with clinical 
outcomes, including efficacy


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•
To explore the relationship of population PK derived exposure parameters to biomarker, 
safety, and efficacy data using a model-based approach
3.2
Overall Study Design and Plan
This is a single-arm, multicenter, Phase 2 study of lenvatinib in combination with everolimus
(lenvatinib 18 mg/day + everolimus 5 mg/day) in subjects with unresectable advanced or 
metastatic nccRCC who have not received any chemotherapy for advanced disease. A 
Simon’s Two-Stage Design has been implemented in 31 enrolled subjects. Sixteen subjects 
were enrolled in Stage 1 with more than 2 responders as assessed by ORR, so the study 
proceeded to Stage 2 in which 15 more subjects were enrolled. In the final analysis of 31 
subjects, at least 6 responders are required to show a statistically significant improvement of 
ORR over historical control in the same patient population.
The study consisted of 3 Phases: a Pretreatment Phase (Screening and Baseline Periods), a 
Treatment Phase (Starting on Cycle 1, Day 1), and a Post-treatment Phase (End of Treatment 
Visit and survival Follow Up). The study’s Schedules of Procedures and Assessments for all 
study phases are explained in Table 5 of Protocol Amendment 01.   
Subjects who discontinued one of the study drugs due to its toxicities might continue to 
receive the other study drug as long as they demonstrated clinical benefit. Subjects would 
discontinue both study drugs at the time of documented disease progression, development of 
unacceptable toxicity, withdrawal of consent, or study termination by the sponsor.
4
DETERMINATION OF SAMPLE SIZE
The sample size was calculated using Simon’s Two-Stage Design for the primary endpoint 
ORR assuming an ORR of 25% from this study versus an historical control of 8% (Hudes et 
el., 2007). A total of approximately 31 subjects, including 16 in Stage 1, were planned to be 
enrolled in the study. The actual number of subjects accrued depended on the results from 
Stage 1. If ≤1 responders were observed in the first 16 subjects treated (Stage 1), the 
enrollment should be stopped. The total sample size would be the actual number of subjects 
enrolled at the time of termination of the trial. If ≥2 responders were observed in Stage 1, the 
study proceeded to Stage 2 and a total of 31 subjects would be enrolled. At least 6 responders 
in 31 subjects are required to claim superiority of the study treatment over the historical 
control. This design yielded a one-sided α, type I error, of 0.0319 and power of 0.8053 in 
Stages 1 and 2 combined.
5
STATISTICAL METHODS
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, 25th percentile (Q1), 75th percentile (Q3), minimum and maximum.  
Categorical variables will be summarized as number (percentage) of subjects.


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5.1
Study Endpoints
5.1.1
Primary Endpoint
The Primary efficacy endpoint is ORR based on investigator assessment, defined as the 
proportion of subjects who have a best overall response (BOR) of complete response (CR) or 
partial response (PR). Confirmation of CR and PR must have been performed ≥4 weeks after 
response was first documented. Subjects whose overall response cannot be determined will
be considered as not having an objective response.
5.1.2
Secondary Endpoints
The secondary efficacy endpoints are:
•
PFS based on investigator assessments – defined as the time date of first dose of study 
drug to date of first documentation of disease progression or death, whichever occurs 
first. The censoring rules are detailed in Section 8.3.  
•
OS – defined as the time from the date of first dose of study drug until date of death from 
any cause. In the absence of death before data cutoff, subjects will be censored either at 
the date last known to be alive or the date of data cutoff, whichever came earlier.
5.1.3
Exploratory Endpoints 
The exploratory endpoints are:
•
ORR based on IIR assessment.
•
PFS based on IIR assessment.
•
CBR is the proportion of subjects who have a BOR of CR or PR or durable stable disease 
(SD). SD must be achieved at ≥ 7 weeks after the first study drug to be considered as a 
best overall response. Durable SD is a subset of SD with the duration of ≥ 23 weeks after 
the first study drug. The CBR will be determined based on both investigator and IIR 
assessments.
•
DCR is the proportion of subjects who have a BOR of CR, PR, or SD. The DCR will be 
determined based on both investigator and IIR assessments.
•
DOR is defined as the time from the date that the criteria are met for CR or PR 
(whichever is recorded first) to the date that progressive disease (PD) is objectively 
documented or death, whichever occurs first. The start time is the first recorded instance 
of response, not the date when the response is confirmed. Only responders will be 
included in this analysis. The DOR will be determined based on both investigator and IIR 
assessments.


