Clinical trial NCT02454478
Conditions: Carcinoma, Renal Cell
Keywords: lenvatinib Everolimus Carcinoma Unresectable advanced renal cell carcinoma Metastatic renal cell carcinoma
Sponsor: Eisai Co., Ltd.
Start date: 2015-07-01; Completion date: 2017-05-29
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Phase 1 study to investigate the tolerability and safety of lenvatinib in combination with Everolimus in participants with unresectable advanced or metastatic RCC.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Lenvatinib intervention 2: Everolimus
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
Clinical Study Protocol 
E7080-J081-112 
 
Date: March 25, 2015 
Confidential  
 
Page 1 of 80 
1 
TITLE PAGE 
 
 
Clinical Study Protocol 
 
Study Protocol Number: 
E7080-J081-112 
Study Protocol Title: 
Phase 1 Study of Lenvatinib in Combination with Everolimus in Subjects with 
Unresectable Advanced or Metastatic Renal Cell Carcinoma  
Sponsor: 
Eisai Co., Ltd. 
 
 
Name of Active 
Ingredient: 
E7080/Lenvatinib Mesilate  
 
Indication: 
Unresectable advanced or metastatic renal cell carcinoma 
 
Phase of  
Development: 
Phase 1 
Approval Date: 
V 1.0 
25 Mar 2015 (original protocol) 
 
 
 
GCP Statement: 
This study is to be performed in full compliance with International 
Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) and all 
applicable local Good Clinical Practice (GCP) and regulations.  All 
required study documentation will be archived as required by 
regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential. It contains proprietary information of 
Eisai (the sponsor).  Any viewing or disclosure of such information 
that is not authorized in writing by the sponsor is strictly prohibited. 
Such information may be used solely for the purpose of reviewing or 
performing this study. 


 
Clinical Study Protocol 
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Date: March 25, 2015 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.;E7080 
Name of Active Ingredient: Lenvatinib Mesilate 
Study Protocol Title  
Phase 1 Study of Lenvatinib in Combination with Everolimus in Subjects with 
Unresectable Advanced or Metastatic Renal Cell Carcinoma  
Investigators: TBD 
Study Regions (Country) or Center 
Country: Japan 
Study center(s): 3 to 5  
Study Period and Phase of Development 
Jun 2015 – Sep 2017 (planned) 
Phase 1 
Objectives 
Primary Objective: 
• To investigate tolerability and safety of lenvatinib in combination with 
everolimus in subjects with unresectable advanced or metastatic renal cell 
carcinoma (RCC). 
 
Secondary objectives 
• To assess the pharmacokinetic (PK) of lenvatinib and everolimus 
• To assess the preliminary anticancer effects of lenvatinib in combination with 
everolimus  


 
Clinical Study Protocol 
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Date: March 25, 2015 
Confidential  
 
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Study Design 
This is a Phase 1 study of lenvatinib in combination with everolimus in subjects with 
unresectable advanced or metastatic renal cell carcinoma (RCC). 
Subjects will be enrolled in this study after obtaining informed consent and confirming the 
eligibility. One treatment cycle is defined as 28 days.  Lenvatinib will be administered at 
starting dose of 18mg in combination with everolimus at starting dose of 5 mg both orally 
once daily continuously.  Dose limiting toxicity (DLT) will be observed during Cycle 1 
(28 days following the initial dosing) to investigate tolerability and safety.  Treatment will 
continue until disease progression, development of unacceptable toxicity, subject requests 
to discontinue withdrawal of consent or study termination by sponsor.A total of six subjects 
will be initially enrolled.  Enrollment will be interrupted when DLT is observed in two or 
more subjects.  Investigators and sponsor will review the nature and severity of all the 
DLTs and make a decision if enrollment of up to six subjects and further additions of three 
to six subjects are feasible and necessary.  The suggestions by the independent medical 
advisor can be collected, if necessary.The study sponsor and investigators will consider the 
nature and severity of DLT during cycle 1 and also unacceptable toxicities that cannot be 
managed with dose interruption and/or reduction and overall toxicities until Cycle 2 on the 
evaluation of the tolerability of combination therapy.  The suggestions by the independent 
medical advisor can be collected, if necessary.If the dose level of lenvatinib 18 
mg/everolimus 5 mg QD is not tolerable such that more than one-third of subjects 
experience DLTs during Cycle 1 and/or unacceptable toxicities that cannot be managed 
with dose interruption and/or reduction are observed until Cycle 2, it will be considered that 
additional subjects are enrolled to the next lower cohort (lenvatinib 14 mg and everolimus 
5mg once daily administration). 


 
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If a subject has no DLT and fails to administer ≥ 75% of the planned dosage of lenvatinib and/or 
everolimus as a result of a reason other than treatment related toxicity up to Cycle 1 Day 28, this subject 
will not be included in the DLT assessment population and another subject will be added for 
replacement.Investigator and sponsor will make a decision for selection of subject to be included in DLT 
assessment population and additional subject will be considered as needed.DLT is defined as toxicity 
related to this combination therapy of the following indicated in below Table.Table : Dose Limiting 
Toxicities (DLT) 
Toxicity 
Category 
Toxicity/CTCAE Grade 
Hematologic 
• 
Grade 4 neutropenia lasting >7 days 
 
• 
Grade 3 febrile neutropenia (axillary temperature ≥38.5ºC and neutrophils 
<1×103/µL (<1000/mm3) 
 
• 
Grade ≥3 thrombocytopenia lasting >7 days or requiring blood transfusion 
Non-hematologic 
toxicity 
• 
Grade 3 non-hematologic toxicities lasting >7 days except for the following: 
 
Clinically insignificant or transient abnormal laboratory findings   
 
Able to be controlled by maximal supportive therapy  
Grade ≥3 hyperamylasemia or hyperlipasemia without clinical or other 
evidence of pancreatitis are not regarded as a DLT.  
• 
Grade ≥3 Nausea, vomiting or diarrhea lasting >7 days despite maximal medical 
therapy  
• 
Hypertension uncontrolled by medication  
• 
Any thromboembolic event including cerebrovascular hemorrhage/events 
Medication 
compliance 
• 
Failure to administer ≥75% of the planned dosage of lenvatinib or 
everolimus as a result of treatment related toxicity 
Number of Subjects 
6 to 12 (planned) 
Inclusion Criteria 
1. Voluntary agreement to provide written informed consent of this study 
2. Willing and able to comply with all aspects of the protocol after being fully informed 
of the content 
3. Males or females aged ≥20 years at the time of informed consent 
4. Histological or cytological confirmation of RCC 
5. Subjects must have confirmed diagnosis of unresectable advanced and/or metastatic 
RCC 
6. Disease progression following VEGF targeted therapy 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1 
8. Adequately controlled blood pressure with or without the use of antihypertensive 
agents (defined as BP ≤150/90 mmHg at screening and no change in 
antihypertensive therapy within 1 week prior to the Cycle 1 Day 1 
9. Subjects with adequate function of major organs: 


 
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Date: March 25, 2015 
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a. Hemoglobin ≥9.0 g/dL 
b. Neutrophil count ≥1.5×103 /μL 
c. Platelets ≥10×104 /μL 
d. Total bilirubin ≤1.5 mg/dL × upper limit of normal specified by the testing 
laboratory (ULN) 
e. Alkaline phosphatase (ALP), AST and ALT ≤ 3.0 x ULN (≤ 5.0 x ULN for patients 
with the liver metastasis) 
f. Creatinine clearance ≥40 mL/min calculated per the Cockroft and Gault formula 
Male:  (140–age)×weight (kg)÷72×Serum creatinine (mg/dL) 
Female:  0.85×(140–age)×weight(kg)÷72×Serum creatine (mg/dL) 
10. Adequate blood coagulation function, defined as international normalized ratio 
(INR) ≤1.5 
11. Survival expectation of 3 months or longer after study enrollment 
12. Washout period required from the end of prior treatment to the start of study drug 
administration will be as follows: 
a. Anticancer therapies: 
• Other investigational drug or antibody therapy: ≥4 weeks 
• Chemotherapy (except small-molecule targeted therapy), surgical therapy, 
radiation therapy: ≥3 weeks 
• Endocrine therapy, immunotherapy, small-molecule targeted therapy: ≥2 weeks. 
b. Supportive therapies: 
Blood transfusion, blood preparations, hematopietic growth factors including 
G-CSF preparations: ≥2 weeks 
13. Females of childbearing potential must not have had unprotected sexual intercourse 
within 28 days before subject registration and must agree to use a highly effective 
method of contraception (e.g., use of an intrauterine device, condom with 
spermicide*, a contraceptive implant**, an oral contraceptive*, or have a 
vasectomized partner with confirmed azoospermia)Note throughout the entire study 
period and for 30 days after final administration of investigational drug.  If 
currently abstinent, the subject must agree to use a double-barrier method as 
described above if she becomes sexually active during this study period or for 30 
days after investigational drug discontinuation.  Females who are using hormonal 
contraceptives must have been on a stable dose of the same hormonal contraceptive 
product for at least 4 weeks before administration and must continue to use the same 
contraceptive during this study and for 30 days after investigational drug 
discontinuation.  
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 (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, 


 
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all with surgery at least one month before administration 
Females of childbearing potential must not have had unprotected sexual intercourse 
within 28 days before subject registration and must agree to use a highly effective 
method of contraception (e.g., use of an intrauterine device, condom with spermicide*, 
a contraceptive implant**, an oral contraceptive*, or have a vasectomized partner with 
confirmed azoospermia)Note throughout the entire study period and for 30 days after 
final administration of investigational drug.  If currently abstinent, the subject must 
agree to use a double-barrier method as described above if she becomes sexually active 
during this study period or for 30 days after investigational drug discontinuation.  
Females who are using hormonal contraceptives must have been on a stable dose of 
the same hormonal contraceptive product for at least 4 weeks before administration 
and must continue to use the same contraceptive during this study and for 30 days after 
investigational drug discontinuation.  
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 (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, 
all with surgery at least one month before administration. 
Note: Whether or not a pharmaceutical agent or medical device has been approved and certified in Japan (* : yes, 
** : no) 
14. Male subjects and their female partners must meet the criteria above (i.e., not of 
childbearing potential or practicing highly effective contraception throughout this 
study period and for 30 days after final administration of investigational drug) 
 
Exclusion Criteria 
1. Subjects with CNS metastases are not eligible, unless they have completed local 
therapy and have discontinued the use of corticosteroids for this indication for at 
least 4 weeks before starting treatment in this study.  Any signs (eg, radiologic) or 
symptoms of brain metastases must be stable for at least 4 weeks before starting 
study treatment.  
2. Prior exposure to lenvatinib 
3. Subjects who have not recovered from toxicities to ≤ Grade 1 as a result of prior 
anticancer therapy, except alopecia 
4. Major surgery within 3 weeks prior to the first dose of lenvatinib  
5. Subjects having ≥2+ proteinuria on urine dipstick testing will undergo a 24-hour 
urine collection for quantitative assessment of proteinuria.  Subjects with a urine 
protein ≥1 g/24 hours will be ineligible. 
6. Uncontrollable diabetes as defined by fasting glucose >1.5×ULN 
7. Fasting total cholesterol >7.75 mmol/L (>300 mg/dL) 
8. Fasting triglycerides >2.5×ULN 
9. Gastrointestinal malabsorption, a history of gastroenterostomy, inability of oral 
administration, or any other condition that might affect the absorption of lenvatinib 


 
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and/or everolimus  
10. Significant cardiovascular impairment: 
a. Congestive heart failure than New York Heart Association (NYHA) Class II 
within 6 months of the first dose of study drug 
b. Unstable angina, myocardial infarction or stroke within 6 months of the first dose 
of study drug 
c. Prolongation of QTc (Friderica formula) interval >480 ms 
d. Cardiac arrhythmia requiring medical treatment for cardiovascular impairment 
11. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR 
monitoring, eg, warfarin or similar agents. Treatment with low molecular weight 
heparin is permitted. 
12. Active hemoptysis (bright red blood of at least 0.5 teaspoon or 2.5 mL) within 3 
weeks of the first dose of study drug 
13. Active infections that require systemic treatment  
14. Human immunodeficiency virus (HIV) positive 
15. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In 
addition, if negative for HBsAg but HBcAb and/or HBsAb positive, an HBV DNA 
test will be performed and if positive the subject will be excluded 
16. A history of interstitial pneumonia with clinical manifestation or as confirmed by 
means of diagnostic imaging 
17. Medical need for the continued use of potent or moderate inhibitors of CYP3A or 
P-gp, or potent or moderate inducer of CYP3A.  Subjects are eligible if 7 days or 
longer have passed since the last use of such agents prior to the first dose of study 
drug. 
18. Known intolerance to lenvatinib (or any of the excipients) or known hypersensitivity 
to everolimus (or any of the excipients) or rapamycins (sirolimus, temsirolimus and 
so on) 
19. Alcohol or drug dependency or abuse, inability to comply with every aspects of the 
study protocol, or any physical or mental conditions that in the opinion of the 
investigators would preclude the subject’s participation in the study  
20. Females who are pregnant or breastfeeding (not eligible even she discontinues 
breastfeeding) 
21. Any medical or other condition which, in the opinion of the investigator, would 
preclude participation in a clinical trial 


 
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Study Treatment(s) 
Lenvatinib is provided as 4 mg and 10 mg capsules by the study sponsor.  Study site will 
be responsible for obtaining everolimus tablets commercially from local source. 
Administration 
Lenvatinib and everolimus will be administered orally at the same time once a day in 
28-day cycles. 
In cycle 1, lenvatinib and everolimus will be administered orally on a fasting state in the 
morning, followed by a 1-hour food fast.  In cycle 2 or later, lenvatinib and everolimus 
will be administered consistently either before or after food.  The starting doses will be 
18mg for lenvatinib and 5mg for everolimus. 


 
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Drug interruption and dose reduction  
1. Cycle 1 
a. If DLT occurs: 
Lenvatinib and everolimus should be interrupted immediately.  Treatment may be 
resumed in Cycle 2 at one lower dose level of lenvatinib and/or reduction of 
everolimus to 5 mg every other day or discontinuation of everolimus if toxicity is 
resolved to Grade 0–1 or baseline and investigator or subinvestigator decides to 
continue the study. 
b. No DLT 
Lenvatinib and everolimus will be interrupted if judged to be clinically needed by 
investigators, and may be resumed at the same dose level at appropriate timing.  No 
dose reduction is permitted. 
2. Cycle 2 and onward 
Dose reduction and interruption for subjects who experience lenvatinib and/or 
everolimus related toxicity will follow the instructions shown in below Table.  Dose 
reductions occur in succession based on the previous dose level (14, 10, 8 mg/day).  
Any dose modification must be discussed with the sponsor when toxicities occur at the 
dose of 8 mg/day.  Once the dose has been reduced, it cannot be increased at a later 
date.  For management of hypertension and interstitial lung disease, refer to 
instructions ‘9.4.2 Management of Hypertension’ and ‘9.4.7 Management of interstitial 
lung disease’ before consulting the table below, as appropriate. 
 
Table : Dose Reduction and Interruption Instructions for Lenvatinib/Everolimus Combination 
Treatmenta 
Lenvatinib/Everolimus 
Treatment-Related Toxicityb,c,d 
During Therapy 
Adjusted Dose 
Grade 1or Tolerable Grade 2b 
Continue treatment 
No change 
Intolerable Grade 2b or Grade 3 
Interrupt lenvatinib and 
everolimus until resolved to 
Grade 0–1 or baseline  
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. 
Dose reduction lenvatinib by one level and/or 
reduce everolimus to 5 mg every other day or 
discontinuation of everolimus and resume the 
treatment. 
Grade4c 
Discontinue study treatment 
a:. 
An interruption of study treatment for more than 28 days due to treatment-related toxicity will require a discussion with the 
sponsor before treatment can be resumed. 
b: 
Tolerability Grade 2 toxicities will be judged by the study investigators to be intolerable. 
c: 
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3. 
d:  Initiate optimal medical management for nausea, vomiting, diarrhea prior to any treatment interruption, or dose reduction. If 
uncontrolled, the management will be followed by this guideline. 
Duration of Treatment 
Treatment will continue until disease progression, development of unacceptable toxicity, 


 
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subject requests to discontinue, withdrawal of consent, or study termination by sponsor. 
Concomitant Drug/Therapy 
The following therapies are prohibited: 
1. From the time of subject enrollment to off-treatment observation 
a. Anticancer treatment other than lenvatinib and everolimus (eg, surgery, 
chemotherapy, endocrine therapy, palliative radiotherapy, immunotherapy). 
b. Other investigational drugs 
c. Any agent that potently inhibits CYP3A or P-gp 
d. Live vaccine (freeze-dried live attenuated rubella, oral poliomyelitis vaccine, 
freeze-dried BCG, etc.) 
2. Cycle 1 
a. Any agent that potently and moderately inhibits CYP3A or P-gp, or any agent that 
potently and moderately induces CYP3A 
Assessments 
Safety and Tolerability 
Safety assessment will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs): periodic laboratory test value, vital signs, 12-lead ECGs, 
echocardiograms or multiple gated acquisition scan (MUGA) including left ventricular 
ejection fraction (LVEF), ECOG-PS, physical examination.  Severity of AEs will be 
graded according to CTCAE v4.03.  DLT will be evaluated for the tolerability of 
lenvatinib in combination with everolimus. 
Pharmacokinetic (PK) Assessments 
Plasma concentrations of lenvatinib and whole-blood concentrations of everolimus will be 
measured to assess pharmacokinetics. 
Efficacy Assessments 
Tumor assessment will be performed by investigator using RECIST 1.1 at Screening, every 
8 weeks after start of the study treatment, and as clinically indicated.  Best Overall 
Response (BOR) will be used for the assessment. 


 
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Bioanalytical Methods 
Plasma concentrations of lenvatinib and whole-blood concentrations of everolimus will be 
measured by using validated methods. 
Statistical Methods 
Analysis Sets 
DLT Analysis Set is the group of subjects who have completed treatment Cycle 1 without 
major protocol deviation with at least 75% of treatment compliance and were assessed for 
DLT, and subjects who have experienced DLT during Cycle 1.  Subjects with less than 
75% treatment compliance to lenvatinib or everolimus due to a reason other than toxicity 
up to Cycle 1 Day 28 will not be included in this analysis set.  Safety Analysis 
Set/Efficacy Analysis Set is the group of subjects who received at least 1 dose of lenvatinib. 
Pharmacokinetic (PK) Analysis Set is the group of subjects who received at least 1 dose of 
lenvatinib and had sufficient PK data to derive at least one PK parameter. 
Following analysis will be performed for total subjects or by initial dose group (if 
applicable). 
Tolerability/Safety Analyses 
All tolerability analyses will be performed on the DLT Analysis Set.  The number and 
percentage of subjects with DLT will be calculated.  DLT will also be summarized per 
type of toxicity.  The Safety Analysis Set will be used for all other safety analyses.  The 
number and percentage of subjects with all AEs and SAEs observed after first dosing will 
be summarized and listed by SOC, PT, and severity.  Summary statistics will be presented 
for laboratory test values, vital sign, and 12-lead ECG parameters.  If needed, the changes 
from baseline will also be summarized. 


 
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Pharmacokinetic Analysis 
Lenvatinib plasma concentrations and everolimus whole-blood concentrations will be 
summarized and listed for the subjects who have at least 1 evaluable data in the Safety 
Analysis Set.  The PK Analysis Set will be used for all other analyses including 
summaries of lenvatinib plasma concentrations, everolimus whole-blood concentrations 
and PK parameters.  Concentrations – time profiles of lenvatinib and everlolimus will be 
plotted and investigated.  Using non-compartmental analysis methods, plasma 
concentrations of lenvatinib and whole-blood concentration of everolimus will be 
calculated to determine the PK parameters including Cmax, tmax, AUC at first administration 
(Cycle 1 Day 1) and repeated administration (Cycle 1 Day 15). 
Efficacy Analyses 
Efficacy analyses will be based on the Efficacy Analysis Set.  BOR will be summarized 
using RECIST 1.1.  BOR consists of CR, PR, SD, PD and NE.  Objective response rate 
(ORR) and disease control rate (DCR) will be calculated with an exact 2-side 95% CI.  
ORR is defined as the proportion of subjects who have BOR of CR or PR.  DCR is 
defined as the proportion of CR, PR or SD.  Subjects with non-target disease only will be 
assigned to SD category if the BOR is non-CR/non-PD.   SD has to be achieved at ≥7 weeks 
after first dose.  CR and PR do not have to be confirmed at ≥4-week assessment.  If applicable, 
a waterfall plot will be presented for the percent changes from baseline in the sum of the 
diameters of target lesions at postbaseline nadir.  If applicable, time profiles of tumor 
marker will be plotted and investigated. 
Interim Analysis  
No interim analysis is planned in this study. 
Sample Size Rationale 
The primary objective of this study is to investigate the tolerability and safety of lenvatinib 
in combination with everolimus.  Hence neither clinical hypothesis nor judgment criteria 
are set, the sample size is not based on statistical consideration.  The 6 to 12 subjects per 
initial dose group are considered to be adequate to obtain some preliminary data for the 
assessment of safety. 
 


