Conditions: Solid Tumors
Keywords: solid tumors non-small cell lung cancer predominantly clear cell renal cell carcinoma endometrial carcinoma urothelial carcinoma squamous cell carcinoma of the head and neck non-uveal melanoma E7080 lenvatinib pembrolizumab Japan
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This is an open-label Phase 1b study designed to confirm the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with selected solid tumors (non-small cell lung cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma \[excluding uveal melanoma\]).

Detailed description:

Arms:
arm 1: Participants with selected tumors will receive oral lenvatinib at a starting dose of 20 milligrams (mg) once daily in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle until disease progression, development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the study.

Interventions: intervention 1: lenvatinib intervention 2: pembrolizumab
Intervention descriptions: intervention 1: lenvatinib capsules intervention 2: pembrolizumab intravenous infusion

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol
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1
TITLE PAGE
Clinical Study Protocol
Study Protocol Number:
E7080-J081-115
Study Protocol Title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subjects with Selected Solid Tumors
Sponsor:
Eisai Co., Ltd.
4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan
Investigational Product 
Name:
Lenvatinib (E7080/LENVIMA™) and Pembrolizumab (MK-
3475/KEYTRUDA®)
Indication:
Solid tumors
Phase:
Phase 1b
Approval Date:
V1.0
14 Sep 2016 (Original Protocol)
16 Jun 2017 (Amendement 01)
10 Apr 2018 (Amendement 02)
05 Apr 2019 (Amendement 03)
14 Feb 2020 (Amendement 04)
07 Apr 2020 (Amendement 05)
GCP Statement:
This study is to be performed in full compliance with Japan’s 
Good Clinical Practice (GCP) and all applicable regulations.  
All required study documentation will be archived as required 
by regulatory authorities.
Confidentiality 
Statement:
This document is confidential.  It contains proprietary 
information of Eisai (the sponsor).  Any viewing or disclosure 
of such information that is not authorized in writing by the 
sponsor is strictly prohibited.  Such information may be used 
solely for the purpose of reviewing or performing this study.
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Summary of Changes
Revisions to Amendment 05
Date: 07 Apr 2020
Change
Rationale
Affected Protocol Sections
Change Study Period and Phase 
of Development
For extending study period.

Clinical Protocol synopsis
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2
CLINICAL PROTOCOL SYNOPSIS
Compound No.: E7080, MK-3475
Name of Active Ingredient: Lenvatinib, Pembrolizumab
Study Protocol Title
An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects with Selected Solid 
Tumors
Study Regions (Country) or Center
One center in Japan
Study Period and Phase of Development
54 months (plan)
Phase 1b
Objectives
Primary Objective

To confirm the tolerability and safety for combination of lenvatinib plus pembrolizumab in 
subjects with selected solid tumors
Secondary Objectives

To evaluate the following efficacy endpoints by Immune-related Response Evaluation Criteria 
In Solid Tumors (irRECIST) and modified RECIST 1.1:
-
Objective response rate (ORR)
-
Duration of response (DOR)

To assess the pharmacokinetic (PK) profile of lenvatinib and pembrolizumab

To detect anti-drug antibodies for pembrolizumab (ADA)
Exploratory Objectives

To evaluate the following efficacy endpoints by irRECIST and modified RECIST 1.1:
-
Progression-free survival (PFS)
-
Time to response (TTR)
-
Disease control rate (DCR)
-
Clinical benefit rate (CBR)

To investigate the relationship between candidate biomarkers and anti-tumor activity of 
lenvatinib in combination with pembrolizumab:
-
To explore blood and tumor markers (such as programmed cell death protein 1 ligand 1 
[PD-L1] expression levels, cytokine and angiogenic factor profiling), and immune cell 
profiling and evaluate their relationship with clinical outcomes including anti-tumor 
activity of lenvatinib in combination with pembrolizumab
Study Design
Overall Design
This is an open-label Phase 1b study. This study will confirm the tolerability and safety of 
lenvatinib in combination with pembrolizumab in subjects with selected solid tumors.  Subjects in 
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this study will have one of the following tumors: non-small cell lung cancer, predominantly clear 
cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of 
the head and neck, or melanoma (excluding uveal melanoma).  
This study will begin with lenvatinib 20 mg/day orally and pembrolizumab 200 mg (every 3 weeks 
[Q3W], intravenous [IV]) in subjects with selected solid tumors on a 21-day treatment cycle.  For 
the confirmation of the tolerability of the dose level, dose limiting toxicities (DLTs) will be 
evaluated during the first cycle (21 days).  
If 0 or 1of 6 subjects in a given dose level cohort experiences a DLT, the dose level will be 
considered tolerable.  
Enrollment will be interrupted if 2 or more DLTs are observed at any dose level, and after sponsor 
and investigators’ review, enrollment may continue for up to 6 subjects based on the nature and 
severity of the DLTs.  Once 6 subjects are enrolled, then, 4 additional subjects (10 subjects in total) 
will be added and that dose level will be considered tolerable if DLT is observed in 3 or less of 
the10 subjects in total.  An independent medical advisor as third party should be consulted for the 
review as needed.
A lower dose level of lenvatinib of 14 mg once daily (QD) in combination with 200 mg 
pembrolizumab Q3W or study discontinuation will be considered, if 20 mg lenvatinib plus 200 mg 
pembrolizumab dose level is not tolerable, upon discussions between the sponsor and investigators, 
and the protocol will be amended as necessary.  An independent medical advisor as third party 
should be consulted for the consideration as needed.
If there is a potential subject who is not evaluable for DLT (eg, subject who fails to administer 
≥75% of the planned dosage of lenvatinib due to a reason other than treatment related toxicity 
during Cycle 1), the investigator and sponsor will discuss whether or not to include the subject in 
the DLT Analysis Set. If subject is not evaluable for DLT then the subject will be replaced.
A DLT is defined as any of the following:

Any of the hematological or nonhematological toxicities noted in the table below considered 
to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1

Failure to administer ≥75% of the planned dosage of lenvatinib as a result of treatment-related 
toxicity during Cycle 1

Subjects who discontinue treatment due to treatment-related toxicity in Cycle 1

Greater than 2 weeks delay in starting pembrolizumab in Cycle 2 because of a treatment-
related toxicity, even if the toxicity does not meet DLT criteria
Dose Limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic
Grade 4 neutropenia for ≥7 days
Grade 3 or Grade 4 febrile neutropeniaa
Thrombocytopenia <25,000/mm3 associated with bleeding and/or 
that requires platelet transfusion
Other nonhematologic 
toxicity
Any other Grade 4 or a Grade 5 toxicity
Grade 3 toxicities lasting >3 days excluding:
Nausea, vomiting, and diarrhea controlled by medical intervention 
within 72 hours.
Grade 3 rash in the absence of desquamation, no mucosal 
involvement, does not require steroids, and resolves to Grade 1 by 
the next scheduled dose of pembrolizumab.
Grade 3 hypertension not able to be controlled by medication 
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Grade 3 or above gastrointestinal perforation
Grade 3 or above wound dehiscence requiring medical or surgical 
intervention
Any grade thromboembolic event
Any Grade 3 nonhematologic laboratory value if:
Medical intervention is required to treat the subject, or the 
abnormality leads to hospitalization
ANC = absolute neutrophil count, CTCAE = Common Terminology Criteria for Adverse Events v4.03.
a:
Febrile neutropenia Grade 3 or Grade 4:  
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained 
temperature of ≥38 °C (100.4 °F) for more than 1 hour.
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained 
temperature of ≥38 °C (100.4 °F) for more than 1 hour, with life-threatening consequences and urgent 
intervention indicated.
Toxicities with a clear alternative explanation (eg, due to disease progression) or transient 
(≤72 hours) abnormal laboratory values without associated clinically significant signs or symptoms 
based on investigator determination can be deemed a non-DLT.
Study Phases
The study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase.
The Pretreatment Phase will last no longer than 28 days and includes:
A Screening Period, to obtain informed consent and establish protocol eligibility, and a Baseline 
Period, to confirm protocol eligibility prior to treatment.  
The Treatment Phase consists of the first cycle (21 days) for each subject.  The Treatment Phase
for each subject ends after completing Cycle 1 of treatment or if they discontinue early.  Those 
subjects who discontinue study treatment in Cycle 1 transition to the Off Treatment (Off-Tx) Visit 
of the Follow-up Period of the Extension Phase.  Those who complete Cycle 1 transition to the 
Treatment Period of the Extension Phase.
Extension Phase
The Extension Phase begins after a subject completes Cycle 1 and ends when the subject completes 
the Off-Tx Visit.  It consists of a Treatment Period and a Follow-up Period.
Treatment Period (Extension Phase):  Subjects still receiving study treatment at the end of the 
Treatment Phase will continue to receive the same treatment.  Those subjects who discontinue 
study treatment transition to the Off-Tx Visit of the Follow-up Period of the Extension Phase.  
Follow-up Period (Extension Phase): The Follow-up Period consists of the Off-Tx Visit.  The 
Off-Tx Visit will occur within 30 days following the last dose of study treatment.
Number of Subjects
This study will enroll between 6 and 10 evaluable subjects with selected solid tumors.
Inclusion Criteria
1.
Histologically and/or cytologically confirmed selected solid tumor types that have 
progressed after treatment with standard therapies or for which there are no other 
appropriate therapies available.  If nivolumab or pembrolizumab is an approved therapy for 
the subject’s tumor type, but the subject has not been treated with it, the investigator may 
enroll the subject in this study. 
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The selected tumor types are: non-small cell lung cancer, predominantly clear cell renal cell 
carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the 
head and neck, or melanoma (excluding uveal melanoma)
2.
At least 1 measurable target lesion according to modified RECIST 1.1
3.
Subjects must have an Eastern Cooperative Oncology Group (ECOG)-Performance Status 
(PS) of 0 to 1.
4.
Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications 
within 1 week prior to the Cycle 1/Day 1 (C1D1)
5.
Adequate renal function defined as creatinine ≤1.5 times the upper limit of normal (ULN) or 
calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with 
creatinine levels >1.5×ULN
6.
Adequate bone marrow function: 

Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5×103/μL)

Platelets ≥100,000/mm3 (≥100×109/L)

Hemoglobin ≥9.0 g/dL
7.
Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5
8.
Adequate liver function as evidenced by bilirubin ≤1.5×ULN and alkaline phosphatase
(ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN (in 
the case of liver metastases ≤5×ULN).  In case ALP is >3×ULN (in the absence of liver 
metastases) or >5×ULN (in the presence of liver metastases) AND the subject also is known 
to have bone metastases, the liver specific ALP must be separated from the total and used to 
assess the liver function instead of the total ALP. 
9.
Males or females age ≥20 years at the time of informed consent
10. Life expectancy of 12 weeks or more
11. Subjects with known brain metastases will be eligible if they have completed the primary 
brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery, or complete 
surgical resection) and if they have remained clinically stable, asymptomatic, and off of 
steroids for at least 28 days.  
12. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol  
13. Archival tumor tissue or a newly obtained biopsy must be available prior to the first dose of 
study drug for biomarker analysis.  Subjects with inaccessible tumors for biopsy specimens 
can be enrolled without a biopsy upon consultation and agreement by the sponsor.  
Note: In case of submitting unstained cut slides, freshly cut slides should be submitted to 
the testing laboratory within 14 days from when the slides are cut.  
Exclusion Criteria
1.
Prior anticancer treatment within 28 days (or 5 times the half-life time, whichever is shorter) 
or any investigational agent within 28 days prior to the first dose of study drugs.  All 
toxicities related to prior treatments must be resolved to Grade ≤1(except alopecia).  
Note: Refer to inclusion criteria regarding Hypertention.
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2.
Biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks 
before study entry.  Chronic erythropoietin therapy is permitted provided that no dose 
adjustments were made within 2 months before first dose of study treatment.  
3.
Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, 
excluding cancer types such as melanoma and non-small cell lung cancer where prior 
treatment with one anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed.  
4.
Subjects must have recovered adequately from any complications from major surgery prior 
to starting therapy.
5.
Subjects having ≥2+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria.  Subjects with urine protein ≥1 g/24-hour will be 
ineligible.
6.
Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib
7.
New York Heart Association congestive heart failure of grade II or above, unstable angina, 
myocardial infarction within the past 6 months, or serious cardiac arrhythmia associated 
with significant cardiovascular impairment within the past 6 months
8.
Prolongation of QTc (Fridericia formula) interval to >480 ms
9.
Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first 
dose of study drug
10. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.  The degree of 
tumor invasion/infiltration of major blood vessels (eg, carotid artery) should be considered 
because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis 
following lenvatinib therapy.  
11. Active infection (any infection requiring systemic treatment)
12. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or 
Hepatitis C.
13. Serious nonhealing wound, ulcer, or bone fracture
14. Known intolerance to either of the study drugs (or any of the excipients)
15. History of organ allograft  
16. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical trial
17. Excluding the primary tumor leading to enrollment in this study, any other active 
malignancy (except for definitively treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 
months
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.  
The use of physiologic doses of corticosteroids (up to 7.5 mg/d of prednisone or equivalent) 
may be approved after consultation with the sponsor.  
19. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs).  Replacement 
therapy (eg, thyroxine [T4], insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
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20. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis,
or has a history of interstitial lung disease.
21. Has received a live-virus vaccination within 30 days of planned treatment start.  Seasonal flu 
vaccines that do not contain live virus are permitted.
22. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
23. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin 
[hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or hCG]).  
A separate baseline assessment is required if a negative screening pregnancy test was 
obtained more than 72 hours before the first dose of study drug.
24. Females of childbearing potential* who:

do not agree to use a highly effective method of contraception for the entire 
study period and for 120 days after study drug discontinuation ie:
o
total abstinence (if it is their preferred and usual lifestyle)
o
an intrauterine device (IUD) or hormone releasing system (IUS)
o
a contraceptive implant
o
an oral contraceptive** (with additional barrier method)
OR

do not have a vasectomized partner with confirmed azoospermia.
For sites outside of the European Union (EU), it is permissible that if a highly effective 
method of contraception is not appropriate or acceptable to the subject, then the subject 
must agree to use a medically acceptable method of contraception, ie double barrier 
methods of contraception such as condom plus diaphragm or cervical/vault cap with 
spermicide.
NOTES:
* All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate age 
group, and without other known or suspected cause] or have been sterilized surgically 
[i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with 
surgery at least 1 month before dosing]
** Must be on a stable dose of the same oral hormonal contraceptive product for at least 4 
weeks before dosing with study drug and for the duration of the study.
25. Male subjects who are partners of women of childbearing potential must use a condom + 
spermicide and their female partners if of childbearing potential must use a highly effective 
method of contraception (see methods described in Exclusion Criterion #24) beginning at 
least 1 menstrual cycle prior to starting study drug(s), throughout the entire study period, 
and for 120 days after the last dose of study drug, unless the male subjects are totally 
sexually abstinent or have undergone a successful vasectomy with confirmed azoospermia 
or unless the female partners have been sterilized surgically or are otherwise proven sterile.  
Study Treatments
Lenvatinib
Lenvatinib is provided as 4-mg and 10-mg capsules.  Lenvatinib will be administered with water 
orally once a day (with or without food) in 21-day cycles at approximately the same time each day.  
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On Day 1 of each cycle, in case concomitantly administered, it will be administered approximately 
within 1 hour after completion of pembrolizumab administration.
Pembrolizumab
Pembrolizumab will be provided as a sterile, preservative-free, white to off-white lyophilized 
powder in single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 
2 mL of reconstituted solution contains 50 mg of pembrolizumab.  
Alternatively, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for IV infusion.  Each vial 
contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of solution contains 25 mg of 
pembrolizumab.  
Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, Q3W 
(25 minutes to 40 minutes are acceptable).  The Pharmacy Manual contains specific instructions for 
the preparation of the pembrolizumab infusion and administration of infusion solution.  
Pembrolizumab will be administered until 2 years after C1D1 at the longest.
Study Treatment Dose Modification
1.
Cycle 1
a.
If DLT occurs:
Lenvatinib and infusion of pembrolizumab should be interrupted immediately.  Treatment may be 
resumed in Cycle 2 of pembrolizumab at the same dose (except the toxicity which requires the 
permanent discontinuation according to the guidance) and at 1 lower dose level of lenvatinib if 
toxicity is resolved to Grade 0–1 (or torelable Grade 2 in case of lenvatinib treatment-related 
toxicity) or baseline and investigators decides to continue the study.
b.
No DLT
Lenvatinib will be interrupted if judged to be clinically needed by investigators, and may be 
resumed at the same dose level at appropriate timing.  
2.
Cycle 2 and onward
Lenvatinib
Lenvatinib dose reduction and interruption for subjects who experience lenvatinib-pembrolizumab 
combination therapy-related toxicity will be in accordance with the dose reduction instructions 
shown in the tables below for this study, respectively.
For management of hypertension and proteinuria, refer to the main protocol text for instructions
before consulting the table below, as appropriate.  Any dose reduction below 4 mg/day (4 mg every 
other day) must be discussed with the sponsor.  Once the dose has been reduced, it cannot be 
increased at a later date.  
Lenvatinib 
Treatment-related 
Toxicitya,b
During Therapy
Adjusted Dosef
Grade 1, Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d and Grade 3g
First occurrence
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1
Reduce lenvatinib by 1 dose level
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Second occurrence 
(same toxicity or new 
toxicity)
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1
Reduce lenvatinib by 1 more dose level
Third occurrence
(same toxicity or new 
toxicity)
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1
Reduce lenvatinib by 1 more dose level
Fourth occurrence
(same toxicity or new 
toxicity)
Interrupt lenvatinib until resolved to 
tolerable Grade 2, or Grade 0-1
Reduce lenvatinib by 1 more dose level
Grade 4e, g: Discontinue lenvatinib
BMI = body mass index.  
a:
An interruption of lenvatinib treatment for more than 21 days will require a discussion with the sponsor 
before treatment can be resumed.
b:
Excluding alopecia.  Initiate optimal medical management for nausea, vomiting, hypothyroidism and/or 
diarrhea prior to any lenvatinib interruption or dose reduction.
c:
Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable.
d:
Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, 
Grade 1 weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight remains 
stable for at least 1 week and they reached the normal BMI (if the weight loss occurred but it is still above 
normal BMI, they can restart the study treatment at a lower dose once the weight has been stable for at least 1 
week).  Normal BMI should be used as the new baseline for further dose reductions.
e:
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
f:
Refer to the table below for adjusted dose.
g:
For asymptomatic Grade ≥3 elevations of amylase and lipase, the sponsor should be consulted to obtain 
permission to continue treatment.
Lenvatinib in Combination with Pembrolizumab Toxicity
Initial Lenvatinib Dose (mg, QD)
Adjusted Dose To Be Administered (mg, QD)
Reduction 1
Reduction 2
Reduction 3
Reduction 4
20
14
10
8
4a
14
10
8
4a
QD = once daily.
a:
Consult the sponsor for further dose reduction recommendations.  
General Guidelines for Holding Periods of Lenvatinib due to Procedures:
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 
2 days after, once there is evidence of adequate healing and no risk of bleeding.  Needle biopsies 
(fine needle aspirations and core needle aspiration) are usually considered minor procedures.
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the procedure and 
then restarted once there is clear wound healing and no risk of bleeding, but at least 1 week after 
the procedure.  It is up to the investigator to determine if it is a major or minor procedure.  Usually 
a major procedure implies general anesthesia.
Pembrolizumab
Adverse events (AEs) (both nonserious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These AEs may occur shortly after the first dose or several 
months after the last dose of treatment.  Pembrolizumab must be withheld for drug-related toxicities 
and severe or life-threatening AEs as per the table below. See Section 9.4.1.5 for supportive care 
guidelines, including use of corticosteroids.
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Toxicity
Hold Treatment 
for Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
Diarrhea/Colitis
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
AST, ALT, or 
Increased Bilirubin
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose.
3-4
Permanently discontinue (see 
exception below)a
Permanently discontinue
Type 1 Diabetes 
Mellitus (if new 
onset) or 
Hyperglycemia
T1DM or
3-4
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure.
Resume pembrolizumab when subjects 
are clinically and metabolically stable.
Hypophysitis
2-4
Toxicity resolves to Grade 0-1.  
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy 
is instituted.
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
Hyperthyroidism 
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted.
Infusion Reaction
2b
Toxicity resolves to Grade 0-1
Permanently discontinue if toxicity 
develops despite adequate 
premedication 
3-4
Permanently discontinue
Permanently discontinue
Pneumonitis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
3-4
Recurrent 2
Permanently discontinue
Permanently discontinue
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Renal Failure or 
Nephritis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
All Other Drug-
Related Toxicityc, d
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE that 
recurs or any life-threatening event.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, T1DM = type 1 diabetes mellitus.  
a:
For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by 
greater than or equal to 50% relative to baseline and lasts for at least 1 week then subjects should be discontinued.
b:
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 50 mL/h).  Otherwise dosing will be held until symptoms resolve and the 
subject should be premedicated for the next scheduled dose; Refer to Infusion Reaction Treatment Guidelines.
c:
Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which treatment with 
study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose.
d:
For asymptomatic Grade ≥3 elevations of amylase and lipase, the sponsor should be consulted to obtain 
permission to continue treatment.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, and/or 
holidays).  Subjects should be placed back on study treatment within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the sponsor. The reason for interruption should be 
documented in the subject's study record.
Duration of Study
Study duration for each subject is estimated to be:

Pretreatment Phase: 28 days

Treatment Phase: 21 days (Cycle 1)

Extension Phase: Subjects will continue to receive study treatment until disease progression, 
development of unacceptable toxicity, withdrawal of consent, or sponsor termination of the 
study.
Concomitant Drug/Therapy
Prohibited Concomitant Medications
Subjects should not receive other antitumor therapies while on study.  If a subject receives additional 
antitumor therapies, such as chemotherapy, hormone therapy, palliative radiotherapy, or 
immunotherapy, this will be judged to represent evidence of disease progression, and continuation of 
the study medication and further participation in the study must be discussed and agreed upon with 
the sponsor.
Subjects are prohibited from receiving the following therapies during the Pretreatment, Treatment, 
and Extension Phase of this study:  

Anticancer therapies such as chemotherapy, tyrosine kinase inhibitors (TKIs), antitumor 
interventions (surgical resection, thoracocentesis, etc.), or immunotherapy
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
Investigational agents other than lenvatinib and pembrolizumab

Radiation therapy
Note:  Palliative radiotherapy of up to 2 painful pre-existing, non-target bone metastases 
without being considered progressive disease may be considered on an exceptional case by 
case basis after consultation with the sponsor.  Administration of palliative radiation therapy 
will be considered clinical progression for the purposes of determining PFS.