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5.2
Study Subjects
5.2.1
Definitions of Analysis Sets
The Full Analysis Set (FAS) includes subjects who received at least one dose of the study 
drugs. This will be the analysis set for all efficacy and safety evaluations.
The Evaluable Analysis Set (EAS, a subset of the Full Analysis Set) includes all subjects 
who have both an evaluable baseline tumor assessment and an evaluable postbaseline tumor 
assessment per investigator, unless subjects are discontinued because of disease progression 
or toxicity. This will be used for the sensitivity analyses of efficacy for investigator 
assessments.
An evaluable post-baseline tumor assessment will be determined by a completed overall 
tumor timepoint response assessment that is not NE. Similarly, an evaluable baseline 
assessment will have a diameter recorded for target lesions, or a non-target assessment that is 
not ‘NE’ or ‘NA’.  
The PK Analysis Set will include all subjects who received at least one dose of study drug 
and have evaluable lenvatinib plasma and/or everolimus whole blood concentration data.
5.2.2
Subject Disposition
The number (percentage) of enrolled subjects and screen failures will be summarized. 
Reasons for screen failure will also be tabulated.
Subject disposition on study treatment (treatment ongoing at data cutoff date, treatment 
discontinued, and the primary reason for discontinuation) will be summarized. Study status at 
data cutoff and reason for discontinue from study will also be summarized using data from 
the survival follow-ups. 
Distribution of subjects by sites in the United States will also be summarized. 
5.2.3
Protocol Deviations
All protocol deviations will be determined prior to database lock and will be agreed upon by 
a review of individual subject data. Major protocol deviations will be summarized and listed 
by each category.
5.2.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the FAS will be summarized. 
Demographic summaries will be repeated for the EAS.
Continuous demographic and baseline variables include age, BMI, weight, and height;
categorical variables include sex, age group (≤65 years, >65 years), ethnicity and race.  Other 
variables at study entry include: pregnancy test, ECOG performance status, NYHA, TNM 


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classification (T-Primary Tumor, N-Regional Lymph Nodes, M-Distant Metastasis), 
Anatomic Stage (I, II, III, IV), time from original diagnosis to first dose, age at diagnosis, 
location of primary tumor, subtypes of nccRCC (Papillary, Chromophobe, CDC, RMC, 
Unclassified, Other), number of target lesions and total sum of target lesion diameters.  
MEDICAL HISTORY
The number (percentage) of subjects reporting a history of any medical condition and current 
medical condition, as recorded on the CRF, will be summarized. A subject data listing will 
also be provided. Medical History will be coded using MedDRA (version 22.0), and 
summarized on the FAS by System Organ Class (SOC) and Preferred term (PT).
5.2.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code
using 
the 
World 
Health 
Organization 
Drug 
Dictionary 
(WHO 
DD) 
(version 
WHODDMAR18_HD_B2).
Prior medications will be defined as medications that started before the first dose of study 
drug. Concomitant medications will be defined as medications that (1) started before the first 
dose of study drug and were continuing at the time of the first dose of study drug, or (2) 
started on or after the date of the first dose of study drug up to 28 days after the subject’s last 
dose. Medications started after 28 days of the last dose of study drug will be considered as 
post-treatment medications.
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the FAS by Anatomical Therapeutic Chemical (ATC) class and WHO DD 
PT. All medications will be presented in subject data listings.
Frequencies [n (%)] of previous anticancer medication will be displayed on the FAS by ATC 
class and WHO DD preferred term.  In addition, previous anticancer medication will be 
summarized on the FAS in terms of number of regimens, duration of last regimen, best 
response for last regimen, time from end of last regimen to first dose, and therapeutic setting 
( adjuvant / locally advanced / neoadjuvant / metastatic / maintenance / unknown ).
The following data on previous radiotherapy will be summarized on the FAS: time from last 
radiotherapy to first dose, site of previous radiotherapy, progression of tumor lesion at the 
site since radiotherapy (yes/no), and number of all previous radiotherapy treatments.
The non-pharmacological procedures and palliative radiotherapy will be only presented in 
subject data listings.
New anticancer medication and procedures during survival follow-up will be summarized on 
the FAS respectively by ATC class and preferred term, and by SOC and preferred term.