 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE ..................................................................................................................... 1 
2 
CLINICAL PROTOCOL SYNOPSIS ............................................................................... 2 
3 
TABLE OF CONTENTS ................................................................................................ 13 
LIST OF IN-TEXT TABLES .................................................................................................. 16 
LIST OF IN-TEXT FIGURES ................................................................................................ 16 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................. 17 
5 
ETHICS ........................................................................................................................... 19 
5.1 
Institutional Review Boards/Independent Ethics Committees .............................. 19 
5.2 
Ethical Conduct of the Study ................................................................................. 19 
5.3 
Subject Information and Informed Consent .......................................................... 19 
6 
INVESTIGATORS AND STUDY PERSONNEL .......................................................... 20 
7 
INTRODUCTION ........................................................................................................... 21 
7.1 
Indication ............................................................................................................... 21 
7.2 
Lenvatinib Mesylate (Lenvatinib) ......................................................................... 22 
7.3 
Concomitant use of Lenvatinib and Everolimus for RCC patients ....................... 23 
7.3.1 
Everolimus ................................................................................................... 23 
7.3.2 
Overseas Phase 1/2 study............................................................................. 23 
7.3.2.1 
Phase 1 part ........................................................................................ 23 
7.3.2.2 
Phase 2 part ........................................................................................ 24 
7.4 
Expected Adverse Events ...................................................................................... 25 
7.5 
Study Rationale ...................................................................................................... 26 
8 
STUDY OBJECTIVES ................................................................................................... 27 
8.1 
Primary Objective .................................................................................................. 27 
8.2 
Secondary Objectives ............................................................................................ 27 
9 
INVESTIGATIONAL PLAN .......................................................................................... 27 
9.1 
Overall Study Design and Plan .............................................................................. 27 
9.1.1 
Pretreatment Period ..................................................................................... 29 
9.1.1.1 
Treatment Period ............................................................................... 29 
9.1.1.2 
Follow-up Period ............................................................................... 30 
9.2 
Discussion of Study Design, Including Choice of Control Groups ....................... 30 
9.3 
Selection of Study Population ............................................................................... 30 
9.3.1 
Inclusion Criteria ......................................................................................... 30 
9.3.2 
Exclusion Criteria ........................................................................................ 32 
9.3.3 
Removal of Subjects from Therapy or Assessment ..................................... 33 
9.3.3.1 
Discontinuation for Individual Subjects ............................................ 34 
9.4 
Treatments ............................................................................................................. 34 


 
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9.4.1 
Drug interruption and dose reduction .......................................................... 34 
9.4.2 
Management of Hypertension...................................................................... 35 
9.4.3 
Management of Proteinuria ......................................................................... 37 
9.4.4 
Management of Hepatotoxicity ................................................................... 37 
9.4.5 
Management of Thromboembolic Events ................................................... 38 
9.4.6 
Management of Posterior Reversible Encephalopathy Syndrome (PRES) . 38 
9.4.7 
Management of Interstitial Lung Disease .................................................... 38 
9.4.8 
Management of Infectious Disease .............................................................. 39 
9.4.9 
Management of Hyperglycemia and Hyperlipidemia.................................. 39 
9.4.10 
Management of Stomatitis ........................................................................... 40 
9.4.11 
Points to Consider on Determination of DLT ............................................. 40 
9.4.12 
Identity of Investigational Products ............................................................. 41 
9.4.12.1 
Chemical Name, Structural Formula of Lenvatinib (E7080) ............ 41 
9.4.12.2 
Labeling for Study Drug .................................................................... 41 
9.4.12.3 
Storage Conditions............................................................................. 42 
9.4.13 
Method of Assigning Subjects to Treatment Groups .................................. 42 
9.4.14 
Selection of Doses in the Study ................................................................... 43 
9.4.15 
Selection and Timing of Dose for Each Subject .......................................... 44 
9.4.16 
Blinding ....................................................................................................... 44 
9.4.17 
Prior and Concomitant Therapy................................................................... 44 
9.4.18 
Concomitant Therapies ................................................................................ 44 
9.4.18.1 
Prohibited Concomitant Drugs and Therapies ................................... 44 
9.4.18.2 
Limited Use of Concomitant Therapies and Drugs ........................... 45 
9.4.18.3 
Drug–Drug Interactions ..................................................................... 45 
9.4.19 
Treatment Compliance................................................................................. 45 
9.4.20 
Drug Supplies and Accountability ............................................................... 45 
9.5 
STUDY ASSESSMENT ....................................................................................... 46 
9.5.1 
Assessments ................................................................................................. 46 
9.5.1.1 
Demography ...................................................................................... 46 
9.5.1.2 
Baseline Assessments ........................................................................ 46 
9.5.1.3 
Safety Assessments ............................................................................ 47 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic and 
Other Biomarker Assessments ........................................................... 53 
9.5.1.5 
Efficacy Assessments ........................................................................ 54 
9.5.1.6 
Assessments of Study Drug Administration ...................................... 56 
9.5.1.7 
Assessments of Concomitant Drugs and Therapies........................... 56 
9.5.2 
Schedule of Procedures/Assessments .......................................................... 57 
9.5.2.1 
Schedule of Procedures/Assessments ................................................ 57 
9.5.3 
Appropriateness of Measurements .............................................................. 61 


 
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9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations .............................................................. 61 
9.5.4.1 
Reporting of Serious Adverse Events ................................................ 61 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug through 
Breastfeeding ..................................................................................... 61 
9.5.4.3 
Reporting of Events Association with Special Situations ................. 62 
9.5.4.4 
Expedited Reporting .......................................................................... 63 
9.5.4.5 
Breaking the Blind ............................................................................. 63 
9.5.4.6 
Regulatory Reporting of Adverse Events .......................................... 63 
9.5.5 
Completion/Discontinuation of Subjects ..................................................... 63 
9.5.6 
Abuse or Diversion of Study Drug (or recreational use) ............................. 63 
9.5.7 
Confirmation of Medical Care by Another Physician ................................. 63 
9.6 
Data Quality Assurance ......................................................................................... 64 
9.6.1 
Data Collection ............................................................................................ 64 
9.6.2 
Clinical Data Management .......................................................................... 64 
9.7 
Statistical Methods................................................................................................. 65 
9.7.1 
Statistical and Analytical Plans ................................................................... 65 
9.7.1.1 
Study Endpoints ................................................................................. 65 
9.7.1.2 
Definitions of Analysis Sets .............................................................. 65 
9.7.1.3 
Handling of Data................................................................................ 65 
9.7.1.4 
Subject Disposition ............................................................................ 66 
9.7.1.5 
Demographic and Other Baseline Characteristics ............................. 66 
9.7.1.6 
Prior and Concomitant Therapy......................................................... 66 
9.7.1.7 
Efficacy Analyses .............................................................................. 66 
9.7.1.8 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ................................................................ 67 
9.7.1.9 
Safety Analyses ................................................................................. 67 
9.7.2 
Determination of Sample Size ..................................................................... 70 
9.7.3 
Interim Analysis........................................................................................... 70 
9.7.4 
Other Statistical/Analytical Issues ............................................................... 70 
9.7.5 
Procedure for Revising the Statistical Analysis Plan .................................. 70 
10 REFERENCE LIST ......................................................................................................... 70 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) ....... 74 
11.1 
Changes to the Protocol ......................................................................................... 74 
11.2 
Adherence to the Protocol ..................................................................................... 74 
11.3 
Monitoring Procedures .......................................................................................... 74 
11.4 
Recording of Data .................................................................................................. 75 
11.5 
Identification of Source Data ................................................................................. 75 
11.6 
Retention of Records ............................................................................................. 77 
11.7 
Auditing Procedures and Inspection ...................................................................... 77 


 
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11.8 
Handling of Study Drug......................................................................................... 77 
11.9 
Publication of Results ............................................................................................ 78 
11.10 Disclosure and Confidentiality .............................................................................. 78 
11.11 Discontinuation of Study ....................................................................................... 78 
11.12 Subject Insurance and Indemnity........................................................................... 79 
12 APPENDICES ................................................................................................................. 80 
 
LIST OF IN-TEXT TABLES 
Table 1. Dose Limiting Toxicities (DLT).......................................................................... 28 
Table 2. Dose Reduction and Interruption Instructions for Lenvatinib/Everolimus 
Combination Treatmenta .............................................................................................. 35 
Table 3.Clinical Laboratory Tests ..................................................................................... 51 
Table 4.Pharmacokinetic Sampling Time Points .............................................................. 54 
Table 5.Schedule of Procedures/Assessments in Study E7080-J081-112 ......................... 58 
 
LIST OF IN-TEXT FIGURES 
Figure 1  
Study Design .............................................................................................. 29 
Figure 2  
Subject Enrollment Procedure ................................................................... 43 
 
 


 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (GPT) 
AST 
aspartate aminotransferase (GOT) 
AUC 
area under the plasma concentration-time curve 
BOR 
best overall response 
BUN 
blood urea nitrogen 
Cmax 
maximum observed concentration 
CPK 
creatine phosphokinase 
CR 
complete response 
CRP 
C-reactive protein 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CYP/CYP3A 
cytochrome P450/cytochrome P450 3A 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
ECOG  
Eastern Cooperative Oncology Group 
FGF 
fibroblast growth factor 
FGFR 
fibroblast growth factor receptor 
FT4 
Free thyroxine 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HBs 
hepatitis B virus surface  
HBc 
hepatitis B virus core 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IAP 
immunosuppressive acidic protein 
IFN 
interferon 
INR 
international normalized ratio 
LDH 
lactate dehydrogenase 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin 
MUGA 
multiple-gated acquisition technique 
NE 
not evaluable 
NYHA 
New York Heart Association 


 
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Abbreviation 
Term 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PDGF 
platelet derived growth factor 
PDGFRα 
platelet derived growth factor receptor α 
PFS 
progression free survival 
P-gp 
P-glycoprotein 
PR 
partial response 
PRES 
posterior reversible encephalopathy syndrome 
PS 
performance status 
PT 
preferred term 
QT 
QT interval 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumor 
RTK 
receptor tyrosine kinase 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedures 
SpO2 
oxyhemoglobin saturation measured by pulse oximetry 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment emergent markedly abnormal laboratory values 
TKI 
tyrosine kinase inhibitor 
tmax 
time at which the highest drug concentration occurs 
TNM Classification 
tumor, nodes, metastasis classification 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 


 
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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) constituted and functioning 
in accordance with ICH E6 (Good Clinical Practice) and any local regulations.  Any 
protocol amendment or revision to the ICF will be resubmitted to the IRB for review and 
approval, except for changes involving only logistical or administrative aspects of the study 
(eg, change in CRA[s], change of telephone number[s]). Documentation of IRB 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 chairman must be 
sent to the head of the medical institution) with a copy to the sponsor before study start and 
the release of any study drug to the site by the sponsor or its designee.  If the IRB decides to 
suspend or terminate the study, the head of the medical institution will immediately send the 
notice of study suspension or termination by the IRB/IEC to the sponsor.Study progress is to 
be reported to IRBs annually (or as required) by the investigator or the head of the medical 
institution, depending on local regulatory obligations.  The sponsor will submit, depending 
on local regulations, periodic reports and inform the IRB, the investigator and the relevant 
IRB via the head of the medical institution) of any reportable adverse events (AEs) per GCP 
guidelines and local IRB standards of practice.  Upon completion of the study, the 
investigator will provide the IRB with a brief report of the outcome of the study, if required. 
 
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 
• GCP 
• Article 14, Paragraph 3, and Article 80-2 of the Pharmaceuticals, Medical devices 
and Other Therapeutic Products Act (Law No. 145, 1960) for studies conducted in 
Japan, in addition to Japan’s GCP 
 
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, 


 
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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-approved ICF must be prepared in accordance with GCP, and all applicable local 
regulations.  Each subject must sign an approved ICF before study participation.  The form 
must be signed and dated by the appropriate parties.  The original, signed ICF for each 
subject will be verified by the sponsor and kept on file according to local procedures at the 
site.The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at three to five investigational sites in Japan.The name and telephone and fax 
numbers of the sponsor are listed in the Appendix 3. 
 


 
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7 
INTRODUCTION 
7.1 
Indication 
Renal Cell Carcinoma (RCC) is a rare tumor type representing 3% of all cancers in adults, 
accounting for 90% of the total renal cancers (National Comprehensive Cancer Network, 
2015).  In 2012, estimate of the worldwide incidence of renal cancers (renal pelvis and 
ureters included) was 330,000 of which 210,000 were men and 120,000 were women.  The 
total of 140,000 deaths was estimated to have occurred, of which 90,000 were men and 
50,000 were women (Ferlay J, et al., 2015).  In Japan, annual incidence of renal cancers 
(renal pelvis, ureters, and other unknown site in the urinary system are included) is 
approximately 18,000 and the number of death (renal pelvis, ureters, and other unknown site 
in the urinary system are excluded) is approximately 4,500 (Foundation for Promotion of 
Cancer Research, 2013).There are three main histologic types of renal cell carcinoma; clear 
cell-type tumors account for approximately 80% of RCC, followed by papillary type (10 to 
15%), and chromophobe cell type (3 to 5%) (National Comprehensive Cancer Network, 
2015. ，Rini BI, et al., 2009).The risk factors for RCC include obesity, smoking, 
hypertension, dialysis treatment, and von Hippel-Lindau disease.  When a patient is initially 
diagnosed with RCC, localized tumor is present in 45% of cases, followed by 30% of 
metastasis, and 25% of locally-advanced tumor.  The prognosis is poor at stage IV with 
locally-advanced or distant metastasis, with only 10% of 5-year survival (Molina AM and 
Motzer RJ, 2008，Motzer RJ, et al., 1996, National Cancer Center, Department of Internal 
Medicine, 2013).The treatment options for RCC are surgery and/or anti-cancer medication, 
depending on the disease stage.  Anti-cancer medication commonly used to treat 
unrespectable or metastatic RCC include: agents targeting vascular endothelial growth factor 
(VEGF) and VEGF receptor (VEGFR) such as bevacizumab, sunitinib, sorafenib, pazopanib, 
axitinib, and agents targeting mammalian target of rapamycin (mTOR) such as timsirolimus 
and everolimus (National Comprehensive Cancer Network, 2015., Escudier B, et al., 2014). 
Cytokine (eg, interferon) has been widely used in the treatment of RCC but tyrosine kinase 
inhibitors (TKI) that block VEGFR, such as sunitinib and pazopanib, are administered as the 
first-line treatment in recent years.  Type of second-line and subsequent treatments vary 
depending on the drug administered in the previous treatment. Among these available agents, 
everolimus was confirmed to be efficacious with 1.8% ORR, median PFS of 4.9 months, and 
overall OS of 14.8 months when administered to metastatic RCC patients with disease 
progression following sunitinib or sorafenib treatment (Motzer RJ, et al., 2008).In a phase 3 
study comparing the efficacy of axitinib and sorafenib as second-line treatment in RCC 
subjects who previously received cytokine or sunitinib treatment, axitinib demonstrated 
higher efficacy with the ORR 23.0% (12.0% for sorafenib), median PFS 6.7 months (4.7 
months for sorafenib), and median OS 20.1 months (19.2 months for sorafenib) (Rini BI, et 
al., 2011). 
Based on above findings, axitinib or everolimus would likely be the second-line treatment 
option for RCC patients who were previously treated with TKI.Although many treatment 
options are available for patients with incurable, unresectable or advanced RCC, the 


 
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prognosis remains poor and development of new agents and treatment to improve clinical 
outcome of the second or third line treatments are anticipated.   
7.2 
Lenvatinib Mesylate (Lenvatinib)  
VEGFR is expressed in vascular endothelial cells, playing a vital role for physiological and 
pathological angiogenesis and lymphogenesis or in the malignant cells led by VEGF ligand 
stimulation (Ellis LM and Hicklin DJ, 2008，Ferrara N, et al., 2003，Hattori K, et al., 2002，
Laakkonen P, et al., 2007, Tammela T and Alitalo K, 2010).Fibroblast growth factors 
receptor (FGFR), platelet-derived Growth Factor receptor-α (PDGFRα), RET, and KIT are 
also known to be associated with angiogenesis, proliferation, or both (St Bernard, et al., 2005，
Turner and Grose, 2012，Matsui, et al., 2004，Hirota, et al., 1998，Williams, 2002，
Kondo, et al., 2006，Phay and Shah, 2010, Gild, et al., 2011，Hirota, et al., 2003, Oseini 
and Roberts, 2009) and an effective anticancer treatment may be established if their receptors, 
tyrosine kinases (RTKs) are inhibited simultaneously. Lenvatinib Mesylate (E7080) was 
developed at Eisai Tsukuba Research Laboratories to explore agents that inhibit RTKs 
activities associated with tumor angiogenesis.  It is a multikinase inhibitor that exhibits 
potent inhibitory effects not only on VEGFR1 to VEGFR 3 at the level of inhibition constant 
Ki 1 nmol/L, but also on FGFR 1 to FGFR4 and KITs.In nonclinical studies, lenvatinib 
showed inhibitory activities dose-dependently in VEGFR2-driven phosphorylation, tube 
formation and proliferation in human vascular endothelial cells (human umbilical vein 
endothelial cell – HUVEC) induced by VEGF.  In vivo study where human cancer cells are 
transplanted in immune deficient mouse models, lenvatinib also demonstrated high 
anticancer effect in a wide variety of cancers including RCC. In addition, safety results in 
non-clinical studies showed lenvatinib was well tolerated within the therapeutic range.Three 
phase 1 studies were conducted in Japan, US, and Europe with different regimen to determine 
the safety, tolerability and pharmacokinetics of lenvatinib.  Treatment regimen for each 
study was: continuous once daily for E7080-E044-101 (Europe), continuous twice daily for 
E7080-A001-102 (US), and twice daily for 2 weeks with dosing intervals of one week for 
E7080-J081-103 (Japan).  Based on the results from these studies, a continuous dose of 24 
mg once daily has been selected to treat solid tumors for ongoing lenvatinib development.The 
tolerability in 24 mg once daily continuous dose in Japanese subjects was confirmed in 
another study conducted in Japan (E7080-J081-105).  There was no significant difference in 
tolerability and pharmacokinetics among subjects in Japan, Europe, and US.lenvatinib is 
expected to be efficacious regardless of cancer type; clinical studies are being conducted for 
various solid malignancies including thyroid carcinoma, hepatocellular carcinoma, RCC, 
non-small-cell lung cancer, endometrial cancer, glioma, malignant melanoma, and ovarian 
cancer. Based on the results from Phase 2 studies conducted in Japan and overseas, and 
multi-center global Phase 3 studies, lenvatinib was approved in February 2015 for the 
treatment of patients with locally recurrent or metastatic, progressive radioioactive 
iodine-refractory differentiated thyroid cancer.  Approvals in Europe and Japan are also 
underway in 2015.  


 
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7.3 
Concomitant use of Lenvatinib and Everolimus for RCC patients 
Common treatment options for RCC patients include VEGF, VEGFR, or mTOR target agents 
as first or second-line treatment.  However, most patients do not respond well and become 
resistant to the currently available drugs, resulting in disease progression.  Therefore, 
combination of lenvatinib and everolimus to simultaneously inhibit VEGF and mTOR 
signaling pathways seem logical as they both play a key role in exacerbation and 
development of resistance.  The treatment is expected to enhance effectiveness of each 
agent and overcome treatment-resistance.    
As of today, combination therapy of existing TKI agent and mTOR inhibitor is yet to be 
approved.   
 
7.3.1 
Everolimus 
Everolimus inhibits mTOR, a type of serine/threonine protein kinase.  It is known that 
mTOR is a downstream factor of P13K/Akt, comprising PI3K/Akt/mTOR signaling pathway.  
Functional abnormalities of molecules comprising this pathway are associated with various 
human cancer pathophysiology and have been confirmed for its significance in tumor genesis 
(Seeliger H, et al., 2007).  Everolimus blocks intercellular signaling by inhibiting mTOR.  
This is believed to suppress proliferation, VEGF production by tumor cell, and proliferation 
of vascular endothelial cells, thereby controlling neoangiogenesis and exert anticancer 
effect.In Japan, everolimus has been approved for following conditions: unresectable, 
non-curable or metastatic RCC, pancreatic neuroendocrine tumors, unresectable or recurrent 
breast cancer, renal angiomyolipoma associated with nodular sclerosis, subependymal giant 
cell astrocytoma associated with nodular sclerosis. 
7.3.2 
Overseas Phase 1/2 study 
Phase 1 and 2 studies (Study 205) were conducted to compare efficacy and safety of 
lenvatinib alone, everlolimus alone, or combination of the two when administered to 
advanced or metastatic RCC patients following prior VEGF-targeted treatment.  
 
7.3.2.1 
Phase 1 part 
In Phase 1 part, the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of 
lenvatinib was determined when administered in combination with everolimus in subjects 
with unresectable advanced or metastatic RCC following prior VEGF-targeted treatment.  
Recommended dose of lenvatinib in combination with everlolimus for Phase 2 was also 
determined (Molina AM, et al., 2014). 
One treatment cycle was defined as 28 days.  Lenvatinib was administered at starting dose 
of 12 mg/day in combination with everolimus at starting dose of 5 mg/day (Cohort 1).  
Lenvatinib was subsequently titrated to 18 mg/day (Cohort 2) and 24 mg/day (Cohort 3) 
while starting dose of everolimus (5mg/day) was maintained.  In Cohort 4, everlolimus was 


 
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titrated to 10 mg/day.  Subjects were enrolled in the treatment group at which MTD was 
determined, up to the minimum of 10 subjects. 
Number of subjects enrolled in Cohorts 1, 2, and 3 were 7, 11, and 2, respectively. 
DLTs seen in each cohort were: one subject in Cohort 1 (Grade 3 abdominal pain), one 
subject in Cohort 2 (Failure to administer ≥75% of planed dose due to Grade 3 increased 
creatine phosphokinase, Grade 2 fatigue, Grade 1 gastroesophageal reflux disease), two 
subjects in Cohort 3 (Grade 3 nausea and vomiting [1 subject], (Failure to administer ≥75% 
of planed dose due to Grade 2 stomatitis [1 subject]).  Cohort 4 was not treated.  Based on 
these findings, recommended doses for combination therapy in Phase 2 were determined to 
be lenvatinib 18 mg/day and everolimus 5 mg/day. 
 