Live vaccines within 30 days prior to the first dose of study treatment and while participating 
in the study.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine.  
Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed.  
However, intranasal influenza vaccines (eg, Flu-Mist®) are live attenuated vaccines, and are 
not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest of suspected immunologic etiology.  The use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor.
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies.
For subjects who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management, continuation of the study medication and further participation in 
the study must be discussed and agreed upon with the sponsor.  Subjects may receive other 
medications that the investigator deems to be medically necessary.  
The Exclusion Criteria describes other medications that are prohibited in this clinical study.
Assessments
Efficacy
Tumor assessments will be performed by the investigators based on both irRECIST and modified 
RECIST 1.1. Treatment decisions by the investigator will be based on irRECIST.  All scans for 
tumor assessments performed during the study should be archived in accordance with the standard 
local practice.  They must be accessible in the event of a sponsor request to submit them for central 
review.  
Tumor assessments will be carried out during the Pretreatment Phase and then every 6 weeks 
(±1 week; counting from C1D1) until Week 24, then every 9 weeks (±1 week) during treatment 
cycles in the Extension Phase.  Computed tomography (CT) /magnetic resonance imaging (MRI)
scans of chest, abdomen, and pelvis and of other known sites of disease will be obtained at 
Screening (within 28 days prior to C1D1), at all tumor assessment time points, and as indicated 
clinically.  Color photographs containing a milimeter scale must be taken of all skin lesions being 
used as target lesions.  Historical standard of care scans that are performed with scanning 
parameters consistent with the requirements for this protocol within 28 days prior to dosing are 
acceptable.
MRI may be used instead of CT for head, neck, abdomen, and pelvis; however, the chest must be 
assessed using CT.  Chest disease may not be followed using chest x-ray.  
A brain scan (CT with contrast or MRI pre- and post-gadolinium) must be performed at Screening 
to assess potential central nervous system (CNS) disease and/or metastases.  For subjects with 
previously treated eligible brain metastases, a brain scan must be performed at all tumor assessment 
time points.  For all subjects, a follow-up brain scan must be performed to confirm complete 
response (irCR), or if clinically indicated.  
The tumor assessment schedule should not be affected by interruptions in study treatment.
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Subjects going off treatment without disease progression (excluding the subject with CR at off-
treatment visit) will also undergo tumor assessments per the Schedule of Procedures/Assessments 
until disease progression is documented or another anticancer therapy is initiated.  
The same method of assessment must be used at all time points as was used at Screening.  
Throughout the study it is critical that the same imaging methodology be applied and contrast be 
consistently provided unless IV contrast becomes medically contraindicated during the course of 
treatment or the dose of contrast needs to be adjusted based on the subject’s health status.  
Bone scans will be performed at Screening, every 24 weeks (as needed), or sooner if clinically 
indicated, and at confirmation of irCR.  Lesions identified on bone scans must be verified and 
followed with correlative cross-sectional imaging.
In order for stable disease (irSD) to be considered the best overall response (BOR), it must occur 
≥5 weeks following the first dose of study drug.
The first radiological assessment of tumor response status will be performed at Week 6 (±1 week), 
unless there is clinical indication warranting earlier radiologic imaging.  Responses (irPR [partial 
response] or irCR) should be confirmed no less than 4 weeks after the initial response, but 
generally at the next scheduled tumor assessment time point.
If the time point tumor assessment is progressive disease (PD), treatment should continue and 
tumor assessments be repeated at least 4 weeks later, but generally at the next scheduled tumor 
assessment time point in order to confirm irPD.  If repeat imaging shows a reduction in the tumor 
burden compared to the initial tumor assessment demonstrating PD, treatment may be continued as 
per treatment schedule.  If repeat imaging confirms irPD, subjects will be discontinued from study 
treatment.  In determining the tumor time point response, investigators should consider all target 
lesions as well as nontarget lesions and new lesions.
The decision to continue study treatment after the first evidence of PD is at the investigator’s 
discretion based on the clinical status of the subject.
Subjects may continue receiving study treatment while waiting for confirmation of irPD if they are 
clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating
disease progression

No decline in ECOG-PS

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (eg, cord compression) requiring
urgent alternative medical intervention
If irPD is confirmed and the subject is experiencing extraordinary clinical benefit, the site must 
contact the sponsor to discuss continuing treatment.
Tumor assessments per modified RECIST 1.1 will follow Eisenhauer, et al. (2009); however, up to 
10 target lesions, up to 5 per organ, may be selected (as opposed to a maximum of 5 target lesions, 
up to 2 per organ).  Responses (PR or CR) should be confirmed no less than 4 weeks after the 
initial response, but generally at the next scheduled tumor assessment time point.  In order for SD 
to be considered BOR, it must occur ≥5 weeks following the first dose of study drug.
Pharmacokinetic
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be measured.  
Serum ADA will be also measured.
Pharmacodynamic/Pharmacogenomic
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Blood and Tissue Biomarkers:  Blood samples for the development of exploratory predictive 
biomarkers will be collected from consented subjects prior to the first dose of study drug (C1D1), 
on Cycle 1/Day 15 (C1D15), and on Day 1 of subsequent cycles up to and including Cycle 18, and 
at the Off-Tx assessment.  Subjects will be required to provide an archival tumor tissue sample 
and/or a fresh biopsy of tumor before treatment for biomarker analyses (subjects with inaccessible 
tumors for biopsy specimens can be enrolled without a biopsy upon consultation and agreement by 
the sponsor).  Biomarker discovery and/or validation will be performed to identify blood or tumor 
biomarkers that may be useful to predict subject response to lenvatinib and/or pembrolizumab, as 
determined by evaluation of response-related and/or safety-related outcomes as well as for 
potential use in diagnostic development.  Blood serum samples from subjects receiving lenvatinib
and pembrolizumab may be analyzed using global proteomic methods, enzyme-linked 
immunosorbent assay (ELISA), multiplex bead-based immunoassay, or other assays/methods or
new technology.  In addition, biomarkers identified in other lenvatinib clinical studies may also be 
assessed in the biomarker samples collected from subjects enrolled in this study. The decision to 
perform exploratory biomarker analysis may be based on the clinical outcome of this study and/or 
the signals observed in other clinical studies or other information available at that time.
Archived, formalin-fixed paraffin-embedded (FFPE) tissue or a newly obtained biopsy will be 
collected from all consented subjects for potential assessment of mutations and other genetic 
alterations or genes and/or proteins including PD-1/PD-L1/PD-L2 status and other relevant 
biomarkers (eg, tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid [RNA] signature 
profiles, mutational load) which may be important in the development and progression of cancer as 
well as for potential use in diagnostic development.  Appropriate technology/methodologies will be 
used based on the amount of tumor tissue available.
Optional fresh paired tumor biopsies will be collected from consented subjects to examine markers 
including markers of target engagement, relevant pharmacodynamic biomarkers, and potential 
markers of response.  Fresh biopsies should be limited to readily accessible tumor lesions (eg, skin,
peripheral lymph nodes, liver metastases that can be readily accessed using CT guidance).  
Subjects should have the biopsy before administration of the first dose of study drug and at a time 
point 3-6 weeks after the first dose (if they have recovered adequately from the biopsy taken prior 
to starting therapy and investigators judge that it is medically acceptable to have a biopsy).
A blood plasma sample to isolate circulating cell free nucleic acids (cf-nucleic acids) and a whole 
blood sample for immune cell profiling will be collected from consented subjects prior to the first 
dose of study drug (C1D1), and then pre-dose on C1D15 and Day 1 of subsequent cycles up to and 
including Cycle 18 and at the off-treatment assessment.  Cf-nucleic acid isolated from plasma 
samples may be used to obtain circulating tumor DNA (ctDNA) and explore tumor genetic 
alterations such as mutations observed in archival tumor samples as well as those which develop 
during drug treatment.  Genomic DNA extracted from blood samples may be used to confirm 
whether the DNA sequence variants observed in DNA extracted from tumor material are limited to 
the tumor and to assess the immune response.
Data obtained will be used for research to assist in developing safer and more effective treatments 
and will not be used to change the diagnosis of the subject or alter the therapy of the subject.  The 
DNA will not be used to determine or predict risks for diseases that an individual subject does not 
currently have.  Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 
15 years to assist in any research scientific questions related to lenvatinib/pembrolizumab, cancer,
and/or for potential diagnostic development.  
Instructions for the processing, storage, and shipping of samples will be provided in the Laboratory 
Manual.  
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Safety
Safety assessments will consist of monitoring and recording all adverse events (AEs) and serious 
adverse events (SAEs), using Common Terminology Criteria for Adverse Events (CTCAE) v4.03;
regular laboratory evaluation for hematology, blood chemistry, and urine values; regular 
performance of physical examinations, periodic measurement of vital signs, and 
electrocardiograms (ECGs); and echocardiograms or multigated acquisition (MUGA) scans 
including left ventricular ejection fraction (LVEF).
Bioanalytical Methods
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be measured 
by using validated methods.  Serum ADA will be detected by using validated methods.
Statistical Methods
Study Endpoints
The following endpoints will be defined in 2 ways based on irRECIST and modified RECIST 1.1.
ORR is defined as the proportion of subjects who have BOR of (ir)CR or (ir)PR at the time of data 
cutoff.
ORR(Week 24) is defined as the proportion of subjects who have BOR of (ir)CR(Week 24) or 
(ir)PR(Week 24) as of the Week 24 tumor assessment time point.
DOR is defined as the time from the first documentation of (ir)CR or (ir)PR to the date of first 
documentation of disease progression (based on irRECIST and modified RECIST 1.1) or death 
(whichever occurs first).
PFS is defined as the time from the first study dose date to the date of first documentation of 
disease progression (based on irRECIST and modified RECIST 1.1) or death (whichever occurs 
first).  
TTR is defined as the time from the date of first study dose to the date of first documentation of 
(ir)CR or (ir)PR.
DCR is defined as the proportion of subjects who have BOR of (ir)CR or (ir)PR or (ir)SD
(minimum duration from C1D1 to (ir)SD ≥5 weeks).
CBR is defined as the proportion of subjects who have BOR of (ir)CR or (ir)PR or durable (ir)SD
(duration of (ir)SD ≥23 weeks).
Analysis Sets
DLT Analysis Set will include all subjects who have completed Cycle 1 without major protocol 
deviation with at least 75% of study drug compliance and are assessed for DLT, and subjects who 
have experienced DLT during Cycle 1.  This will be the analysis set to confirm tolerability.
Safety Analysis Set/Efficacy Analysis Set will include all subjects who received at least 1 dose of
study drug.
PK Analysis Set will include all subjects who have received at least 1 dose of lenvatinib and
pembrolizumab, and have evaluable concentration data.
Efficacy Analyses
Efficacy analyses will be based on the Efficacy Analysis Set.  BOR will be summarized, and ORR, 
ORR(Week 24), and their corresponding exact 2-sided 95% confidence interval (CI) will be calculated.
DOR will also be summarized and plotted over time by Kaplan-Meier method.  Likewise, PFS and 
TTR will be analyzed as needed. If applicable, DCR, CBR, and their corresponding exact 2-sided 
95% CI will also be calculated. If applicable, a waterfall plot will be presented for the percent 
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changes from baseline in the sum of the diameters of target lesions at postbaseline nadir (ie,
maximum tumor shrinkage).
Pharmacokinetic and/or Pharmacodynamic Analyses
Pharmacokinetic
The primary PK parameters of lenvatinib under combination will be calculated using 
noncompartmental analysis and compared with historical data after single dose using the PK 
analysis set.  If warranted, additional analyses may be performed.  PK data for lenvatinib and 
pembrolizumab is planned to be analyzed using nonlinear mixed effects modeling.  Based on PK 
data obtained in this study and from other studies, a population PK analysis may be performed to 
characterize PK parameters to support the proposed dosing regimen.  PK data for lenvatinib and 
pembrolizumab may also be used to explore the exposure-response relationships for antitumor 
activity/efficacy as well as biomarkers and safety in the proposed patient population, if feasible.  
The results of these analyses, if performed, will be reported separately.  For serum ADA levels, a 
listing of results will be made.
Pharmacodynamic
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic and/or 
imaging biomarkers will be summarized using descriptive statistics. PK/pharmacodynamic
relationships will be explored graphically and may be investigated by model-based analyses.  
Details of the analysis will be provided in a separate analysis plan.  The results of these analyses, if 
performed, will be reported separately.
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.  Safety analyses will be performed on the Safety Analysis
Set.  The number (percentage) of subjects with treatment-emergent AEs (TEAEs) and treatment-
emergent SAEs will be summarized by system organ class (SOC) and preferred term (PT).  
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.
Sample Size Rationale
A sample size of 6 to 10 subjects in this study.  This is not based on statistical power 
considerations.  
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3
TABLE OF CONTENTS
1
TITLE PAGE ................................................................................................................1
2
CLINICAL PROTOCOL SYNOPSIS............................................................................2
3
TABLE OF CONTENTS.............................................................................................17
4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................22
5
ETHICS.......................................................................................................................26
5.1
Institutional Review Boards ...............................................................................26
5.2
Ethical Conduct of the Study..............................................................................26
5.3
Subject Information and Informed Consent ........................................................26
6
INVESTIGATORS AND STUDY PERSONNEL .......................................................27
7
INTRODUCTION.......................................................................................................28
7.1
Indication...........................................................................................................28
7.1.1
Lenvatinib ................................................................................................28
7.1.2
PD-1 Inhibitors and Pembrolizumab.........................................................29
7.2
Combination of Lenvatinib Plus Pembrolizumab................................................31
7.2.1
Nonclinical...............................................................................................31
7.2.2
Clinical Studies ........................................................................................31
7.2.2.1
E7080-A001-111 (Phase 1b/2 of Lenvatinib Plus Pembrolizumab 
for Selected Solid Tumors in US) .....................................................31
7.2.2.2
E7080-J081-116 (Phase 1b of Lenvatinib Plus Pembrolizumab 
for Hepatocellular Carcinoma in Japan and US)................................32
7.3
Study Rationale..................................................................................................32
8
STUDY OBJECTIVES................................................................................................34
8.1
Primary Objective ..............................................................................................34
8.2
Secondary Objectives.........................................................................................34
8.3
Exploratory Objectives.......................................................................................34
9
INVESTIGATIONAL PLAN ......................................................................................35
9.1
Overall Study Design and Plan...........................................................................35
9.1.1
Pretreatment Phase ...................................................................................38
9.1.1.1
Screening Period...............................................................................38
9.1.1.2
Baseline Period.................................................................................38
9.1.2
Treatment Phase.......................................................................................39
9.1.3
Extension Phase .......................................................................................39
9.1.3.1
Treatment Period ..............................................................................39
9.1.3.2
Follow-up Period..............................................................................39
9.2
Discussion of Study Design................................................................................39
9.3
Selection of Study Population ............................................................................40
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9.3.1
Inclusion Criteria......................................................................................40
9.3.2
Exclusion Criteria.....................................................................................41
9.3.3
Removal of Subjects From Therapy or Assessment ..................................43
9.3.3.1
Discontinuation Criteria by Subject...................................................44
9.4
Treatments.........................................................................................................44
9.4.1
Treatments Administered..........................................................................44
9.4.1.1
Lenvatinib ........................................................................................44
9.4.1.2
Pembrolizumab.................................................................................44
9.4.1.3
Criteria for Interruption of Treatment, Dose Reduction and 
Resumption of Treatment..................................................................45
9.4.1.4
Supportive Care Guidelines for Lenvatinib .......................................50
9.4.1.5
Supportive Care Guidelines for Pembrolizumab................................52
9.4.2
Identity of Investigational Products ..........................................................56
9.4.2.1
Chemical Name, Structural Formula of Lenvatinib ...........................56
9.4.2.2
Information of Pembrolizumab .........................................................56
9.4.2.3
Labeling for Study Drug ...................................................................57
9.4.2.4
Storage Conditions ...........................................................................57
9.4.3
Method of Assigning Subjects to Treatment Groups.................................57
9.4.4
Selection of Doses in the Study ................................................................57
9.4.5
Selection and Timing of Dose for Each Subject........................................58
9.4.6
Blinding ...................................................................................................58
9.4.7
Prior and Concomitant Therapy................................................................58
9.4.7.1
Drug–Drug Interactions ....................................................................59
9.4.7.2
Prohibited Concomitant Medications/Vaccinations ...........................59
9.4.8
Treatment Compliance .............................................................................60
9.4.9
Drug Supplies and Accountability ............................................................60
9.5
Study Assessments.............................................................................................61
9.5.1
Assessments .............................................................................................61
9.5.1.1
Demography.....................................................................................61
9.5.1.2
Baseline Assessments .......................................................................61
9.5.1.3
Efficacy Assessments .......................................................................62
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments ..........................................................65
9.5.1.5
Safety Assessments...........................................................................69
9.5.2
Schedule of Procedures/Assessments........................................................74
9.5.2.1
Schedule of Procedures/Assessments................................................74
9.5.2.2
Description of Procedures/Assessments Schedule .............................80
9.5.3
Appropriateness of Measurements............................................................80
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9.5.4
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ...........................................................80
9.5.4.1
Reporting of Serious Adverse Events................................................80
9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding....................................................................................81
9.5.4.3
Reporting of Events Associated with Special Situations....................81
9.5.4.4
Expedited Reporting .........................................................................82
9.5.4.5
Breaking the Blind............................................................................82
9.5.4.6
Regulatory Reporting of Adverse Events ..........................................82
9.5.5
Completion/Discontinuation of Subjects...................................................82
9.5.6
Abuse or Diversion of Study Drug............................................................83
9.5.7
Confirmation of Medical Care by Another Physician................................83
9.6
Data Quality Assurance......................................................................................83
9.6.1
Data Collection.........................................................................................83
9.6.2
Clinical Data Management .......................................................................83
9.7
Statistical Methods.............................................................................................84
9.7.1
Statistical and Analytical Plans.................................................................84
9.7.1.1
Study Endpoints................................................................................84
9.7.1.2
Definitions of Analysis Sets..............................................................85
9.7.1.3
Subject Disposition...........................................................................85
9.7.1.4
Demographic and Other Baseline Characteristics..............................85
9.7.1.5
Prior and Concomitant Therapy ........................................................85
9.7.1.6
Efficacy Analyses.............................................................................86
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses................................................................86
9.7.1.8
Tolerability/Safety Analyses.............................................................86
9.7.2
Determination of Sample Size ..................................................................88
9.7.3
Interim Analysis.......................................................................................88
9.7.4
No interim analysis is planned for this study.  Other 
Statistical/Analytical Issues ......................................................................88
9.7.5
Procedure for Revising the Statistical Analysis Plan.................................89
10
REFERENCE LIST.....................................................................................................90
11
PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES).......93
11.1
Changes to the Protocol......................................................................................93
11.2
Adherence to the Protocol..................................................................................93
11.3
Monitoring Procedures.......................................................................................93
11.4
Recording of Data..............................................................................................94
11.5
Identification of Source Data..............................................................................94
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11.6
Retention of Records..........................................................................................95
11.7
Auditing Procedures and Inspection ...................................................................96
11.8
Handling of Study Drug .....................................................................................96
11.9
Publication of Results ........................................................................................96
11.10 Disclosure and Confidentiality ...........................................................................96
11.11 Discontinuation of Study....................................................................................97
11.12 Subject Insurance and Indemnity........................................................................97
12
APPENDICES.............................................................................................................98
LIST OF IN-TEXT TABLES
Table 1 
Dose Limiting Toxicities ........................................................................37
Table 2
Dose Modifications for Lenvatinib .........................................................45
Table 3 
Dose Reduction Recommendations for Lenvatinib in Combination 
With Pembrolizumab..............................................................................46
Table 4
Dose Modification Guidelines for Pembrolizumab-Related Adverse 
Events ....................................................................................................48
Table 5 
Infusion Reaction Treatment Guidelines.................................................55
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease...................................................................................................64
Table 7
Blood Sampling Schedule for Pharmacokinetic Assessments..................66
Table 8
Blood Sampling Schedule for Anti-pembrolizumab Antibodies
(ADAs) ..................................................................................................67
Table 9
Clinical Laboratory Tests........................................................................73
Table 10 
Schedule of Procedures/Assessments in the Pretreatment, Treatment, 
and Extension Phases..............................................................................75
LIST OF IN-TEXT FIGURES
Figure 1 
Confirmation of the Tolerability .............................................................36
Figure 2
Study Design..........................................................................................38
LIST OF APPENDICES
Appendix 1
Immune-related Response Evaluation Criteria in Solid Tumors ..............99
Appendix 2
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) 104
Appendix 3
Common Terminology Criteria for Adverse Events (CTCAE) 
Version 4.03.........................................................................................105
Appendix 4
New York Heart Association (NYHA) Cardiac Disease Classification..106
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Appendix 5
Clinical Studies Evaluating Drug–Drug Interactions with Lenvatinib....107
Appendix 6
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Research 108
Appendix 7
KEYTRUDA® Package Insert ..............................................................111
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
ADA
anti-drug antibody
AE
adverse event
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BOR
best overall response
BP
blood pressure 
C#/D#
Cycle#/Day#
CBR
clinical benefit rate
cf-nucleic acid
cell free nucleic acid
CI
confidence interval
CLIA
clinical laboratory improvement amendments
Cmax
maximum concentration
CNS
central nervous system
CR
complete response
CRA
clinical research associate
CRF
case report form
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events 
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DCR
disease control rate
DKA
diabetic ketoacidosis
DLT
dose limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
DVT
deep vein thrombosis
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Abbreviation
Term
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
epidermal growth factor receptor
ELISA
enzyme-linked immunosorbent assay
EU
European Union
FDA
United States Food and Drug Administration
FFPE
formalin-fixed paraffin-embedded
FGFR
fibroblast growth factor receptor
GCP
Good Clinical Practice
G-CSF
granulocyte colony-stimulating factor
GI
gastrointestinal
hCG
human chorionic gonadotropin
HIV
human immunodeficiency virus
HNSCC
squamous cell carcinoma of head and neck
ICF
informed consent form
ICH
International Conference on Harmonisation
IL-10
interleukin 10
INR
international normalized ratio
irAE
immune-related adverse event
IRB
institutional review board
irCR
immune-related complete response
irPD
immune-related progression disease
irPR
immune-related partial response
irRC
immune-related response criteria
IRR
independent radiologic review
irRECIST
immune-related RECIST
irSD
immune-related stable disease
ITT
intent to treat
IUD
intrauterine device
IUS
intrauterine system
IV
intravenous
IxRS
interactive voice/web response system
KIT
a stem cell factor receptor
LC/MS/MS
liquid chromatography with tandem mass spectrometry
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Abbreviation
Term
LDi
longest diameter
LLT
lower level term
LMWH
low-molecular-weight heparin
LVEF
left ventricular ejection fraction
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition
NCI
National Cancer Institute
NE
not evaluable
NSAIDs
nonsteroidal antiinflammatory drugs
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
Off-Tx
off treatment
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein 1
PDGFR
platelet-derived growth factor receptor
PD-L1 (or 2)
PD-1 ligand 1 (or 2)
PET
positron emission tomography
PFS
progression-free survival
P-gp
P-glycoprotein
PI
principal investigator
PK
pharmacokinetics
PO
per os
PR
partial response
PRES
posterior reversible encephalopathy syndrome
PS
performance status
PT
preferred term
Q3W
every 3 weeks
QD
once daily
QT
time from the beginning of the QRS complex to the end of the T wave
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Abbreviation
Term
QTc
QT interval corrected for heart rate
RP2D
recommended Phase 2 dose
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RET
ret proto-oncogene
RF
radiofrequency
RNA
ribonucleic acid
RTK
receptor tyrosine kinase
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SDi
short axis
SI
Système International
SOC
system organ class
SOD
sum of diameter
SOP
standard operating procedure
T1DM
type 1 diabetes mellitus
T4
thyroxine
TACE
transcatheter arterial chemo-embolization
TAM
tumor-associated macrophage
TEAE
treatment-emergent adverse event
TEMAV
treatment-emergent markedly abnormal laboratory values
TGFβ
transforming growth factor, beta 1
TKI
tyrosine kinase inhibitor
tmax
time to maximum concentration
TNM
tumor-node-metastasis
TSH
thyroid stimulating hormone
TTR
time to response
ULN
upper limit of normal
US
United States
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood cell
WHO DD
World Health Organization Drug Dictionary
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5
ETHICS
5.1
Institutional Review Boards
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 Japan’s Good Clinical Practice (GCP).  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 
Clinical Research Associate [CRA], change of telephone number).  Documentation of IRB 
compliance with Japan’s GCP 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 to the sponsor.
Study progress is to be reported to IRBs annually (or as required) by the investigator via the 
head of the medical institution according to Japan’s GCP.  The investigator(s) or the sponsor 
will submit, depending on local regulations, periodic reports and inform the investigator and 
the relevant IRB via the head of the medical institution of any reportable adverse events 
(AEs) per Japan’s GCP and local IRB standards of practice.  Upon completion of the study, 
the investigator via the head of the medical institution will provide the IRB and the sponsor
with a brief report of the outcome of the study.
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 Japan’s GCP guidelines as 
required by the following:

Principles of the World Medical Association Declaration of Helsinki

Japan’s 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 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 
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participation in the study is voluntary, that he/she may withdraw from the study at any time, 
and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician.
This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject should understand the statement before signing and 
dating it and will be given a copy of the signed document.  If a subject is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After the 
ICF and any other written information to be provided to subjects is read and explained to the 
subject, and after the subject has orally consented to the subject’s participation in the study 
and, if capable of doing so, has signed and personally dated the ICF, the witness should sign 
and personally date the consent form.  The subject will be asked to sign an ICF 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 Japan’s 
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.
For pharmacogenomic assessments, subjects will be asked to sign an additional consent for 
these assessments (see Section 9.5.1.4.2).
6
INVESTIGATORS AND STUDY PERSONNEL
This study will be conducted by qualified investigators under the sponsorship of Eisai (the 
sponsor) at 1 investigational site in Japan. Additional sites will be considered as needed.  
The name and telephone and fax numbers of the sponsor’s responsible medical officer and 
other contact personnel at the sponsor are listed in the Attachment 1.
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7
INTRODUCTION
The goal of Study E7080-J081-115, which will be conducted in patients, is to confirm the 
tolerability and safety for combination of lenvatinib plus pembrolizumab in Japanese subjects
with selected solid tumors: non-small cell lung cancer, predominantly clear cell renal cell 
carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the 
head and neck, or melanoma (excluding uveal melanoma).
7.1
Indication
7.1.1
Lenvatinib
Vascular endothelial growth factor receptor (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 vascular endothelial growth factor (VEGF) ligand stimulation 
(Ellis LM, et al., 2008, Ferrara N, et al., 2003, Hattori K, et al., 2002, Laakkonen P, et al., 
2007, Tammela T, et al., 2010).  Fibroblast growth factor 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 R, et al., 2005, Turner N, et al., 2012, Matsui
J, et al., 2004, Hirota S, et al., 1998, Williams D, 2002, Kondo T, et al., 2006, Phay JE, et al., 
2010, Gild ML, et al., 2011, Hirota S, et al., 2003, Oseini AM, et al., 2009) and an effective 
anticancer treatment may be established if their receptor tyrosine kinases (RTKs) are 
inhibited simultaneously. 
Lenvatinib mesylate 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. In addition, safety results in 
nonclinical 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 1 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 patients was confirmed in 
another study conducted in Japan (E7080-J081-105).  There was no significant difference in 
tolerability and pharmacokinetics among patients in Japan, Europe, and US.
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Lenvatinib is expected to be efficacious regardless of cancer type; clinical studies are being 
conducted for various solid malignancies including thyroid carcinoma, hepatocellular 
carcinoma, renal cell carcinoma, non-small-cell lung cancer, endometrial cancer, glioma, 
malignant melanoma, and ovarian cancer. 
Lenvatinib is approved in the US for the treatment of patients with locally recurrent or 
metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer, and 
approved in Japan with an indication for unresectable thyroid cancer.
As outlined below, data from Phase 2 clinical studies showed lenvatinib monotherapy has 
antitumor activity in multiple other tumors.
In patients with locally advanced or metastatic non-squamous non small cell lung cancer
(NSCLC), treated with lenvatinib 24 mg once daily + best supportive care, lenvatinib was 
found to be active with longer survival in these patients who had had 2 or more lines of prior 
treatment.  Overall survival (OS) was the primary objective of this study (E7080-703).  
In a 3 arm study of lenvatinib 24 mg once daily, everolimus 10 mg once daily, and the 
combination of lenvatinib 18 mg with everolimus 5 mg in patients with unresectable 
advanced or metastatic renal cell carcinoma (E7080-G000-205), lenvatinib monotherapy
showed plonongation of PFS compared with everolimus monotherapy.  
In a study (E7080-G000-204) to evaluate the antitumor activity of lenvatinib 24 mg once 
daily in female patients with surgically unresectable endometrial cancer who have disease 
progression following 1 prior platinum-based, systemic chemotherapy regimen, the objective 
response rate (ORR) (complete response [CR] + partial response [PR]) was 14.3% based on 
the assessments by independent radiologic review (IRR), the primary endpoint of the study.  
The ORR based on investigator assessments was 21.1%, indicating that lenvatinib is active as 
a second-line treatment in patients with advanced endometrial cancer.
A study was conducted to determine the activity of lenvatinib 24 mg once daily in previously 
treated patients with unresectable Stage III or Stage IV melanoma (E7080-G000-206).  The 
primary endpoint of the study was ORR, based on IRR assessment for the intent-to-treat 
(ITT) population.  The ORR was 8.6% in patients with melanoma not harboring the V600E 
BRAF mutation and 9.0% in patients with melanoma harboring the activating BRAF 
mutations (mainly the V600E mutation).  All were partial responses.
7.1.2
PD-1 Inhibitors and Pembrolizumab
Antitumor immunity is often ineffective due to the tight regulation associated with the 
maintenance of immune homeostasis (Stagg J, et al., 2013).  Recent studies have shown that 
cancer cells, as well as stromal cells and immune cells in the cancer microenvironment can 
upregulate expression of the B7 family of inhibitory molecules.  These are peripheral 
membrane proteins found on activated antigen presenting cells (Coico R, et al., 2003).  
Compelling evidence indicates that B7 proteins can suppress T-cell responses (Chen L, 2004,
Sharpe AH, et al., 2002) aiding tumor immune evasion.  These negative signals are largely 
provided by 2 members of the B7-family.  One of these is programmed cell death protein 1 
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(PD-1, also known as B7-H1).  PD-1 limits T cell effector functions within tissues by 
negatively regulating antitumor CD8 T cell responses.  By upregulating ligands for PD-1, 
tumor cells block antitumor immune responses in the tumour microenvironment.  Indeed, 
expression of the PD-1 ligand, PD-L1, has been shown to be associated with poor prognosis 
in melanoma and hepatocellular carcinoma (Gadiot J, et al., 2011, Gao Q, et al., 2009,
Topalian SL, et al., 2012).
Clinically, blockade of PD-1 or PD-L1, using monoclonal antibodies, has demonstrated 
substantial clinical activity in patients with metastatic melanoma, renal cell carcinoma, 
NSCLC, bladder, head and neck cancers, and other tumors (Brahmer JR, et al., 2012, Hamid
O, et al., 2013, Philips GK, et al., 2015, Robert C, et al., 2014).
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD 1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda™ (pembrolizumab) is indicated for the treatment of patients 
across a number of indications.  For more details on specific indications refer to the Investigator 
brochure.
A pembrolizumab population pharmacokinetic (PK) analysis has been performed using data 
from 476 subjects.  Based on the resulting population PK model, clearance and volume 
parameters of pembrolizumab were found to be dependent on body weight.  The relationship 
between clearance and body weight, with an allometric exponent of 0.59, is within the range 
observed for other antibodies and would support both body weight normalized dosing or a 
fixed dose across all body weights.  Pembrolizumab has a similar safety and efficacy profile 
over the range of doses ranging from 2 mg/kg to 10 mg/kg (Robert C, et al., 2014).  The 
differences in exposure for a 200 mg every 3 weeks (Q3W) regimen, the dose proposed for 
this study, relative to the approved 2 mg/kg Q3W regimen in the US Package Insert (see 
Appendix ) are anticipated to remain well within the established exposure margins of 0.5- to 
5.0-fold for pembrolizumab in the melanoma indication.  These exposure margins are based 
on the similar efficacy and safety seen in patients with melanoma at 10 mg/kg Q3W versus 
the dose regimen of 2 mg/kg Q3W (ie, a 5-fold higher dose and exposure) noted above.  The 
population PK evaluation revealed that there was no significant impact of tumor burden on 
exposure.  In addition, exposure was similar between the NSCLC and melanoma indications.  
Therefore, there are no anticipated changes in exposure between different indication settings.
No dose reduction is allowed for pembrolizumab in this study.  
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7.2
Combination of Lenvatinib Plus Pembrolizumab
7.2.1
Nonclinical
It is reported that VEGF/VEGFR signal exhibits proangiogenic properties but also has a key 
role in the induction of an immunosuppressive microenvironment (Gabrilovich DI, et al., 
1996, Huang Y, et al., 2007, Terme M, et al., 2013, Voron T, et al., 2015). Therefore, it is 
expected that lenvatinib which inhibit VEGFR can also have immune modulating activity.
The effect of combining lenvatinib with PD-1/L1 (programmed death, ligand 1) monoclonal 
antibodies (mAbs) has been investigated in the CT26 murine colorectal cancer syngeneic 
model (PD-L1 mAb) as well as the LL/2 murine lung cancer syngeneic model (PD-1 mAb).  
Combination treatment with lenvatinib and PD-1/L1 mAb showed significant and superior 
antitumor effects compared with either compound alone.  Tumor-associated macrophage 
(TAM) cells express PD-L1 at a higher level than cancer cells in the CT26 syngeneic model, 
and lenvatinib significantly decreased the TAM population (Kato Y, et al., 2015).  Because 
TAM cells produced interleukin 10 (IL-10) and transforming growth factor, beta 1 (TGFβ) 
(Noy R, et al., 2014), lenvatinib might increase antitumor immunity in the CT26 model and 
up-regulate the effect of the PD-1 signal inhibitors.  
Thus, immune-modulating effect of lenvatinib may result in potent combination effect with 
PD-1 signal inhibitors.
7.2.2
Clinical Studies
7.2.2.1
E7080-A001-111 (Phase 1b/2 of Lenvatinib Plus Pembrolizumab for Selected 
Solid Tumors in US)
E7080-A001-111 (Study 111) is an open-label Phase 1b/2 study in subjects with selected 
solid tumors (NSCLC, predominantly clear cell renal cell carcinoma, endometrial carcinoma, 
urothelial carcinoma, squamous cell carcinoma of the head and neck, or melanoma
[excluding uveal melanoma]), which is conducted in US.
In Phase 1b, subjects were to enroll in 1-3 dose levels to determine and confirm the 
maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of lenvatinib in 
combination with pembrolizumab.  The dose of pembrolizumab did not change during the 
MTD phase, while lenvatinib started at 24 mg and then be reduced, if necessary, to either 
20 mg or 14 mg.  In the lenvatinib 24 mg cohort, 2 DLTs were observed in the first 3 subjects 
(2 renal cell carcinoma and 1 NSCLC): Grade 3 fatigue and Grade 3 arthralgia.  The dose 
was de-escalated to 20 mg/day lenvatinib and 10 additional subjects (total of 6 renal cell 
carcinoma, 1 NSCLC, 1 Melanoma and 2 Endometrial) started the treatment. There were no 
DLTs in the lenvatinib 20 mg cohort, and the MTD and RP2D are confirmed at 20 mg 
lenvatinib once daily (QD) in combination with 200 mg Q3W of pembrolizumab.  
In Phase 2, subjects are assigned by tumor type to up to 6 cohorts to receive the MTD to 
assess the safety and efficacy of the combination in the selected tumor-types.  This phase is 
ongoing.
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7.2.2.2
E7080-J081-116 (Phase 1b of Lenvatinib Plus Pembrolizumab for 
Hepatocellular Carcinoma in Japan and US)
E7080-J081-116 (Study 116) is an open-label, single arm, multicenter, Phase 1b study in 
subject with hepatocellular carcinoma, which is conducted in Japan and US.  Primary 
objective of this study is to evaluate the tolerability and safety of lenvatinib in combination 
with pembrolizumab in subjects with Hepatocellular Carcinoma.  This study is ongoing.
7.3
Study Rationale
This is a Phase 1b study of lenvatinib in combination with pembrolizumab in Japanese 
subjects with selected solid tumors (NSCLC, predominantly clear cell renal cell carcinoma, 
endometrial carcinoma, urothelial carcinoma, squamous cell carcinoma of the head and neck,
or melanoma [excluding uveal melanoma]). Lenvatinib will be administered at starting dose 
of 20 mg QD in combination with pembrolizumab 200 mg Q3W.  DLT will be evaluated
during Cycle 1 (21 days following the initial dosing) to confirm 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 tolerability and safety for combination of lenvatinib 20 mg QD at starting dose and 
pembrolizumab 200 mg Q3W, which was determined asMTD and RP2D in Study 111, will 
be confirmed in Japanese subjects in this Study 115.
Lenvatinib monotherapy was tolerated up to the dose of 24 mg QD continuous administration 
in Japanese patients with solid tumor, and similar results were observed in Europe and US.  
Regarding pembrolizumab, which has not been approved in Japan at this time, there has been 
no significant difference in tolerability and pharmacokinetics noted between Japanese and 
non-Japanese patients. However, the combination regimen of lenvatinib and pembrolizumab 
has never been studied in Japan; therefore, the tolerability and pharmacokinetics in Japanese 
patients are still unknown. 
The dose of pembrolizumab planned to be studied in this trial is 200 mg Q3W, which is the 
recommended dose of pembrolizumab based on the well-established safety and efficacy 
profile in solid tumors. 
In KEYNOTE-001, an open-label Phase I study was conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, and anti-tumor activity of single agent 
pembrolizumab. The dose escalation portion of this trial evaluated 3 dose levels, 1 mg/kg, 
3 mg/kg and 10 mg/kg, administered every 2 weeks (Q2W) and dose expansion cohorts 
evaluated 2 mg/kg Q3W and 10 mg/kg Q3W in subjects with advanced solid tumors. All 
dose levels were well tolerated and no dose-limiting toxicities were observed.  This first-in-
human study of pembrolizumab showed evidence of target engagement and objective 
evidence of tumor size reduction at all dose levels. No maximum tolerated dose has been 
identified. In addition, 2 randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed, and 1
randomized cohort evaluating 10 mg/kg Q3W versus 10 mg/kg Q2W has also been 
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completed. The clinical efficacy and safety data demonstrate a lack of important differences 
in efficacy or safety profile across doses. 
An integrated body of evidence suggests that 200 mg Q3W is expected to provide similar 
response to 2 mg/kg Q3W, 10 mg/kg Q3W and 10 mg/kg Q2W. Previously, a flat 
pembrolizumab exposure-response relationship for efficacy and safety has been found in 
subjects with melanoma in the range of doses between 2 mg/kg and 10 mg/kg.  Exposures for 
200 mg Q3W are expected to lie within this range and will be close to those obtained with 
2 mg/kg Q3W dose.  
A population PK model, which characterized the influence of body weight and other patient 
covariates on exposure, has been developed. The PK profile of pembrolizumab is consistent 
with that of other humanized monoclonal antibodies, which typically have a low clearance 
and a limited volume of distribution. The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure range established 
in melanoma as associated with maximal clinical response.  PK properties of pembrolizumab, 
and specifically the weight-dependency in clearance and volume of distribution are 
consistent with no meaningful advantage to weight-based dosing relative to fixed dosing.  
In translating to other tumor indications, similarly flat exposure-response relationships for 
efficacy and safety as observed in subjects with melanoma can be expected, as the anti-tumor 
effect of pembrolizumab is driven through immune system activation rather than through a 
direct interaction with tumor cells, rendering it independent of the specific tumor type.  In 
addition, available PK results in subjects with melanoma, NSCLC, and other tumor types 
support a lack of meaningful difference in pharmacokinetic exposures obtained at tested 
doses among tumor types.  Thus the 200 mg Q3W fixed-dose regimen is considered an 
appropriate fixed dose for other tumor indications as well.  
There has been no significant difference in tolerability and PK profile noted between 
Japanese and non-Japanese patients.
The pembrolizumab 200 mg Q3W fixed-dose regimen is considered an appropriate fixed 
dose for other tumor indications as above.
Based on above, this study was considered scientifically rational and designed based on the 
previous findings to evaluate the tolerability, safety, and pharmacokinetics of lenvatinib plus
pembrolizumab combination therapy in Japanese subjects.
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8
STUDY OBJECTIVES
8.1
Primary Objective