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5.2.6
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study. Clinical 
research associates will review treatment compliance during investigational site visits and at 
the completion of the study. Treatment compliance will not be summarized since the data 
will not be entered into the clinical database. However, dose modifications (i.e., reduction/ 
interruption) will be summarized in Section 5.6.1.
5.3
Data Analysis General Considerations
5.3.1
Pooling of Centers 
This study is a multicenter study. Subjects from all centers will be pooled together for all the 
analyses.
5.3.2
Adjustments for Covariates
Not applicable.
5.3.3
Multiple Comparisons/Multiplicity
The overall type I error is controlled at 0.05 in the hypothesis tests of the primary endpoint.  
No multiplicity adjustments for the tests of secondary endpoints will be made in this 
exploratory trial.  A two-sided alpha of 0.05 will be used in the tests unless otherwise 
specified.
5.3.4
Examination of Subgroups
No subgroup analyses are planned for this study.
5.3.5
Handling of Missing Data, Dropouts, and Outliers
Rules for missing dates for AE and concomitant medications are set out in Section 8.5.  For 
PFS analysis, drop-outs will be censored according to the rules described in Section 8.3. 
Potential outlier values will be investigated. They will be analyzed as originally reported in 
the locked database.
5.3.6
Other Considerations
Not applicable.
5.4
Efficacy Analyses
Tumor response data utilized in the efficacy analyses will be obtained from both 
investigator’s assessment of the imaging scans and independent image review. Tumor 
response will be assessed by RECIST 1.1 criteria (Eisenhauer et al 2009).


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5.4.1
Primary Efficacy Analyses
The primary analysis is the comparison of ORR assessed by investigator in the FAS to the 
rate from historical data. Subjects who do not have a tumor assessment for any reason will be 
considered non-responders and included in the denominator when calculating the response 
rate. Confirmation of CR and PR must have been performed ≥4 weeks after response was 
first documented; full details are described in Section 8.4.  
ORR from historical control data is assumed to be 8%. An ORR equal to 25% constitutes a 
clinically meaningful improvement in ORR for this trial. Hence, the null and alternative 
hypotheses are set as follows: 
H0: ORR = 8% vs. Ha: ORR ≥ 25%
Simon’s Two-Stage Design is used in hypothesis testing for the primary endpoint, ORR.  The 
interim futility analysis after Stage 1 allowed for an early evaluation of efficacy results in 
order to stop the trial early for futility, when the interim results suggested the trial was
unlikely to achieve statistical significance. As detailed in Table 1, the trial would stop early 
at the interim stage if no more than 1 responder out of 16 subjects was observed. Otherwise, 
the trial proceeded to the second stage and with a total of 31 subjects recruited. Six responses 
for the primary efficacy endpoint in the final analysis are required to conclude statistical 
significance at the second stage. 
Table 1 Simon's Two-Stage Design for Interim Futility and Final Analyses of ORR
Threshold
Interim Analysis
Continue if >=2 responders when n1=16
Final Analysis
Reject H0 if >=6 responders when n=31
H0 = null hypothesis, n = sample size for Stages 1 and 2 subjects combined, n1 = sample size for Stage 1 
subjects, ORR = objective response rate
Final Analysis 
Since there were more than 1 responder out of the first 16 treated subjects, study proceeded 
to Stage 2 to include 31 total treated subjects. The final analysis will take place after all
subjects have been enrolled and on study treatment for at least 6 months or have discontinued 
due to disease progression, death or toxicity.
A 2-sided Clopper-Pearson 95% confidence interval (CI) will be constructed for ORR. The 
percentages for each BOR category (CR, PR, SD, PD, NE/UNK) will be displayed. 
SENSITIVITY ANALYSIS
ORR per investigator tumor assessments will also be summarized in EAS at the final 
analysis. 