7.3.2.2 
Phase 2 part 
In Phase 2 part, subjects with unresectable advanced or metastatic RCC with disease 
progression following one prior VEGF-targeted treatment were randomized to one of the 
following treatment groups to compare the safety and efficacy.  Primary endpoint was PFS. 
• 
Arm A：envatinib 18 mg + everolimus 5 mg 
• Arm B：lenvatinib 24 mg 
• Arm C：everolimus 10 mg 
 
Efficacy 
Number of subjects assigned to each treatment groups were: 51 subjects for Arm A, 52 
subjects for Arm B, and 50 subjects for Arm C.  PFS in Arms A and B were prolonged as 
compared with Arm C.  Median PFS of Arms A, B, and C were 14.6 months, 7.4 months, 
and 5.5 months, respectively.  Hazard ratio (HR) of Arm A to Arm C was 0.40, P<0.001, 
and that of Arm B to Arm C was 0.61, P=0.048.  ORR of each treatment group was 43.1% 
(Arm A), 26.9% (Arm B), and 6.0% (Arm C).  Median overall survival (OS) of Arm A, 
Arm B and Arm C was 25.5 months, 18.4 months, and 17.5 months, respectively.  Hazard 
ratio (HR) of Arm A to Arm C was 0.55, P=0.062, and that of Arm B to Group C was 0.74, 
P=0.290. 
Safety 
Treatment-emergent adverse events (TEAE) experienced by ≥20% of subjects in Arm A 
were: diarrhea, decreased appetite, fatigue, vomiting, hypertension, nausea, cough, 
hypertriglyceridaemia, hypercholesterolaemia, weight decreased, stomatitis, oedema 
peripheral, arthralgia, asthenia, dyspnea, hypothyroidism, proteinuria, and pyrexia.Grade 3 or 
higher TEAEs experienced by ≥5% of subjects in Arm A were: diarrhea, hypertension, 
fatigue, anaemia, hypertriglyceridaemia, vomiting, decreased appetite, dehydration, nausea, 
and thrombocytopenia.  Grade 3 or higher TEAEs that were seen more often in Arm A than 
in Arms B or C by ≥2 subjects were: diarrhea, fatigue, vomiting, dehydration, 


 
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thrombocytopenia, back pain, and general physical health deterioration. Serious TEAEs 
(SAE) experienced by ≥5% of subjects in Arm A were: anaemia, thrombocytopenia, diarrhea, 
and dehydration.  SAEs that were seen more often in Arm A than in Arms B or C by ≥2 
subjects were: thrombocytopenia, diarrhea, dehydration, vomiting, hyperkalaemia, general 
physical health deterioration, and renal impairment.  An AE that resulted in subject death 
was cerebral haemorrhage.Following events were more frequently observed in Arm A than in 
Arms B or C: diarrhea, fatigue, vomiting, dehydration, thrombocytopenia, back pain, general 
physical health deterioration, hyperkalaemia, and renal impairment.  In general, they were 
all manageable by administering symptomatic treatment, dose interuption, or dose reduction 
of study drugs.  The safety profile of combination treatment group (Arm A) was genellary 
similar to those of single-agent treatment Arms (B and C), and no newly discovered safety 
concerns were reported.Above results demonstrated that improved prolongation of PFS and 
OS can be expected in combination treatment of lenvatinib 18 mg/day and everolimus 
5mg/day, compared with everolimus single-agent treatment.  Although adverse drug 
reactions were observed in some patients they were manageable, therefore this combination 
therapy seemed promising for unresectable advanced or metastatic RCC with disease 
progression following  prior one VEGF-target treatment.   
7.4 
Expected Adverse Events 
For lenvatinib, important identified risk include: hypertension, hemorrhage, arterial thromboembolism, 
venous thromboembolism, liver disorder, renal disorder, gastrointestinal perforation/fistula, posterior 
reversible encephalopathy syndrome, cardiac disorder, hand and foot syndrome, infections, 
bone-marrow suppression, hypocalcaemia, delayed wound healing.  Lenvatinib should be 
administered with caution to the patients with hypertension, severe liver disorder, cerebral metastasis, 
thromboembolism or history of thromboembolism, and incomplete wound healing following surgical 
procedure.  Close monitoring are required after lenvatinib administration for: hypertension, uric 
protein, bone-marrow suppression, liver disorder associated with increased AST or ALT, cardiac 
dysfunction, delayed wound healing, fatigue and apathy, dizziness, muscle spasms, serum calcium 
concentration, and level of thyroid-stimulating hormone.For everolimus, important identified risk 
include: interstitial lung disease, infections, renal failure, hyperglycemia, development or 
exacerbation of diabetes, anemia, decreased hemoglobin, decreased  leukopenia, decreased 
lymphopenia, decreased neutropenia, and thrombocytopenia, stomatitis, anaphylaxis, acute 
respiratory 
distress 
syndrome, 
malignancy 
(secondary), 
progressive 
multifocal 
leukoencephalopathy, BK virus nephropathy, thrombotic microangiopathy, pulmonary 
alveolar proteinosis, and pericardial effusion.     
Everolimus should be administered with caution to patients with current conditions or history 
of interstitial pulmonary shadow, comorbid infections, liver dysfunction or hepatitis virus, 
tuberculosis, and elderly patients.  Close monitoring will be required following 
administration of everolimus for: interstitial pulmonary disease，infection or opportunistic 
infection from bacteria, fungi, viruses, protozoa, severe renal disorder, hyperglycemia, 
decreased hemoglobin, decreased lymphopenia, decreased neutropenia, decreased platelet.In 
overseas study (Study 205), Grade 3 or higher cases of diarrhea, fatigue, vomiting, dehydration, 
thrombocytopenia, back pain, general physical health deterioration, hyperkalaemia, and renal 
impairment are more frequently seen in lenvatinib-everolimus combination therapy compared to 


 
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single-agent therapy each.  Cautions should be exercised as effects on adverse events can be 
potentiated by co-administering the two agents. 
 
7.5 
Study Rationale 
This is a Phase 1 study of lenvatinib in combination with everolimus in Japanese subjects with 
unresectable advanced or metastatic RCC.Lenvatinib will be administered at starting dose of 18 mg in 
combination with everolimus at starting dose of 5 mg both orally once daily continuously.  DLT will 
be observed during Cycle 1 (28 days following the initial dosing) to determine the tolerability and 
safety.  Treatment will continue until disease progression, development of intolerable toxicity, 
subject requests to discontinue, withdrawal of consent, or study termination by sponsor.The same 
regimen, lenvatinib 18 mg/day and everolimus 5 mg/day, will be employed based on the results 
obtained in the overseas study (Study 205) and is also considered for future global studies including 
Japan.Single-agent treatment of lenvatinib was tolerated up to the dose of 24 mg/day continuous 
administration in Japanese patients with solid tumor and similar results were observed in Europe and 
US.  Everolimus has been approved in Japan, US, and Europe, for treatment of RCC patients at dose 
of 10 mg/day once daily continuous administration.  No significant difference in tolerability has 
been noted between Japanese and non-Japanese patients.However, this combination regimen has 
never been studied in Japan; the tolerability and pharmacokinetics in Japanese patients are unknown.   
For this reason, this study was considered scientifically rational and designed based on the previous 
findings to evaluate the tolerability, safety, and pharmacokinetics of lenvatinib- everolimus 
combination therapy. 


 
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8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
• To investigate tolerability and safety of lenvatinib in combination with everolimus 
in subjects with unresectable advanced or metastatic renal cell carcinoma (RCC) 
 
8.2 
Secondary Objectives 
• To assess the pharmacokinetic (PK) of lenvatinib and everolimus 
• To assess the preliminary anticancer effects of lenvatinib in combination with 
everolimus 
 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This is a non-randomized, open-label, multi-center Phase 1 study (E7080-J081-112) of lenvatinib in 
combination with everolimus in subjects with unresectable advanced or metastatic RCC.  Subjects 
will be enrolled in this study after informed consent is obtained and eligibility is confirmed. 
One treatment cycle is defined as 28 days.  Lenvatinib will be administered at starting dose of 18 mg 
in combination with everolimus at starting dose of 5 mg both orally once daily continuously.  DLT 
will be observed during Cycle 1 (28 days following the initial dosing) to investigate tolerability and 
safety.  Treatment will continue until disease progression, development of unacceptable toxicity, 
subject requests to discontinue, withdrawal of consent, or study termination by sponsor. 
A total of six subjects will be initially enrolled.  Enrollment will be interrupted when DLT is 
observed in two or more subjects.  Investigators and sponsor will review the nature and severity of 
all the DLTs and make a decision if enrollment of up to six subjects and further additions of three to 
six subjects are feasible and necessary.  Suggestions by the independent medical advisor will be 
collected, if necessary. 
The study sponsor and investigators will consider the nature and severity of DLT during Cycle 1 as 
well as unacceptable toxicities that cannot be managed with dose interruption and/or reduction and 
overall toxicities up to Cycle 2 on the evaluation of tolerability in combination therapy.  The 
suggestions by the independent medical advisor can be collected, if necessary. 
Additional subjects maybe enrolled to the lower cohort (lenvatinib 14 mg and everolimus 5 mg once 
daily administration) in the following cases: over one-third of subjects experiences DLTs during 
Cycle 1, development of unacceptable, development of unmanageable toxicity with dose interruption 
and/or reduction up to Cycle 2, tolerability cannot be confirmed with dose level of lenvatinib 
18 mg/everolimus 5 mg QD. 


 
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If a subject has no DLT but fails to receive ≥ 75% of the planned dosage of lenvatinib and/or 
everolimus up to Cycle 1 Day 21, due to a reason other than treatment related toxicity, this subject 
will not be included in the DLT assessment population and a new subject will be added for 
replacement. 
Subjects will discontinue study treatment at the time of disease progression, development of 
unacceptable toxicity, withdrawal of consent, or qualifies any of the criteria described in ‘9.3.3.1 
Discontinuation for Individual Subjects’.  The discontinuation assessments will occur within 7 days 
and off-treatment visit on 30th day after the final dose of study treatment.   
DLT is defined as toxicity related to this combination therapy as indicated below. 
Table 1. Dose Limiting Toxicities (DLT) 
Toxicity 
Category 
Toxicity/CTCAE Grade 
Hematologic 
• 
Grade 4 neutropenia lasting >7 days 
 
• 
Grade 3 febrile neutropenia (axillary temperature ≥38.5ºC and neutrophils 
<1×103/µL (<1000/mm3) 
 
• 
Grade ≥3 thrombocytopenia lasting >7 days or requiring blood transfusion 
Non-hematologic 
toxicity 
• 
Grade 3 non-hematologic toxicities lasting >7 days except for the following: 
 
Clinically insignificant or transient abnormal laboratory findings   
 
Able to be controlled by maximal supportive therapy  
Grade ≥3 hyperamylasemia or hyperlipasemia without clinical or other 
evidence of pancreatitis are not regarded as a DLT.  
• 
Grade ≥3 Nausea, vomiting or diarrhea lasting >7 days despite maximal medical 
therapy  
• 
Hypertension uncontrolled by medication  
• 
Any thromboembolic event including cerebrovascular hemorrhage/events 
Medication 
compliance 
• 
Failure to administer ≥75% of the planned dosage of lenvatinib or 
everolimus as a result of treatment related toxicity 
 
Overall study design is presented below. 


 
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Figure 1  
Study Design 
9.1.1 
Pretreatment Period 
Pretreatment Period will consist of obtaining informed consent, screening procedures, subject 
enrollment and baseline assessments.  Each subject must be explained the nature of the study and 
sign an informed consent form before any study-specific procedures are performed.  Investigators 
must confirm the eligibility of each subject during screening procedures.  
All Screening procedures are to be completed within 28 days prior to the Cycle 1 Day 1 and eligible 
subjects will be enrolled.  All Baseline assessments are to be completed within 7 days prior to the 
Cycle 1 Day 1 and subjects’ eligibility will be confirmed. 
9.1.1.1 
Treatment Period 
Treatment Period will consist of two parts: Cycle 1 and following cycles. 
One treatment cycle is defined as 28 days.  Lenvatinib will be administered at starting dose of 18 mg 
in combination with everolimus at starting dose of 5 mg both orally once daily continuously.  DLT 
will be observed during Cycle 1 (28 days following the initial dosing) to investigate tolerability and 
safety.  Treatment will continue until disease progression, development of unacceptable toxicity, 
subject requests to discontinue, withdrawal of consent, or study termination by sponsor. 
Subjects will be required to stay at the clinic during Cycle 1 in principle, however, they may be 
allowed to go home temporarily, be discharged or receive treatment as outpatient per investigators’ 
discretion.   
 
Cycle 1 
30 days 
following the 
last 
administration 
Within 7 days 
Treatment Period 
Pretreatment Period 
Informed Consent
Screening procedure 
Enrollment
Dosing
Off-treatment visit
Final Dosing
Screening  
Follow-up Period 
Within 28 
days 
Baseline assessment
Cycle 2 and onward 
DLT observation 
Discontinuation 
Assessment 
28 days/cycle 


 
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9.1.1.2 
Follow-up Period 
Follow-up Period will include discontinuation assessments and off-treatment visit.  Subject will 
discontinue study treatment if he/she qualifies for any of the criteria listed in Section 9.3.3.1.  The 
discontinuation assessments will occur within 7 days and the off-treatment assessments on 30 days (+ 
7 days) after the final dose of study treatment. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
Control group is not employed in this study.  Rationale of study design is described in 
Section 7.5 ‘Study Rationale’ of this protocol. 
9.3 
Selection of Study Population 
A total of 6 to 12 subjects will be enrolled in 3 to 5 investigational sites in Japan.  Subjects who meet 
all of the inclusion criteria or none of the exclusion criteria will be eligible to receive study drug. 
9.3.1 
Inclusion Criteria 
1. Subjects must meet all of the following criteria to be included in this study:Voluntary 
agreement to provide written informed consent of this study 
2. Willing and able to comply with all aspects of the protocol after being fully informed 
of the content 
3. Males or females aged ≥20 years at the time of informed consent 
4. Histological or cytological confirmation of RCC 
5. Subjects must have confirmed diagnosis of unresectable advanced and/or metastatic 
RCC 
6. Disease progression following VEGF targeted therapy 
7. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1 
8. Adequately controlled blood pressure with or without the use of antihypertensive 
agents (defined as BP ≤150/90 mmHg at screening and no change in antihypertensive 
therapy within 1 week prior to the Cycle 1 Day 1 
9. Subjects with adequate function of major organs: 
a. 
Hemoglobin ≥9.0 g/dL 
b. 
Neutrophil count ≥1.5×103 /μL 
c. 
Platelets ≥10×104 /μL 
d. 
Total bilirubin ≤1.5×upper limit of normal specified by the testing laboratory (ULN) 
e. 
Alkaline phosphatase (ALP), AST and ALT ≤ 3.0 x ULN (≤ 5.0 x ULN for patients with the 
liver metastasis) 
f. 
Creatinine clearance ≥40 mL/min calculated per the Cockroft and Gault formula 
Male:  (140–age)×weight (kg)÷72×Serum creatinine (mg/dL) 
Female:  0.85×(140–age)×weight(kg)÷72×Serum creatine (mg/dL) 


 
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10. Adequate blood coagulation function, defined as international normalized ratio (INR) 
≤1.5 
11. Survival expectation of 3 months or longer after study enrollment 
12. Washout period required from the end of prior treatment to the start of study drug 
administration will be as follows: 
a. Anticancer therapies: 
• 
Other investigational drug or antibody therapy: ≥4 weeks 
• 
Chemotherapy (except small-molecule targeted therapy), surgical therapy, radiation 
therapy: ≥3 weeks 
• 
Endocrine therapy, immunotherapy, small-molecule targeted therapy: ≥2 weeks 
b. Supportive therapies: 
 Blood transfusion, blood preparations, hematopietic growth factors including G-CSF 
preparations: ≥2 weeks 
13. Females of childbearing potential must not have had unprotected sexual intercourse 
within 28 days before subject registration and must agree to use a highly effective 
method of contraception (e.g., use of an intrauterine device, condom with spermicide*, 
a contraceptive implant**, an oral contraceptive*, or have a vasectomized partner with 
confirmed azoospermia)Note throughout the entire study period and for 30 days after 
final administration of investigational drug.  If currently abstinent, the subject must 
agree to use a double-barrier method as described above if she becomes sexually 
active during this study period or for 30 days after investigational drug discontinuation.  
Females who are using hormonal contraceptives must have been on a stable dose of 
the same hormonal contraceptive product for at least 4 weeks before administration 
and must continue to use the same contraceptive during this study and for 30 days after 
investigational drug discontinuation.  
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 (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, 
all with surgery at least one month before administration 
Females of childbearing potential must not have had unprotected sexual intercourse 
within 28 days before subject registration and must agree to use a highly effective 
method of contraception (e.g., use of an intrauterine device, condom with spermicide*, 
a contraceptive implant**, an oral contraceptive*, or have a vasectomized partner with 
confirmed azoospermia)Note throughout the entire study period and for 30 days after 
final administration of investigational drug.  If currently abstinent, the subject must 
agree to use a double-barrier method as described above if she becomes sexually 
active during this study period or for 30 days after investigational drug discontinuation.  
Females who are using hormonal contraceptives must have been on a stable dose of 
the same hormonal contraceptive product for at least 4 weeks before administration 
and must continue to use the same contraceptive during this study and for 30 days after 
investigational drug discontinuation.  
All females will be considered to be of childbearing potential unless they are 


 
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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 (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, 
all with surgery at least one month before administration. 
Note: Whether or not a pharmaceutical agent or medical device has been approved and 
certified in Japan (* : yes, ** : no) 
 
14. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they 
and their female partners must meet the criteria above (i.e., not of childbearing 
potential or practicing highly effective contraception throughout the study period and 
for 30 days after study drug discontinuation). 
 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Subjects with CNS metastases are not eligible, unless they have completed local 
therapy and have discontinued the use of corticosteroids for this indication for at least 
4 weeks before starting treatment in this study.  Any signs (eg, radiologic) or 
symptoms of brain metastases must be stable for at least 4 weeks before starting study 
treatment. 
2. Prior exposure to lenvatinib 
3. Subjects who have not recovered from toxicities to ≤ Grade 1 as a result of prior 
anticancer therapy, except alopecia 
4. Major surgery within 3 weeks prior to the first dose of lenvatinib 
5. Subjects having ≥2+ proteinuria on urine dipstick testing will undergo a 24-hour urine 
collection for quantitative assessment of proteinuria.  Subjects with a urine protein ≥1 
g/24 hours will be ineligible. 
6. Uncontrollable diabetes as defined by fasting glucose >1.5×ULN 
7. Fasting total cholesterol >7.75 mmol/L (>300 mg/dL) 
8. Fasting triglycerides >2.5×ULN 
9. Gastrointestinal malabsorption, a history of gastroenterostomy, inability of oral 
administration, or any other condition that might affect the absorption of lenvatinib 
and/or everolimus 
10. Significant cardiovascular impairment: 
a. Congestive heart failure than New York Heart Association (NYHA) Class II within 
6 months of the first dose of study drug 
b. Unstable angina, myocardial infarction or stroke within 6 months of the first dose 
of study drug 
c. Prolongation of QTc (Friderica formula) interval >480 ms 
d. Cardiac arrhythmia requiring medical treatment for cardiovascular impairment 


 
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11. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR 
monitoring, eg, warfarin or similar agents.  Treatment with low molecular weight 
heparin is permitted. 
12. Active hemoptysis (bright red blood of at least 0.5 teaspoon or 2.5 mL) within 3 weeks 
of the first dose of study drug 
13. Active infections that require systemic treatment 
14. Human immunodeficiency virus (HIV) positive 
15. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg.  In 
addition, if negative for HBsAg but HBcAb and/or HBsAb positive, an HBV DNA test 
will be performed and if positive the subject will be excluded 
16. A history of interstitial pneumonia with clinical manifestation or as confirmed by 
means of diagnostic imaging 
17. Medical need for the continued use of potent or moderate inhibitors of CYP3A or P-gp, 
or potent or moderate inducer of CYP3A.  Subjects are eligible if 7 days or longer 
have passed since the last use of such agents prior to the first dose of study drug. 
18. Known intolerance to lenvatinib (or any of the excipients) or known hypersensitivity 
to everolimus (or any of the excipients) or rapamycins (sirolimus, temsirolimus and so 
on) 
19. Alcohol or drug dependency or abuse, inability to comply with every aspects of the 
study protocol, or any physical or mental conditions that in the opinion of the 
investigators would preclude the subject’s participation in the study 
20. Females who are pregnant or breastfeeding (not eligible even she discontinues 
breastfeeding) 
21. Any medical or other condition which, in the opinion of the investigator, would 
preclude participation in a clinical trial 
 
9.3.3 
Removal of Subjects from Therapy or Assessment 
The investigator may discontinue treating a subject with study treatment or withdraw the 
subject from the study at any time for safety or administrative reasons.  The subject may 
decide to discontinue study treatment or withdraw from the study at any time for any reason.  
The reason for discontinuation will be documented.  If a subject discontinues study 
treatment, the subject will enter the Follow-up Period and complete protocol-specified 
off-treatment visits, procedures, and survival follow-up unless the subject withdraws consent. 
The investigator should confirm whether a subject will withdraw from study treatment but 
agree to continue protocol-specified, off-treatment study visits, procedures, and survival 
follow-up, or whether the subject will withdraw consent.  If a subject withdraws consent, 
the date will be documented in the source documents.  The Subject Disposition CRF page 
will be completed indicating the primary reason for discontinuation and all other reason(s) 
contributing to the subject’s discontinuation from treatment.  In addition, the date of last 
dose of study drug(s) will be recorded on the CRF. 


 
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9.3.3.1 
Discontinuation for Individual Subjects 
1. Subjects will continue to receive study treatment unless:  Subject wishes to 
discontinue the treatment or withdraw the consent   
2.  Significant violation in eligibility is confirmed after subject’s study enrollment 
3.  Subject experiences an AE that is difficult to continue the study treatment, in the 
opinion of investigator or subinvestigator. 
4.  Subject is pregnant 
5.  Disease progression is observed.  Subject will be able to continue study treatment if 
investigator or subinvestigator judges that the clinical benefit will outweigh.  
6.  Investigator or subinvestigator’s decision to discontinue the treatment. 
 
When subject withdraws from lenvatinib, everlolimus will also be discontinued.  Discontinuation 
assessments will be performed within 7 days and the final observation will be conducted on 30 days 
(+7 days) after the final dose of study treatment.  
9.4 
Treatments 
Lenvatinib and everlolimus will be orally administered to subjects once daily in a 28-day cycle.   
During Cycle 1, subjects will receive the drugs in the morning after fasting with no food consumption 
for one hour postdose.  In Cycle 2 and onward, subjects will receive study drug either fasted 
condition or at after meal and maintain the same dosing condition once it is decided.    
Lenvatinib will be administered at starting dose of 18 mg in combination with everolimus at starting 
dose of 5 mg. 
9.4.1 
Drug interruption and dose reduction 
1. Cycle 1 
a. If DLT occurs: 
Lenvatinib and everolimus must be interrupted immediately.  Treatment may be 
resumed in Cycle 2 at one lower dose level of lenvatinib and/or reduction of everolimus 
to 5 mg every other day or discontinuation of everolimus if toxicity is resolved to Grade 
0–1 or baseline and investigator or subinvestigator decides to continue the study. 
b.  No DLT: 
Lenvatinib and everolimus will be interrupted if judged to be clinically needed by 
investigators, and may be resumed at the same dose level at appropriate timing.  No 
dose reduction is permitted. 
 
2.  Cycle 2 and onward 
Dose reduction and interruption for subjects who experience lenvatinib and/or 
everolimus related toxicity will follow the instructions shown in Table 2.  Dose 


 
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reductions occur in succession based on the previous dose level (14, 10, 8 mg/day).  
Any dose modification must be discussed with the sponsor when toxicities occur at the 
dose of 8 mg/day.  Once the dose has been reduced, it cannot be increased at a later 
date.  For management of hypertension and interstitial lung disease, refer to 
instructions ‘9.4.2 Management of Hypertension’ and ‘9.4.7 Management of interstitial 
lung disease’ before consulting the table below, as appropriate. 
 