To confirm the tolerability and safety for combination of lenvatinib plus pembrolizumab
in subjects with selected solid tumors
8.2
Secondary Objectives

To evaluate the following efficacy endpoints by Immune-related Response Evaluation 
Criteria In Solid Tumors (irRECIST) and modified RECIST 1.1: 
-
Objective response rate (ORR)
-
Duration of response (DOR)

To assess the pharmacokinetic (PK) profile of lenvatinib and pembrolizumab

To detect anti-drug antibodies for pembrolizumab (ADA)
8.3
Exploratory Objectives

To evaluate the following efficacy endpoints by irRECIST and modified RECIST 1.1: 
-
Progression-free survival (PFS) 
-
Time to response (TTR)
-
Disease control rate (DCR)
-
Clinical benefit rate (CBR) 

To investigate the relationship between candidate biomarkers and anti-tumor activity of 
lenvatinib in combination with pembrolizumab:
-
To explore blood and tumor markers (such as programmed cell death protein 1 ligand 
[PD-L1] expression levels, cytokine and angiogenic factor profiling), and immune 
cell profiling and evaluate their relationship with clinical outcomes including anti-
tumor activity of lenvatinib in combination with pembrolizumab
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9
INVESTIGATIONAL PLAN
9.1
Overall Study Design and Plan
E7080-J081-115 is an open-label Phase 1b study.  This study will confirm the tolerability and 
safety of lenvatinib in combination with pembrolizumab in subjects with selected solid 
tumors.  Subjects in this study will have one of the following tumors: non-small cell lung 
cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial 
carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal 
melanoma).
This study will begin with lenvatinib 20 mg/day orally and pembrolizumab 200 mg (every 
3 weeks [Q3W], intravenous [IV]) in subjects with selected solid tumors on a 21-day 
treatment cycle.  For the confirmation of the tolerability of the dose level, dose limiting 
toxicities (DLTs) will be evaluated during the first cycle (21 days).  
If 0 or 1of 6 subjects in a given dose level cohort experiences a DLT, the dose level will be 
considered tolerable (Figure 1).  
Enrollment will be interrupted if 2 or more DLTs are observed at any dose level, and after 
sponsor and investigators’ review, enrollment may continue for up to 6 subjects based on the 
nature and severity of the DLTs.  Once 6 subjects are enrolled, then, 4 additional subjects (10 
subjects in total) will be added and that dose level will be considered tolerable if DLT is 
observed in 3 or less of the10 subjects in total (Figure 1).  An independent medical advisor as 
third party should be consulted for the review as needed.
A lower dose level of lenvatinib of 14 mg QD in combination with 200 mg pembrolizumab 
Q3W or study discontinuation will be considered, if 20 mg lenvatinib plus 200 mg 
pembrolizumab dose level is not tolerable, upon discussions between the sponsor and 
investigators (Figure 1), and the protocol will be amended as necessary.  An independent 
medical advisor as third party should be consulted for the consideration as needed.
If there is a potential subject who is not evaluable for DLT (eg, subject who fails to 
administer ≥75% of the planned dosage of lenvatinib due to a reason other than treatment 
related toxicity during Cycle 1), the investigator and sponsor will discuss wheter or not to
include the subject in the DLT Analysis Set. If subject is not evaluable for DLT then the 
subject will be replaced.
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Figure 1
Confirmation of the Tolerability
DLT = dose limiting toxicity, IV = intravenous, PO = per os, Q3W = every 3 weeks.  
A DLT is defined as any of the following:

Any of the hematological or nonhematological toxicities noted in Table 1 considered to 
be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1

Failure to administer ≥75% of the planned dosage of lenvatinib as a result of treatment-
related toxicity during Cycle 1

Subjects who discontinue treatment due to treatment-related toxicity in Cycle 1

Greater than 2 weeks delay in starting pembrolizumab in Cycle 2 because of a treatment-
related toxicity, even if the toxicity does not meet DLT criteria
Not tolerable upon discussions 
between the sponsor and investigators
Dose Level 1
20 mg lenvatinib (PO, daily)
+ 200 mg pembrolizumab (IV, Q3W)
Tolerable
≤1/6 DLT
Dose Level 2
14 mg lenvatinib (PO, daily)
+ 200 mg pembrolizumab (IV, Q3W)
≤1/6 DLT
≥2/6 DLTs
≥2/6 DLTs
≤3/10 DLTs
Addition
4 Subjects
Addition
4 Subjects
Tolerable
≤3/10 DLTs
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Table 1
Dose Limiting Toxicities
Toxicity Category
Toxicity CTCAE Grade
Hematologic

Grade 4 neutropenia for ≥7 days

Grade 3 or Grade 4 febrile neutropeniaa

Thrombocytopenia <25,000/mm3 associated with bleeding and/or which requires
platelet transfusion
Other 
nonhematologic 
toxicity

Any other Grade 4 or a Grade 5 toxicity

Grade 3 toxicities lasting >3 days excluding:

Nausea, vomiting, and diarrhea controlled by medical intervention within 72 
hours

Grade 3 rash in the absence of desquamation, no mucosal involvement, does 
not require steroids, and resolves to Grade 1 by the next scheduled dose of 
pembrolizumab.

Grade 3 hypertension not able to be controlled by medication 

Grade 3 or above gastrointestinal perforation

Grade 3 or above wound dehiscence requiring medical or surgical intervention

Any grade thromboembolic event
Any Grade 3 nonhematologic laboratory value if:

Medical intervention is required to treat the subject, or

The abnormality leads to hospitalization
ANC = absolute neutrophil count, CTCAE = Common Terminology Criteria for Adverse Events v4.03.
a:
Febrile neutropenia Grade 3 or Grade 4:  
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of ≥38 °C 
(100.4 °F) for more than 1 hour.
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 °C (101 °F) or a sustained temperature of 
≥38 °C (100.4 °F) for more than 1 hour, with life-threatening consequences and urgent intervention indicated.
Toxicities with a clear alternative explanation (eg, due to disease progression) or transient 
(≤72 hours), abnormal laboratory values without associated clinically significant signs or 
symptoms based on investigator determination, can be deemed a non-DLT.
The study will be conducted in 3 phases: a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase (Figure 2).
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Figure 2
Study Design
DLT = dose limiting toxicity, IV = intravenous, Q3W = every 3 weeks.  
9.1.1
Pretreatment Phase
The Pretreatment Phase will last no longer than 28 days and will include a Screening Period 
and a Baseline Period.
9.1.1.1
Screening Period
Screening will occur between Day –28 and Day –3.  The purpose of the Screening Period is 
to obtain informed consent and to establish protocol eligibility.  Informed consent will be 
obtained after the study has been fully explained to each subject and before the conduct of 
any screening procedures or assessments.  Procedures to be followed when obtaining 
informed consent are detailed in Section 5.3.  Tumor assessments performed up to 28 days 
prior to dosing are acceptable as screening tumor assessments if they are consistent with the 
requirements for this protocol.  
The Screening Disposition case report form (CRF) page must be completed to indicate 
whether the subject is eligible to participate in the study and to provide reasons for screen 
failure, if applicable.
9.1.1.2
Baseline Period
The purpose of the Baseline Period is to confirm protocol eligibility as specified in the 
inclusion/exclusion criteria.  Baseline assessments may be performed from Day –3 to Day –1
or on Cycle 1/Day 1 (C1D1) prior to dosing.  
21 days per cycle
Pretreatment
Treatment
Extension
Screening
Informed consent
Enrollment
Baseline
First dose
≤28 days
≤3 days
Final dose
Off-Treatment Visit
Follow-up
Cycle 1
Treatment (Cycle 2 & onward)
≤30 days
DLT observation
Administer lenvatinib 20 mg/day 
or 14 mg/day orally and 
pembrolizub 200 mg Q3W IV
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Subjects who complete the Baseline Period and meet the criteria for inclusion/exclusion 
(Sections 9.3.1 and 9.3.2) will begin the Treatment Phase.
9.1.2
Treatment Phase
The Treatment Phase consists of the first cycle (21 days) for each subject. The Treatment 
Phase for each subject ends after they complete Cycle 1 of treatment or if they discontinue 
early.  Those subjects who discontinue study treatment in Cycle 1 transition to the Off 
Treatment (Off-Tx) Visit of the Follow-up Period of the Extension Phase.  Those who
complete Cycle 1 transition to the Treatment Period of the Extension Phase.  
Subjects will be required to stay at the site during Cycle 1 in principle; however, they may be 
allowed to receive treatment as outpatient at the investigators’ discretion based on the safety 
of the subject.  
9.1.3
Extension Phase
The Extension Phase begins after a subject completes Cycle 1 and ends when the subject 
completes the Off-Tx Visit.  Subjects will continue to receive study treatment until disease 
progression, development of unacceptable toxicity, withdrawal of consent, or sponsor 
termination of the study.  The Extension Phase consists of 2 periods, the Treatment Period 
and the Follow-up Period.  
9.1.3.1
Treatment Period
Subjects still receiving study treatment at the end of the Treatment Phase will continue to 
receive the same study treatment in the Treatment Period of the Extension Phase. Those 
subjects who discontinue study treatment transition to the Off-Tx Visit of the Follow-up 
Period of the Extension Phase.
9.1.3.2
Follow-up Period
The Follow-up Period consists of the Off-Tx Visit.  The Off-Tx Visit will occur within 
30 days following the last dose of study treatment.  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.
9.2
Discussion of Study Design
The study design follows well-established designs for Phase 1b oncology studies, including 
ongoing studies featuring co-administration of oncology drugs with different mechanisms of 
action and PD-1 inhibitors.  The design allows for rapid identification of tumors types which 
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will respond to the combination of a tyrosine kinase inhibitor (TKI) with a PD-1 inhibitor.  
The tumor types to be studied in this study (non-small cell lung cancer, predominantly clear 
cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, squamous cell 
carcinoma of head and neck, or melanoma [excluding uveal melanoma]) have shown 
response to lenvatinib and/or a PD-1 inhibitor in other studies where the drug products were 
individually administered.  
9.3
Selection of Study Population
Subjects who do not meet all of the inclusion criteria or who meet any of the exclusion 
criteria will not be eligible to receive study drug.  This study will enroll between 6 and 10 
evaluable subjects with selected solid tumors.
9.3.1
Inclusion Criteria
Subjects must meet all of the following criteria to be included in this study:
1. Histologically and/or cytologically confirmed selected solid tumor types that have 
progressed after treatment with standard therapies or for which there are no other 
appropriate therapies available.  If nivolumab or pembrolizumab is an approved therapy 
for the subject’s tumor type, but the subject has not been treated with it, the investigator 
may enroll the subject in this study.  The selected tumor types are: non-small cell lung 
cancer, predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial 
carcinoma, squamous cell carcinoma of the head and neck, or melanoma (excluding uveal 
melanoma).
2. At least 1 measurable target lesion according to modified RECIST1.1
3. Subjects must have an Eastern Cooperative Oncology Group (ECOG)-Performance 
Status (PS) of 0 to 1.
4. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive 
medications within 1 week prior to the Cycle 1/Day 1 (C1D1)
5. Adequate renal function defined as creatinine ≤1.5 times the upper limit of normal (ULN)
or calculated creatinine clearance ≥40 mL/min per the Cockcroft and Gault formula with 
creatinine levels >1.5×ULN
6. Adequate bone marrow function: 

Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5×103/μL)

Platelets ≥100,000/mm3 (≥100×109/L)

Hemoglobin ≥9.0 g/dL
7. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤1.5
8. Adequate liver function as evidenced by bilirubin ≤1.5×ULN and alkaline phosphatase
(ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤3×ULN 
(in the case of liver metastases ≤5×ULN).  In case ALP is >3×ULN (in the absence of 
liver metastases) or >5×ULN (in the presence of liver metastases) AND the subject also 
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is known to have bone metastases, the liver specific ALP must be separated from the total 
and used to assess the liver function instead of the total ALP.
9. Males or females age ≥20 years at the time of informed consent
10. Life expectancy of 12 weeks or more
11. Subjects with known brain metastases will be eligible if they have completed the primary 
brain therapy (such as whole brain radiotherapy, stereotactic radiosurgery or complete 
surgical resection) and if they have remained clinically stable, asymptomatic and off of 
steroids for at least 28 days.
12. Voluntary agreement to provide written informed consent and the willingness and ability 
to comply with all aspects of the protocol.
13. Archival tumor tissue or a newly obtained biopsy must be available prior to the first dose 
of study drug for biomarker analysis.  Subjects with inaccessible tumors for biopsy 
specimens can be enrolled without a biopsy upon consultation and agreement by the 
sponsor.  
Note: In case of submitting unstained cut slides, freshly cut slides should be submitted to 
the testing laboratory within 14 days from when the slides are cut.  See Section 9.5.1.4.2
in the protocol for an explanation.
9.3.2
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from this study:
1. Prior anticancer treatment within 28 days (or 5 times the half-life, whichever is shorter) 
or any investigational agent within 28 days prior to the first dose of study drugs.  All 
toxicities related to prior treatments must be resolved to Grade ≤1 (except alopecia).  
Note: Refer to inclusion criteria regarding Hypertention.
2. Biologic response modifiers (eg, granulocyte colony-stimulating factor) within 4 weeks 
before study entry.  Chronic erythropoietin therapy is permitted provided that no dose 
adjustments were made within 2 months before first dose of study treatment.
3. Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, 
excluding cancer types such as melanoma and non-small cell lung cancer where prior 
treatment with one anti-PD-1, anti-PD-L1, or anti-PD-L2 agent is allowed.  
4. Subjects must have recovered adequately from any complications from major surgery 
prior to starting therapy.
5. Subjects having ≥2+ proteinuria on urinalysis will undergo 24-hour urine collection for 
quantitative assessment of proteinuria.  Subjects with urine protein ≥1 g/24-hour will be 
ineligible.
6. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib
7. New York Heart Association congestive heart failure of grade II or above, unstable 
angina, myocardial infarction within the past 6 months, or serious cardiac arrhythmia 
associated with significant cardiovascular impairment within the past 6 months
8. Prolongation of QTc (Fridericia formula) interval to >480 ms
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9. Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the 
first dose of study drug
10. Bleeding or thrombotic disorders or subjects at risk for severe hemorrhage.  The degree 
of tumor invasion/infiltration of major blood vessels (eg, carotid artery) should be 
considered because of the potential risk of severe hemorrhage associated with tumor 
shrinkage/necrosis following lenvatinib therapy.
11. Active infection (any infection requiring systemic treatment)
12. Subject is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B 
or Hepatitis C.
13. Serious nonhealing wound, ulcer, or bone fracture
14. Known intolerance to either of the study drugs (or any of the excipients)
15. History of organ allograft
16. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical study
17. Excluding the primary tumor leading to enrollment in this study, any other active 
malignancy (except for definitively treated melanoma in-situ, basal or squamous cell 
carcinoma of the skin, or carcinoma in-situ of the bladder or cervix) within the past 24 
months
18. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study 
treatment.  The use of physiologic doses of corticosteroids (up to 7.5 mg/d of prednisone 
or equivalent) may be approved after consultation with the sponsor.  
19. Active autoimmune disease that has required systemic treatment in past 2 years (ie, with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine [T4], insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
20. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis, or has a history of interstitial lung disease. 
21. Has received a live-virus vaccination within 30 days of planned treatment start.  Seasonal 
flu vaccines that do not contain live virus are permitted.
22. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
23. Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a 
positive beta-human chorionic gonadotropin [ß-hCG] or human chorionic gonadotropin 
[hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-hCG [or 
hCG]).  A separate baseline assessment is required if a negative screening pregnancy test 
was obtained more than 72 hours before the first dose of study drug.
24. Females of childbearing potential* who:

do not agree to use a highly effective method of contraception for the entire 
study period and for 120 days after study drug discontinuation ie:
o
total abstinence (if it is their preferred and usual lifestyle) 
o
an intrauterine device (IUD) or hormone releasing system (IUS) 
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o
a contraceptive implant
o
an oral contraceptive** (with additional barrier method) 
OR