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5.4.2
Secondary Efficacy Analyses
All analyses of secondary efficacy endpoints will be performed in FAS. PFS assessed by 
investigator will also be summarized in EAS.
The PFS assessed by the investigator and OS will be analyzed using Kaplan–Meier product
limit estimates. Median PFS and OS will be presented with two-sided 95% Brookmeyer-
Crowley confidence intervals (CIs) if estimable. In addition, the cumulative probability of 
PFS at 3, 6, and 12 months and the cumulative probability of OS at 6, 12, and 18 months will 
be reported along with the 95% CIs using Kaplan-Meier product limit method and 
Greenwood log-log formula. The censoring rules for PFS are detailed in Section 8.3.  
The cumulative PFS and OS will be plotted over time.
5.4.3
Other Efficacy Analyses
ORR and PFS based on IIR assessment will be analyzed the same as ORR and PFS per 
investigator assessments, separately. DCR and CBR for both investigator and IIR 
assessments will be evaluated using the same method as used for ORR.
DOR for both investigator and IIR assessments will be summarized for subjects with BOR of 
CR or PR. The censoring rule is the same as that of PFS censoring when applicable. KM
estimated quantiles and their 95% CIs, using the generalized Brookmeyer and Crowley 
method will be provided.
In addition, waterfall plots will be presented on the percentage changes from baseline to post-
baseline nadir in sum of diameters of the target lesions per investigator and IIR assessments.
5.5
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses
5.5.1
Pharmacokinetic Analyses
Individual listings with a summary of plasma concentrations of lenvatinib and a figure 
containing lenvatinib plasma concentrations versus PK sampling time will be provided by 
subject in the Pharmacokinetic Analysis Set. Other PK analyses will be described in a 
separate analysis plan.
5.5.2
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses
Not Applicable.
5.6
Safety Analyses
All safety analyses will be performed based on Full Analysis Set. Safety data will be 
summarized on an “as treated” basis using descriptive statistics (i.e., n, mean, standard 


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deviation, median, minimum, maximum for continuous variables; n [%] for categorical 
variables). Safety variables include treatment-emergent adverse events (TEAEs), clinical 
laboratory parameters, vital signs, 12-lead ECG results, ECOG. Abnormal values will be 
flagged.
Study Day 1 for all safety analyses is defined as the date of the first dose of study drug.
5.6.1
Extent of Exposure
The duration of treatment (months), calculated as (Date of last dose – Date of first dose 
+1)/(365.25/12)  will be summarized with descriptive statistics for lenvatinib and everolimus 
combined and separately. 
Following variables will be summarized separately for lenvatinib and everolimus:
•
Total cumulative dose (mg) per subject is defined as the sum of all doses actually taken 
by subject.
•
Dose intensity (mg/day) per subject is defined as the total cumulative dose (mg) per 
subject divided by the total duration of treatment in days.
•
Relative dose intensity per subject is defined as 100 times the dose intensity divided by 
the starting planned dose.
•
Number of subjects with dose reductions, dose interruptions and treatment 
discontinuation.
•
Time to first dose reduction (weeks) for applicable subjects.
Subject data listings will be provided for all dosing records, and for the above calculated 
summary statistics.
5.6.2
Adverse Events
AEs will be graded by the investigators using CTCAE v4.03.  The AE verbatim descriptions 
(investigator terms from the CRF) will be classified into standardized medical terminology 
using the Medical Dictionary for Regulatory Activities (MedDRA). Adverse events will be 
coded to the MedDRA (version 22.0) lower level term (LLT) closest to the verbatim term. 
The linked MedDRA preferred term (PT) and primary system organ class (SOC) are also 
captured in the database.
A treatment-emergent AE (TEAE) is defined as an AE that emerges during treatment or up to 
28 days following last dose of study drug, having been absent at pretreatment (Baseline) or 
•
Reemerges during treatment or up to 28 days following last dose of study drug, having 
been present at pretreatment (Baseline) but stopped before treatment, or 