Table 2. Dose Reduction and Interruption Instructions for Lenvatinib/Everolimus 
Combination Treatmenta 
Lenvatinib/Everolimus 
Treatment-Related Toxicityb,c,d 
During Therapy 
Adjusted Dose 
Grade 1or Tolerable Grade 
2b 
Continue treatment 
No change 
Intolerable Grade 2b or 
Grade 3 
Interrupt lenvatinib and 
everolimus until resolved 
to Grade 0–1 or baseline  
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. 
Dose reduction lenvatinib by one level 
and/or reduce everolimus to 5 mg every 
other day or discontinuation of everolimus 
and resume the treatment. 
Grade4c 
Discontinue study treatment 
a: 
An interruption of study treatment for more than 28 days due to treatment-related toxicity will require 
a discussion with the sponsor before treatment can be resumed. 
b: Tolerability Grade 2 toxicities will be judged by the study investigators to be intolerable. 
c: 
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 
3. 
d:  Initiate optimal medical management for nausea, vomiting, diarrhea prior to any treatment 
interruption, or dose reduction.  If uncontrolled, the management will be followed by this guideline. 
9.4.2 
Management of Hypertension 
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling.  
Early detection and effective management of hypertension are important to minimize the 
need for lenvatinib dose interruptions and reductions. 
The following guideline should be followed for the management of hypertension: 
1. Ensure that subjects have BP ≤ 150/90 mm Hg at the time of study entry 
2.  If known to be hypertensive, confirm that the subject has been on a stable dose of 
antihypertensive therapy for at least 1 week before Cycle 1/Day 1. 
3. Antihypertensive agents should be started as soon as elevated BP (systolic BP ≥ 140 
mm Hg or diastolic BP ≥ 90 mm Hg) is confirmed on two assessments a minimum of 
30 minutes apart.  One BP assessment is defined as the mean value of two 
measurements at least 5 minutes apart.  The choice of antihypertensive treatment 


 
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should be individualized to the subject’s clinical circumstances and follow standard 
medical practice. 
4. For previously normotensive subjects, appropriate antihypertensive therapy should be 
started when systolic BP ≥ 140 mm Hg or diastolic BP ≥ 90 mm Hg is first observed 
on two assessments a minimum of 30 minutes apart.  For those subjects already on 
antihypertensive medication, treatment modification may be necessary if hypertension 
persists.  For subjects with hypertension and proteinuria, appropriate therapy, eg, 
angiotensin-converting enzyme inhibitor or angiotensin-II receptor antagonist is 
preferred. 
5. Lenvatinib and everolimus should be withheld in any instance where a subject is at 
imminent risk to develop a hypertensive crisis or has significant risk factors for severe 
complications of uncontrolled hypertension (eg, BP ≥ 160/100 mm Hg, significant risk 
factors for cardiac disease, intracerebral hemorrhage, or other significant 
co-morbidities).  Once the subject has been on the same hypertensive medications for 
at least 48 hours and the BP is controlled, lenvatinib should be resumed as described 
below. 
6.  The following guidelines should be followed for the management of systolic BP ≥ 
160 mm Hg or diastolic BP ≥ 100 mm Hg confirmed on repeat measurements after 30 
minutes: 
• Continue lenvatinib and everolimus, and institute antihypertensive therapy for 
subjects not already receiving antihypertensive medication 
• For the subjects already on antihypertensive medication, dose or medication 
choice should be modified per investigators judgment. 
• If systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg persists despite 
maximal antihypertensive therapy, then lenvatinib and everolimus administrations 
should be interrupted and restarted at a dose of one level lower for lenvatinib only 
when systolic BP ≤ 150 mm Hg and diastolic BP ≤ 95 mm Hg and the subject has 
been on a stable dose of antihypertensive medication for at least 48 hours.  Dose 
for everolimus will remain the same. 
• If systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg recurs with the reduced 
dose of lenvatinib despite optimal management of hypertension with 
antihypertensive medications (either by dose increase or the addition of a different 
class of antihypertensive), then lenvatinib and everolimus administrations should 
be interrupted and restarted at a dose of another lower level for lenvatinib, only 
when systolic BP ≤ 150 mm Hg and diastolic BP ≤ 95 mm Hg and the subject has 
been on a stable dose of antihypertensive medication for at least 48 hours.  Dose 
for everolimus will remain the same. 
• During the Treatment Period, both in the Randomization Phase and in the 
Extension Phase, subjects with systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 
mm Hg must have their BP monitored every 2 weeks (on Day 15 or more 
frequently as clinical indicated) until systolic BP has been ≤ 150 mm Hg and 
diastolic BP has been ≤ 95 mm Hg for 3 consecutive months.  If a repeat event of 


 
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systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg occurs, the subject must 
resume the Day 15 evaluation until systolic BP has been ≤ 150 mm Hg and 
diastolic BP has been ≤ 95 mm Hg for 3 consecutive months. 
 
7.  If Grade 4 hypertension (life-threatening consequences) is observed, appropriate medical 
management will be introduced and lenvatinib and everolimus will be discontinued. 
 
9.4.3 
Management of Proteinuria 
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments (Table 5) and as clinically indicated.  Guidelines for assessment 
and management of proteinuria are summarized as follows: 
• Initial episode of proteinuria: If proteinuria ≥ 2+ is detected on urine dipstick 
testing, lenvatinib and everolimus 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 CTCAE v4.03 (Appendix 6) will be 
based on the 24-hour urine collection for total protein result.  Dosing will be 
managed based on the grade of proteinuria according to Table 2. 
• Second and the subsequent episode of proteinuria：If proteinuria 3+ or 4+ is 
detected on urine dipstick testing, lenvatinib and everolimus will be continued and 
a 24-hour urine collection for total protein will be obtained to verify the grade of 
proteinuria.  Dosing will be managed based on the grade of proteinuria according 
to Table 2.  If proteinuria ≥2+ continues and is clinically indicated, a 24-hour 
urine collection for total protein will be obtained to verify the grade of proteinuria. 
• Urine dipstick testing for subjects with proteinuria ≥ 2+ should be performed 
every 2 weeks (on Day 15 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 the Day 15 urine dipstick testing 
for evaluation of proteinuria until results are 1+ or negative for 3 consecutive 
months. 
 
9.4.4 
Management of Hepatotoxicity 
Regular monitoring of liver function tests (eg, alanine transaminase [ALT], aspartate 
transaminase [AST], bilirubin levels) should be conducted as detailed in the Schedule of 
Visits and Procedures (Table 5) and as clinically indicated.  If signs occur indicating a 
decrease in liver function by 1 grade or more from baseline, the instructions contained in 
Table 2 of the protocol should be followed, “Study Treatment Dose Reduction and 
Interruption Instructions”.  Appropriate supportive care should be provided together with 
close monitoring.  If hepatic failure occurs both lenvatinib and everolimus must be 
discontinued. 


 
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9.4.5 
Management of Thromboembolic Events 
Subjects should be advised to pay attention to the symptoms suggestive of venous 
thromboembolic events, which include acute onset of dyspnea, chest pain, cough, hemoptysis, 
tachypnea, tachycardia, cyanosis, DVT signs including lower-extremity swelling, redness and 
warmth to touch or tenderness.  In case any of these signs or symptoms appears, subjects 
should be instructed to report such signs and symptoms promptly to the treating physician.  
If a thromboembolic event is confirmed, instructions contained in Table 2 of the protocol 
should be followed, “Study Treatment Dose Reduction and Interruption Instructions.” 
Appropriate supportive care should be provided together with close monitoring.  If a subject 
experiences life-threatening (Grade 4) thromboembolic reactions, including pulmonary 
embolism, both lenvatinib and everolimus must be discontinued. 
9.4.6 
Management of Posterior Reversible Encephalopathy Syndrome (PRES) 
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 that can present with headache, seizure, lethargy, confusion, altered mental function, 
blindness, and other visual or neurological disturbances.  Mild to severe hypertension may 
be present.  MRI is necessary to confirm the diagnosis of PRES.  Appropriate measures 
should be taken to control blood pressure.  In subjects with signs or symptoms of PRES, 
dose interruptions, reductions, or discontinuation of both lenvatinib and everolimus may be 
required per instructions included in Table 2. 
 
9.4.7 
Management of Interstitial Lung Disease 
Interstitial lung disease (pneumonitis, lung disease, lung infiltration, alveolitis, pulmonary 
alveolar haemorrhage and pulmonary toxicity) is a frequently reported adverse reaction when 
treated with rapamycin derivative including everlolimus, and it can be fetal in rare cases.  If 
breathing conditions of unknown cause are observed, the subject must be appropriately 
examined to rule out possible causes such as infection, neoplasm, and other nondrug related 
conditions to confirm diagnosis of lung disease. 
Following procedures should be followed when determining dose of lenvatinib and 
everolimus for subject with lung disease. 
• Radiology findings indicate lung disease but asymptomatic (Grade 1): Continue 
treatment without dose adjustment, however, study treatment may be discontinued 
depending on the subject’s condition. 
• Moderate (Grade 2) condition: Interrupt study treatment (lenvatinib and 
everolimus) and consider using adrenal cortical hormone.  If it is resolved to 
Grade 0-1 or baseline, resume study treatment at the same dose level as before the 
interruption.  If it does not resolve within 28 days, subject will treated with 


 
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lenvatinib alone after resolving to Grade 0-1 or baseline, according to his/her 
clinical condition.  Investigator will make a decision on whether the subject can 
resume the treatment and if so, as well as the dose level.  Everolimus must not be 
concomitantly administered. 
• Consider using adrenal cortical hormone if Grade 2 lung diseasea recurs despite of 
appropriate management.  If it is resolved to Grade 0-1 or baseline, resume study 
treatment at the same dose level as before the interruption.  If it does not resolve 
within 28 days, subject will be treated with lenvatinib alone after resolving to 
Grade 0-1 or baseline, according to his/her clinical condition.  Investigator will 
make a decision on whether the subject can resume the treatment and if so, as well 
as the dose level.  Everolimus must not be concomitantly administered. 
• Severe (Grade 3) condition: Interrupt study treatment (lenvatinib and everolimus) 
and consider using adrenal cortical hormone.  If it is resolved to Grade 0-1 or 
baseline, resume study treatment with lenvatinib alone after resolving to Grade 
0-1 or baseline according to his/her clinical condition.  Investigator will make a 
decision on whether the subject can resume the study treatment and if so, as well 
as the dose level.  Everolimus must not be concomitantly administered. 
• If a subject experiences life-threatening (Grade 4) event, both lenvatinib and 
everolimus must be discontinued. 
 
9.4.8 
Management of Infectious Disease 
Everolimus is known to decreases immune system activities while increasing the risk of 
developing infection.  Subjects should be closely monitored for signs and symptoms of 
infections to immediately administer proper medical intervention.  Dose adjustment of 
everlolimus may be required.  Dose interruptions and reductions of lenvatinib and 
everolimus will be determined per instructions included in Table 2. 
9.4.9 
Management of Hyperglycemia and Hyperlipidemia 
Hyperglycemia, hyperlipidemia, and hypertriglyceridemia are commonly seen as an adverse 
reaction in patients treated with rapamycin, including everlolimus.  Subjects need to have 
well regulated blood sugar level before being enrolled in the study.  
Measurement of blood sugar level will be taken at subject visits as specified in Table 5.  If 
sugar level exceeds standards specified by the study site, measurement should be taken after 
at least 6 hours of fasting (water is permitted).  CTCAE Grade will be given to the sugar 
level measured at fasted condition.  Insulin and/or oral antihyperglycemic drug may be 
administered (or dose increase if subject is already taking) as needed. 
Antihyperglycemic drug will be selected according to individual clinical condition.  
Concomitant use of everolimus and CYP3A or P-gp inhibitors and inducers (see Appendix 2) 
should be avoided in accordance with the standard medical procedure.  


 
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Dose interruptions, reductions, or discontinuation of lenvatinib and everolimus will be determined per 
instructions included in Table 2.   
9.4.10 
Management of Stomatitis 
Instruction for daily oral care should be given to subjects prior to study initiation and proper 
gargling and brushing should be continued throughout the study period.  In general, sodium 
gualenate hydrate is recommended for mouth rinsing and gargling, and mouthwash products 
containing alcohol, hydrogen peroxide, or iodine should be avoided.  For mild to moderate 
pain, a topical anesthetic such as lidocaine, acetaminophen, or Non-Steroidal 
Anti-Inflammatory Drugs can be used.  To relieve moderate to severe pain, consider using 
narcotic-analgesic agents. 
Dose interruptions, reductions, or discontinuation of lenvatinib and everolimus will be 
determined per instructions included in Table 2. 
9.4.11 
Points to Consider on Determination of DLT 
1.  Grade 4 neutropenia is observed 
a.  Additional tests will be performed as needed to confirm duration of the event. 
b.  If Grade 4 is present on Day 8 and beyond (Day 1 defined as the day the event was 
confirmed to be Grade 4), the event will be judged as ‘duration ≥7 days’.  If the 
event doesn’t resolve and hematology tests cannot be performed on Day 8, the 
investigator will discuss with sponsor on handling of the event.  Consult with 
independent medical advisor, as needed.  
2.  Grade 3 or Grade 4 thrombopenia is observed: 
a.  Additional tests will be performed as needed to confirm duration of the event. 
b.  If Grade 3 or 4 continues on Day 8 and beyond (Day 1 defined as the day the 
event was confirmed to be Grade 3 or 4), the event will be judged as ‘duration ≥7 
days’.  If the event doesn’t resolve and hematology tests cannot be performed on 
Day 8, the investigator will discuss with sponsor on handling of the event.  
Consult with independent medical advisor, as needed. 
3.  Grade 3 or Grade 4 noonhematologic toxicities is observed 
a.  Additional tests will be performed as needed to confirm duration of the event. 
b.  If Grade 3 or 4 continues on Day 8 and beyond (Day 1 defined as the day the 
event was confirmed to be Grade 3), the event will be judged as ‘duration ≥7 days.  
If the event doesn’t resolve and hematology tests cannot be performed on Day 8, 
the investigator will discuss with sponsor on handling of the event.  Consult with 
independent medical advisor, as needed. 
4.  If a subject experiences unexpected AEs that is not listed on ‘Table 1 Dose Limiting Toxicity 
(DLT)’ and requires discontinuation from treatment, investigator will discuss with sponsor on 
handling of the event.  Consult with independent medical advisor, as needed. 
 


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Date: March 25, 2015 
Confidential  
 
Page 42 of 80 
9.4.12.3 
Storage Conditions 
Study drug will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The investigator or designee is responsible for 
ensuring that the temperature is monitored throughout the total duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house validated data acquisition system, a mechanical recording device, such as a 
calibrated chart recorder, or by manual means, such that minimum and maximum 
thermometric values over a specific time period can be recorded and retrieved as required. 
9.4.13 
Method of Assigning Subjects to Treatment Groups 
1. This is a non-blind study.  Study drug will be administered to subjects who were 
confirmed for eligibility (see Section 9.3) and submitted a written consent form.  This 
study will not be randomized.  Procedure for subject enrollment is shown in Figure 2. 
Unique subject ID numbers prescribed by the sponsor will be assigned to subjects who 
signed ICF and their names and numbers will be recorded accordingly in the Subject 
Screening List. 
2.  Subjects will be screened for enrollment eligibility.  The results will be recorded in 
the Subject Screening List by the investigator or subinvestigator. 
3.  Subjects’ screening results and dispositions will be entered in the subject enrollment 
form (Appendix 5), which then will be faxed to the subject enrollment center. 
4.  Once the fax is received, the enrollment center will review subjects’ eligibility.  If 
ineligible subject is found, the center will fill in the designated form with details and 
fax to the investigators who will review the center’s assessment, and remove the 
subject from the study. 
5.  If missing entries or discrepancies are found on the enrollment form, the center will 
check with investigators or study coordinator. 
6. For subjects who were confirmed for eligibility, the center will fill in the enrollment 
form with subject ID number, date and dose, and the form will be faxed to 
investigators. 
7.  Investigators or study coordinator will review the enrollment form. 
 


 
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Confidential  
 
Page 43 of 80 
 
Investigational Site 
Subject Enrollment Center 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
Ineligible       Eligible 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 2  
Subject Enrollment Procedure 
 
9.4.14 
Selection of Doses in the Study 
See Section 7.5 ‘Study Rationale’ for selection of doses in this study. 
Fax Enrollment sheet 
Communication via fax 
Assign 
Subject 
ID 
Number 
Not 
enrolled 
Fill in Subject 
Enrollment 
Form 
Fax Enrollment Form to the Center
Inquiries 
Enroll 
Fill in Screening 
Failure Form, 
record reasons  
Confirm reasons for 
screening failure 
(Remove from study) 
Fill in Enrollment Form: 
 
• 
Enrollment date 
• 
Subject ID Number 
Review the content of 
Enrollment Form  
Ineligible 
(1) 
Screening: 
Confirmation of subject 
eligibility 
Make 
entries 
in 
Subject 
Screening 
(2) 
(3) 
(4) 
(7) 
Confirmation of 
eligibility 
(6) 
Eligible 
(5) 


 
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9.4.15 
Selection and Timing of Dose for Each Subject 
See Section 9.4 ‘Study Treatment’ for dose selection and timing for each subject. 
9.4.16 
Blinding 
The study will not be blinded. 
9.4.17 
Prior and Concomitant Therapy 
Any medications (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent and for 30 days after the last 
dose of study treatment) will be recorded on the CRF.  The investigator will record on the 
Adverse Event CRF any AE for which the concomitant medication/therapy was administered.  
Name of the medication, the starting dose (for treatment of primary disease only), and dates 
of initial and last administration will be recorded on the CRF.  
Medication or fluid infusion administered as pretreatment for surgery, examination, or drug 
administration will not be considered concomitant drugs.  Name of concomitant therapy, 
dates of initial and last administration will be recorded on the CRF. 
9.4.18 
Concomitant Therapies 
Investigator and subinvestigator will conduct study in compliance with prohibited 
concomitant drugs and therapies guidelines to ensure subject safety and accurately assess 
study treatment.  Study treatment must be discontinued at once if any prohibited 
concomitant drug or therapy becomes necessary.  Prohibited drug or therapy can be 
administered to subject per discretion of investigator or subinvestigator giving full attention 
to subject safety and development of AEs.  
9.4.18.1 
Prohibited Concomitant Drugs and Therapies 
1.  Prohibited from the time of subject enrollment for this study until discontinuation 
from this study 
a.  Anti-cancer therapy other than lenvatinib and everolimus (surgery, anti-cancet 
medication, endocrine therapy,  palliative radiotherapy or immunotherapy, etc.). 
b.  Other investigational drugs. 
c.  Any agent that potently inhibits CYP3A or P-gp 
d.  Live vaccine (freeze-dried live attenuated rubella, oral poliomyelitis vaccine, 
freeze-dried BCG, etc.) 
2.  Prohibited during Cycle 1 
a.  Any agent that potently or moderately inhibits CYP3A or P-gp, or potently or 
moderately induces CYP3A. 
 


 
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9.4.18.2 
Limited Use of Concomitant Therapies and Drugs 
Drugs that are not prohibited for concomitant use include drugs used to treat complications or 
AEs or drugs used to ameliorate symptoms (including blood products, blood transfusions, 
fluid transfusions, antibiotics, steroids, antidiarrheal drugs, and tranquilizers, etc.).  These 
drugs and treatments can be concomitantly used, based on the judgment of the investigator or 
subinvestigator.In Cycle 2 and onward, agents that potently or moderately inhibit CYP3A or 
P-gp, and potently or moderately induce CYP3A will be allowed to a limited extent. 
9.4.18.3 
Drug–Drug Interactions 
Lenvatinib is a substrate of P-gp and CYP3A, primarily metabolized by CYP3A and 
aldehyde oxidase while everolimus is a substrate of P-gp and CYP3A, primarily metabolized 
by CYP3A.  Co-administration of drugs that potently or moderately induces CYP3A or P-pg 
with lenvatinib could affect the metabolism of lenvatinib and everolimus leading to possible 
development of toxic effect due to increase in plasma concentration.Drugs that potently or 
moderately induce CYP3A will accelerate metabolism of lenvatinib and everolimus causing 
decrease in plasma concentration and reduced therapeutic response.  
Refer to Appendix 2 for drugs that can impact on activities of drug-metabolizing enzyme 
CYP3A. 
9.4.19 
Treatment Compliance 
Records of treatment compliance for each subject will be kept during the study.  Clinical 
research associates (CRAs) will review treatment compliance during investigational site 
visits and at the completion of the study. 
9.4.20 
Drug Supplies and Accountability 
The investigator and the study staff (or the designated pharmacist) will be responsible for the 
accountability of all study drugs/study supplies (dispensing, inventory, and record keeping) 
following the sponsor’s instructions and adherence to Good Clinical Practice (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.An accurate and timely record of the receipt of all study drugs, 
dispensing of study drug to the subject, collection of unused study drug returned by the 
subject (unused drug 1), collection of drug shipped to the site but not dispensed to subjects 
(unused drug 2) and subsequent return of unused study drug to the sponsor (sum of unused 
drugs 1 and 2) must be maintained.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, and (d) 
documentation of returns to 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.  As applicable, all unused study 


 
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drugs/study supplies and empty and partially empty containers from used study drugs/study 
supplies are to be returned to the investigatorUnused study drugs that are to be returned from 
the site will be collected by sponsor’s representative personally and will be returned to the 
sponsor’s designated central or local depot(s).  Drug accountability will be reviewed during 
investigational site visits and at the completion of the study. 
 
9.5 
STUDY ASSESSMENT 
9.5.1 
Assessments 
9.5.1.1 
Demography 
Investigator, subinvestigator or clinical research associates will investigate the subjects who 
provided written informed consent for eligibility to fill out a ‘Subject Registration Form’.  
In addition, patient characteristics will be collected for items below, which will be recorded 
on the CRF.  Information available from the Subject Registration Form may be used for 
recording on the CRF without repeating the process. 
1. Subject ID Number 
2. Date of obtaining written Informed Consent 
3. Sex 
4. Ethnicity 
5. Race 
6. Date of birth 
 
9.5.1.2 
Baseline Assessments 
MEDICAL HISTORY, CURRENT CONDITIONS, PHYSICAL EXAMINATION 
All medical history and conditions confirmed at Screening will be documented in the CRF if 
they are judged by the investigators to have impact on the assessment of efficacy, safety or 
pharmacokinetic profile.  Prior treatment and diagnosis on the primary disease will also be 
investigated. 
1. Original tumor diagnosis (date of diagnosis, diagnostic method ［histology/cytology］, 
histological type, staging［TNM classification.  See Appendix 6］) 
2. Previous anti-cancer therapy for renal cell carcinoma 
a. Surgical therapy (date, modality) 
b. Radiotherapy (site of radiotherapy, end date of radiotherapy) 
c. Anti-cancer medication (medication name, initial dose, start/end date of medication, 
reason for discontinuation) 
d. Other anti-cancer procedure (procedure name, end date of procedure) 


 
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9.5.1.3 
Safety Assessments 
Safety assessments will consist of monitoring and recording all AEs and SAEs including 
CTCAE v4.03 grades (for increasing/decreasing severity), DLT, laboratory test value 
(hematology, blood chemistry, urine values), vital signs, 12-ECGs, and echocardiograms or 
MUGA scans including left ventricular ejection fraction (LVEF); chest CT scan, ECOG-PS 
and the physical examination as detailed in the Schedule of Procedures/Assessments (Table 
5). 
ADVERSE EVENTS AND OTHER EVENTS OF INTEREST  
An adverse event is any untoward medical occurrence in a subject or clinical investigation subject 
administered an investigational product.  An AE does not necessarily have a causal relationship with 
the study drug.  For this study, the study drug is lenvatinib. 
The criteria for identifying adverse events are: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational 
product, whether or not considered related to the investigational product.  If a 
diagnosis was made based solely on the sign and symptom, the identified medical 
condition or disease will be considered as AE.  
• Any new disease or exacerbation of an existing disease.  However, worsening of 
the primary disease should be captured under efficacy assessments as disease 
progression rather than as an AE 
• Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (e.g., ECG or x-ray) that results in symptoms. 
• Any deterioration in nonprotocol-required measurements of a laboratory value or 
other clinical test (e.g., ECG or x-ray) that results in a change in treatment or 
discontinuation from study drug 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
• An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, whether prescribed in the 
protocol or not 
 
All AEs encountered during the clinical 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 consent through the last visit.  Subjects may receive other 
anti-cancer treatment within 30 days after the final administration of study drug if his/her 
cancer conditions necessitate.  In this case, off-treatment observation must be conducted 
before initiation of other anti-cancer treatment.  For SAEs, all events occurred until 30 days 


 
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Page 48 of 80 
after the subject’s last dose will be collected.  If subject was withdrawn prior to and during 
screening evaluations due to findings meeting the definition of an AE, its severity will be 
recorded on the Adverse Events CRF. 
All laboratory abnormalities meeting the criteria to qualify as an AE should be recorded on 
the CRF.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an 
isolated laboratory abnormality should be classified as an adverse event. 
A laboratory result should be considered by the investigators to be an AE regardless of the 
presence of an abnormality laboratory test if it: 
• Results in the withdrawal of study drug 
• Results in withholding of study drug pending some investigational outcome  
• Results in an intervention, based on medical evaluation (e.g., potassium 
supplement for hypokalemia) 
• Results in any out of range laboratory value that in the investigator’s judgment 
fulfills the definitions of an AE with regard to the subject’s medical profile 
• Increases in severity compared to baseline by ≥ 2 CTCAE v4.03 grades, with the 
exception of lymphocytes, albumin, cholesterol, glucose.  For these tests, a 
change of ≥ 2 grades will be evaluated by the investigator to determine if they are 
of clinical significance and, if so, will be considered an adverse event. 
 