do not have a vasectomized partner with confirmed azoospermia. 
For sites outside of the European Union (EU), it is permissible that if a highly 
effective method of contraception is not appropriate or acceptable to the subject, 
then the subject must agree to use a medically acceptable method of contraception, 
ie double barrier methods of contraception such as condom plus diaphragm or 
cervical/vault cap with spermicide.
NOTES:
* All females will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, 
all with surgery at least 1 month before dosing]
** Must be on a stable dose of the same oral hormonal contraceptive product for at 
least 4 weeks before dosing with study drug and for the duration of the study.
25. Male subjects who are partners of women of childbearing potential must use a condom + 
spermicide and their female partners if of childbearing potential must use a highly 
effective method of contraception (see methods described in Exclusion Criterion #24) 
beginning at least 1 menstrual cycle prior to starting study drug(s), throughout the entire 
study period, and for 120 days after the last dose of study drug, unless the male subjects 
are totally sexually abstinent or have undergone a successful vasectomy with confirmed 
azoospermia or unless the female partners have been sterilized surgically or are otherwise 
proven sterile.  
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 and procedures 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 and procedures, or whether the subject will 
withdraw consent.  If a subject withdraws consent, the date will be documented in the source 
documents.  The Discontinuation From Treatment CRF page will be completed indicating the 
primary reason for discontinuation from treatment.  In addition, the date of last dose of study 
drug(s) will be recorded on the Study Drug Dosing CRF page.
During the Follow-up Period, subjects who have discontinued study treatment without 
progression (excluding the subject with CR at off-treatment visit) should have disease 
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assessments until disease progression is documented or another anticancer therapy is 
initiated. The investigator will discontinue the study of the subject in the event of the
sponsor request to discontinue the study for medical reasons or any other reason (see Section
11.11).  
9.3.3.1
Discontinuation Criteria by Subject
If a subject meets any of the following criteria, the investigor will discontinue treating a 
subject with study treatment or withdraw the subject from the study.  
1. Evidence of disease progression or emergence of new lesion(s). (Treatment decisions by 
the investigator will be based on irRECIST.) If irPD is confirmed and the subject is 
experiencing extraordinary clinical benefit, site must contact sponsor to discuss 
continuing treatment (see Section 9.5.1.3).
2. Withdrawal of consent by subject
3. Presence of adverse event that prohibits continuation with therapy
4. Pregnancy
5. Subject is turned to be non-compliant with the protocol and ineligible in view of safety 
issue.
6. Study discontinuation is appropriate judged by the investigator or subinvestigator.
7. Subject is found to be ineligible after the registration.
9.4
Treatments
9.4.1
Treatments Administered
9.4.1.1
Lenvatinib
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  On Day 1 of each cycle, in case 
concomitantly administered, it will be administered approximately within 1 hour after 
completion of pembrolizumab administration.  
9.4.1.2
Pembrolizumab
Pembrolizumab (200 mg) will be administered as a 30-minute IV infusion, Q3W (infusions 
lasting between 25 minutes to 40 minutes are acceptable).  The Pharmacy Manual contains 
specific instructions for the preparation of the pembrolizumab infusion and administration of 
infusion solution.
Pembrolizumab will be administered until 2 years after C1D1 at the longest.
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting.
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Study treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle (except for Cycle 2) due to administrative reasons. Study 
treatment with pembrolizumab of Cycle 3 should be skipped if pembrolizumab is 
administered on Day 4 or later in Cycle 2 due to treatment-related toxicity or any other 
reason.  
9.4.1.3
Criteria for Interruption of Treatment, Dose Reduction and Resumption of 
Treatment
9.4.1.3.1
CYCLE 1
Dose Modificaton in the Event of DLT
Lenvatinib and infusion of pembrolizumab should be interrupted immediately.  Treatment 
may be resumed in Cycle 2 of pembrolizumab at the same dose (except the toxicity which 
requires the permanent discontinuation according to the guidance) and at 1 lower dose level 
of lenvatinib if toxicity is resolved to Grade 0–1 (or torelable Grade 2 in case of lenvatinib 
treatment-related toxicity) or baseline and investigators decides to continue the study.  
Dose Modificaton in the Event of No DLT
Lenvatinib will be interrupted if judged to be clinically needed by investigators, and may be 
resumed at the same dose level at appropriate timing.  
9.4.1.3.2
CYCLE 2 AND ONWARD
Lenvatinib
Lenvatinib dose reduction and interruption for subjects who experience 
lenvatinib-pembrolizumab combination therapy-related toxicity will be in accordance with 
the guidelines provided in Table 2 and Table 3, respectively, for this study.  
For management of hypertension and proteinuria, refer to the main protocol text for 
instructions before consulting the table below, as appropriate. See Table 3 for dose 
reductions.  Any dose reduction below 4 mg/day (4 mg every other day) must be discussed 
with the sponsor.  Once the dose has been reduced, it cannot be increased at a later date.  
Table 2
Dose Modifications for Lenvatinib
Lenvatinib Treatment-
Related Toxicitya,b
During Therapy
Adjusted Dosef
Grade 1, Tolerable Grade 2
Continue treatment
No change
Intolerable Grade 2c,d and Grade 3g
First occurrence
Interrupt lenvatinib until resolved 
to tolerable Grade 2 or Grade 0-1
Reduce lenvatinib by 1 dose level
Second occurrence 
(same toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to tolerable Grade 2 or Grade 0-1
Reduce lenvatinib by 1 more dose 
level
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Third occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to tolerable Grade 2 or Grade 0-1
Reduce lenvatinib by 1 more dose 
level
Fourth occurrence
(same toxicity or new toxicity)
Interrupt lenvatinib until resolved 
to tolerable Grade 2 or Grade 0-1
Reduce lenvatinib by 1 more dose 
level
Grade 4e, g: Discontinue lenvatinib
BMI = body mass index.  
a:
An interruption of lenvatinib treatment for more than 21 days will require a discussion with the sponsor before 
treatment can be resumed.
b:
Excluding alopecia.  Initiate optimal medical management for nausea, vomiting, hypothyroidism and/or diarrhea 
prior to any lenvatinib interruption or dose reduction.
c:
Applicable only to Grade 2 toxicities judged by subject and/or physician to be intolerable.
d:
Obese subjects with weight loss do not need to return to the baseline weight or 10% of baseline weight (ie, Grade 
1 weight loss).  These subjects will restart the study drug(s) at a lower dose once their weight remains stable for 
at least 1 week and they reached the normal BMI (if the weight loss occurred but it is still above normal BMI, 
they can restart the study treatment at a lower dose once the weight has been stable for at least 1 week).  Normal 
BMI should be used as the new baseline for further dose reductions.
e:
Excluding laboratory abnormalities judged to be non-life-threatening, in which case manage as Grade 3.
f:
Refer to Table 3 for adjusted dose.
g:
For asymptomatic Grade ≥3 elevations of amylase and lipase, the sponsor should be consulted to obtain 
permission to continue treatment.
Table 3
Dose Reduction Recommendations for Lenvatinib in 
Combination With Pembrolizumab
Initial
Lenvatinib Dose
(mg, QD)
Adjusted Dose To Be Administered (mg, QD)
Reduction 1
Reduction 2
Reduction 3
Reduction 4
20
14
10
8
4a
14
10
8
4a
QD = once daily.
a.  Consult sponsor for further dose reduction recommendations.
General Guidelines for Holding Periods of Lenvatinib due to Procedures:
For minor procedures, lenvatinib should be stopped 2 days before the procedure and restarted 
2 days after, once there is evidence of adequate healing and no risk of bleeding.  Needle 
biopsies (fine needle aspirations and core needle aspiration) are usually considered minor 
procedures.
For major procedures, lenvatinib should be stopped 1 week (5 half-lives) before the 
procedure and then restarted once there is clear wound healing and no risk of bleeding, but at 
least 1 week after the procedure.  It is up to the investigator to determine if it is a major or 
minor procedure.  Usually a major procedure implies general anesthesia.
Pembrolizumab
Adverse events (AEs) (both nonserious and serious) associated with pembrolizumab 
exposure may represent an immunologic etiology.  These AEs may occur shortly after the 
first dose or several months after the last dose of treatment.  Pembrolizumab must be 
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withheld for drug-related toxicities and severe or life-threatening AEs as per Table 4 below.  
See Section 9.4.1.5 for supportive care guidelines, including use of corticosteroids.
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Table 4
Dose Modification Guidelines for Pembrolizumab-Related 
Adverse Events
Toxicity
Hold Treatment 
For Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
Diarrhea/Colitis
2-3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
AST, ALT, or 
Increased Bilirubin
2
Toxicity resolves to Grade 0-1 Toxicity does not resolve within 
12 weeks of last dose.
3-4
Permanently discontinue
(see exception below)a
Permanently discontinue
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia
T1DM or
3-4
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure.
Resume pembrolizumab when 
subjects are clinically and 
metabolically stable.
Hypophysitis
2-4
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy 
is instituted.
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
Hyperthyroidism 
3
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Hypothyroidism
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted.
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Table 4
Dose Modification Guidelines for Pembrolizumab-Related 
Adverse Events
Toxicity
Hold Treatment 
For Grade
Timing for Restarting 
Treatment
Treatment Discontinuation
Infusion Reaction
2b
Toxicity resolves to Grade 0-1
Permanently discontinue if toxicity 
develops despite adequate 
premedication 
3-4
Permanently discontinue
Permanently discontinue
Pneumonitis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
3-4
Recurrent 2
Permanently discontinue
Permanently discontinue
Renal Failure or 
Nephritis
2
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
3-4
Permanently discontinue
Permanently discontinue
All Other Drug-
Related Toxicityc, d
3 or Severe
Toxicity resolves to Grade 0-1
Toxicity does not resolve within 
12 weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks.
4
Permanently discontinue
Permanently discontinue
Note: Permanently discontinue for any severe or Grade 3 (Grade 2 for pneumonitis) drug-related AE 
that recurs or any life-threatening event.
ALT = alanine aminotransferase, AST = aspartate aminotransferase, T1DM = type 1 diabetes mellitus.  
a:
For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then subjects 
should be discontinued.
b:
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/h to 50 mL/h).  Otherwise dosing will be held until symptoms 
resolve and the subject should be premedicated for the next scheduled dose; Refer to Table 5 (Infusion 
Reaction Treatment Guidelines).  
c:
Subjects with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion.  Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose.
d:
For asymptomatic Grade ≥3 elevations of amylase and lipase, the sponsor should be consulted to obtain 
permission to continue treatment.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (eg, elective surgery, unrelated medical events, subject vacation, 
and/or holidays).  Subjects should be placed back on study treatment within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the sponsor.  The reason for 
interruption should be documented in the subject's study record.
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9.4.1.4
Supportive Care Guidelines for Lenvatinib
9.4.1.4.1 MANAGEMENT OF HYPERTENSION
Hypertension is a recognized side effect of treatment with drugs inhibiting VEGF signaling.  
Investigators should therefore ensure that subjects enrolled to receive treatment with 
lenvatinib have BP of ≤150/90 mmHg at the time of study entry and, if known to be 
hypertensive, have been on a stable dose of antihypertensive therapy for at least 1 week 
before C1D1.  Early detection and effective management of hypertension are important to 
minimize the need for lenvatinib dose interruptions and reductions.  Antihypertensive agents 
should be started as soon as elevated BP (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg) is confirmed on 2 assessments a minimum of 1 hour apart.  One BP assessment 
is defined as the mean value of 3 measurements at least 5 minutes apart.  The choice of 
antihypertensive treatment should be individualized to the subject’s clinical circumstances 
and follow standard medical practice.  For previously normotensive subjects, appropriate
antihypertensive therapy should be started when systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg is first observed on 2 assessments a minimum of 1 hour 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 (Kilfoy, et al., 2009).  
Lenvatinib should be withheld in any instance where a subject is at imminent risk to develop 
a hypertensive crisis or has significant risk factors for severe complications of uncontrolled 
hypertension (eg, BP ≥160/100 mmHg, significant risk factors for cardiac disease, 
intracerebral hemorrhage, or other significant co-morbidities).  Once the subject has been on 
the same hypertensive medications for at least 48 hours and the BP is controlled, lenvatinib 
should be resumed as described below.
During the Treatment Phase and the Treatment Period in the Extension Phase, subjects with 
systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on 
Day 15 or more frequently as clinically indicated until systolic BP has been ≤150 mmHg and 
diastolic BP has been ≤95 mmHg for 3 consecutive months.  If a repeat event of systolic BP 
≥160 mmHg or diastolic BP ≥100 mmHg occurs, the subject must resume the Day 15 
evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 
3 consecutive months.
The following guidelines should be followed for the management of systolic BP ≥160 mmHg 
or diastolic BP ≥100 mmHg confirmed on repeat measurements after 1 hour:

Continue lenvatinib and institute antihypertensive therapy for subjects not already 
receiving antihypertensive medication.

For those subjects already on antihypertensive medication, dose or medication choice 
should be modified as per the investigator.

If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg persists despite maximal 
antihypertensive therapy, then lenvatinib administration should be interrupted and 
restarted at 1 lower dose level as specified in Table 3 only when systolic BP ≤150 mmHg 
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and diastolic BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.
The following guidelines should be followed for the management of Grade 4 hypertension 
(life-threatening consequences):

Institute appropriate medical management.

Discontinue study drug.
9.4.1.4.2 MANAGEMENT OF PROTEINURIA
Regular assessment for proteinuria should be conducted as detailed in the Schedule of 
Procedures/Assessments.  Guidelines for assessment and management of proteinuria are 
summarized as follows:

Initial episode of proteinuria:  If proteinuria ≥2+ is detected on urine dipstick testing, 
study drug 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 Common Terminology Criteria for Adverse Events (CTCAE) v4.03
(Appendix 3) will be based on the 24-hour urine collection for total protein result.  
Management of lenvatinib administration will be based on the grade of proteinuria 
according to Table 2.

During the Treatment Phase and the Treatment Period in the Extension Phase, urine 
dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 of each 
cycle or more frequently as clinically indicated, until the results have been 1+ or negative 
for 3 consecutive months.  Any subsequent increases in the level of proteinuria higher 
than 2+ on urine dipstick testing must be confirmed with a 24-hour urine collection and 
graded according to the dose reduction and interruption instructions provided in the
Table 2.  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.  
9.4.1.4.3 MANAGEMENT OF HEPATOTOXICITY
Regular monitoring of liver function tests (eg, ALT, AST, bilirubin levels) should be 
conducted as detailed in the Schedule of Procedures/Assessments 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.  Appropriate supportive 
care should be provided together with close monitoring.  If hepatic failure occurs, the study 
drug must be discontinued.
9.4.1.4.4 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, deep vein thrombosis (DVT) signs including 
lower-extremity swelling, redness and warmth to touch or tenderness.  In case any of these 
signs or symptoms appear, subjects should be instructed to report such signs and symptoms 
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promptly to the treating physician.  If a thromboembolic event is confirmed, instructions 
contained in Table 2 of the protocol should be followed. Appropriate supportive care should 
be provided together with close monitoring.  If a subject experiences life-threatening (Grade 
4) thromboembolic reactions, including pulmonary embolism, the study drug must be 
discontinued.  
9.4.1.4.5
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.  Magnetic resonance imaging (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 may be required per 
instructions included in Table 2.  Please refer to the Investigator's Brochure for further 
information on lenvatinib, including the full set of special warnings and precautions for use.
9.4.1.4.6
MANAGEMENT OF HYPOCALCEMIA
Serum calcium should be monitored every 3 weeks per the Schedule of 
Procedures/Assessments.  Hypocalcemia should be treated per institutional guidelines (eg, 
using, as appropriate, calcium, magnesium, and Vitamin D supplementation) until resolution.  
9.4.1.4.7
MANAGEMENT OF GASTROINTESTINAL PERFORATION OR FISTULA FORMATION
Study treatment should be discontinued in any subjects who develop gastrointestinal
perforation or life-threatening fistula.  
9.4.1.4.8
MANAGEMENT OF DIARRHEA
An anti-diarrheal agent should be recommended to the subject at the start of study treatment
and subjects should be instructed and educated to initiate anti-diarrheal treatment at the first
onset of soft bowel movements. The choice of anti-diarrheal agent should be individualized
to the subject’s clinical circumstances and follow standard medical practice. If
signs/symptoms of diarrhea persist despite optimal medical management, instructions
contained in Table 2 of the protocol should be followed.  
9.4.1.5
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below.  Where appropriate, these
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional antiinflammatory agents if symptoms do not improve with administration of 
corticosteroids.  Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased.  For each disorder, attempts should be made 
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to rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care.  The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  

Pneumonitis: 
-
For Grade 2 events, treat with systemic corticosteroids.  When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks.
-
For Grade 3-4 events or recurrent Grade 2, immediately treat with intravenous 
steroids. Administer additional antiinflammatory measures, as needed.
-
Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration.

Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
-
All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider gastrointestinal (GI) consultation and endoscopy to confirm or rule out 
colitis.
-
For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
-
For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids.  
-
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 Diabetes Mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis
(DKA):
-
For T1DM or Grade 3-4 Hyperglycemia
◦
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
◦
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  

Hypophysitis:
-
For Grade 2 events, treat with corticosteroids.  When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks.  
Replacement of appropriate hormones may be required as the steroid dose is tapered.
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-
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids.  When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks.  Replacement of appropriate 
hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment.  Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
-
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):
◦
In hyperthyroidism, nonselective beta-blockers (eg, propranolol) are suggested as 
initial therapy.
◦
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care.
-
Grade 3-4 hyperthyroidism:
◦
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids.  
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  Replacement of appropriate hormones may 
be required as the steroid dose is tapered.