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•
Worsens in severity during treatment or up to 28 days following last dose of study drug 
relative to the pretreatment state, when the AE is continuous.
Only those AEs that are treatment emergent will be included in summary tables. All AEs, 
treatment emergent or otherwise, will be presented in subject data listings.
An overview table, including the incidence of and the number of subjects with TEAEs, 
TEAEs with grade 3 or above, treatment-related TEAEs, serious adverse events (SAEs), 
deaths, and TEAEs that led to study drug withdrawal, dose reduction, or dose interruption 
will be provided. Treatment-related events are considered by the investigator to be related to 
study treatment or with missing assessment of the causal relationship.   
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by SOC, PT and CTCAE grade. A subject will be counted only once within a SOC and PT, 
even if the subject experienced more than one TEAE within a specific SOC and PT, and the
highest grade will be chosen. This table will be repeated by PT and CTCAE grade in 
descending order of frequency. 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC, PT and CTCAE grade.  The number (percentage) of subjects with SAEs, treatment-
related SAEs, TEAEs leading to discontinuation from study drug, and TEAEs leading to dose 
modification will be summarized by SOC, PT and CTCAE grade in separate tables.   
Separate subject data listings of all AEs, fatal AEs, grade 3 or above AEs, SAEs, AEs leading 
to discontinuation from study drug, and AEs leading to dose modification will be provided.
A listing of all deaths will be provided, and an overall summary of deaths will be computed: 
deaths within 28 days of the last dose and death after 28 days of the last dose.
In addition, clinically significant TEAEs will be generated and summary of these clinically 
significant TEAEs will be provided. Appendix 13.1 includes the list of clinically significant 
TEAEs.
5.6.3
Laboratory Values
Clinical laboratory tests to be performed include hematology, chemistry and urinalysis.  
Laboratory results will be summarized as appropriate, using the International System of units
(SI). For all quantitative hematology and chemistry parameters listed in
Table 2, the actual value and the change from baseline to each post-baseline visit (with at 
least 10% of subjects) will be summarized by visit using descriptive statistics. 


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Laboratory parameters will be categorized according to CTCAE v4.03 grades and shifts from 
baseline CTCAE grades to worst post-baseline values (high/low separately where applicable)
will be assessed.
Table 2  Clinical Laboratory Tests


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Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, WBC count with 
differential (bands, basophils eosinophils, lymphocytes, monocytes, 
neutrophils), and ANC 
Chemistry
   Electrolytes
Bicarbonate, chloride, magnesium, potassium, sodium
   Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
   Renal function tests
Blood urea/blood urea nitrogen, creatinine
  Thyroid function testsa
TSH and free T4
   Pregnancy test
Serum β-hCG (if urine not tested)
   Fasting blood tests
Glucose, lipids (total cholesterol, LDL-C, HDL-C, triglycerides)
   Other
Albumin, amylase, calcium, lactate dehydrogenase, lipase, 
phosphorus, total protein, uric acid
Urinalysis
Glucose, ketones, pH, protein, RBCs, specific gravity
   Pregnancy test
Urine β-hCG(if serum not tested)
ANC = absolute neutrophil count, β hCG=beta-human chorionic gonadotropin, HDL-C=high density 
lipoprotein-C, LDL-C=low density lipoprotein-C, RBC=red blood cells, T4=thyroxine, TSH=thyroid 
stimulating hormone, WBC=white blood cells. 
a:  Thyroid function will be assessed at the Screening Visit, at Baseline/C1D1, Day 1 of every cycle (starting at 
C2) throughout the study, and at the End of Treatment Visit.
5.6.4
Vital Signs
Descriptive statistics for vital signs parameters (i.e., diastolic blood pressure [DBP] and 
systolic blood pressure [SBP], pulse rate, respiratory rate, temperature, weight) and changes 
from baseline will be presented for each visit (with at least 10% of subjects). Vital signs will 
be listed by subject.
Blood pressure will also be summarized using a shift table by visit by categories defined based 
on CTCAE grades (version 4.03): Grade 1 (Pre-Hypertension: SBP 120—139 mmHg or DBP 80 
– 89 mmHg), Grade 2 (Stage 1 Hypertension: SBP 140—159 mmHg or DBP 90—99 mmHg), 
Grade 3 (Stage 2 Hypertension: SBP ≥ 160 mmHg or DBP ≥ 100 mmHg).
5.6.5
Electrocardiograms
Descriptive statistics for ECG parameters and change from baseline will be presented by visit 
(with at least 10% of subjects).  ECG findings (categorized as normal; abnormal, not 
clinically significant; and abnormal, clinically significant) will be summarized, and the 
related shift table (from Baseline to Worst Post-Baseline) will be presented.  