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is being 
reported as an AE, should be considered an AE if the QTc interval (Friderica formula) is > 450 ms 
and there is an increase of > 60 ms from baseline.  Any ECG abnormality that the investigator 
considers as an AE should be reported as such. 
All AEs must be followed until resolution or for 30 days after the subject’s last dose, whichever 
comes first.  Serious adverse events will be followed until the event resolves or the event or sequelae 
stabilize. 
 
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
Assessing Severity of Adverse Events 


 
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AEs will be graded on a 5-point scale according to CTCAE v4.03.  Investigators will report 
CTCAE grades for all AEs (for a change in severity). 
Assessing Relationship to lenvatinib or everolimus 
Items to be considered when assessing the relationship of an AE to lenvatinib or everolimus 
are: 
• Temporal relationship of the onset of the event to the initiation of lenvatinib or 
everolimus 
• The course of the event, especially the effect of discontinuation of lenvatinib or 
everolimus or reintroduction of lenvatinib or everolimus, as applicable 
• Whether the event is known to be associated with the lenvatinib or everolimus 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 to lenvatinib or everolimus 
Related 
A causal relationship between lenvatinib or everolimus and the AE is a reasonable 
possibility 
Not 
Related 
A causal relationship between lenvatinib or everolimus and the AE is not a 
reasonable possibility.  
 
SERIOUS ADVERSE EVENTS AND OTHER EVENTS OF INTEREST 
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.  
In addition to the above, other events of interest include pregnancy or exposure to study drug 
through breastfeeding; AEs associated with study drug overdose, misuse, abuse, or 
medication error; any treatment-emergent significant laboratory abnormality (Section 
9.5.3and9.5.4).  These events of interest 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 (a case of 
normal births is excluded) associated with events of interest 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” (i.e., 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 (e.g., battery replacement) that 
was in place prior to study entry 
 
PHYSICAL EXAMINATION 
Physical examinations will be performed as designated on the Schedule of 
Procedures/Assessments (Table 5). A 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.  Documentation of the physical examination will 
be included in the source documentation at the investigational site.  Changes from screening 
physical examination findings that meet the definition of an AE will be recorded on the 
Adverse Events CRF. 
VITAL SIGNS, WEIGHT AND HEIGHT MEASUREMENTS 
Vital sign measurements (ie, systolic and diastolic blood pressure [BP］[mmHg], pulse [bpm], 
body temperature [°C], weight [kg] and height [cm, at Screening only] ) will be obtained as 
designated in the Schedule of Procedures/Assessments (Table 5). 


 
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BP and pulse will be obtained after subjects have been resting.  BP will be measured on the 
same arm and, preferably by the same clinical staff at each timepoint as far as possible.   
One BP assessment is defined as the mean value of 2 measurements at least 5 minutes apart.  
For subjects with an elevated BP (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg), 
confirmation should be obtained by performing another measurement after 30 minutes. 
LABORATORY MEASUREMENTS 
Clinical laboratory tests include hematology, blood chemistry and urinalysis (Table 3).  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. 
Table 3.Clinical Laboratory Tests 
Category 
Tests 
Hematology 
RBC, hemoglobin, hematocrit, platelet count, WBC, WBC with 
differential (neutrophils, lymphocytes, monocytes, eosinophils, 
basophils) 
Blood coagulation 
INRa 
Blood chemistry 
 
Liver function tests 
ALP, AST, ALT, total bilirubin, conjugated (direct) bilirubin 
Renal function tests 
BUN，creatinine 
Other 
glucose b, albumin, total cholesterol b, triglycerides b, LDH, total 
protein, Na, K, Cl, Ca, Mg, inorganic phosphorus, amylase c, lipase, 
CPK c 
Endocrinologyd 
TSH, FT4 
Viral testse 
HIV antibodies, HCV antibodies, HBs antigen, HBs antibodies, 
HBc antibodies，(HBV-DNA as needed) 
Urinalysisf 
pH，protein，glucose，occult blood (or hemoglobin) 
Pregnancy test 
hCG or β-hCG (urine or serum) 
a:  INR should be performed as part of the screening assessment and when clinically indicated 
b:  Will be measured under fasted conditions at Screening and Baseline.  If glucose level exceeds ULN, 
glucose measurement will be taken after being fasted for at least 6 hours (water is permitted) in the 
following assessments.  
c:  Amylase isoenzymes (pancreatic and salivary type) and CPK isoenzymes (CK-MM and CK-MB) should be 
evaluated if amylase or CPK is greater than 3 x the upper limit of normal 
d:  Thyroid antibody test should be performed if clinically indicated. 
e:  At screening evaluation only 
f:  If urine dipstick testing suggests a urinary tract infection, or if clinically indicated, a urine microscopy, 
culture, and sensitivity should be performed at the institution’s laboratory 


 
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A laboratory abnormality may meet the criteria to qualify as an AE as described in this protocol 
(Section 9.5.1.3.1) and the CRF Completion Guidelines.  In these instances, the AE corresponding to 
the laboratory abnormality will be recorded on the Adverse Event CRF. 
If AEs were assessed during unscheduled clinic visits, all the data corresponding to the laboratory 
abnormality will be recorded on the CRF. 
ELECTROCARDIOGRAMS 
Twelve-lead 
ECG 
will 
be 
performed 
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 
may be used. 
ECG parameters (HR，PR interval，QRS interval，QRS axis，QT interval，QTcF interval，
RR interval) will be recorded on the CRF. 
ECG findings (normal，abnormal, not clinically significant，abnormal clinically significant) 
will also be recorded on the CRF. 
QTc will be corrected using Fridericia’s formula (QTcF). 
An ECG abnormality may meet the criteria of an AE as described in this protocol (Section 
9.5.1.3.1) and the CRF Completion Guidelines.  In these instances, the AE corresponding to 
the laboratory abnormality will be recorded on the Adverse Event CRF. 
NYHA CLASSIFICATION FOR CARDIAC FUNCTION 
Subjects will be assessed for cardiac function at Screening using NYHA classification system 
(Appendix 1).  
ECOG-PS 
 
ECOG-PS will be assessed as designated on the Schedule of Procedures/Assessments (Table 5).  See 
Appendix 9. 
ASSESSMENT OF INTERSTITIAL LUNG DISEASE 
Subjects will be evaluated for interstitial lung disease by means of chest X-ray, CT and SpO2 
level, as designated on the Schedule of Procedures/Assessments (Table 5).  The result will 
be documented in the medical record at the site.  Changes from screening findings that meet 
the definition of an AE will be recorded on the Adverse Events CRF. 


 
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OTHER SAFETY ASSESSMENTS 
Echocardiogram or A multiple gated acquisition (MUGA) scan 
A multiple gated acquisition (MUGA) scan (using technetium-99mpertechnetate) or an 
echocardiogram to assess LVEF will be performed during the Screening Visit, every 16 weeks or 
sooner if clinically indicated), at discontinuation (within one week or sooner).  Echocardiogram or 
MUGA scans should be performed locally in accordance with the institution’s standard practice.  
Whichever modality is used for an individual subject at baseline should be repeated for all subsequent 
LVEF assessments for that subject.  Left ventricular ejection fractions as assessed by the institution 
will be entered onto the CRF.   
Viral Tests 
A blood sample will be taken for HIV antibodies, HCV antibodies, HBs antigen, HBs 
antibodies, HBc antibodies at Screening.  HBV-DNA test will be performed as needed.  
HBV-DNA data acquired within 28 days of initial dosing or before obtaining informed 
consent may be used if available. 
Pregnancy Tests 
An hCG or β-hCG test (serum or urine) will be performed for premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months as designated 
on the Schedule of Procedures/Assessments (Table 5). 
 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic and Other 
Biomarker Assessments 
PHARMACOKINETIC ASSESSMENTS 
Blood samples will be collected at the time points shown in Table 4 from each subject for measuring 
plasma lenvatinib concentration and whole blood everolimus concentration, using a validated 
analytical method.  For subjects who discontinued study, samples should also be collected as far as 
possible.  Total volume to be drawn at each timepoint will be 6 mL (3 mL for plasma lenvatinib 
concentration, 3 mL for whole blood everolimus concentration).  Collection, handling and logistic 
procedures of obtained samples will be detailed in Appendix 8.  The actual time of each sample 
collection will be recorded on the CRF.  Dosage and time of lenvatinib and everolimus 
administration on the day before and the day of PK analysis sampling will be recorded on the CRF 
(Section 9.5.1.6 Treatment Compliance).  Date and time of last food intake before study drug 
administration on Cycle 1 Day 1 and Day 15 will also be recorded on the CRF. 


 
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Table 4.Pharmacokinetic Sampling Time Points 
Days 
Time (on each Day) 
Acceptable time-window 
(approximate) 
Total Volume 
Collected (mL) 
Cycle 1 Day 1 
Predose 
≤–60 min 
6 mL each 
(3 mL x 2) 
1 h postdose 
≤±15 min 
2 h postdose 
≤±15 min 
4 h postdose 
≤±15 min 
8 h postdose 
≤±60 min 
Cycle 1 Day 2 
Predose 
(24 hours after dosing 
on Day 1) 
≤–60 min 
Cycle 1 Day 15 
Predose 
≤–60 min 
6 mL each 
(3 mL x 2) 
1 h postdose 
≤±15 min 
2 h postdose 
≤±15 min 
4 h postdose 
≤±15 min 
8 h postdose 
≤±60 min 
Cycle 1 Day 16 
Predose 
(24 hours after dosing 
on Day 1) 
≤–60 min 
 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Not applicable 
9.5.1.5 
Efficacy Assessments  
Tumor assessments will be performed using RECIST 1.1 (Appendix 7) by the investigators.  
Anti-tumor effect will be assessed by appropriate imaging modality such as CT or MRI, with images 
taken under the same conditions at screening.  Tumor assessments will be performed at screening 
and recorded on the CRF for: overall (presence of target lesion［tumor and/or lymph node］and 
non-target lesion); target lesion (lesion site, diameter, date of assessment, modality); non-target lesion 
(lesion site, diameter, date of assessment, modality).  Subsequently, target and non-target lesion, the 
presence or absence, location, date of emergence and diagnosis modality of new lesion as well as 
overall response will be investigated and recorded in the CRF.  
Evaluations of the anti-tumor effect or safety may be performed by a third party as required.  In this 
case, image data, if requested by the sponsor, will be provided by the investigator, subinvestigator, or 
clinical coordinator via an electronic medium. 


 
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TUMOR EVALUATIONS 
Chest X-rays will not be used for the evaluation of target lesions. 
Modality used for involved body part is indicated below: 
• Brain：CT or MRI   
• Chest：CT 
• Abdomen：CT or MRI 
• Pelvis：CT or MRI 
• Bone：bone scintigraphy or whole-body MRI (screening), CT or MRI 
• Others：CT , MRI, etc. 
• Lesions that are visible or palpable: Clinical evaluation 
 
1. CT or MRI 
CT or MRI will be performed with contrast enhancement unless the subject is allergic to 
oral/IV contrast, in which case CT without contrast will be performed.  Low-dose CT 
transmission scans from a positron emission tomography-CT (PET-CT) combination 
scanner, CT images for attenuation correction, or ultrasound should not be used for tumor 
assessment. 
a. Screening 
• Brain, chest, abdomen, pelvis, and known or newly suspected lesion will be 
evaluated  
• Data acquired prior to subject’s informed consent may be used as screening data if 
the assessment was conducted within 28 days of initial study drug administration. 
 
b. Cycle 1 and onward 
• Chest, abdomen, pelvis, site where lesion was observed at screening or any areas 
of newly suspected lesion should be assessed. 
 
2. Assessment of bone lesion 
Perform bone scan (scintigraphy or whole-body bone MRI) at screening.  If the subject 
has had a bone scan performed within 6 weeks of initial study drug administration, the data 
may be used even if it is prior to obtaining informed consent.  If a bone lesion is to be 
followed as a non-target lesion, it is preferable that this be done using CT or MRI.  For 
non-target bone lesions that can be followed only on bone scans, bone scans should be 
performed every 24 weeks or sooner as clinically indicated.  A time point response other 
than not evaluable (NE) will be allowed despite an individual lesion assessment of NE for 


 
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weeks when bone scans are not required.  The same methodology and scan acquisition 
techniques used at screening should be used throughout the study to ensure comparability, 
unless tracer becomes unavailable. 
 
3. Clinical evaluation 
For evaluation of visible lesions, documentation by color photography including a ruler to 
estimate the size of the lesion is suggested.  Palpable lesions will be assessed by clinical 
evaluation and the results will be recorded on the source document.  Where color digital 
photos of skin lesions are to be recorded, a millimeter scale ruler and a label showing the 
Subject ID Number and the date should be included in the photo.  Measurements should 
be performed with calipers. 
Tumor lesion will be assessed at screening, every 8 weeks starting from Cycle 1 Day 1 (i.e., 
Day 1 of odd-numbered Cycle, with time windows of +/- 7 days) and at discontinuation (+ 
7 days), by the same modality every time.  Additional assessments will be conducted if 
clinically indicated.  Data obtained within 28 days prior to discontinuation will be used as 
discontinuation data if available. 
TUMOR MARKERS 
Tumor marker tests such as C-reactive protein (CRP) and immunosuppressive acidic protein 
(IAP) will be conducted at screening if clinically indicated, however, evaluation is not 
required if appropriate marker does not exist. 
Following the evaluation at screening, tumor marker will be assessed every 8 weeks starting 
from Cycle 1 Day 1 (i.e., Day 1 of odd-numbered Cycle, with time windows of +/- 7 days) 
and at discontinuation (+/- 7 days).  Data obtained within 28 days prior to discontinuation 
will be used as discontinuation data. 
9.5.1.6 
Assessments of Study Drug Administration 
Investigator, subinvestigator, or clinical research associates will provide subjects with dosing 
instruction.  Treatment compliance including the dosage and date of lenvatinib and 
Everolimus administration will be reviewed and recorded on the CRF.  Dosing time will 
also be recorded on the day and the day before PK assessment date as shown on Table 4. 
9.5.1.7 
Assessments of Concomitant Drugs and Therapies 
Investigator, subinvestigator, or clinical research associates will instruct subjects to comply 
with requirements indicated in ‘Section 9.4.18.1 Prohibited Concomitant Drugs and 
Therapies’.  Compliance status will be reviewed as follows: 
1. Concomitant medication 
All medications that started after the date of informed consent up to completion of the last 
observation period will be investigated for the following items at each clinic visit and 


 
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recorded on the CRF.  If subjects receive medical care by another physician at other 
department or medical institution, investigators may inquire the attending physician about the 
treatment given to the subject concerned. 
Subjects may receive other anti-cancer treatment within 30 days after the final administration 
if his/her cancer conditions necessitate.  In this case, off-treatment observation must be 
conducted before initiation of other anti-cancer treatment. 
Concomitant medication name, Reason for use (indication), Start and end date (if continuing 
after the off-treatment observation, indicate as such) 
2. Concomitant therapies 
All therapies that started after the day of informed consent up to completion of last 
observation period will be investigated at each clinic visit and recorded on the CRF.  
If subjects receive medical care by another physician at other department or medical 
institution, investigators may inquire the attending physician about the treatment given to the 
subject concerned. 
Concomitant therapies name, Reason for use (indication), Start and end date (if continuing 
after the off-treatment observation, indicate as such) 
9.5.2 
Schedule of Procedures/Assessments 
9.5.2.1 
Schedule of Procedures/Assessments 
The Schedules of Procedures/Assessments are shown in Table 5. 
 


 
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Table 5.Schedule of Procedures/Assessments in Study E7080-J081-112 
 
Pre-Treatment 
Treatment Period 
Follow-up Period 
 
Screeninga 
Baselineb 
Cycle 1 
Cycle 2 
Cycle 3～ 
Disconti
nuation 
Off-treatment 
observation e 
Day 
Within 28 
days predose 
Within 7 days 
predose  
1 
8 
（±2） 
15 
（±2） 
22 
（±2） 
1 
（±3） 
8c 
（±3） 
15 
（±3） 
22e 
（±3） 
1 
（±3） 
15d 
（±3） 
(+7) 
30 days after 
last dosing (+7) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data/Medical record 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
NYHA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis/medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood coagulation test( INR) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Xm 
 
ECOG-PS 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Xm 
 
12- Lead ECG  
X 
 
 
 
 
 
X 
 
 
 
Xl 
 
Xm 
 
Vital signs 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
X 
Physical Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
X 
Hematology 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
X 
Blood chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
X 
Urinalysis 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xm 
X 
Pregnancy test (if applicable) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Endocrinology test 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
Xm 
 
Blood sample for PK analysis 
 
 
Xj 
 
Xj 
 
 
 
 
 
 
 
 
 
Tumor assessment 
Xg 
 
Xk 
Xn 
 
Assessment of interstitial lung 
disease 
Xh 
 
Xh 
Xn 
 


 
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MUGA or echocardiogram 
Xi 
 
Xi 
Xn 
 
lenvatinib/everolimus 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEsf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant 
medications/therapies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a:  Screening tests are performed only if subject gives consent 
b:  For assessments scheduled for both at screening and baseline, the screening data can serve as the baseline data, if performed within 7 days prior to the 
initial dosing 
c:  Assessments/procedures on Cycle 2 Day 8 and Day 22 can be skipped only if subject’s safety is assured by investigator/subinvestigator. 
d:  Assessments/procedures on Day 15 of Cycle 3 or later can be skipped only if subject’s safety is assured by investigator/subinvestigator.  Subjects with 
systolic BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg must have their BP monitored every 2 weeks (on Day 15 or more frequently as clinically 
indicated) until systolic BP has been ≤ 150 mm Hg and diastolic BP has been ≤ 95 mm Hg for 3 consecutive months.  If a repeat event of systolic 
BP ≥ 160 mm Hg or diastolic BP ≥ 100 mm Hg occurs, the subject must resume the Day 15 evaluation until systolic BP has been ≤ 150 mm Hg and 
diastolic BP has been ≤ 95 mm Hg for 3 consecutive months.  Urine dipstick testing for subjects with proteinuria ≥ 2+ should be performed every 2 
weeks (on Day 15 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 the Day 15 urine dipstick testing for evaluation of proteinuria until results are 1+ or negative for 3 
consecutive months.  Subjects will return to the clinic for the Day 15 visit if BP monitoring or urine dipstick testing is required as specified above.  
e:  Subjects may receive other anti-cancer treatment within 30 days after the final administration if his/her cancer conditions necessitate.  In this case, 
off-treatment observation must be conducted before initiation of other anti-cancer treatment.  
f:  SAEs, regardless of relationship to study drug treatment, must be reported as soon as possible within 1 working day.  AEs will be recorded for 30 days 
after last dose.  During cycle 1 and if clinically indicated, repeat AE assessments at least every 7 days until restarting administration during 
treatment interruption due to AEs. 
g:  Data obtained prior to informed consent as well as within 28 days prior to start of study treatment may be used.  Assessments on the brain, chest, 
abdomen, pelvis or any other areas of known or suspected disease will be performed.  Bone Scan will be performed within 6 week prior to start of 
study treatment.  If clinical indicated, tumor markers such as CRP and IAP will be measured. 
h:  Assessment of interstitial lung disease will be performed by chest X-ray and CT, and SpO2.  X-ray and CT will be performed at screening and every 8 
weeks (±7days) from Cycle1 Day1.  SpO2 will be performed at screening and Day1 of each cycle from Cycle2.  Additional assessments maybe 
performed if clinically indicated. 
i:  MUGA or echocardiogram will be performed at screening and every 16 weeks (ie, Day 1 of every 4 cycles［±7days］) from Cycle1 Day1.  Additional 
assessments maybe performed if clinically indicated. 
j:  Cycle 1 Day1/Day15: Samples collected at predose, 1,2,4,8, and 24 (predose on the following day) hours postdose. 
k:  Tumor assessments will be performed every 8 weeks (ie, Day 1 of odd-number Cycles［±7days］).  Additional assessments maybe performed if 
clinically indicated.  Assessments on the chest, abdomen, pelvis, and other areas of known disease at Screening plus newly suspected disease will 


 
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be performed every time.  Bone scan will be performed every 24 weeks (ie, Day 1 of every 6 cycles［±14days］) if needed.  Additional 
assessments maybe performed if clinically indicated.  Tumor marker will be measured if the marker is measured in screening. 
l:  12- Lead ECG will be performed every 8 weeks (ie, Day 1 of odd-number Cycles［±7days］) from Cycle 3. 
m:  Data obtained within 7 days prior to the study discontinuation can serve as discontinuation data, if available 
n:  Data obtained within 28 days prior to the study discontinuation can serve as discontinuation data, if available. 