Hepatic:
-
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).
◦
Treat with IV or oral corticosteroids
-
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
-
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
-
For Grade 2 events, treat with corticosteroids.
-
For Grade 3-4 events, treat with systemic corticosteroids.
-
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab.
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Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion interruption but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤24 h
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 100 
mL/h to 50 mL/h).  Otherwise dosing will be held 
until symptoms resolve and the subject should be 
premedicated for the next scheduled dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study treatment 
administration.
Subject may be premedicated 
1.5h (±30 minutes) prior to 
infusion of pembrolizumab
with:
Diphenhydramine 50 mg 
orally (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
orally (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued from 
further study treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration.
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Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
CTCAE = Common Terminology Criteria for Adverse Events v4.03, IV = intravenous, NCI = National Cancer Institute, 
NSAID = nonsteroidal antiinflammatory drug.
9.4.2
Identity of Investigational Products
Lenvatinib and pembrolizumab will be supplied by the sponsor in appropriately labeled 
containers.  
Lenvatinib will be provided as 4-mg and 10-mg capsules.  Lenvatinib is formulated with 
calcium carbonate, mannitol, microcrystalline cellulose, hydroxypropylcellulose, low-
substituted hydroxypropylcellulose, and talc.
Pembrolizumab may be provided as a sterile, preservative-free, white to off-white 
lyophilized powder in single-use vials. Each vial will be reconstituted and diluted for 
intravenous infusion. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab 
and is formulated in L-histidine (3.1 mg), polysorbate-80 (0.4 mg), sucrose (140 mg).  The 
solution may contain hydrochloric acid/sodium hydroxide to adjust pH to 5.5.  
Alternatively, pembrolizumab may be provided as a sterile, preservative-free, clear to slightly 
opalescent, colorless to slightly yellow solution that requires dilution for intravenous 
infusion.  Each vial contains 100 mg of pembrolizumab in 4 mL of solution.  Each 1 mL of 
solution contains 25 mg of pembrolizumab and is formulated in L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection.
9.4.2.1
Chemical Name, Structural Formula of Lenvatinib
LENVIMA is the mesylate salt of lenvatinib.  Its chemical name is 4-[3-chloro-4-(N’-
cyclopropylureido)phenoxy]-7-methoxyquinoline-6 carboxamide methanesulfonate.  The 
molecular formula is C21H19ClN4O4 • CH4O3S, and the molecular weight of the mesylate salt 
is 522.96.  The chemical structure of lenvatinib mesylate is:
9.4.2.2
Information of Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between 
PD-1 and its ligands, PD-L1 and PD-L2.  Pembrolizumab is an IgG4 kappa immunoglobulin 
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with an approximate molecular weight of 149 kDa. (See Appendix for KEYTRUDA®
package insert.)
9.4.2.3
Labeling for Study Drug
The following information has to be labeled:  

For clinical study use only

Name and address of the sponsor

Chemical name or drug identifier

Lot number or batch number

Storage conditions, expiration date if necessary
9.4.2.4
Storage Conditions
Study drugs will be stored in accordance with the labeled storage conditions.  Temperature 
monitoring is required at the storage location to ensure that the study drug is maintained 
within an established temperature range.  The pharmacist or its 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.
9.4.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, single-arm study.  All subjects who provide signed informed consent to 
participate in this study and satisfy all eligibility requirements (see Section 9.3) will receive
lenvatinib in combination with pembrolizumab.  There is no randomization in this study.
9.4.4
Selection of Doses in the Study
As for the evaluating of lenvatinib in combination with pembrolizumab, an open-label Phase 
1b/2 study in subjects with selected solid tumors (Study 111) is conducting in US.  In 
Phase 1b of Study 111, subjects were to enroll in 1-3 dose levels to determine and confirm 
the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of lenvatinib in 
combination with pembrolizumab.  The dose of pembrolizumab did not change during the 
MTD phase, while lenvatinib started at 24 mg and then be reduced, if necessary, to either 
20 mg or 14 mg.  In the lenvatinib 24 mg cohort, 2 DLTs were observed in the first 3
subjects.  The dose was de-escalated to 20 mg/day lenvatinib and 10 additional subjects 
started the treatment. There were no DLTs in the 2nd cohort, and the MTD and RP2D are 
confirmed at 20 mg lenvatinib QD in combination with 200 mg Q3W of pembrolizumab.  
Therefore, the starting dose of lenvatinib and the dose of pembrolizumab in this study are set 
to 20 mg/day QD and 200 mg Q3W, respectively.  
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9.4.5
Selection and Timing of Dose for Each Subject
Lenvatinib will be administered with water orally once a day (with or without food) in 
21-day cycles at approximately the same time each day.  On Day 1 of each cycle, in case 
concomitantly administered, it will be administered approximately within 1 hour after 
completion of pembrolizumab administration.
Pembrolizumab will be administered as a dose of 200 mg as a 30-minute IV infusion, Q3W 
(infusion durations of 25 minutes to 40 minutes are acceptable).  The Pharmacy Manual 
contains specific instructions for the preparation of the pembrolizumab infusion and its
administration. Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. Study treatment of pembrolizumab may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle (except for 
Cycle 2) due to administrative reasons.  Study treatment with pembrolizumab of Cycle 3 
should be skipped if pembrolizumab is administered on Day 4 or later in Cycle 2 due to 
treatment-related toxicity or any other reason.  
9.4.6
Blinding
The study will not be blinded.
9.4.7
Prior and Concomitant Therapy
All prior medications (including over-the-counter medications) administered 30 days before 
the first dose of study drug and any concomitant therapy administered to the subject during 
the course of the study (starting at the date of informed consent) until 30 days after the final 
dose of study drug will be recorded.  A concomitant therapy will not be recorded if other 
anticancer treatment is started.  
Any medication that is considered necessary for the subject’s health and that is not expected 
to interfere with the evaluation of or interact with lenvatinib or pembrolizumab may be 
continued during the study.
Treatment of complications or AEs, or therapy to ameliorate symptoms (including blood 
products, blood transfusions, fluid transfusions, antibiotics, and antidiarrheal drugs), may be 
given at the discretion of the investigator, unless it is expected to interfere with the evaluation 
of (or to interact with) lenvatinib or pembrolizumab.
Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and low-molecular-weight heparin 
(LMWH) are permissible but should be used with caution.  Granulocyte colony-stimulating 
factor (G-CSF) or equivalent may be used in accordance with American Society of Clinical 
Oncology (ASCO), institutional, or national guidelines.  Erythropoietin may be used 
according to ASCO, institutional, or national guidelines, but the subject should be carefully 
monitored for increases in red blood cell (RBC) counts.
The investigator will record on the Adverse Event CRF any AE for which the concomitant 
medication/therapy was administered.
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9.4.7.1
Drug–Drug Interactions
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 (CYP) 
enzymes (Study No. XT063020) suggests a low risk of lenvatinib interference with the PK of 
other drugs metabolized by CYP enzymes which are co-administered in usual clinic practice.  
Nonclinical studies identify CYP3A4 as an important enzyme responsible for human hepatic 
metabolism of lenvatinib.  However, clinical studies conducted to test these findings showed 
that co-administration of lenvatinib with CYP3A4/P-glycoprotein (P-gp) inhibitors or 
inducers is not of clinical concern (see Appendix 4 for a summary of clinical findings).  
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab.  Pembrolizumab is a monoclonal antibody; pharmacokinetic interactions 
with lenvatinib (and vice-versa) are not expected.
9.4.7.2
Prohibited Concomitant Medications/Vaccinations
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination 
may be required.  The investigator should discuss any questions regarding this with the 
sponsor.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on study therapy or vaccination schedule requires the mutual agreement of the 
investigator, the sponsor, and the subject.
9.4.7.2.1
PROHIBITED CONCOMITANT MEDICATIONS
Subjects should not receive other antitumor therapies while on study.  If a subject receives
additional antitumor therapies, such as chemotherapy, hormone therapy, palliative 
radiotherapy, or immunotherapy, this will be judged to represent evidence of disease 
progression, and continuation of the study medication and further participation in the study 
must be discussed and agreed upon with the sponsor.  
Subjects are prohibited from receiving the following therapies during the Pretreatment,
Treatment, and Extension Phase of this study:

Anticancer therapies such as chemotherapy, TKIs, antitumor interventions (surgical 
resection, thoracocentesis, etc.), or immunotherapy

Investigational agents other than lenvatinib and pembrolizumab

Radiation therapy 
-
Note:  Palliative radiotherapy of up to 2 painful pre-existing, non-target bone 
metastases without being considered progressive disease may be considered on an 
exceptional case by case basis after consultation with the sponsor.  Administration of 
palliative radiation therapy will be considered clinical progression for the purposes of 
determining PFS.
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
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and 
typhoid (oral) vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed.  However, intranasal influenza vaccines (eg, Flu-Mist®) 
are live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the sponsor.
-
Note:  Inhaled steroids are allowed for management of asthma or seasonal allergies.
For subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management, continuation of the study medication 
and further participation in the study must be discussed and agreed upon with the sponsor.  
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describes other medications that are prohibited in this clinical study.
The following concomitant medications are allowed:

Thyroid hormone suppressive therapy 

Adjuvant hormonal therapy for history of definitively treated breast or prostate cancer 

Anticoagulants including LMWH, warfarin, anti-Xa agents 

Antiinflammatory agents (Note:  use of steroids is not permitted except as outlined in 
Section 9.4.1.5 to manage immune-related adverse event [irAEs])

Bisphosphonates

Supportive care guidelines for pembrolizumab (see Section 9.4.1.5)

Antihypertensive therapy (including additional antihypertensive treatment as appropriate 
if BP increases once the patient has been enrolled)
9.4.8
Treatment Compliance
Records of treatment compliance for each subject will be kept during the study.  CRAs will 
review treatment compliance during site visits and at the completion of the study.
9.4.9
Drug Supplies and Accountability
The pharmacist or its designee will be responsible for the accountability of all study drugs 
(dispensing, inventory, and record keeping) following the sponsor’s instructions and 
adherence to Japan’s GCP guidelines as well as other requirements.
Under no circumstances will the investigator allow the study drugs to be used other than as 
directed by this protocol.  Study drugs will not be dispensed to any individual who is not 
enrolled in the study.  
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The pharmacist or its designee must maintain an accurate and timely record of the following:  
receipt of all study drugs, dispensing of study drugs to the subject, collection and 
reconciliation of unused study drugs that are either returned by the subjects or shipped to site 
but not dispensed to subjects, and return of reconciled study drugs to the sponsor or (where 
applicable) destruction of reconciled study drugs at the site.  This includes, but may not be 
limited to:  (a) documentation of receipt of study drugs, (b) study drugs dispensing/return 
reconciliation log, (c) study drugs accountability log, and (d) documentation of returns to the 
sponsor.  
The study drugs and inventory records must be made available, upon request, for inspection 
by a designated representative of the sponsor or a representative of a health authority.  Upon 
completion of drug accountability and reconciliation procedures by the pharmacist’s or its 
designee’s personnel and documentation procedures by the sponsor’s personnel, all unused 
study drugs are to be returned to the sponsor. Study drugs may be removed from the site and 
hand delivered to the central or local depot by sponsor representatives.  
Drug accountability will be reviewed during site visits and at the completion of the study.
9.5
Study Assessments
9.5.1
Assessments
9.5.1.1
Demography
Subject demography information will be collected at the Screening Visit.  Demography 
information includes date of birth (or age), sex, race and ethnicity. Baseline characteristics 
will include ECOG-PS, New York Heart Association (NYHA) cardiac disease classification, 
tumor-node-metastasis (TNM) staging at initial diagnosis, and tumor mutation status
(Appendix 2, Appendix 4).
9.5.1.2
Baseline Assessments
9.5.1.2.1
MEDICAL HISTORY AND PHYSICAL EXAMINATIONS
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All clinically significant medical and surgical history must be noted in the Medical 
History and Current Medical Conditions CRF.  
The following prior therapy and diagnosis on the primary disease will also be investigated:  
1. First tumor diagnosis (date of diagnosis, diagnostic method [histology/cytology], 
histological type, staging [TNM classification])
2. Previous anti-cancer therapy for primary disease
a.
Surgical therapy (date, surgical procedure)
b. Radiotherapy (site of radiotherapy, end date of radiotherapy)
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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)
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 10).  Documentation of the physical examination will be 
included in the source documentation at the site.  Significant findings at the Screening Visit 
will be recorded on the Medical History and Current Medical Conditions CRF.  Changes 
from screening physical examination findings that meet the definition of an AE will be 
recorded on the Adverse Events CRF.
9.5.1.3
Efficacy Assessments
All efficacy endpoints will be based on the tumor assessments performed by the investigators
using both irRECIST and modified RECIST 1.1. Treatment decisions by the Investigator 
will be based on irRECIST.  All scans for tumor assessments performed during the study 
should be archived in accordance with the standard local practice.  They must be accessible
in the event of a sponsor request to submit them for central review.
Tumor assessments will be carried out during the Pretreatment Phase and then every 6 weeks 
(±1 week; counting from C1D1) until Week 24, then every 9 weeks (±1 week) during 
treatment cycles in the Extension Phase. Computed tomography (CT) /MRI scans of chest, 
abdomen, and pelvis and of other known sites of disease will be obtained at Screening 
(within 28 days prior to C1D1), at all tumor assessment time points, and as indicated 
clinically.  Color photographs containing a milimeter scale must be taken of all skin lesions 
being used as target lesions.  Historical standard of care scans that are performed with 
scanning parameters consistent with the requirements for this protocol within 28 days prior to 
dosing are acceptable (scans before informed consent would be acceptable).  Subjects with 
squamous cell carcinoma of head and neck (HNSCC) must also have head and neck scans 
performed.
The CT scan should be a diagnostic quality spiral or multidetector CT with iodinated IV 
contrast, and the MRI scan should be performed with IV gadolinium chelate.  Scans of the 
neck, abdomen, pelvis, and other areas of the body may be done with MRI instead of CT, but 
evaluation of the chest must be done with CT.  If iodinated IV contrast is contraindicated, the 
chest evaluation should be done with non-contrast CT, and the abdomen and pelvis 
evaluation should be performed using either CT with oral contrast (without IV contrast) or 
MRI with gadolinium chelate IV contrast (the latter is preferred).  Spiral/multidetector CT 
should be performed with a 5-mm contiguous slice reconstruction algorithm.  If body MRI 
scans are performed, contiguous slices of 5 mm are also recommended.  
Low-dose non-contrast CT transmission scans from a positron emission tomography-CT 
(PET-CT) combination scanner are not acceptable.  Ultrasound should not be used for 
radiographic tumor assessment.  Chest disease may not be followed using chest x-ray.  
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A brain scan (CT with contrast or MRI pre- and post-gadolinium) must be performed at 
Screening to assess potential central nervous system (CNS) disease and/or metastases.  For 
subjects with previously treated eligible brain metastases, a brain scan must be performed at 
all tumor assessment time points.  For all subjects (except for subjects with HNSCC), a 
follow-up brain scan must be performed to confirm irCR or if clinically indicated.  
The tumor assessment schedule should not be affected by interruptions in study treatment.
Subjects going off treatment without disease progression (excluding the subject with CR at 
off-treatment visit) will also undergo tumor assessments per the Schedule of 
Procedures/Assessments until disease progression is documented or another anticancer 
therapy is initiated.  The investigator will discontinue the study of the subject in the event of 
the sponsor request to discontinue the study for medical reasons or any other reason (see 
Section 11.11).
The same method of assessment used at Screening must be used at all time points.  
Throughout the study it is critical that the same imaging methodology be applied and contrast 
be consistently provided unless IV contrast becomes medically contraindicated during the 
course of treatment or the dose of contrast needs to be adjusted based on the subject’s health 
status.  
Bone scans will be performed (except for subjects with HNSCC) at Screening, every 
24 weeks (as needed), or sooner if clinically indicated, and at confirmation of irCR.  A bone 
scan (99m-technetium-based scintigraphy, whole body bone MRI, or 18F-NaF-PET) to assess 
bone metastases will be performed within 6 weeks prior to C1D1 (historical scans are 
acceptable) and then every 24 weeks (within that 24th week) from C1D1 for all tumor types 
except for HNSCC, or sooner if clinically indicated.  In subjects whose body CT/MRI scans 
indicate that irCR has been achieved, except for subjects with HNSCC, a bone scan will be 
required at confirmation of irCR to exclude new bone metastases.  The same methodology 
and acquisition techniques used at Screening should be used throughout the study to ensure 
comparability.  Lesions detected on bone scans must be followed with cross-sectional 
imaging.  
In order for stable disease (irSD) to be considered the best overall response (BOR), it must 
occur ≥5 weeks following the first dose of study drug.
The first radiological assessment of tumor response status will be performed at Week 6 
(±1 week), unless there is clinical indication warranting earlier radiologic imaging. 
Responses (irPR or irCR) should be confirmed no less than 4 weeks after the initial response, 
but generally at the next scheduled tumor assessment time point.
If the time point tumor assessment is progressive disease (PD), treatment should continue and 
tumor assessments be repeated at least 4 weeks later, but generally at the next scheduled 
tumor assessment time point in order to confirm irPD.  If repeat imaging shows a reduction 
in the tumor burden compared to the initial tumor assessment demonstrating PD, treatment 
may be continued as per treatment schedule.  If repeat imaging confirms irPD, subjects will 
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be discontinued from study treatment.  In determining the tumor time point response, 
investigators should consider all target lesions as well as nontarget lesions and new lesions.  
The decision to continue study treatment after the first evidence of PD is at the investigator’s 
discretion based on the clinical status of the subject as described in Table 6 below.  
Subjects may continue receiving study treatment while waiting for confirmation of irPD if 
they are clinically stable as defined by the following criteria:

Absence of signs and symptoms (including worsening of laboratory values) indicating
disease progression