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5.6.6
Other Safety Analyses
ECOG Performance Status will be provided in a listing and a shift table of baseline ECOG 
result versus worst post-baseline value will be presented.
5.7
Other Analyses
No other analyses are planned.
5.8
Exploratory Analyses
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriate titled and labeled as exploratory and will be clearly 
distinguished from planned analyses when results are reported in the Clinical Study Report.
6
INTERIM ANALYSES
An interim analysis was planned to be performed by the sponsor after 16 subjects in Stage 1 
have completed at least 2 tumor assessments (e.g., Week 16 tumor assessments), unless 
discontinued due to disease progression, death or toxicity. However, the formal interim 
analysis was waived and the study continued to Stage 2 because more than one responders
were confirmed before the planned interim analysis and the safety profiles of both drugs were
acceptable. 
7
CHANGES IN THE PLANNED ANALYSES
Treatment duration will be analyzed in months instead of nominal cycles mentioned in the 
protocol. The number (percentage) of subjects with TEAEs will be summarized by worst 
CTCAE grade instead of the maximum severity (mild, moderate, or severe by highest 
CTCAE grade) mentioned in the protocol. Protocol mentioned that the number (percentage) 
of subjects with TEAEs will also be summarized by relationship to each study drug and 
combined, however, only the relationship to combined drug will be summarized based on the 
data collection in the CRF.
Biomarker related analyses are no longer planned for this study, therefore, the 
Pharmacodynamic Analysis Set will not be defined in the analysis dataset. 
8
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING
8.1
Baseline
Baseline is defined as the most recently non-missing value collected before the first dose.
8.2
Day to Month to Year
1 month = 30.4375 days; 1 year = 365.25 days. 


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8.3
Censoring Rule
The PFS derivation rules in Table 3 follow the publication by the Food and Drug 
Administration (FDA), “Guidance for Industry Clinical Trial Endpoints for the Approval of 
Cancer Drugs and Biologics (2007)”.
Table 3  Censoring Rules for Analysis of Progression-Free Survival
No. Situation
Date of Progression or Censoring
Outcome
1
No baseline or post-baseline 
tumor assessments
Date of first dose
Censored
2
Progression documented 
between scheduled visits
Date of first radiological PD assessment
Progressed
3
No progression at the time of 
data cut-off or discontinuation 
from study treatment
Date of last adequate radiologic assessment prior to or 
on date of data cut-off or discontinuation from study 
treatment, or date of the first dose if no adequate post 
baseline tumor assessment was conducted.   
Censored
4
New anticancer treatment 
started
Date of last adequate radiologic assessment prior to or 
on date of new anticancer treatment, or date of the first 
dose if no adequate post baseline tumor assessment was 
conducted.   
Censored
5
Death before first PD 
assessment
Date of death
Progressed
6
Death between adequate 
assessment visits*
Date of death
Progressed
7
Death or progression after more 
than one missed visits**
Date of last adequate radiologic assessment before 
missed tumor assessments, or date of the first dose if no 
adequate post baseline tumor assessment was conducted.
Censored
CR = complete response, PD = progressive disease, PR = partial response, SD = stable disease,
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or PD.
New anticancer treatment includes palliative radiotherapy.
** More than one missed visits is defined as having either one of the following two durations being longer than 18 weeks - 1 
day, which is 125 days ( = ((8+1) x 2 x 7) – 1) for subjects on the every 8 week tumor assessment schedule in this study:
duration between two consecutive tumor assessments; or duration between the last adequate tumor assessment and death or 
PD.
The priority of the censoring rules is as follows:
1. If the subject had PD or death within 4 weeks of study drug discontinuation, the following sequence will be applied:

If a subject did not have baseline tumor assessment (No. 1), the subject will be censored on date of first dose. 
However, if the subject died within 125 days after first dose and did not receive new anticancer treatment, the date 
of death will be the PFS event date (not censored).