 
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9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies of RCC.   
The assessments of safety and tolerability to be performed in this study, including 
hematology analyses, blood chemistry tests, urinalysis, vital signs, 12-lead ECG, ECOG-PS, 
chest CT scan, physical examinations 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 SAEs, irrespective of relationship to study treatment, must be reported on a completed 
SAE form by email, fax, or spoken communication as soon as possible, but no later than one 
business day from the date the investigator becomes aware of the event. 
Deaths and life-threatening events should be reported by telephone immediately but no later 
than one business day.  Other SAEs must be reported to the sponsor on a completed SAE 
form no later than 5 business days. 
Serious adverse events, regardless of causality assessment, must be collected through the 
termination visit and for 30 days following study drug discontinuation, whichever is longer.  
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 (and/or 
protocol-specified 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 Appendix 3. 
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. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment or any exposure to study drug through breastfeeding 
during study treatment or within 30 days of last study treatment, must be reported.  If an 


 
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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 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 Appendix 3.  The 
Pregnancy Report Form (Appendix 11) must be used for reporting.  All pregnancies must be 
followed to outcome.  The outcome of the pregnancy must be reported using the prescribed 
format (Appendix 12) 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 Association with Special Situations 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows: 
 
Overdose 
Accidental or intentional use of the study drug in an amount higher than the 
protocol-defined dose 
Misuse 
Intentional and inappropriate use of study drug not in accordance with the protocol 
Abuse 
Sporadic or persistent intentional excessive use of study drug accompanied by 
harmful physical or psychological effects 
Medication 
error 
Any unintentional event that causes or leads to inappropriate study drug use or 
subject harm while the study drug is in the control of 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 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. 


 
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9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators, the head of the medical institution and regulatory 
authorities of reportable events, in compliance with applicable regulatory requirements, on an 
expedited basis (ie, within specific time frames).  For this reason, it is imperative that sites 
provide complete SAE information in the manner detailed in Section 9.5.4.1 
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 from 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 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 reason.  In 
addition to the primary reason, the subject may indicate 1 or more of secondary reasons for 
discontinuation.  Study disposition information will be collected on the Subject Disposition 
CRF. 
9.5.6 
Abuse or Diversion of Study Drug (or recreational use) 
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 


 
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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 GCP 
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 must sign the completed CRF to attest 
to its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 


 
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9.7 
Statistical Methods 
Statistical analyses will be performed after database has been locked, 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.  
All analyses will be performed for total subjects and by initial dose group (if applicable). 
9.7.1.1 
Study Endpoints 
PRIMARY ENDPOINTS 
Dose limiting toxicity (DLT) 
Safety variables (AEs, clinical laboratory results, vital signs, weight, ECG, ECOG-PS, 
LVEF) 
SECONDARY ENDPOINTS 
PK parameters including Cmax，tmax，AUC of lenvatinib and everolimus  
Best overall response (BOR), objective response rate (ORR), DCR, disease control rate 
(DCR) and change from baseline in sum of diameters of target lesion (if appropriate)   
9.7.1.2 
Definitions of Analysis Sets 
DLT Analysis Set is the group of subjects who have completed treatment Cycle 1 without 
major protocol deviation with at least 75% of treatment compliance and were assessed for 
DLT, and subjects who have experienced DLT during Cycle 1.  Subjects with less than 75% 
treatment compliance to lenvatinib or everolimus due to a reason other than toxicity up to 
Cycle 1 Day 28 will not be included in this analysis set. 
Safety Analysis Set/Efficacy Analysis Set is the group of subjects who received at least 1 
dose of lenvatinib. 
Pharmacokinetic (PK) Analysis Set is the group of subjects who received at least 1 dose of 
lenvatinib and had sufficient PK data to derive at least one PK parameter. 
9.7.1.3 
Handling of Data 
Details of handling on missing data, rejected data, and abnormal data will be provided in the 
SAP. 


 
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9.7.1.4 
Subject Disposition 
Screening subjects table will include the number of subjects who are enrolled (ie, subjects 
who signed informed consent), are eligible, failed screening, the primary reason, and other 
reason for screen failures.  Subject disposition table will include the number of subjects who 
are treated/not treated, completed/discontinued the study, the primary reason, and other 
reason for the study discontinuation.  Similarly, the number of subjects who 
completed/discontinued the study treatment, the primary reason, and, other reason for the 
study treatment discontinuation will also be summarized. 
A subject who completed the study is defined as whose DLT assessment has been completed 
adequately.  A subject who completed the study treatment is defined as who discontinued 
study treatment due to disease progression or study cut-off. 
9.7.1.5 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safe Analysis set will be summarized.  
Continuous demographic and baseline variables include age, weight; categorical variables 
include sex, race, ethnicity, ECOG-PS, diagnostic information (site of primary lesion, 
histological type, disease stage), and prior therapy (surgery, radiotherapy, anti-cancer 
medication, and other therapies), if any.  
9.7.1.6 
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 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set), Anatomical Therapeutic Chemical (ATC) class (ie, <specify 
relevant ATC classes> [eg, anatomical class, therapeutic class, pharmacologic class, 
chemical class]), and WHO DD preferred term.  Prior medications will be defined as 
medications that stopped before the first dose of study drug.  Concomitant medications will 
be defined as medications that started after the date of the first dose of study drug up to 30 
days after the subject’s last dose.  All medications will be presented in subject data listings. 
9.7.1.7 
Efficacy Analyses 
ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT 
Since this study is phase 1, primary endpoint is not defined. 
Efficacy analyses will be based on the Efficacy Analysis Set.  Best overall response (BOR) 
will be summarized using RECIST 1.1.  BOR consists of CR (complete response), PR 
(partial response), SD (stable disease), PD (progressive disease) and NE (not evaluable).  
ORR (objective response rate) and DCR (disease control rate) will be calculated with an 
exact 2-side 95% CI.  ORR is defined as the proportion of subjects who have BOR of CR or 
PR.  DCR is defended as the proportion of CR, PR or SD. 


 
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Subjects with non-target disease only will be assigned to SD category if the BOR is 
non-CR/non-PD.   SD has to be achieved at ≥7 weeks after first dose.  CR and PR do not 
have to be confirmed at ≥4 week’s assessment.  If applicable, a waterfall plot will be 
presented for the percent changes from baseline in the sum of the diameters of target lesions 
at postbaseline nadir.  If applicable, time profiles of tumor marker will be plotted and 
investigated. 
ANALYSIS OF THE SECONDARY EFFICACY ENDPOINT 
Not applicable. 
ANALYSIS OF THE EXPLORATORY EFFICACY ENDPOINT 
Not applicable 
9.7.1.8 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses 
PHARMACOKINETIC ANALYSES 
Lenvatinib plasma concentrations and everolimus whole-blood concentrations will be 
summarized and listed for the subjects who have at least 1 evaluable data in the Safety 
Analysis Set.  The PK Analysis Set will be used for all other analyses including summaries 
of lenvatinib plasma concentrations, everolimus whole-blood concentrations and PK 
parameters.  Concentrations – time profiles of lenvatinib and everlolimus will be plotted and 
investigated.  Using non-compartmental analysis methods, plasma concentrations of 
lenvatinib and whole-blood concentration of everolimus will be calculated to determine the 
PK parameters including Cmax, tmax, AUC at first administration (Cycle 1 Day 1) and repeated 
administration (Cycle 1 Day 15). 
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
Not applicable. 
9.7.1.9 
Safety Analyses 
All tolerability analyses will be performed on the DLT Analysis Set.  The number and 
percentage of subjects with DLT will be calculated.  DLT will also be summarized per type 
of toxicity.  The Safety Analysis Set will be used for all other safety analyses.  The number 
and percentage of subjects with all AEs and SAEs observed after first dosing will be 
summarized and listed by SOC, PT, and severity.  Summary statistics will be presented for 
laboratory test values, vital sign, and 12-lead ECG parameters.  If needed, the changes from 
baseline will also be summarized. 


 
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EXTENT OF EXPOSURE 
The number of cycles, duration of treatment, total exposure time, total number and dose of 
the drug administered, dosing strength, and total ratio of dosage administered/total dosage 
planned will be summarized for both lenvatinib and everolimus in each subject. 
ADVERSE EVENTS 
1. Analysis of DLT 
Tolerability analyses will be performed using the DLT Analysis Set.  The number and 
percentage of subjects with DLT will be calculated.  DLT will also be summarized per type 
of toxicity. 
 
2.  Analyses of AEs 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using ICH Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA lower level term (LLT) closest 
to the verbatim term.  The linked MedDRA preferred term (PT) and primary system organ 
class (SOC) are also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during and up 
to 30 days of 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 number (percentage) of subjects with TEAE will be summarized by SOC and PT.  A 
subject will be counted only once within a SOC and PT, even if the subject experienced more 
than 1 TEAE within a specific SOC and PT.  The number (percentage) of subjects with 
TEAEs will be summarized by highest grade according to CTCAE ver. 4.03. 
The number (percentage) of subjects with treatment-related (lenvatinib or everolims) TEAEs 
will be summarized by MedDRA SOC and PT.  The number (percentage) of subjects with 
treatment-related TEAEs will be summarized by highest CTCAE grade. 
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
or TEAEs leading to death, study drug withdrawal, and dose reduction or dose interruption 
will be summarized by MedDRA SOC and PT.  Subject data listings of all serious adverse 


 
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events, AEs leading to death, leading to discontinuation from study treatment, dose reduction 
and dose interruption will be provided. 
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units.  For all 
quantitative parameters listed in Section 9.5.1.3.3, the actual value and the change from 
baseline to each postbaseline visit will be summarized by visit using descriptive statistics.  
Qualitative parameters will be summarized by number and percentage of subjects, and 
changes from baseline to each postbaseline visit will be reported using shift tables.  
Percentages will be based on the number of subjects with both nonmissing baseline and 
relevant postbaseline results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range.  CTCAE v4.03 will be used to identify subjects with treatment emergent 
markedly abnormal laboratory values (TEMAV).  A TEMAV is defined as a postbaseline 
value with an increase from baseline to a grade of 2 or higher.  When displaying the 
incidence of TEMAVs, each subject may be counted once in the laboratory parameter high 
and in the laboratory parameter low categories, as applicable. 
VITAL SIGNS 
Summary statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
and temperature), and weight and changes from baseline will be presented by visit. 
ELECTROCARDIOGRAMS 
The results of ECG assessments performed at each visit will be evaluated.  Summary 
statistics for ECG parameters and changes from baseline will be presented by visit. 
 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to each visit.  
In addition, the number (percentage) of subjects who met below criteria at least once in QTcF 
will be presented: 
Absolute QTcF interval prolongation: 
• QTcF interval >450 ms  
• QTcF interval >480 ms  
• QTcF interval >500 ms  
 
Change from baseline in QTcF interval:  


 
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• QTcF interval increases from baseline >30 ms  
• QTcF interval increases from baseline >60 ms  
OTHER SAFETY TESTS 
1. LVEF 
 
Electrocardiograms or multiple-gated acquisition technique will be performed at each site.  
LVEF and change from baseline will be summarized at each visit. 
 
2. ECOG-PS 
ECOG PS will be summarized by scale at each visit and by highest postbaseline scale. 
9.7.2 
Determination of Sample Size 
The primary objective of this study is to investigate the tolerability and safety of lenvatinib in 
combination with everolimus.  Hence neither clinical hypothesis nor judgement criteria are 
set, the sample size is not based on statistical consideration.  The 6 to 12 subjects per initial 
dose group are considered to be adequate to obtain some preliminary data for the assessment 
of safety. 
9.7.3 
Interim Analysis 
No interim analysis is planned for this study. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 
 
10 REFERENCE LIST 
Ellis LM, Hicklin DJ. VEGF-targeted therapy: mechanisms of anti-tumor activity. Nat Rev 
Cancer. 2008;8(8):579-91. 


 
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Escudier B, Porta C, Schmidinger M, Algaba F, Patard JJ, Khoo V, Eisen T, Horwich A, 
ESMO Guidelines Working Group. Renal cell carcinoma: ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25 Suppl 3 
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence 
and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J 
Cancer. 2015;136(5):E359-86. 
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 
2003;9(6):669-76. 
Gild ML, Bullock M, Robinson BG, Clifton-Bligh R. Multikinase inhibitors: a new option 
for the treatment of thyroid cancer. Nat Rev Endocrinol. 2011;7(10):617-24. 
Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, et al. Placental growth factor 
reconstitutes hematopoiesis by recruiting VEGFR1+ stem cells from bone-marrow 
microenvironment. Nat Med. 2002;8(8):841-9. 
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. 
Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 
1998;279(5350):577-80. 
Hirota S, Ohashi A, Nishida T, Isozaki K, Kinoshita K, Shinomura Y, et al.  
Gain-of-function mutations of platelet-derived growth factor receptor α gene in 
gastrointestinal stromal tumors. Gastroenterology. 2003;125(3):660-7. 
Kondo T, Ezzat S, Asa SL. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat 
Rev Cancer. 2006;6(4):292-306. 
Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, et al. Vascular 
endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer 
Res. 2007;67(2):593-9. 
Matsui J, Wakabayashi T, Asada M, Yoshimatsu K, Okada M.  Stem cell factor/c-kit 
signaling promotes the survival, migration, and capillary tube formation of human umbilical 
vein endothelial cells. J Biol Chem. 2004;279(18):18600-7.  
Molina AM, Motzer RJ. Current algorithms and prognostic factors in the treatment of 
metastatic renal cell carcinoma. Clin Genitourin Cancer. 2008;6 Suppl 1:S7-13 


 
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Molina AM, Hutson TE, Larkin J, Gold AM, Wood K, Carter D, Motzer R, Michaelson MD. 
A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in 
combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer 
Chemother Pharmacol. 2014 ;73(1):181-9 
Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med. 
1996;335(12):865-75. 
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson 
JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A; 
RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a 
double-blind, randomized, placebo-controlled phase III trial. Lancet. 2008;372(9637):449-56 
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology 
(NCCN Guidelines) Kidney Cancer Version 3 2015. 2015. 
Okamoto K, Ikemori-Kawada M, Jestel A, von König K, Funahashi Y, Matsushima T, 
Tsuruoka A, Inoue A, Matsui J. Distinct binding mode of multikinase inhibitor lenvatinib 
revealed by biochemical characterization. ACS Med Chem Lett. 2014;6(1):89-94. 
Oseini AM, Roberts LR.  PDGFRα: a new therapeutic target in the treatment of 
hepatocellular carcinoma?  Expert Opin Ther Targets. 2009;13(4):443-54. 
Phay JE, Shah MH.  Targeting RET receptor tyrosine kinase activation in cancer. Clin 
Cancer Res. 2010;16(24):5936-41.  
Rini BI, Campbell SC, Escudier B. Renal cell carcinoma. Lancet. 2009;373(9669):1119-32. 
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, 
Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou YC, Castellano D, Lim HY, Uemura 
H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ. Comparative effectiveness of 
axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 
trial. Lancet. 2011;378(9807):1931-9. 
Seeliger H, Guba M, Kleespies A, Jauch KW, Bruns CJ. Role of mTOR in solid tumor 
systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. 
Cancer Metastasis Rev 2007;26:611–21 
St Bernard R, Zheng L, Liu W, Winer D, Asa SL, Ezzat S.  Fibroblast growth factor 
receptors as molecular targets in thyroid carcinoma.  Endocrinology. 2005; 146(3):1145-53.  


 
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Tammela T, Alitalo K.  Lymphangiogenesis: Molecular mechanisms and future promise. 
Cell. 2010;140(4):460-76 
Turner N, Grose R.  Fibroblast growth factor signalling: from development to cancer. Nat 
Rev Cancer. 2010;10(2):116-29. 
Williams D. Cancer after nuclear fallout: lessons from the Chernobyl accident. Nat Rev 
Cancer. 2002;2(7):543-9.  
Foundation for Promotion of Cancer Research.  Cancer Statistics :13. 2013 
National Cancer Center, Department of Internal Medicine: A manual for medical residents in 
cancer treatment, vol. 6, Igaku shoin. 2013;196-201. 
 


 
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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 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 head of the medical 
institution should be kept informed of such changes as required by local regulations.  In 
these cases, the sponsor may be required to send a letter to the head of the medical institution 
detailing such changes. 
11.2 Adherence to the Protocol 
The investigator will conduct the study in strict accordance with the protocol. 
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 head of the 
medical institution will allow the CRA to inspect the clinical, laboratory, and pharmacy 
facilities to assure compliance with GCP and local regulatory requirements.  The CRFs and 
subject’s corresponding original medical records (source documents) are to be fully available 
for review by the sponsor’s representatives at regular intervals.  These reviews verify 
adherence to study protocol and data accuracy in accordance with local regulations.  All 
records at the site are subject to inspection by the local auditing agency and IRB/IEC review. 
In accordance with GCP, source documents include, but are not limited to, the following:  
• Clinic, office, or hospital charts  
• Copies or transcribed health care provider notes which 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, EEGs, polysomnographs, pulmonary 
function tests) regardless of how these images are stored, including microfiche 
and photographic negatives  
• Pain, QOL, or medical history questionnaires completed by subjects  
• Records of telephone contacts  
• Diaries or evaluation checklists  
• Drug distribution and accountability logs maintained in pharmacies or by research 
personnel  
• Laboratory results and other laboratory test outputs (eg, urine pregnancy test 
result documentation and urine dip-sticks)  
• Correspondence regarding a study subject’s treatment between physicians or 
memoranda sent to the IRBs/IECs  
• CRF components (eg, questionnaires) that are completed directly by subjects and 
serve as their own source  
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as 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 medical records (1) to (8) will not be considered source data.  
1. For the followings, data recorded directly on the CRF are to be considered source data  
• Demographic data (age, race, etc.) 
• NYHA cardiac function classification – date of evaluation, NYHA class 
• Treatment history: Name, starting and ending date of the medication, starting 
dosage and reason for discontinuation  
• ECG results- normal/abnormal 
• Results of follow-up evaluation in subject who discontinued – in all categories 


 
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• Tumor evaluation : TNM classification 
• Tumor assessment: presence of target and non-target lesion 
• Target lesion: location, size in diameter, evaluation date and time 
• Non-target lesion: location, evaluation date and time 
• Newly discovered lesion : location and date of confirmation, if present 
• Dose and dosing date of lenvatinib and everolimus 
• Drug concentration measurement : dates and time of dosing, blood sampling, and 
food consumptions 
• Discontinuation :  reason for discontinuation 
• Information concerning AEs: CTC AE Grade (for items not specified in CTC), 
outcome, causal relationship to lenvatinib and/or everolimus, severity of the AE, 
relation to overdose 
• Concomitant drug (s) : reason for administration 
• Concomitant therapy(ies): type of therapy, condition for which are being treated 
• Other relevant information 
 
2.  Source data for informed consent  
Informed consent form 
 
3.  Source data for tests and examinations 
Test results sheet (and/or electronic data)  
 
4.  Source data for pathological assessment 
Test results sheet (and/or electronic data) 
 
5.  Source data for tumor assessment 
Imaging record (and/or electronic form).  CSR is to be considered source data for 
assessment if it includes measured values 
 
6.  Source data for ECG recordings 
Recorded ECG charts (and/or electronic data) 
 
7.  Shipping record of samples to outside laboratories 


 
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Shipping slip 
 
8.  Source data for subject enrollment 
Subject enrollment form, list of enrolled subjects, list of ineligible subjects, etc. 
 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the 
investigator, the head of the medical institution or the designated representative is 
responsible for retaining all study documents, including but not limited to the protocol, 
copies of CRFs, the Investigator's Brochure, and regulatory agency registration documents 
(eg, ICFs, and IRB/IEC correspondence).  The site should plan to retain study documents, 
as directed by the sponsor, for at least 3 years after the last approval of a marketing 
application and until there are no pending or contemplated marketing applications 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 the 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.  A government regulatory authority may request inspections during the study or 
after its completion. 
11.8 Handling of Study Drug 
All study drugs will be supplied to the principal investigator (or a designated pharmacist) by 
the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist) must maintain an accurate record of the shipment and dispensing of 
the study drug in a drug accountability ledger, a copy of which must be given to the sponsor 
at the end of the study.  An accurate record of the date and amount of study drug dispensed 
to each subject must be available for inspection at any time.  The CRA will visit the site and 
review these documents along with all other study conduct documents at appropriate 
intervals once study drug has been received by the site. 


 
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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 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).  


 
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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 
Appendix 1: NYHA Cardiac Disease Classification 
Appendix 2: Names of Drug Affecting Drug Metabolizing Enzyme CYP3A4 and P-gp 
Activities 
Appendix 3:  Study Administrative Structure 
Appendix 4:  Drug Labeling and Packaging 
Appendix 5:  Subject Enrollment Form 
Appendix 6:  TNM classification for renal cell carcinoma 
Appendix 7:  RECIST-Based Tumor Assessment 
Appendix 8:  Procedures for Collecting, Handling, and Shipping Blood Samples for Drug 
Concentration Measurements 
Appendix 9: ECOG Performance Status 
Appendix 10:  Serious Adverse Event Report 
Appendix 11:  Pregnancy Report 
Appendix 12:  Pregnancy Outcome Report 
 

SAP_001.pdf: 
16.1.9
Documentation of Statistical Methods
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Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7080-J081-112 
Study Protocol 
Title: 
Phase 1 Study of lenvatinib in Combination with Everolimus in 
Subjects with Unresectable Advanced or Metastatic Renal Cell 
Carcinoma 
Date: 
08 Feb 2016 
Version: 
Version 2.0 
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Statistical Analysis Plan 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................6 
3.1 
Study Objectives ......................................................................................................6 
3.1.1 
Primary Objectives.........................................................................................6 
3.1.2 
Secondary Objectives.....................................................................................6 
3.2 
Overall Study Design and Plan ................................................................................6 
3.2.1 
Overall Study Design and Plan ......................................................................6 
3.2.2 
Pretreatment Period ........................................................................................9 
3.2.3 
Treatment Period ............................................................................................9 
3.2.4 
Follow-up Period ...........................................................................................9 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................9 
5 
STATISTICAL METHODS ............................................................................................10 
5.1 
Study Endpoints .....................................................................................................10 
5.1.1 
Primary Endpoint .........................................................................................10 
5.1.2 
Secondary Endpoints ...................................................................................10 
5.1.2.1 
Pharmacokinetic (PK) Endpoints .......................................................10 
5.2 
Study Subjects ........................................................................................................11 
5.2.1 
Definitions of Analysis Sets.........................................................................11 
5.2.2 
Subject Disposition ......................................................................................11 
5.2.3 
Protocol Deviations ......................................................................................12 
5.2.4 
Demographic and Other Baseline Characteristics .......................................12 
5.2.5 
Prior and Concomitant Therapy ...................................................................12 
5.2.6 
Treatment Compliance .................................................................................12 
5.3 
Data Analysis General Considerations ..................................................................13 
5.3.1 
Pooling of Centers........................................................................................13 
5.3.2 
Adjustments for Covariates..........................................................................13 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................13 
5.3.4 
Examination of Subgroups ...........................................................................13 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................13 
5.3.6 
Other Considerations ...................................................................................13 
5.4 
Efficacy Analyses ..................................................................................................13 
5.4.1 
Primary Efficacy Analysis ...........................................................................13 
5.4.2 
Secondary Efficacy Analysis .......................................................................16 
5.4.3 
Other Efficacy Analysis ...............................................................................16 
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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................17 
5.5.1 
Pharmacokinetic Analyses ...........................................................................17 
5.5.1.1 
Plasma or Blood Concentration and its PK Parameter Analysis .......17 
5.5.1.2 
Pharmacokinetic Data Figures ...........................................................17 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....18 
5.6 
Safety Analyses ......................................................................................................18 
5.6.1 
Extent of Exposure .......................................................................................18 
5.6.2 
Adverse Events ............................................................................................19 
5.6.3 
Laboratory Values ........................................................................................20 
5.6.4 
Vital Signs ....................................................................................................21 
5.6.5 
Electrocardiograms ......................................................................................21 
5.6.6 
Other Safety Analyses..................................................................................22 
5.7 
Other Analyses .......................................................................................................22 
5.8 
Exploratory Analyses .............................................................................................22 
6 
INTERIM ANALYSES ...................................................................................................22 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................22 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................23 
8.1 
General Data Handling ..........................................................................................23 
8.2 
Pharmacokinetic Data Handling ............................................................................25 
8.2.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Everolimus Blood and Concentration ..........................................................25 
8.2.2 
BLQ Handling for Calculation of PK Parameters .......................................25 
8.2.3 
BLQ Handling for Developing Concentration-Time Profiles .....................25 
8.2.4 
Handling of Anomalous Concentration Values ...........................................25 
8.2.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters ....................................................................................................26 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................27 
10 STATISTICAL SOFTWARE ..........................................................................................27 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................27 
12 REFERENCES ................................................................................................................27 
13 APPENDICES .................................................................................................................28 
13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 ..............................................................................28 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
AUC 
area under the plasma concentration-time curve 
BLQ 
below the limit of quantification 
BOR 
best overall response 
CI 
confidence interval 
CL/F 
apparent total clearance following oral administration 
Cmax 
maximum observed plasma concentration 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
Css,av 
average steady-state concentration 
Css,max 
maximum observed plasma concentration at steady state 
Css,min 
minimum observed plasma concentration at steady state 
CTCAE 
common toxicity criteria for adverse events 
CV 
coefficient of variation 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
LLOQ 
lower limit of quantification 
LLT 
lower level term 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NE 
not evaluable 
ORR 
objective response rate 
PD 
pharmacodynamic(s) / progressive disease  
PFS 
progression free survival 
PK 
pharmacokinetic(s) 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
PTF 
peak-trough fluctuation 
QD 
quaque die 
Rac 
accumulation index 
RCC 
renal cell carcinoma 
RECIST 
response evaluation criteria in solid tumor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation / stable disease 
SI 
système international 
SOC 
system organ class 
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Abbreviation 
Term 
t1/2 
terminal elimination phase half-life 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TLGs 
tables, listings and graphs 
tmax 
time at which the highest drug concentration occurs 
tss,max 
time at which the highest drug concentration occurs at steady state 
Vz/F 
apparent volume of distribution at terminal phase 
WHO DD 
World Health Organization drug dictionary 
λz 
terminal phase rate constant 
 
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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-
J081-112. 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
• 
To investigate tolerability and safety of lenvatinib in combination with everolimus in 
subjects with unresectable advanced or metastatic renal cell carcinoma (RCC). 
 