No decline in ECOG-PS

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
If irPD is confirmed and the subject is experiencing extraordinary clinical benefit, site must 
contact sponsor to discuss continuing treatment.
Tumor assessments per modified RECIST 1.1 will follow Eisenhauer, et al. (2009), however, 
up to 10 target lesions, up to 5 per organ, may be selected (as opposed to the maximum of 5 
target lesions, up to 2 per organ, mentioned in Eisenhauer, et al. [2009]).  Responses (PR or 
CR) should be confirmed no less than 4 weeks after the initial response, but generally at the 
next scheduled tumor assessment time point.  In order for SD to be considered BOR, it must 
occur ≥5 weeks following the first dose of study drug.
Table 6
Imaging and Treatment After First Radiologic Evidence of 
Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st 
radiologic 
evidence of 
PD
Repeat imaging at >4 
weeks (next TA time 
point) to confirm PD
May continue study 
treatment at the 
Investigator’s 
discretion while 
awaiting 
confirmatory scans 
Repeat imaging at >4 
weeks to confirm PD 
per physician 
discretion only
Discontinue 
treatment
Subsequent 
scan 
confirms 
PD
No additional 
imaging required
Discontinue 
treatment
No additional 
imaging required
N/A
Subsequent 
scan shows 
SD, PR or 
CR
Continue regularly 
scheduled imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments 
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion
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CR = complete response, PR = partial response, SD = stable disease, PD = progression disease, N/A = not 
applicable, TA = tumor assessment.
9.5.1.4
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Assessments
A schedule of lenvatinib and pembrolizumab PK, pharmacodynamic, and pharmacogenomic
sampling is shown in the Schedule of Procedures/Assessments (Table 10).
9.5.1.4.1
PHARMACOKINETIC ASSESSMENTS
Plasma Lenvatinib and Serum Pembrolizumab Concentrations
Plasma concentrations of lenvatinib and serum concentrations of pembrolizumab will be 
measured. Blood samples will be collected as specified in Table 10.  Table 7 presents the 
detailed blood sampling schedule for pharmacokinetic assessments.  See the Laboratory 
Manual for a description of collection, handling, and shipping procedures for PK samples.
Samples from all subjects will be analyzed.  Plasma lenvatinib concentrations of analytes will 
be quantified by liquid chromatography with tandem mass spectrometry (LC/MS/MS) 
methodology using a previously validated assay.  Serum concentrations of pembrolizumab
will be measured by using validated methods.
The actual time and date of PK blood collection will be recorded on the CRF. The actual 
time, date, and dose of lenvatinib administered on Days 1, 14, and 15 of Cycle 1 will be 
recorded in the CRF. The actual start/stop time of infusion, date, and dose of pembrolizumab
administered will be recorded in the CRF.  Date and time of last food intake before study 
drug administration on Days 1 and 15 of Cycle 1 will also be recorded in the CRF.
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Table 7
Blood Sampling Schedule for Pharmacokinetic Assessments
Lenvatinib
Days
Time (on each Day)
Acceptable time-window
(approximate)
C1D1
Predose of pembrolizumab
≤24 h before infusion
1 h postdose of lenvatinib
±15 min
2 h postdose of lenvatinib
±15 min
4 h postdose of lenvatinib
±15 min
8 h postdose of lenvatinib
±60 min
24 h postdose of lenvatinib
≤–60 min
C1D15
Predose of lenvatinib
≤–60 min
1 h postdose of lenvatinib
±15 min
2 h postdose of lenvatinib
±15 min
4 h postdose of lenvatinib
±15 min
8 h postdose of lenvatinib
±60 min
24 h postdose of lenvatinib
≤–60 min
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Table 7
Blood Sampling Schedule for Pharmacokinetic Assessments
Pembrolizumab
Days
Time (on each Day)
Acceptable time-window
(approximate)
C1D1
Predose of pembrolizumab
≤24 h before infusion
C2D1
Predose of pembrolizumab
≤24 h before infusion
C4D1
Predose of pembrolizumab
≤24 h before infusion
C6D1
Predose of pembrolizumab
≤24 h before infusion
C8D1
Predose of pembrolizumab
≤24 h before infusion
Day 1 in every 4 
cycles after Cycle 8
Predose of pembrolizumab
≤24 h before infusion
End of treatment
Within 30 days after discontinuation or 
until the initiation of other anticancer 
treatment, whichever earlier
–
C#D# = Cycle #/Day #.
Serum Anti-pembrolizumab Antibodies (ADA)
Serum ADA will be measured.  
Blood samples will be collected as specified in Table 10.  Table 8 presents the detailed blood 
sampling schedule for anti-pembrolizumab antibodies (ADAs).  See the Laboratory Manual
for a description of collection, handling, and shipping procedures for blood samples.  
Serum ADA will be detected by using validated methods.  
The actual time and date of blood collection for ADA will be recorded on the CRF.  
Table 8
Blood Sampling Schedule for Anti-pembrolizumab Antibodies
(ADAs)
Anti-pembrolizumab Antibodies (ADA)
Days
Time (on each Day)
Acceptable time-window
C1D1
Predose of pembrolizumab
≤24 h before infusion
C2D1
Predose of pembrolizumab
≤24 h before infusion
C4D1
Predose of pembrolizumab
≤24 h before infusion
C6D1
Predose of pembrolizumab
≤24 h before infusion
C8D1
Predose of pembrolizumab
≤24 h before infusion
Day 1 in every 4 
cycles after Cycle 8
Predose of pembrolizumab
≤24 h before infusion
End of treatment
Within 30 days afeter discontinuation 
or until the initiation of other 
anticancer treatment, whichever earlier
–
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C#D# = Cycle #/Day #.
9.5.1.4.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER, ASSESSMENTS
A schedule of biomarker sampling is shown in the Schedule of Procedures/Assessments
(Table 10).  
Blood samples for the development of exploratory predictive biomarkers will be collected 
from consented subjects prior to the first dose of study drug, on Cycle 1/Day 15 (C1D15), 
and on Day 1 of subsequent cycles up to and including Cycle 18, and at the Off-Tx 
assessment.  Subjects will be required to provide an archival tumor tissue sample and/or a 
fresh biopsy of tumor before treatment for biomarker analyses (subjects with inaccessible 
tumors for biopsy specimens can be enrolled without a biopsy upon consultation and 
agreement by the sponsor).  An archival tumor sample from the most recent surgery or 
biopsy will be collected.  Biomarker discovery and/or validation will be performed to 
identify blood or tumor biomarkers which may be useful to predict subject response to 
lenvatinib and/or pembrolizumab, as determined by evaluation of response-related and/or 
safety-related outcomes as well as for potential use in diagnostic development.  Blood serum 
samples from subjects receiving lenvatinib and pembrolizumab may be analyzed using global 
proteomic methods, enzyme-linked immunosorbent assay (ELISA), multiplex bead-based 
immunoassay, or other assays/methods or new technology.  In addition, biomarkers identified 
in other lenvatinib clinical studies may also be assessed in the biomarker samples collected 
from subjects enrolled in this study. The decision to perform exploratory biomarker analysis 
may be based on the clinical outcome of this study and/or the signals observed in other 
clinical studies or other information available at that time.
Archived, formalin-fixed paraffin-embedded (FFPE) tissue or a newly obtained biopsy will 
be collected from all consented subjects for potential assessment of mutations and other 
genetic alterations or genes and/or proteins including PD-1/PD-L1/PD-L2 status and other 
relevant biomarkers (eg, tumor infiltrating lymphocytes, T-cell repertoire, ribonucleic acid 
[RNA] signature profiles mutational load), which may be important in the development and 
progression of cancer as well as for potential use in diagnostic development.  Appropriate 
technology/methodologies will be used based on the amount of tumor tissue available.  
Note: For PD-1/PD-L1/PD-L2 status, submission of FFPE tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted 
to the testing laboratory within 14 days from the site slide sectioning date; otherwise, a 
new specimen will be requested.
Optional fresh paired tumor biopsies will be collected from consented subjects to examine 
markers including markers of target engagement, relevant pharmacodynamic biomarkers, and 
potential markers of response. Fresh biopsies should be limited to readily accessible tumor 
lesions (eg, skin, peripheral lymph nodes, liver metastases which can be readily accessed 
using CT guidance).  Subjects should have the biopsy before administration of the first dose 
of study drug and at a time point 3-6 weeks after the first dose (if they have recovered 
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adequately from the biopsy taken prior to starting therapy and investigators judge that it is 
medically acceptable to have a biopsy).
A blood plasma sample to isolate circulating cell free nucleic acids (cf-nucleic acids) and a 
whole blood sample for immune cell profiling will be collected from consented subjects prior 
to the first dose of study drug (C1D1), and then pre-dose on C1D15 and Day 1 of subsequent 
cycles up to and including Cycle 18 and at the off-treatment assessment.  Cf-nucleic acid 
isolated from plasma samples may be used to obtain circulating tumor DNA (ctDNA) and 
explore tumor genetic alterations such as mutations observed in archival tumor samples as 
well as those which develop during drug treatment.  Genomic DNA extracted from blood 
samples may be used to confirm whether the DNA sequence variants observed in DNA 
extracted from tumor material are limited to the tumor and to assess the immune response.
Data obtained will be used for research to assist in developing safer and more effective 
treatments and will not be used to change the diagnosis of the subject or alter the therapy of 
the subject.  All analyses will be limited to correlations relevant to diseases and clinical 
ourcomes related to therapy of lenvatinib and pembrolizumab. The DNA will not be used to 
determine or predict risks for diseases that an individual subject does not currently have.  
Any sample or derivatives (DNA, RNA, and protein) may be stored for up to 15 years to 
assist in any research scientific questions related to lenvatinib/pembrolizumab, cancer and/or 
for potential diagnostic development.  
Instructions for the processing, storage, and shipping of samples will be provided in the 
Laboratory Manual.
9.5.1.5
Safety Assessments
Safety assessments will consist of monitoring and recording all AEs, including all CTCAE 
v4.03 grades (for both increasing and decreasing severity), and serious adverse events 
(SAEs); regular monitoring of hematology, blood chemistry, and urine values; periodic 
measurement of vital signs and electrocardiogram (ECGs); echocardiograms or multigated
acquisition (MUGA) scans including left ventricular ejection fraction (LVEF); and 
performance of physical examinations as detailed in Table 10.
9.5.1.5.1
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the investigational 
products are lenvatinib and pembrolizumab.  
The criteria for identifying AEs in this study are:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
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symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE.)

Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE.

Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug

Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline)

An abnormal laboratory test result should be considered an AE if the identified 
laboratory abnormality leads to any type of intervention, withdrawal of study drug, or 
withholding of study drug, whether prescribed in the protocol or not.
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, should be collected beginning from the time the 
subject signs the study ICF and for 30 days after the last dose of study treatment.  For SAEs, 
all events occurring until 30 days after the subject’s last dose will be collected. From 30 days 
after the last dose, SAEs will be collected through 90 days after the last dose or until the 
subject initiates new anticancer therapy, whichever is earlier.  An AE will not be reported on 
the Adverse Event CRF if other anticancer treatment is started.  All SAEs will be reported on 
the Adverse Event 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 AE.  Any laboratory abnormality 
considered to constitute an AE should be reported on the Adverse Event CRF.  
Abnormal ECG (QTc) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTc interval is more than 450 ms 
and there is an increase of more than 60 ms from baseline.  Any ECG abnormality that the 
investigator considers as an AE should be reported as such.
Progression of malignant disease (PD) should not be recorded as an adverse event in studies 
where it is included as an endpoint for underlying disease.  If the progression leads to an 
untoward medical occurrence (increased pain, pleural effusion, etc), then this medical 
occurrence should be the adverse event.
All AEs must be followed for 30 days after the subject’s last dose, or until resolution, 
whichever comes first.  All SAEs must be followed to resolution or, if resolution is unlikely, 
to stabilization.
Every effort must be made by the investigator to categorize each AE according to its 
severity and its relationship to the study treatment.
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Assessing Severity of Adverse Events
Adverse events will be graded on a 5-point scale according to CTCAE v4.03 (Appendix 3).  
Investigators will report CTCAE grades for all AEs (for both increasing and decreasing 
severity).  
Assessing Relationship to Study Treatment
Items to be considered when assessing the relationship of an AE to the study treatment are:

Temporal relationship of the onset of the event to the initiation of the study treatment

The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable

Whether the event is known to be associated with the study treatment or with other 
similar treatments

The presence of risk factors in the study subject known to increase the occurrence of the 
event

The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event
Classification of Causality
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question:
Is there a reasonable possibility that the study drug caused the AE?
Yes (related)
A causal relationship between the study drug and the AE is a reasonable 
possibility.
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility.
9.5.1.5.2
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS
A serious adverse event (SAE) is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug)
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Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
Events of clinical interest for this study include:
1. 
an elevated AST or ALT laboratory value that is greater than or equal to 3 × ULN and 
an elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at 
the same time, an ALP laboratory value that is less than 2 × ULN, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.
Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  The study site guidance 
for assessment and follow up of these criteria can be found in the Investigator Trial 
File Binder (or equivalent).
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; and AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures but are to be considered as SAEs only if they meet one of 
the above criteria.  All AEs associated with special situations are to be reported on the CRF
whether or not they meet the criteria for SAEs.  
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization.
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization:

Hospitalizations for respite care 

Planned hospitalizations required by the protocol

Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration)

Hospitalization for administration of study drug or insertion of access for administration 
of study drug