If a subject had new anticancer treatment before PD or death (No. 4), the subject will be censored on the date of 
the last tumor assessment prior to or on the date of new anticancer treatment.

If a subject missed more than one assessment before PD or death (No. 7), the subject will be censored on the date 
of the last tumor assessment before PD or death. Note that if a subject is censored by both this criterion and the 
anticancer treatment criteria, the earliest censoring date will be used.

Otherwise, if a subject had an event (No. 2, No. 5, or No. 6), the earliest event date will be used.


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2. If a subject did not have PD or death, the censoring date will be the earliest censoring date if the subject met multiple 
censoring criteria (No. 1, No. 3, No. 4, No. 7).
8.4
Best Overall Response (BOR)
Best Overall Response does not consider tumor assessments after 1st documented PD, new 
anticancer treatment and more than one consecutive missing tumor assessments. BOR is 
defined according to the following order of operations:
1. If subject does not have a baseline tumor assessment, then BOR=NE / UNK
2. Else confirmed CR will be derived by the following rules:

Consecutive CR [CR/NE] CR (>= 28 days between the first CR and last CR)
3. Else if not confirmed CR, the confirmed PR will be determined by the following 
rules:

Consecutive PR [CR/PR/NE] CR/PR (>= 28 days between the first PR and the last CR/PR)

Consecutive PR SD CR/PR (>= 28 days between the first PR and the second PR/CR)
4. Else if not confirmed CR or PR, BOR of SD will be determined by the following 
rules:

Consecutive PR SD (>=28 days between PR and SD)

Any timepoint with response CR/PR/SD/Non-CR/Non-PD that is 49 days after the first dose date
5. Else if not confirmed CR or PR, or SD, and any timepoint with response PD, then 
BOR=PD
6. Else if not confirmed CR or PR, or SD or PD, then BOR=NE / UNK
8.5
Missing Date Handling
Missing data will not be imputed unless otherwise stated in the SAP or in the footnote of an 
output. Missing data will not be included in any analysis unless otherwise specified. When 
relevant, the number of subjects with missing data will be presented
8.5.1
Adverse Event with Missing Dates
If the missing start and/or end dates of the AE did not indicate that the AE started prior to the 
study treatment or after the 28th day post last study treatment, it will be classified 
conservatively as the TEAE (Section 5.6.2). This data handling is just for the determination 
of TEAEs no imputation will be performed to AE start/end dates in datasets and listings.


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8.5.2
Medication with Date Missing or Partially Missing
See Section 5.2.5 for the missing date handling in determination of prior and concomitant 
medications. 
9
PROGRAMMING SPECIFICATIONS
The rules for programming derivations and dataset specifications are provided in a separate 
document (analysis datasets specification).
10 STATISTICAL SOFTWARE
All statistical analyses will be performed using SAS version 9.3 or higher.
11 MOCK TABLES, LISTINGS, AND GRAPHS
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail.
12 REFERENCES
Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03.  United States 
Department of Health and Human Services, National Institutes of Health, National Cancer 
Institute, Washington, DC, USA, June 14, 2010.
Criteria Committee, New York Heart Association. Nomenclature and criteria for diagnosis of 
diseases of the heart and great vessels. 9th ed. Boston: Little, Brown & Co; 1994. p. 253-6.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, editors. Kidney. In: AJCC 
Cancer staging manual. 7th ed. New York: Springer, 2010. p. 479-89.
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.
Oken MM, Creech RH, Torney DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55.


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13 APPENDICES
13.1
Clinically Significant TEAEs per MedDRA Version 22.0
The following are the Clinically Significant AE groups considered in the analyses. 
For Lenvatinib:
1. Arterial TE Events
2. Cardiac Dysfunction
3. Fistula Formation
4. GI Perforation
5. Haemorrhage terms (excl laboratory terms)
6. Hepatotoxicity
7. Hypertension
8. Hypocalcemia
9. Hypothyroidism
10. Palmar plantar erythrodysesthesia
11. Posterior reversible encephalopathy syndrome
12. Proteinuria
13. Torsade de pointes/QT prolongation
14. Renal Events
For Everolimus:
1. Dyslipidaemia
2. Angioedema
3. Interstitial lung disease
4. Rash
5. Stomatitis


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13.2
Eastern Cooperative Oncology Group Performance Status
Scale
ECOG Performance Status
0
Fully active, able to carry on all predisease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (eg, light house work, office work).
2
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours.
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair.
5
Dead.
ECOG = Eastern Cooperative Oncology Group.
Adapted from Oken MM, et al. Am J Clin Oncol. 1982;5:649-55.