3.1.2 
Secondary Objectives 
• 
To assess the pharmacokinetic (PK) of lenvatinib and everolimus 
• 
To assess the preliminary anticancer effects of lenvatinib in combination with 
everolimus 
 
3.2 
Overall Study Design and Plan 
3.2.1 
Overall Study Design and Plan 
This is a non-randomized, open-label, multi-center Phase 1 study (E7080-J081-112) of 
lenvatinib in combination with everolimus in subjects with unresectable advanced or 
metastatic RCC.  Subjects will be enrolled in this study after informed consent is obtained 
and eligibility is confirmed. 
One treatment cycle is defined as 28 days.  Lenvatinib will be administered at starting dose 
of 18 mg in combination with everolimus at starting dose of 5 mg both orally once daily 
continuously.  DLT will be observed during Cycle 1 (28 days following the initial dosing) to 
investigate tolerability and safety.  Treatment will continue until disease progression, 
development of unacceptable toxicity, subject requests to discontinue, withdrawal of consent, 
or study termination by sponsor. 
A total of six subjects will be initially enrolled.  Enrollment will be interrupted when DLT is 
observed in two or more subjects.  Investigators and sponsor will review the nature and 
severity of all the DLTs and make a decision if enrollment of up to six subjects and further 
additions of three to six subjects are feasible and necessary.  Suggestions by the independent 
medical advisor will be collected, if necessary. 
The study sponsor and investigators will consider the nature and severity of DLT during 
Cycle 1 as well as unacceptable toxicities that cannot be managed with dose interruption 
and/or reduction and overall toxicities up to Cycle 2 on the evaluation of tolerability in 
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combination therapy.  The suggestions by the independent medical advisor can be collected, 
if necessary. 
Additional subjects maybe enrolled to the lower cohort (lenvatinib 14 mg and everolimus 5 
mg once daily administration) in the following cases: over one-third of subjects experiences 
DLTs during Cycle 1, development of unacceptable, development of unmanageable toxicity 
with dose interruption and/or reduction up to Cycle 2, tolerability cannot be confirmed with 
dose level of lenvatinib 18 mg/everolimus 5 mg QD. 
If a subject has no DLT but fails to receive ≥ 75% of the planned dosage of lenvatinib and/or 
everolimus up to Cycle 1 Day 21, due to a reason other than treatment related toxicity, this 
subject will not be included in the DLT assessment population and a new subject will be 
added for replacement. 
Subjects will discontinue study treatment at the time of disease progression, development of 
unacceptable toxicity, withdrawal of consent, or qualifies any of the criteria described in 
‘Discontinuation for Individual Subjects’ in protocol.  The discontinuation assessments will 
occur within 7 days and off-treatment visit on 30th day after the final dose of study treatment.   
DLT is defined as toxicity related to this combination therapy as indicated in Table 1. 
Table 1  Dose Limiting Toxicity 
Toxicity 
Category 
Toxicity/CTCAE Grade 
Hematologic 
• 
Grade 4 neutropenia lasting > 7 days 
 
• 
Grade 3 febrile neutropenia (axillary temperature ≥ 38.5ºC and neutrophils  < 1 x103/µL 
(< 1000/mm3) 
 
• 
Grade ≥ 3 thrombocytopenia lasting > 7 days or requiring blood transfusion 
Non-
hematologic 
toxicity 
• 
Grade 3 non-hematologic toxicities lasting > 7 days except for the following: 
 
Clinically insignificant or transient abnormal laboratory findings   
 
Able to be controlled by maximal supportive therapy  
Grade ≥ 3 hyperamylasemia or hyperlipasemia without clinical or other evidence of 
pancreatitis are not regarded as a DLT. 
 
Grade ≥ 3 nausea, vomiting or diarrhea lasting 7 days which persist despite 
maximal medical therapy 
• 
Hypertension uncontrolled by medication 
• 
Any thromboembolic event including cerebrovascular hemorrhage/events 
Medication 
compliance 
• 
Failure to administer ≥ 75% of the planned dosage of lenvatinib or everolimus as a result 
of treatment related toxicity  
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Overall study design is presented in Figure 1.  
 
 
 
 
 
 
 
 
 
 
Figure 1 Overview of Study Design 
 
 
Cycle 1 
30 days 
following the 
last 
administration 
（+7days）
Within 7 days 
Treatment Period 
Pretreatment Period 
Informed Consent 
Screening procedure 
Enrollment 
Dosing 
Off-treatment visit 
Final Dosing 
Screening  
Follow-up Period 
Within 28 
days 
Baseline assessment
Cycle 2 and onward 
DLT observation 
Discontinuation 
Assessment 
28 days/cycle 
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3.2.2 
Pretreatment Period 
Pretreatment Period will consist of obtaining informed consent, screening procedures, subject 
enrollment and baseline assessments.  Each subject must be explained the nature of the study 
and sign an informed consent form before any study-specific procedures are performed.  
Investigators must confirm the eligibility of each subject during screening procedures.  
All Screening procedures are to be completed within 28 days prior to the Cycle 1 Day 1 and 
eligible subjects will be enrolled.  All Baseline assessments are to be completed within 7 
days prior to the Cycle 1 Day 1 and subjects’ eligibility will be confirmed. 
3.2.3 
Treatment Period 
Treatment Period will consist of two parts: Cycle 1 and following cycles. 
One treatment cycle is defined as 28 days.  Lenvatinib will be administered at starting dose 
of 18mg in combination with everolimus at starting dose of 5 mg both orally once daily 
continuously.  Dose limiting toxicity (DLT) will be observed during Cycle 1 (28 days 
following the initial dosing) to investigate tolerability and safety.  Treatment will continue 
until disease progression, development of unacceptable toxicity, subject requests to 
discontinue, withdrawal of consent, or study termination by sponsor. 
Subjects will be required to stay at the clinic during Cycle 1 as a general rule, however, they 
may be allowed to go home temporarily, be discharged or receive treatment as outpatient per 
investigators’ discretion. 
3.2.4 
Follow-up Period 
Follow-up Period will include discontinuation assessments and off-treatment visit.  Subject 
will discontinue study treatment if he/she qualifies for any of the criteria listed in Section 
9.3.3.1.  The discontinuation assessments will occur within 7 days and off-treatment visit on 
30th day (+ 7 days) after final dose of study treatment. 
4 
DETERMINATION OF SAMPLE SIZE 
The primary objective of this study is to investigate the tolerability and safety of lenvatinib in 
combination with everolimus. Hence neither clinical hypothesis nor judgment criteria are set, 
the sample size is not based on statistical consideration.   The 6 to 12 subjects per initial dose 
group are considered to be adequate to obtain some preliminary data for the assessment of 
safety. 
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5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. 
All analysis will be performed for total subjects and by initial dose group ( if applicable ). 
5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
• 
DLTs 
• 
Safety endpoints ( adverse events, clinical laboratory parameters, vital signs, weight, 12-
lead ECG, ECOG-PS and left ventricular ejection fraction [LVEF]) 
 
5.1.2 
Secondary Endpoints 
• 
PK parameters of lenvatinib and everolimus 
• 
Best overall response (BOR), objective response rate (ORR), disease control rate (DCR), 
and percent change from baseline in the sum of the diameters of target lesions ( if 
applicable ). 
 
5.1.2.1 
Pharmacokinetic (PK) Endpoints 
PK parameters derived by non-compartmental analysis using plasma concentrations of 
lenvatinib and blood concentrations of everolimus which include, but are not limited to, are 
shown as below: 
 
Cmax 
maximum observed concentration 
tmax 
time at which the highest drug concentration occurs 
AUC(0-t) 
area under the concentration-time curve from zero time to time of last quantifiable 
concentration 
AUC(0-ti) 
area under the concentration-time curve from zero (pre-dose) to a given sampling time 
(ti) 
AUC(0-inf) 
area under the concentration-time curve from zero time extrapolated to infinite time 
t1/2 
terminal elimination phase half-life 
CL/F 
apparent total clearance following oral dosing 
Vz/F 
apparent volume of distribution at terminal phase 
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Css,max 
maximum observed concentration at steady state 
Css,min 
minimum observed concentration at steady state 
tss,max 
time at which the highest drug concentration occurs at steady state 
AUC(0-τ) 
area under the concentration-time curve over the dosing interval 
CLss/F 
apparent total clearance following oral administration at steady state 
Css,av 
average steady-state concentration 
Rac(Cmax), Rac(AUC) 
accumulation index 
PTF ratio 
peak-trough fluctuation ratio 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
DLT Analysis Set is the group of subjects who have completed treatment Cycle 1 without 
major protocol deviation with at least 75% of treatment compliance and were assessed for 
DLT, and subjects who have experienced DLT during Cycle 1. Subjects with less than 75% 
treatment compliance to lenvatinib or everolimus due to a reason other than toxicity up to 
Cycle 1 Day 28 will not be included in this analysis set.   
Safety Analysis Set/Efficacy Analysis Set is the group of subjects who received at least 1 
dose of lenvatinib 
Pharmacokinetic Analysis Set is the group of subjects who received at least 1 dose of 
lenvatinib and had sufficient PK data to derive at least 1 PK parameter. 
 
The number of subjects enrolled, the number and the percentage of subjects included in each 
analysis set will be presented.  Subject data listings will be provided. 
5.2.2 
Subject Disposition 
Screening subjects table will include the number of subjects who are enrolled (i.e., subjects 
who signed informed consent), failed screening, and the primary reason for screen failures.  
Subject disposition table will include the number of subjects who are treated, 
completed/discontinued the study. Similarly, the number of subjects who 
completed/discontinued the study treatment, and the primary reason for the study treatment 
discontinuation will also be summarized. 
A subject who completed the study is defined as whose DLT assessment has been completed 
adequately.  A subject who completed the study treatment is defined as who discontinued 
study treatment due to radiological or disease progression or were on-going at the study cut-
off. 
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Subject data listings will be provided. 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock.  All protocol 
deviations identified according to study entry criteria and during treatment will be presented 
in the clinical study report (CSR). 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set and 
Pharmacokinetic Analysis Set will be summarized using summary statistics.  Continuous 
demographic and baseline variables include age, height, and weight; categorical variables 
include sex, race, ethnicity, ECOG PS, NYHA, diagnostic information (metastatic sites, 
number of metastatic site, histological type, time since RCC diagnosis to first dose of study 
treatment, TNM categories and stage), prior therapy (nephrectomy [yes or no], radiotherapy 
[yes or no], sites of radiotherapy, anti-cancer medication [yes or no], type of anti-cancer 
medication [axitinib, everolimus, and so on.],number of VEGF targteted therapy [1 regimen, 
2regimens, 3 regimens]and other therapies [yes or no]), treatment duration and reason for 
discontinuation of last anti-cancer medication, hypertension (yes or no), and creatinine 
clearance ( >= LLN, < LLN and >= 60 mL/min, and 60-40 mL/min). 
The categories for metastatic site, site of previous radiotherapy, type of prior anti-cancer 
medication depend on actual data. 
Subject data listings will be provided. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the case report form (CRF) will be coded 
to an 11-digit code using the World Health Organization Drug Dictionary (WHO DD).  The 
number (percentage) of subjects who took prior and concomitant medications will be 
summarized on the Safety Analysis Set by Anatomical Therapeutic Chemical (ATC) class 
(anatomical class, pharmacological class, and pharmacological sub-class) and WHO DD 
preferred term.  Prior medications are defined as medications that stopped before the first 
dose of study treatment.  Concomitant medications are defined as medications that (1) started 
before the first dose of study treatment and were continuing at the time of the first dose of 
study treatment, or (2) started on or after the date of the first dose of study treatment up to 30 
days after last dose.  Medications received after 30 days of last dose will be considered as 
post treatment medications.  All medications will be presented in subject data listings. 
5.2.6 
Treatment Compliance 
Treatment related protocol deviations will be presented in CSR as provided in section “5.2.3 
Protocol Deviations “. 
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5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
No adjustment for covariates will be performed. 
5.3.3 
Multiple Comparisons/Multiplicity 
No statistical comparison is planned in this study. 
5.3.4 
Examination of Subgroups 
No subgroup analysis is planned in this study. 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
No imputation will be performed for missing data. 
5.3.6 
Other Considerations 
Not applicable. 
5.4 
Efficacy Analyses 
5.4.1 
Primary Efficacy Analysis 
Since this study is phase 1, primary endpoint is not defined. 
Efficacy analyses will be based on the Efficacy Analysis Set.  Based on the tumor 
assessments according to response evaluation criteria in solid tumor (RECIST) 1.1, BOR will 
be summarized.  BOR are complete response (CR), partial response (PR) stable disease (SD), 
progression of disease (PD) and not evaluable (NE).  ORR, DCR and their corresponding 2-
sided 95% confidence intervals (CIs) will be calculated using Cropper-Pearson’s exact 
method.  ORR is defined as the proportion of subjects who achieved BOR of CR or PR. DCR 
is defined as the proportion of subjects who achieved BOR of CR, PR or SD.  Subjects with 
non-target disease only will be assigned to SD category if the BOR is non-CR/non-PD.  SD 
has to be achieved at ≥ 7 weeks after first dose. CR and PR do not have to be confirmed at ≥ 
4 weeks later assessment.  If applicable, a spaghetti plot will be presented for the percent 
changes from baseline in the sum of the diameters of target lesions by subject. 
Median, Q1, and Q3 for progression free survival (PFS) with its 95% CI will be evaluated.  
The number (percentage) of subjects with event/censored will be summarized.  The PFS rate 
with its 95% CI at 4-month, 8-month and 12-month will be calculated using Kaplan-Meier 
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product limit estimates, if applicable.  Kaplan-Meier plots with the number of subjects at risk 
will be presented for PFS. 
PFS is defined as the time from the date of first dose to the date of first documented PD or 
death due to any cause (whichever occurs first).  For subjects who do not have an event 
(documented PD or death from any cause), PFS will be censored.  Censoring rules for PFS 
are shown in Table 2. 
PFS (days) = Date of first documented PD/ death/ Censored date – Date of first dose + 1. 
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Table 2 Censoring Rule of PFS 
Situation 
End Date 
Censor/Event 
Documented PD during the study 
Date of the first assessment 
of the series of the tests that 
determined PD 
Eventa 
Death during the study before 
PD 
Date of death 
Eventa 
No 
baseline 
or 
unreadable 
baseline tumor assessments  
Date of first dose 
Censor 
Treatment discontinuation for 
other than PD or death, and no 
postbaseline tumor assessments 
Date of first dose 
Censor 
Treatment discontinuation for 
other than PD or death with 
postbaseline tumor assessments 
Date 
of 
last 
adequateb 
tumor assessment  
Censor 
New anticancer treatment started 
prior to PD or death 
Date 
of 
last 
adequateb 
tumor assessment prior to 
or on date of new treatment 
Censor 
PD or death after two or more 
missed tumor assessmentsc 
Date 
of 
last 
adequateb 
tumor assessment before 
missed tumor assessment 
Censor 
Subjects still on study without 
PD or death as of data cut off 
Date 
of 
last 
adequateb 
tumor assessment prior to 
or on date of data cut off 
Censor 
a: Earliest date among the two dates will be used in calculating the PFS. 
b: Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD, or PD 
c: Window of two or more missed tumor assessment is defined as duration between the last adequate tumor 
assessment and PD or death is ≥ 127 days, for scan schedule of every 8 weeks ( ±7 days) 
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Duration of response (DOR) is defined as the time from the date of first evaluation of PR or 
CR to the date of first documented PD or death due to any cause (whichever occurs first).  
DOR will be calculated for each subject and shown in only subject data listings. Only 
subjects who achieved at least one PR or CR will be include in calculation of DOR.  For 
subjects who do not have an event (documented PD or death from any cause), DOR will be 
censored.  Censoring rules for DOR are shown in Table 3. 
Table 3 Censoring Rules of DOR 
Situation 
End Date 
Censor/Event 
Documented PD during the study 
Date of the first assessment 
of the series of the tests that 
determined PD 
Eventa 
Death during the study before 
PD 
Date of death 
Eventa 
Treatment discontinuation for 
other than PD or death with 
postbaseline tumor assessments 
Date 
of 
last 
adequateb 
tumor assessment  
Censor 
New anticancer treatment started 
prior to PD or death 
Date 
of 
last 
adequateb 
tumor assessment prior to 
or on date of new treatment 
Censor 
PD or death after two or more 
missed tumor assessmentsc 
Date 
of 
last 
adequateb 
tumor assessment before 
missed tumor assessment 
Censor 
Subjects still on study without 
PD or death as of data cut off 
Date 
of 
last 
adequateb 
tumor assessment prior to 
or on date of data cut off 
Censor 
a: Earliest date among the two dates will be used in calculating the DOR. 
b: Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD, or PD 
c: Window of two or more missed tumor assessment is defined as duration between the last adequate tumor 
assessment and PD or death is ≥ 127 days, for scan schedule of every 8 weeks ( ±7 days) 
 
DOR (days) = Date of first documented PD/ death/ Censored date – Date of first evaluation 
of PR or CR + 1. 
Subject data listings will be provided. 
5.4.2 
Secondary Efficacy Analysis 
Not applicable. 
5.4.3 
Other Efficacy Analysis 
Not applicable. 
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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual lenvatinib plasma concentrations and 
everolimus blood concentrations listings. The PK Analysis Set will be used for the 
summaries of lenvatinib plasma concentrations and everolimus blood concentrations and for 
summaries and listings of PK parameters. 
5.5.1.1 
Plasma or Blood Concentration and its PK Parameter Analysis 
<Concentration> 
Plasma concentration values for lenvatinib and blood concentration values for everolimus 
will be summarized using summary statistics (n, mean, standard deviation [SD], median, 
minimum [min] and maximum [max]) by nominal time point. 
Plasma concentrations of lenvatinib and blood concentrations of everolimus will be listed for 
each subject by actual sampling time. 
<PK Parameter> 
PK parameters will be derived by non-compartmental analysis using WinNonlin software 
(version 6.2.1 or later) according to SWP-SOCS-006.02. 
The following pharmacokinetic parameters for lenvatinib and everolimus will be calculated: 
Cmax ,tmax, AUC(0-t), AUC(0-ti), AUC(0-inf), t1/2, CL/F, Vz/F, Css,max, Css,min, tss,max, AUC(0-τ), 
CLss/F, Css,av, Rac(Cmax), Rac(AUC), PTF ratio. 
Other PK parameters may be calculated as appropriate. 
Summary statistics will be tabulated for the PK parameters of lenvatinib and everolimus.  
Summary statistics (n, mean, SD, median, min, and max) will be presented for all parameters 
(apart from tmax where mean and SD are not required).  In addition, geometric mean 
and %CV will also be presented for all parameters apart from tmax.  
PK parameters of lenvatinib and everolimus for each subject will be listed. 
5.5.1.2 
Pharmacokinetic Data Figures 
The linear and semi-log plots of plasma concentration for lenvatinib and blood concentration 
for everolimus versus actual time will be displayed by individual subjects.  The actual time 
will be plotted on the X axis and the concentrations of lenvatinib and everolimus will be 
plotted on the Y axis. 
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The linear and semi-log mean (+SD) plots of lenvatinib plasma concentration versus nominal 
time will be displayed.  The nominal time will be plotted on the X axis and the mean (+SD) 
will be plotted on the Y axis on the same graph by visit (Cycle 1 Day 1 and Cycle1 Day 15). 
The linear and semi-log mean (+SD) plots of everolimus blood concentration versus nominal 
time will be displayed.  The nominal time will be plotted on the X axis and the mean (+SD)  
will be plotted on the Y axis on the same graph by visit (Cycle 1 Day 1 and Cycle1 Day 15). 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
Not applicable. 
5.6 
Safety Analyses 
The analysis for tolerability will be performed on the DLT Analysis Set.  The Safety 
Analysis Set will be used for all other safety analyses.  Safety data will be summarized on an 
“as treated” basis using summary statistics (e.g., n, mean, SD, median, Q1, Q3, minimum, 
maximum for continuous variables; number [percentage] for categorical variables).  Safety 
variables include treatment-emergent adverse events (TEAEs), clinical laboratory parameters, 
vital signs, weight, LVEF, 12-lead ECG results, and ECOG PS.  Study Day 1 for all safety 
analyses will be defined as the date of the first dose of lenvatinib. 
5.6.1 
Extent of Exposure 
For lenvatinib and everolimus, the number of cycles, the cumulative number of cycles,  
duration of treatment per subject, number of subject months, total number of doses per 
subject, total doses per subject, dose intensity per subject, and relative dose intensity per 
subject will be summarized, separately.  The calculations are below: 
• 
Number of cycles = The last cycle with at least one study treatment dosing 
• 
Duration of treatment (days) = Last dosing date – first dosing date + 1 
• 
Duration of treatment (months) = (Last dosing date – first dosing date + 1) / (365.25/12) 
• 
Number of subject months = (Total of Durations of treatment per subject) / (365.25/12) 
• 
Total number of doses = Sum of days with study treatment dosing 
• 
Total doses (mg) = Sum of all the actual dose 
• 
Dose intensity (mg/days) = Total doses / Duration of treatment 
• 
Relative dose intensity (%) = 100 × Dose intensity / defined starting dose for each dose 
group 
 
The number (percentage) of subjects who experienced dose interruption, dose reduction of 
lenvatinib or everolimus will be provided.  In addition, the cycle of first dose interruption, 
dose reduction, the number of subjects (percentage) with dose interruption, dose reduction by 
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cycle, the frequency of dose interruption, dose reduction during treatment of lenvatinib or 
everolimus will also be summarized. 
Subject data listings will be provided. 
5.6.2 
Adverse Events 
DLTs 
The number (percentage) of subjects who experienced DLT will be summarized.  
Adverse events (AE) 
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 17.1 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) will also be captured in the database. 
A treatment-emergent adverse event (TEAE), defined in “8.1 General Data Handling ”, will 
be included in summary tables.  All AEs, treatment emergent or otherwise, will be presented 
in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by MedDRA SOC and PT.  A subject will be counted only once within a SOC and PT, even 
if the subject experienced more than 1 TEAE within a specific SOC and PT.  The number 
(percentage) of subjects with TEAEs will be summarized by highest grade according to 
common toxicity criteria for adverse events (CTCAE) ver. 4.03.  The number (percentage) of 
subjects with TEAEs with CTCAE grade 3 or above will also be summarized by highest 
grade. 
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
MedDRA SOC and PT.  Treatment-related TEAEs include those events considered by the 
investigator to be related to lenvatinib or everolimus.  The number (percentage) of subjects 
with treatment-related TEAEs will be summarized by highest CTCAE grade.  The number 
(percentage) of subjects with treatment-related TEAEs with CTCAE grade 3 or above will 
also be summarized by highest grade. 
The number (percentage) of subjects with DLTs will be summarized by MedDRA SOC and 
PT.  All DLTs will be presented in subject data listings. 
The number (percentage) of subjects with TEAEs leading to death, treatment-emergent 
serious adverse events (SAEs) will be summarized by MedDRA SOC and PT.  The number 
(percentage) of subjects with treatment-related TEAEs leading to death, treatment-related 
treatment-emergent SAEs will also be summarized by MedDRA SOC and PT.  A subject 
data listing of all serious adverse events, AEs leading to death will be provided. 
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The number (percentage) of subjects with TEAEs leading to dose reduction of lenvatinib 
and/or everolimus (A TEAE leading to discontinuation of only everolimus will be counted as 
a TEAE leading to dose reduction of lenvatinib and/or everolimus in this table), and dose 
interruption of lenvatinib and/or everolimus will be summarized by MedDRA SOC and PT. 
As well as TEAEs, the number (percentage) of subjects with treatment-related TEAEs 
leading to dose reduction of lenvatinib and/or everolimus (A treatment-related TEAE leading 
to discontinuation of only everolimus will be counted as a treatment-related TEAE leading to 
dose reduction of lenvatinib and/or everolimus), and dose interruption of lenvatinib and/or 
everolimus will be summarized by MedDRA SOC and PT. 
The number (percentage) of subjects with TEAEs leading to discontinuation from lenvatinib, 
dose reduction of lenvatinib, and dose interruption of lenvatinib,  discontinuation from 
everolimus, dose reduction of everolimus, and dose interruption of everolimus will also be 
summarized by MedDRA SOC and PT. 
In addition to TEAEs, the number (percentage) of subjects with treatment-related TEAEs 
leading to discontinuation from lenvatinib, dose reduction of lenvatinib, and dose 
interruption of lenvatinib will be summarized by MedDRA SOC and PT.  For these analyses, 
treatment-related TEAEs include those events considered by the investigator to be related to 
lenvatinib.  The number (percentage) of subjects with treatment-related TEAEs leading to 
discontinuation from everolimus, dose reduction of everolimus, and dose interruption of 
everolimus will also be summarized by MedDRA SOC and PT.  For these analyses, 
treatment-related TEAEs include those events considered by the investigator to be related to 
everolimus. 
A subject data listing of AEs leading to discontinuation from study treatment, dose reduction 
and dose interruption will be provided. 
An overview table, including the incidence of and the number of subjects with TEAEs, 
treatment-related TEAEs, TEAEs with CTCAE grade 3 or above, treatment-emergent SAEs, 
deaths, and those TEAEs leading to treatment discontinuation, dose reduction, or dose 
interruption, and corresponding treatment-related TEAEs in above categories will be 
provided. 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units.  For all 
quantitative parameters listed in protocol Section 9.5.1.3.5, the actual value and the change 
from baseline to each postbaseline visit, the highest and lowest postbaseline values will be 
summarized by visit using summary statistics.  Qualitative parameters will be summarized by 
number and percentage of subjects, and changes from baseline to each postbaseline visit and 
the highest postbaseline result will be reported using shift tables.  Percentages will be based 
on the number of subjects with both nonmissing baseline and relevant postbaseline results. 
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Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value is below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  The result of LHN classification will be provided in a subject data listing. 
Laboratory parameters will be graded by CTCAE ver. 4.03 in “13 APPENDICES”.  Changes 
from CTCAE grade at baseline to each postbaseline visit and worst postbaseline will be 
reported using shift tables.  As for thyroid stimulation hormone, values at baseline and worst 
postbaseline will be categorized into ≤0.5, >0.5 – 2.0, >2.0 – 5.5, >5.5 (μIU/mL) and 
summarized.  
CTCAE ver. 4.03 will be used to identify subjects with Treatment-emergent markedly 
abnormal laboratory value (TEMAV).  TEMAV is defined as a value with postbaseline value 
with a grade increase from baseline by 2 or higher.  (i.e., Increasing grade 0 to 2 or higher, 
grade 1 to 3 or higher, grade 2 to 4 or 5.)  For phosphate, TEMAV is defined as a value with 
postbaseline value with a grade increase from baseline by 3 or higher.  The number 
(percentage) of subjects with TEMAV (markedly abnormal high/low) will be summarized by 
visit.  When displaying the incidence of TEMAVs, each subject will be counted once in the 
laboratory parameter high and in the laboratory parameter low categories, as applicable. 
5.6.4 
Vital Signs 
Summary statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
and temperature), and weight and changes from baseline will be presented by time point. 
Subject data listings will be provided. 
5.6.5 
Electrocardiograms 
The results of ECG assessments performed at each visit will be evaluated.  Summary 
statistics for ECG parameters (Heart Rate, RR, PR, QRS, QT, and QTcF) and changes from 
baseline will be presented by time point. 
Shift tables will present changes from baseline in ECG interpretation (categorized as normal; 
abnormal, not clinically significant; and abnormal, clinically significant) to each visit.  
In addition, the number (percentage) of subjects who met below criteria at least once in 
QTcF will be presented: 
Absolute QTcF interval prolongation: 
• 
QTcF interval >450 ms 
• 
QTcF interval >480 ms 
• 
QTcF interval >500 ms 
 
Change from baseline in QTcF interval: 
• 
QTcF interval increases from baseline >30 ms 
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• 
QTcF interval increases from baseline >60 ms 
 
Subject data listings will be provided. 
5.6.6 
Other Safety Analyses 
LVEF  
LVEF and change from baseline will be summarized at each time point. 
The result of LVEF will be categorized into hyperdynamic (>70 %), normal (≥50 – 70%), 
mild dysfunction (≥40 – 50%), moderate dysfunction (≥30 – 40%), Severe dysfunction 
(<30%), and shift from baseline to worst postbaseline will be reported using shift table with 
below levels. 
• 
Hyperdynamic/Normal 
• 
Mild Dysfunction 
• 
Modetate Dysfunction 
• 
Severe Dysfunction 
 
Subject data listings will be provided. 
ECOG PS  
ECOG PS will be summarized by scale at each visit and by highest postbaseline scale.   
Subject data listings will be provided. 
5.7 
Other Analyses 
Not applicable. 
5.8 
Exploratory Analyses 
No exploratory analyses are planned for this study. 
6 
INTERIM ANALYSES 
No interim analysis is planned for this study. 
7 
CHANGES IN THE PLANNED ANALYSES 
The below analyses were added from protocol to establish analyses for CSR: 
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• 
The items of demographic and other baseline characteristics were detailed. 
• 
The analysis for dose interruption and dose reduction were added. 
• 
The analysis for PFS and calculation of DOR were added. 
• 
A waterfall plot for the percent changes from baseline in the sum of the diameters of 
target lesions was replaced to spaghetti plot. 
• 
An overview table of TEAEs was added. 
• 
The analysis for TEAEs and treatment-related TEAEs were enhanced. 
• 
The shift table of laboratory values based on CTCAE grades was added. 
• 
The analysis for TEMAV and its definition were added. 
• 
The categorical analysis for LVEF was added. 
 
The below analysis was deleted from protocol 
• 
The analysis for time course change in tumor marker was deleted as the amount of data 
is not sufficient. 
 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
The data will be handled as follows. The sponsor will determine how to handle all data prior 
to data base lock. 
8.1 
General Data Handling 
Baseline 
Baseline is defined as the last non-missing value observed prior to the first dose of study 
treatment for a given parameter. 
Change from Baseline, Percent Change from Baseline 
Change from baseline is defined as post-baseline value minus baseline value.  
Percent change from baseline is defined as follows: 
% Change from baseline = (Change from baseline/Baseline)*100% 
For any Baseline value of 0, the subject’s corresponding percent change from baseline will 
not be included in the summary statistics table. 
Handling of Missing data 
No imputation will be performed for missing data. 
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Handling of data not within specified periods or within the follow-up period 
All the safety parameters will be used for summary statistic tabulation, except when it is 
irrelevant like the situation that tests scheduled to be conducted before administration of the 
investigational drug are actually conducted after its administration.  Data obtained not within 
the time window specified in the protocol will be handled as missing data for summary tables 
by visit.  Data obtained after the follow-up assessment, which is scheduled for 30 days after 
the last administration of study treatment, will not be used for analysis. 
Handling of multiple data 
In the case of multiple observations within the specified time window of a specific analysis 
visit, the observation closest in date and time to the target visit day will be used in summary 
tables by visit.  If two or more observations have the same distance to the target visit day, the 
one that has the highest CTCAE grade or is furthest away from the normal range will be used 
for safety analyses.  If there are still multiple observations, the handling will be considered 
individually. 
Handling of  below lower quantification values in laboratory results 
In the cases of laboratory result contains below lower quantification (BLQ) value, it will be 
replaced to the lower limit of quantification (LLOQ) for summarizing tables. 
Calculation of creatinine clearance 
To calculate a creatinine clearance (mL/min), the Cockcroft & Cault formula will be used. 
Males: ((140 – age (years))×weight(kg)) / ( Creatinine (serum:mg/dL)×72) 
Females: ((140 – age (years))×weight(kg) ×0.85) / (Creatinine (serum:mg/dL)×72) 
Treatment-emergent adverse event 
A TEAE is defined as an AE that emerged during treatment, having been absent at 
pretreatment or  
• 
Reemerged during treatment, having been present at pretreatment but stopped before 
treatment, or  
• 
Worsened in severity during treatment relative to the pretreatment state, when the AE 
was continuous. 
All the adverse events will be considered as TEAE if the AE onset date was on or after the 
first dose of lenvatinib up to 30 days after last dose of lenvatinib. 
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8.2 
Pharmacokinetic Data Handling 
8.2.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Everolimus Blood and Concentration 
The LLOQ of lenvatinib plasma concentrations is 0.250 ng/mL 
The LLOQ of everolimus blood concentrations is 0.300 ng/mL 
8.2.2 
BLQ Handling for Calculation of PK Parameters 
While calculating PK parameters in WinNonlin, BLQ values will be handled according to 
SWP-SOCS-006.02, for non-compartmental pharmacokinetic analysis. 
8.2.3 
BLQ Handling for Developing Concentration-Time Profiles 
When developing individual concentration-time profiles, BLQ values will be handled 
according to SWP-SOCS-006.02 for non-compartmental pharmacokinetic analysis. 
8.2.4 
Handling of Anomalous Concentration Values 
The handling of anomalous concentration values will follow the guidance in the SWP for 
non-compartmental pharmacokinetic analysis (SWP-SOCS-006.02). 
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8.2.5 
General Rules for Presentation of Drug Concentrations and PK Parameters 
When presenting individual/raw (raw, hereafter) values and summary statistics,  the 
following rule will be applied:  for drug concentrations and concentration-dependent 
pharmacokinetic parameters, all summary statistics (mean, median, geometric mean, SD  and 
coefficient variation (CV) ) will have 3 significant digits.  For tmax, raw values and their 
median are shown in fixed 2 decimal places. 
Variable 
Unit 
N 
Digit rule 
Raw/ 
Minimum/ 
Maximum 
Mean 
Median 
SD 
 
Geometric  
Mean 
CV 
(%) 
drug concentration 
ng/mL 
X 
Significant digits 
3 
3 
3 
- 
- 
Cmax, Css,max, 
Cmin, Css,av 
ng/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
tmax, tss,max 
h 
X 
Fixed decimal 
places 
2 
3 
- 
- 
- 
λz(C1D1&D15) 
1/h 
X 
Significant digits 
3 
(Listing only) 
- 
- 
- 
- 
t1/2(C1D1&D15) 
h 
X 
Significant digits 
3 
3 
3 
3 
3 
AUC(0-t), AUC(0-
inf), AUC(0-ti) 
AUC(0-τ) 
ng•h/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
CL/F, CLss/F 
L/h 
X 
Significant digits 
3 
3 
3 
3 
3 
Vz/F(C1D1&D15) 
L 
X 
Significant digits 
3 
3 
3 
3 
3 
Rac 
 
X 
Significant digits 
3 
3 
3 
3 
3 
PTF ratio 
 
X 
Significant digits 
3 
3 
3 
3 
3 
Mean, SD, geometric mean and CV will not be calculated for tmax, tss,max. 
CV(%)= sqrt(exp[SD**2 of log transformed data]-1)*100 
 
NOTE 
1. The following parameters are reported in the CSR, but appear in Listings only.  They are 
important information to confirm that individual t1/2 and its related parameters such 
asAUC(0-inf) are appropriately derived and allow those PK parameters to be reproduced 
when necessary. 
a. Time points used for estimation of λz (lower and upper) 
b. Number of the time points used for λz 
c. Adjusted regression coefficient (R2adj) 
In Listings, a) are shown in same digits as actual sampling time after dosing used for 
calculation of PK parameters.  For b), integer number is used in Listings.  For c), significant 
3 digits are used in Listing. 
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9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical Analyses will be conducted by Takumi Information Technology, using 
validated standard programs or double programming.  For analyses needed in data review, 
single programming will be used. 
All statistical analyses will be performed using WinNonlin version 6.2.1 or later SAS v 9.3 or 
later. 
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 
• 
FDA Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs 
and Biologics, May 2007 [internet; cited 3 March 2011] Available from: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/ucm071590.pdf.  
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13 APPENDICES 
13.1 National Institute for Health: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03  
National Cancer Institute (NCI) Cancer therapy evaluation program Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 May 2009 (v4.03 June 2010) is available online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
CTCAE grades for selected laboratory parameters are listed in the table below, where ULN is the upper limit of normal and LLN is the 
lower limit of normal.  
 
Lab Parameter  
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hematology  
Hemoglobin (low) 
100 - <LLN (g/L) 
80 - <100 (g/L) 
<80 (g/L) 
__ 
Death 
Hemoglobin (high) 
Increase in >0 - 20 g/L 
above ULN (i.e., Increase 
in >0 - 2 gm/dL above 
ULN) or above baseline if 
baseline is above ULN 
Increase in >20 - 40 g/L 
above ULN (i.e., Increase 
in >2 - 4 gm/dL above 
ULN) or above baseline if 
baseline is above ULN 
Increase in >40 g/L above 
ULN (i.e., Increase in >4 
gm/dL  above ULN) or 
above baseline if baseline is 
above ULN 
__ 
__ 
Platelet Count (PLT) 
(low) 
75 - <LLN (x 10^9/L) 
50 - <75 (x 10^9/L) 
25 - <50 (x 10^9/L) 
<25 (x 10^9/L) 
__ 
White Blood Cell Count 
(WBC) (low) 
3 - <LLN (x 10^9/L) 
2 - <3 (x 10^9/L) 
1 - <2 (x 10^9/L) 
<1 (x 10^9/L) 
__ 
White Blood Cell Count 
(WBC) (high) 
__ 
__ 
>100 x 10^9/L (i.e., 
>100,000/mm^3) 
__ 
Death 
Lymphocytes (low) 
0.8 - <LLN (x 10^9/L) 
0.5 - <0.8 (x 10^9/L) 
0.2 - <0.5 (x 10^9/L) 
<0.2 (x 10^9/L) 
__ 
Lymphocytes (high) 
__  
>4 - 20 (x 10^9/L) (i.e., 
>4,000 - 20,000/mm^3) 
>20 (x 10^9/L) (i.e., > 
20,000/mm^3) 
__ 
__ 
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Lab Parameter  
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Neutrophils (low) 
1.5 - <LLN (x 10^9/L) 
1 - <1.5 (x 10^9/L) 
0.5 - <1 (x 10^9/L) 
<0.5 (x 10^9/L) 
__ 
Blood Coagulation  
INR (high) 
>1 - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
__ 
__ 
Blood Chemistry 
Albumin (low) 
30 - <LLN (g/L) 
20 - <30 (g/L) 
<20 (g/L) 
__ 
Death 
Alkaline Phosphatase 
(ALP) (high) 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
__ 
ALT (SGPT) (high)  
>ULN - 3 x ULN 
>3 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
__ 
AST (SGOT) (high) 
>ULN - 3 x ULN 
>3 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
__ 
Total Bilirubin (high) 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
__ 
Calcium, serum-low 
(hypocalcemia) 
2.0 - <LLN (mmol/L) (i.e., 
8.0 mg/dL - <LLN) * 
1.75 - <2 (mmol/L) (i.e., 
7.0 - <8.0 mg/dL) * 
1.5 - <1.75 (mmol/L) (i.e., 
6.0 - <7.0 mg/dL) * 
<1.5 (mmol/L) (i.e., <6.0 
mg/dL) * 
Death 
Calcium, serum-high 
(hypercalcemia) 
>ULN – 2.9 (mmol/L) (i.e., 
>ULN – 11.5 mg/dL) * 
>2.9 – 3.1 (mmol/L) (i.e., 
>11.5 – 12.5 mg/dL) * 
>3.1 – 3.4 (mmol/L) (i.e., 
>12.5 – 13.5 mg/dL) * 
>3.4 (mmol/L) (i.e., >13.5 
mg/dL) * 
Death 
Cholesterol (high) 
>ULN -7.75 mmol/L 
>7.75 -10.34 mmol/L 
>10.34 -12.92 mmol/L 
>12.92 mmol/L 
__ 
CPK (high) 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
__ 
Creatinine  (high) 
>1 – 1.5 x baseline; >ULN 
– 1.5 x ULN 
>1.5 – 3.0 x baseline; >1.5 
– 3.0 x ULN 
>3.0 x baseline; >3.0 – 6.0 
x ULN 
>6.0 x ULN 
__ 
Glucose, serum-low 
(hypoglycemia)  
3 - <LLN (mmol/L) 
2.2 - <3 (mmol/L) 
1.7 - <2.2 (mmol/L) 
<1.7 (mmol/L) 
Death 
Glucose, serum-high 
(hyperglycemia)  
ULN – 8.9 (mmol/L) 
>8.9 – 13.9 (mmol/L) 
>13.9 – 27.8 (mmol/L) 
>27.8 (mmol/L) 
Death 
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Lab Parameter  
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Lipase (high) 
>ULN - 1.5 x ULN 
>1.5 - 2.0 x ULN 
>2.0 - 5.0 x ULN 
>5.0 x ULN 
__ 
Magnesium (low) 
<LLN - 0.5 (mmol/L) 
<0.5 - 0.4 (mmol/L) 
<0.4 - 0.3 (mmol/L) 
<0.3 (mmol/L) 
Death 
Magnesium (high) 
>ULN - 1.23 (mmol/L) 
__ 
>1.23 - 3.30 (mmol/L) 
>3.30 (mmol/L) 
Death 
Triglyceride 
(hypertriglyceridemia) 
(high) 
1.71 - 3.42 (mmol/L) 
>3.42 - 5.7 (mmol/L) 
>5.7 - 11.4 (mmol/L) 
>11.4 (mmol/L) 
Death 
Phosphate, serum-low 
(hypophosphatemia) 
0.8 - <LLN (mmol/L) 
0.6 - <0.8 (mmol/L) 
0.3 - <0.6 (mmol/L) 
<0.3 (mmol/L) 
Death 
Potassium, serum-low 
(hypokalemia) 
3.0 - <LLN (mmol/L) 
__ 
2.5 - <3.0 (mmol/L) 
<2.5 (mmol/L) 
Death 
Potassium, serum-high 
(hyperkalemia) 
>ULN - 5.5 (mmol/L)  
>5.5 - 6.0 (mmol/L) 
>6.0 - 7.0 (mmol/L)  
>7.0 (mmol/L) 
Death 
Sodium, serum-low 
(hyponatremia) 
130 - <LLN (mmol/L) 
__ 
120 - <130 (mmol/L) 
<120 (mmol/L) 
Death 
Sodium, serum-high 
(hypernatremia) 
>ULN - 150 (mmol/L)  
>150 - 155 (mmol/L) 
>155 - 160 (mmol/L)  
>160 (mmol/L) 
Death 
Urinalysis 
Proteinuria (high) 
1+ proteinuria;  urinary 
protein <1.0 g/24 hrs 
≥2+ proteinuria;  urinary 
protein 1.0 - 3.4 g/24 hrs 
urinary protein >=3.5 g/24 
hrs 
__ 
__ 
* Corrected serum calcium by albumin should be referred. If serum albumin is <4.0 g/dL, the corrected calcium will be calculated using the following formula: 
Corrected calcium (mg/dL) = Total calcium (mg/dL) – 0.8 x [Albumin (g/dL) – 4] 
 
Clinical Study Report
E7080-J081-112
Eisai
Confidential
Page 31 of 32


Clinical Study Report
E7080-J081-112
Eisai
Confidential
Page 32 of 32
PPD
PPD
PPD
PPD