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13.3
New York Heart Association Cardiac Disease Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for heart failure patients 
based on cardiac functional capacity.  Based on NYHA definitions, heart failure subjects are 
to be classified as follows:
Class
NYHA Status
Class I
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II
Subjects with slight, mild limitation of activity; they are comfortable at 
rest or with mild exertion.
Class III
Subjects with marked limitation of activity; they are comfortable only at 
rest.
Class IV
Subjects who should be at complete rest, confined to bed or chair; any 
physical activity brings on discomfort and symptoms occur at rest.
NYHA = New York Heart Association.
Adapted from The Criteria Committee of the New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th ed. 1994:253-6.


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13.4
Common Terminology Criteria for Adverse Events (v4.03)
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
v4.0 [published 28 May 2009 (v4.03:  14 June 2010)] provides descriptive terminology to be 
used for adverse event reporting in clinical trials.  A brief definition is provided to clarify the 
meaning of each AE term.  To increase the accuracy of AE reporting, all adverse event terms 
in CTCAE version 4.0 have been correlated with single-concept, Medical Dictionary for 
Regulatory Activities (MedDRA®) terms.
CTCAE v4.0 grading refers to the severity of the AE.  CTCAE grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Grade
CTCAE Status
1
Mild: asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
2
Moderate: minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL.b
4
Life-threatening consequences: urgent intervention indicated.
5
Death related to adverse event.
CTCAE = Common Terminology Criteria for Adverse Events.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.0.  Available from: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 25 Jun 2015).
For further details regarding MedDRA, refer to the MedDRA website at:
http://www.meddra.org/.  CTCAE v4.03 is available online at:  
http://evs.nci.nih.gov/ftp1/CTCAE/About.html (Accessed 25 Jun 2015).


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13.5
Stage Information for Renal Cell Cancer
http://www.cancer.gov/types/kidney/hp/kidney-treatment-pdq
Definitions of TNM
The TNM Staging System (tumor-node-metastasis) is the most widely used system for cancer 
staging in the world. The staging system for renal cell cancer is based on the degree of tumor 
spread beyond the kidney (Bassil B et al 1985; Golimbu M et al, 1986; Robson CJ et al 
1969). Involvement of blood vessels may not be a poor prognostic sign if the tumor is 
otherwise confined to the substance of the kidney. Abnormal liver function test results may 
be caused by a paraneoplastic syndrome that is reversible with tumor removal, and these 
types of results do not necessarily represent metastatic disease. Except when computed 
tomography (CT) examination is equivocal or when iodinated contrast material is 
contraindicated, CT scanning is as good as or better than magnetic resonance imaging for 
detecting renal masses (Magnetic Resonance Imaging JAMA 1988)
Definitions of TNM
The American Joint Committee on Cancer has designated staging by TNM classification to 
define renal cell cancer (Edge SB et al 2010)
Table 1. Primary Tumor (T)a
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 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 
Gerota fascia.TX Primary tumor cannot be assessed.
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 Gerota fascia (including contiguous extension into the
ipsilateral adrenal gland).


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Table 2. Regional Lymph Nodes (N)a
NX
Regional lymph nodes cannot be assessed.
N0
No regional lymph node metastasis.
N1
Metastases in regional lymph node(s).
Table 3. Distant Metastasis (M)a
MX
No distant metastasis.
M0
Distant metastasis
Table 4. Anatomic Stage/Prognostic Groupsa
Stage
T
N
M
I
T1
N0
M0
II
T2
N0
M0
III
T1 or T2
N1
M0
T3
N0 or N1
M0
IV
T4
Any N
M0
Any T
Any N
M1
aReprinted with permission from AJCC: Kidney. In: Edge SB, Byrd DR, Compton CC, et al., 
eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 479-89.


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SIGNATURE PAGE
Author:  
Date
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ncology Business Group
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