Hospitalization for routine maintenance of a device (eg, battery replacement) that was in 
place before study entry
9.5.1.5.3
LABORATORY MEASUREMENTS
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 9.  The Schedule of Procedures/Assessments (Table 10) shows the 
visits and time points at which blood for clinical laboratory tests and urine for urinalysis will 
be collected in the study.  Clinical laboratory tests will be performed by the local laboratory.  
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If there is ≥ Grade 3 clinically significant hematologic or clinical chemistry toxicity, repeat 
laboratory test and AEs assessment at least every 7 days (until improvement to < Grade 3).  
Table 9
Clinical Laboratory Tests
Category
Parameters
Hematology
Hematocrit, hemoglobin, platelets, RBC count, and WBC count 
with differential
INRb
Clinical Chemistry
Electrolytes
Calcium, chloride, magnesium, phosphorus, potassium, sodium 
Liver function tests
Alanine aminotransferase, alkaline phosphatase, aspartate 
aminotransferase, direct bilirubin, total bilirubin
Renal function tests
Blood urea nitrogen, creatinine
Thyroid function testsa
TSH and free T4 levels 
Other
Albumin, cholesterol, glucose, lactate dehydrogenase, total protein, 
triglycerides, amylase, lipase
Urinalysisc
Glucose, ketones, pH, protein, blood (or hemoglobin), specific 
gravity
RBC = red blood cell, WBC = white blood cell, INR = International Normalized Ratio, T4 = thyroxine, TSH = 
thyroid stimulating hormone.
a:
Thyroid function will be assessed every 2 cycles.
b:
Only at Screening/Baseline and when clinically indicated.
c:
If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and 
sensitivity test should be performed at the institution’s laboratory.  
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis 
samples are to be obtained prior to pembrolizumabadministration and results reviewed prior 
to administration/dispensing of study drug at the beginning of each treatment cycle.  
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the 
AE corresponding to the laboratory abnormality will be recorded on the Adverse Event CRF.  
If AEs were assessed during unscheduled visits, all the data corresponding to the laboratory 
abnormality will be recorded on the CRF.  
9.5.1.5.4
VITAL SIGNS AND WEIGHT MEASUREMENTS
Vital sign measurements (ie, systolic and diastolic BP [mmHg], pulse [beats per minute], 
respiratory rate [per minute], body temperature [in centigrade]), and weight (kg) will be 
obtained at the visits designated in the Schedule of Procedures/Assessments (Table 10) by a 
validated method.  BP and pulse will be measured after the subject has been resting for 5 
minutes.  All BP measurements should be performed on the same arm, preferably by the 
same person.  For subjects with an elevated BP (systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg), confirmation should be obtained by performing 2 measurements a minimum of 
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1-hour apart.  One BP assessment is defined as the mean value of 3 measurements at least 
5 minutes apart.  
Height will be measured at the Screening Visit only. 
9.5.1.5.5
PHYSICAL EXAMINATIONS
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 10).  Documentation of the physical examination will be 
included in the source documentation at the site.  Only changes from screening physical 
examination findings that meet the definition of an AE will be recorded on the Adverse 
Events CRF.
9.5.1.5.6
ELECTROCARDIOGRAMS
ECGs will be obtained as designated in the Schedule of Procedures/Assessments (Table 10).  
Complete, standardized, 12-lead ECG recordings that permit all 12 leads to be displayed on a 
single page with an accompanying lead II rhythm strip below the customary 3×4 lead format 
are to be used.  In addition to a rhythm strip, a minimum of 3 full complexes should be 
recorded from each lead simultaneously.  Subjects must be in the recumbent position or 
sitting for a period of 5 minutes prior to the ECG.
An ECG abnormality may meet the criteria of an AE as described in this protocol (see
Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the AE 
corresponding to the ECG abnormality will be recorded on the Adverse Events CRF.
9.5.1.5.7
ECHOCARDIOGRAM OR MULTIPLE GATED ACQUISITION SCAN 
A MUGA scan (using technetium-99m-pertechnetate) or an echocardiogram to assess LVEF 
will be performed as designated in the Schedule of Procedures/Assessments (Table 10).  
MUGA or echocardiogram scans should be performed locally in accordance with the 
institution’s standard practice.  MUGA scans are the preferred modality; however, whichever 
modality is used for an individual subject at baseline should be repeated for all subsequent 
LVEF assessments for that subject.  LVEFs as assessed by the institution will be entered onto 
the CRF.  
All scans performed during the study should be archived in accordance with the standard 
local practice.  They must be accessible in the event of a sponsor request to submit them for 
central review.
9.5.2
Schedule of Procedures/Assessments
9.5.2.1
Schedule of Procedures/Assessments
Table 10 present the schedule of procedures and assessments for the study.
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Table 10
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga
Baselinea
Cycle 1b
Treatment
(Cycle 2b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6, 8, 10, 12, etc.
7, 9, 11, 13, etc.
Off-Treatment Visitv
Day
–28 to –3
–3 to –1
1
8
15
1
15
Within 30 days after last 
dose
Assessments
S
Informed consent
X
S
Inclusion/exclusion
X
X
S
Demographic data
X
S
ECOG-PS/NYHAc
X
X
X
X
S
TNM staging at diagnosis
X
NS
Medical/surgical history
X
S
Prior medications
X
S
Vital signsd
X
X
X
X
X
X
Xw
X
NS
Physical examinatione
X
Xf
X
X
X
X
X
NS
12-lead ECGg
X
X
X
X
S
MUGA or echocardiogramx
X
X
S
Clinical chemistry & hematologyh, y
X
X
X
X
X
X
S
Thyroid function testsh y
X
X
Xh
X
S
Urinalysis (Dipstick)i y
X
X
X
X
X
Xw
X
S
Pregnancy testj y
X
X
S
Lenvatinib treatment
Throughout
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Table 10
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga
Baselinea
Cycle 1b
Treatment
(Cycle 2b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6, 8, 10, 12, etc.
7, 9, 11, 13, etc.
Off-Treatment Visitv
Day
–28 to –3
–3 to –1
1
8
15
1
15
Within 30 days after last 
dose
Assessments
NS
Pembrolizumab treatmentz
X
X
NS
Lenvatinib PK blood samplesk
X
X
NS
Pembrolizumab PK blood samplesl
X
X
X
NS
Anti-pembrolizumab antibodies 
(ADA) blood samplesm
X
X
X
S
Tumor assessments: CT (MRI)n
X
Counting from C1D1, for the first 24 weeks, every 6 weeks 
(±1 week), or sooner, if clinically indicated, until 
documentation of confirmed disease progression.  After 24 
weeks, tumor assessments must be performed every 9 weeks 
counting from C9D1 (±1 week), or sooner if clinically 
indicated, until documentation of confirmed disease 
progression.  Responses and PD must be confirmed at least 4 
weeks later (usually at the next tumor assessment time 
point).  
X
(unless done within 
previous 4 weeks or subject 
discontinued for PD and 
clinically stable)
NS
CT or MRI of the braino
X
For subjects with previously treated eligible brain 
metastases, brain scan must be performed at Screening and 
all tumor assessment time points.  For all subjects (except 
for subjects with HNSCC), follow-up brain scans should be 
performed to confirm irCR, or if clinically indicated.
X
(unless done within 4 
weeks and as needed)
NS
Bone scanp
X
Bone scans will be performed at Screening (except for subjects with HNSCC), every 
24 weeks(as needed), or sooner if clinically indicated, and at confirmation of irCR.  
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Table 10
Schedule of Procedures/Assessments in the Pretreatment, Treatment, and Extension Phases
CRF
Phase
Pretreatment
Treatment
Extension
Period
Screeninga
Baselinea
Cycle 1b
Treatment
(Cycle 2b & Beyond)
Follow-up Period
Visit
1
2
3
4
5
6, 8, 10, 12, etc.
7, 9, 11, 13, etc.
Off-Treatment Visitv
Day
–28 to –3
–3 to –1
1
8
15
1
15
Within 30 days after last 
dose
Assessments
S
Archival tumor block or slidesq, t
Xq
S
Fresh Tumor Biopsies (additional 
consent required)r
Xr
Xr
S
Blood sample (serum) for 
biomarkerss
X
X
X
X
S
Biomarker (plasma) samples
X
X
X
X
S
Biomarker (whole blood) samples
X
X
X
X
S
Concomitant 
medications/therapiesu
Throughout
S
AEs/SAEsu
Throughout
ADA = anti-drug antibody, AE = adverse event, BP = blood pressure, C#D# = Cycle #/Day #, CRF = case report form, CT = computed tomography, ECG = 
electrocardiogram, ECOG-PS = Eastern Cooperative Oncology Group-Performance Status, HNSCC = squamous cell carcinoma of head and neck, irCR = immune-
related complete response, LVEF = left ventricular ejection fraction, MUGA = multigated acquisition, MRI = magnetic resonance imaging, NYHA = New York 
Heart Association, PD = progressive disease, PK = pharmacokinetics, RR = respiratory rate, SAE = serious adverse event, TNM = tumor-node-metastasis.
a:
The Screening Period extends from Day –28 to Day –3.  Subjects must be screened within 28 days prior to C1D1.  The screening assessment can serve as the baseline 
assessment, if performed within 72 hours before C1D1.  The baseline assessment can be performed from Day –3 to C1D1 (prior to the first dose of study drug).  Informed 
consent may be obtained 4 weeks prior to the start of study drug.  The results of all screening assessments and evaluations must be completed and reviewed by the investigator 
prior to the Baseline Visit.
b:
Efforts should be made to conduct study visits on the day scheduled (±3 days).  Clinical laboratory assessments may be conducted anytime within 72 hours prior to the 
scheduled visit, unless otherwise specified.
c:
ECOG-PS will be evaluated at the Screening and Baseline Visits, on C2D1, and on Day 1 at every subsequent cycle thereafter.  NYHA will only be assessed at the Screening 
Visit.  ECOG and NYHA assessment guidelines are provided in the Appendix of the protocol.
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d:
Assessments will include vital signs (resting BP, pulse, RR, and body temperature), weight, and height.  Height will be measured at the Screening Visit only.  Elevated BP 
(systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg) should be confirmed by 2 assessments 1 hour apart.  One BP assessment is defined as the mean value of 3 
measurements at least 5 minutes apart.  
e:
A physical examination will be performed at the Screening or Baseline Visit, on C1D1, C1D8, and C1D15, on Day 1 of each subsequent cycle, at the Off-Treatment Visit
assessment, and at any time during the study as clinically indicated.  
f:
Required if screening physical examination was performed >7 days prior to C1D1.
g:
Single, 12-lead ECG.  Subjects must be in the recumbent position for a period of 5 minutes prior to the ECG.  During the Treatment Period of the Extension Phase, ECGs will 
be collected on Day 1 of every cycle.
h:
Clinical laboratory tests will be performed by the local laboratory.  Clinical chemistry and hematology results must be reviewed prior to administration of study drug on 
C1D1.  If there is ≥ Grade 3 clinically significant hematologic or clinical chemistry toxicity, repeat laboratory test and AEs assessment at least every 7 days (until 
improvement to < Grade 3).  Thyroid function will be assessed every 2 cycles (C3D1, C5D1, etc.).
i:
Urinalysis will be performed at Screening, Baseline, C1D8, C1D15, and each study visit of every cycle thereafter.  Urinalysis will include glucose, blood (or hemoglobin), 
ketones, pH, protein, specific gravity.  If urinalysis suggests a urinary tract infection, or if clinically indicated, a urine microscopy, culture, and sensitivity test should be 
performed at the institution’s laboratory.  If urine protein is ≥2+ on urinalysis, then see Footnote W.
j:
A serum and/or urine pregnancy test will be performed at the Screening Visit and the Baseline Visit in women of childbearing potential (ie, premenopausal women and 
postmenopausal women who have been amenorrheic for less than 12 months).
k:
Study Treatment PK blood samples drawn predose, 1 (±0.25), 2 (±0.25), 4 (±0.25), 8 (±1), and 24 (–1) hours after the administration on C1D1 and C1D15.
l:
Pre-dose (trough) PK samples will be collected within 24 hours before infusion in Cycles 1, 2, 4, 6 and 8, and every 4 cycles thereafter; and within 30 days after 
discontinuation of study drug (or until the subject starts new anti-cancer therapy).  
m:
Anti-pembrolizumab antibody (ADA) samples will be collected within 24 hours before infusion in Cycles 1, 2, 4, 6 and 8, and every 4 cycles thereafter; and within 30 days 
after discontinuation of study drug (or until the subject starts new anti-cancer therapy).
n:
Screening tumor assessments using CT of the chest, abdomen, and pelvis and other areas of known disease or newly suspected disease should be performed within 28 days 
prior to C1D1.  Subjects with HNSCC must also have scans performed of the head and neck.  Scans of the abdomen, pelvis, and other areas of the body may be done with 
MRI instead of CT, but evaluation of the chest should be done with CT.  CT scans should be performed with iodinated IV contrast and MRI scans with IV gadolinium chelate 
unless there is a medical contraindication to contrast.  If iodinated IV contrast is contraindicated, chest CT should be done without IV contrast.  Tumor assessments of the 
(head, neck), chest, abdomen, and pelvis, and other areas where scans were performed at Screening or for newly suspected disease should be performed as indicated in the 
Schedule of Procedures/Assessments above (or sooner if there is evidence of progressive disease) and should use the same methodology (CT or MRI) and scan acquisition 
techniques (including use or nonuse of IV contrast) as were used for the screening assessments.  Objective responses must be confirmed at least 4 weeks later (eg, generally at 
the next tumor assessment time point).  Suspected PD must also be confirmed at least 4 weeks after the imaging that initially indicated progression.  During the Follow-up 
Period, subjects who have discontinued study treatment without progression (excluding the subject with CR at off-treatment visit) should have disease assessments until 
disease progression is documented or another anticancer therapy is initiated.  
o:
Screening brain scans will be performed by MRI pre- and post- gadolinium or CT with contrast within 4 weeks prior to C1D1.  During the Treatment Phase and the Extension 
Phase, CT/MRI of the brain will be performed if clinically indicated, and after a subject achieves an irCR for confirmation.  For subjects with a history of treated brain 
metastases, brain scans will be performed at every tumor assessment time point.  The same methodology and scan acquisition techniques used at Screening should be used 
throughout the study to ensure comparability.
p:
A bone scan (99m-technetium-based scintigraphy, whole body bone MRI, or 18F-NaF-PET) to assess bone metastases will be performed within 6 weeks prior to C1D1 
(historical scans are acceptable) and then every 24 weeks (within that 24th week) from C1D1 for all tumor types except for HNSCC (as needed), or sooner if clinically 
indicated.  In subjects whose body CT/MRI scans indicate irCR has been achieved, except for subjects with HNSCC, a bone scan will be required at confirmation of irCR to 
exclude new bone metastases.  The same methodology and acquisition techniques used at Screening should be used throughout the study to ensure comparability.  Lesions 
detected on bone scans must be followed with cross-sectional imaging.  
q:
An archival tumor tissue sample must be available prior to first dose.  An archival tumor sample from the most recent surgery or biopsy will be collected. If archival tumor 
tissue sample is not available, please see footnote t.
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r:
Optional fresh paired tumor biopsies will be collected at the Screening Period and at a time point 3-6 weeks after the first dose (if they have recovered adequately from the 
biopsy taken prior to starting therapy and investigators judge that it is medically acceptable to have a biopsy) from consented subjects to examine markers including markers 
of target engagement, relevant pharmacodynamic biomarkers, and potential markers of response.  
s:
Collection of blood sample from consented subjects to be used for biomarker studies.  Samples will be obtained predose at these timepoints: C1D1, C1D15, Day 1 of all 
subsequent cycles up to and including Cycle 18, and at the off-treatment assessment.
t:
If an archival tumor sample for biomarker analysis is not available from subjects, then a newly obtained tumor biopsy must be obtained prior to the first dose.  If a newly 
obtained biopsy is required, it is preferred that the biopsy is obtained from a non-target lesion.  Subjects must have recovered adequately from the biopsy prior to starting 
therapy.  Subjects with inaccessible tumors for biopsy specimens can be enrolled without a biopsy upon consultation and agreement by the sponsor.
u:
Concomitant medications/therapies are recorded for 30 days after last dose or until the subject initiates new anticancer therapy, whichever is earlier.  Collection of AE/SAE 
will be referred to the statement in Safety Assessments.
v:
The off-treatment assessment should occur within 30 days after the final dose of study treatment.  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.  
w:
Vital signs and Urinalysis of C2D15 will be conducted.  Assessments/procedures on Day 15 of Cycle 3 or later can be skipped only if subject’s safety is assured by the 
investigators.
Subjects with systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg must have their BP monitored on Day 15 or more frequently as clinically indicated until systolic BP has 
been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.  If a new event of systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg occurs, the 
subject must resume the Day 15 evaluation until systolic BP has been ≤150 mmHg and diastolic BP has been ≤95 mmHg for 3 consecutive months.  
Urine dipstick testing for subjects with proteinuria ≥2+ should be performed on Day 15 or more frequently as clinically indicated until the results have been 1+ or negative 
for 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.  
Subjects will visit on the Day 15 if BP monitoring or urine dipstick testing is required as specified above.
x:
During the Treatment and Extension Phases, MUGA scans or echocardiograms will be performed to assess LVEF every 24 weeks.
y:
All hematology, blood chemistry (including pregnancy test, as applicable), and urinalysis samples are to be obtained prior to study drug administration and results reviewed 
prior to administration/dispensing of study drug at the beginning of each treatment cycle.  
z:
Pembrolizumab will be administered until 2 years after C1D1 at the longest.  Study treatment with pembrolizumab may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle (except for Cycle 2) due to administrative reasons.  Study treatment with pembrolizumab of Cycle 3 should be skipped if pembrolizumab is 
administered on Day 4 or later in Cycle 2 due to treatment-related toxicity or any other reason.  
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9.5.2.2
Description of Procedures/Assessments Schedule
Refer to Table 10 for the description and timing of each procedure and assessment in the 
Pretreatment and Treatment Phase and the Extension Phase, respectively.
9.5.3
Appropriateness of Measurements
All clinical assessments are standard measurements commonly used in studies involving 
subjects with solid tumors.
The safety assessments to be performed in this study, including hematology analyses, blood 
chemistry tests, urinalysis, vital signs, ECGs, echocardiograms or MUGA scans, 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 SERIOUS ADVERSE EVENTS, regardless of their relationship to study treatment, 
must be reported on a completed SAE form by email or fax as soon as possible but no 
later than 1 business day from the date the investigator becomes aware of the event.
All serious adverse events occurring until 30 days after the subject’s last dose, regardless of 
causality assessment, must be collected.  From 30 days after the last dose, SAEs will be 
collected through 90 days after the subject’s last dose, or until the subject initiates new 
anticancer therapy, whichever is earlier.  All SAEs must be followed to resolution or, if 
resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be related to 
the study treatment or any protocol-required procedure should be reported to the sponsor 
regardless of the length of time that has passed since study completion.
The detailed contact information for reporting of SAEs is provided in the Attachment 1.
For urgent safety issues, please ensure all appropriate medical care is administered to 
the subject and contact the appropriate study team member listed in the Attachment 1.
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality.
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form.
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor.
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9.5.4.2
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding
Any pregnancy in which the estimated date of conception and exposure to study drug through 
breastfeeding must be reported until 30 days after the subject’s last dose. From 30 days after 
the last dose, any pregnancy in which the estimated date of conception is either before the 
last visit or within 120 days of the last study treatment, or until the subject initiates new 
anticancer therapy, whichever is earlier, must be reported.  Also, from 30 days after the last 
dose, any exposure to study drug through breastfeeding during study treatment or within 120 
days of the last study treatment, or until the subject initiates a new anticancer therapy, 
whichever is earlier, must be reported.   
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment.
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Reporting of Serious Adverse Events 
[Section 9.5.4.1]).
Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in the Attachment 1.  The 
Pregnancy Report Form must be used for reporting.  All pregnancies must be followed to 
outcome.  The outcome of the pregnancy must be reported as soon as possible but no later 
than 1 business day from the date the investigator becomes aware of the outcome.
A subject who becomes pregnant must be withdrawn from the study.
9.5.4.3
Reporting of Events Associated with Special Situations
9.5.4.3.1
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE,
MISUSE, ABUSE, OR MEDICATION ERROR
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:
Overdose
Accidental or intentional use of the study drug in an amount higher than 
the protocol-defined dose
Misuse
Intentional and inappropriate use of study drug not in accordance with the
protocol
Abuse
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects
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Medication error Any unintentional event that causes or leads to inappropriate study drug 
use or subject harm while the study drug is in the control of site personnel
or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF.
Note:  Overdose for pembrolizumab is defined as a dose greater than 5 times the 200 mg 
dose.
9.5.4.4
Expedited Reporting
The sponsor must inform investigators, the head of the medical institution, and regulatory 
authorities of reportable events, in compliance with applicable regulatory requirements, on an 
expedited basis (ie, within specific time frames).  For this reason, it is imperative that sites 
provide complete SAE information in the manner described above.
9.5.4.5
Breaking the Blind
Not applicable.
9.5.4.6
Regulatory Reporting of Adverse Events
Adverse events will be reported by the sponsor to regulatory authorities in compliance with 
regulatory requirements and established guidance.  The format of these reports will be 
dictated by the regulatory requirements.
9.5.5
Completion/Discontinuation of Subjects
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 10).
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.  
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons.  
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Subjects who discontinue study treatment prior to completing the Treatment Phase for any 
reason other than a DLT will be replaced.  
9.5.6
Abuse or Diversion of Study Drug
Not applicable.
9.5.7
Confirmation of Medical Care by Another Physician
The investigator will instruct subjects to inform site personnel when they are planning to 
receive medical care by another physician.  At each visit, the investigator will ask the subject 
whether he/she has received medical care by another physician since the last visit or is 
planning to do so in the future.  When the subject is going to receive medical care by another 
physician, the investigator, with the consent of the subject, will inform the other physician 
that the subject is participating in the clinical study.
9.6
Data Quality Assurance
This study will be organized, performed, and reported in compliance with the protocol, 
standard operating procedures (SOPs), working practice documents, and applicable 
regulations and guidelines.  Site audits will be made periodically by the sponsor’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 
Japan’s CGP, 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
All statistical analyses will be performed by the sponsor or designee after the database is 
locked.  Statistical analyses will be performed using SAS software or other validated 
statistical software as required.  Details of the statistical analyses will be included in a 
separate statistical analysis plan (SAP).
9.7.1
Statistical and Analytical Plans
The statistical analyses of the study data are described in this section.  Further details of the 
analytical plan will be provided in the SAP, which will be finalized before database lock.
9.7.1.1
Study Endpoints
9.7.1.1.1
PRIMARY ENDPOINT
The primary objective is to confirm the tolerability and safety for combination of lenvatinib 
plus pembrolizumab in subjects with selected solid tumors. Thus, the primary endpoints will 
be safety related endpoints including DLT. 
9.7.1.1.2
SECONDARY ENDPOINTS
The secondary endpoints related to the efficacy endpoints will be ORR, ORR(Week 24), and 
DOR by irRECIST and modified RECIST 1.1.  These efficacy endpoints are defined as 
follows.  

ORR is defined as the proportion of subjects who have BOR of (ir)CR or (ir)PR at the 
time of data cutoff.  

ORR(Week 24) is defined as the proportion of subjects who have BOR of (ir)CR(Week 24) or 
(ir)PR(Week 24) as of the Week 24 tumor assessment time point.  

DOR is defined as the time from the first documentation of (ir)CR or (ir)PR to the date of 
first documentation of disease progression (based on irRECIST and modified RECIST 
1.1) or death (whichever occurs first).
Determination of the PK profile of lenvatinib and pembrolizumab while subjects are 
receiving combination therapy also is a secondary endpoint.  
Serum ADA will be also measured.
9.7.1.1.3
EXPLORATORY ENDPOINT
The exploratory endpoints related to the efficacy endpoints will be PFS, TTR, DCR, and 
CBR by irRECIST and modified RECIST 1.1.  These efficacy endpoints are defined as 
follows.

PFS is defined as the time from the first study dose date to the date of first 
documentation of disease progression (based on irRECIST and modified RECIST 1.1) or 
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death (whichever occurs first).  If a subject has not experienced disease progression or 
death, then the subject’s data will be censored at the date of the last available tumor 
assessment.  

TTR is defined as the time from the date of first study dose to the date of first 
documentation of (ir)CR or (ir)PR.

DCR is defined as the proportion of subjects who have BOR of (ir)CR or (ir)PR or 
(ir)SD (minimum duration from C1D1 to (ir)SD ≥5 weeks).

CBR is defined as the proportion of subjects who have BOR of (ir)CR or (ir)PR or 
durable (ir)SD (duration of (ir)SD ≥23 weeks).
The exploratory objective is to investigate the relationship between candidate biomarkers and 
anti-tumor activity of lenvatinib in combination with pembrolizumab.  Exploratory endpoints 
will be blood and tumor markers (such as PD-L1 expression levels, cytokine and angiogenic 
factor profiling), and immune cell profiling.
9.7.1.2
Definitions of Analysis Sets
DLT Analysis Set will include all subjects who have completed Cycle 1 without major 
protocol deviation with at least 75% of study drug compliance and are assessed for DLT, and 
subjects who have experienced DLT during Cycle 1.  This will be the analysis set to confirm
tolerability.
Safety Analysis Set/Efficacy Analysis Set will include all subjects who received at least 1 
dose of study drug. 
PK Analysis Set will include all subjects who have received at least 1 dose of lenvatinib and
pembrolizumab, and have evaluable concentration data.
9.7.1.3
Subject Disposition
The number (percentage) of treated subjects will be summarized as well as subjects who 
discontinued from the study treatment and reasons for discontinuation from study treatment
by dose level cohort and overall.
9.7.1.4
Demographic and Other Baseline Characteristics
Demographic and other baseline characteristics for the Efficacy Analysis Set will be 
summarized for each dose level cohort and overall using descriptive statistics.  Continuous 
demographic and baseline variables include age; categorical variables include sex, age group, 
race, region, ECOG-PS, NYHA cardiac disease classification, and TNM staging.  
9.7.1.5
Prior and Concomitant Therapy
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes.  Prior 
medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose 
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of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose.  All 
medications will be presented in subject data listings.
9.7.1.6
Efficacy Analyses
Efficacy analyses will be based on the Efficacy Analysis Set.  Efficacy data will be presented 
for each dose level cohort and/or overall as appropriate.  BOR will be summarized, and ORR,
ORR(Week 24), and their corresponding exact 2-sided 95% confidence interval (CI) will be 
calculated.  DOR will also be summarized and plotted over time by Kaplan-Meier method. 
Likewise, PFS and TTR will be analyzed as needed. If applicable, DCR, CBR, and their 
corresponding exact 2-sided 95% CI will also be calculated. 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 (ie, maximum tumor).  
9.7.1.7
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker
Analyses
9.7.1.7.1
PHARMACOKINETIC ANALYSES
The primary PK parameters of lenvatinib under combination will be calculated using 
noncompartmental analysis and compared with historical data after single dose using the PK 
analysis set.  If warranted, additional analyses may be performed.  PK data for lenvatinib and 
pembrolizumab is planned to be analyzed using nonlinear mixed effects modeling.  Based on 
PK data obtained in this study and from other studies, a population PK analysis may be 
performed to characterize PK parameters to support the proposed dosing regimen.  PK data
for lenvatinib and pembrolizumab may also be used to explore the exposure-response 
relationships for antitumor activity/efficacy as well as biomarkers and safety in the proposed 
patient population, if feasible.  The results of these analyses, if performed, will be reported 
separately.  For serum ADA levels, a listing of results will be made.  
9.7.1.7.2
PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES
The effect of lenvatinib-pembrolizumab combination therapy on soluble, tissue, genetic 
and/or imaging biomarkers will be summarized using descriptive statistics. 
PK/pharmacodynamic relationships will be explored graphically and may be investigated by 
model-based analyses.  Details of the analyses may be described in a separate analysis plan.  
The results of these analyses, if performed, will be reported separately.  
9.7.1.8
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.
Safety analyses will be performed on the Safety Analysis Set.  Safety data will be presented 
for each dose level cohort and/or overall as appropriate.  
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9.7.1.8.1
EXTENT OF EXPOSURE
The number of cycles/days on treatment, quantity of study drug administered, and the 
number of subjects requiring dose reductions, treatment interruption, and treatment 
discontinuation will be summarized.
9.7.1.8.2
ADVERSE EVENTS
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(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 the 
time from the first dose of study drug to 30 days following the last dose of study drug, having 
been absent at pretreatment (Baseline) or 

Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 

Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous.
Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings.
The TEAEs will be summarized.  The incidence of TEAEs will be reported as the number 
(percentage) of subjects with TEAEs by SOC and PT.  A subject will be counted only once 
within an SOC and PT, even if the subject experienced more than 1 TEAE within a specific 
SOC and PT.  The number (percentage) of subjects with TEAEs will also be summarized by 
highest CTCAE grade.
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT. Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade.
The number (percentage) of subjects with TEAEs leading to death will be summarized by 
MedDRA SOC and PT.  A subject data listing of all AEs leading to death will be provided.
The number (percentage) of subjects with treatment-emergent serious adverse events (SAEs) 
will be summarized by MedDRA SOC and PT.  A subject data listing of all SAEs will be 
provided.
The number (percentage) of subjects with TEAEs leading to discontinuation from study drug 
will be summarized by MedDRA SOC and PT.  A subject data listing of all AEs leading to 
discontinuation from study drug will be provided.
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9.7.1.8.3
LABORATORY VALUES
Laboratory results will be summarized using Système International (SI) units, as appropriate.  
For all quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change 
from baseline to each postbaseline visit and to the end of treatment will be summarized by 
visit using descriptive statistics.  Qualitative parameters listed in Section 9.5.1.5.3 will be 
summarized using frequencies (number and percentage of subjects), and changes from 
baseline to each postbaseline visit and to the end of treatment will be reported using shift 
tables.  Percentages will be based on the number of subjects with both nonmissing baseline 
and relevant postbaseline results.
Laboratory parameters will be categorized according to CTCAE v4.03 grades, and shifts 
from baseline CTCAE grades to maximum and final postbaseline grades will be assessed.  
CTCAE v4.03 will be used to identify subjects with treatment-emergent markedly abnormal 
laboratory values (TEMAV).  A more detailed definition of TEMAV will be specified in the 
SAP.  A summary of TEMAVs will be presented overall study period.
9.7.1.8.4
VITAL SIGNS
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, resting pulse, 
respiratory rate, temperature, and weight) and changes from baseline will be presented by 
visit.
9.7.1.8.5
ELECTROCARDIOGRAMS
Change from baseline to each postbaseline visit and to the end of treatment in ECG findings 
(categorized as normal; abnormal, not clinically significant; and abnormal, clinically 
significant) will be summarized by visit using shift tables.  Descriptive statistics for ECG 
parameters and changes from baseline will be presented.
9.7.1.8.6
OTHER SAFETY ANALYSES
Descriptive statistics for LVEF assessed on echocardiogram or MUGA scans and changes 
from baseline will be presented.
9.7.2
Determination of Sample Size
A sample size of 6 to 10 subjects in this study.  This is not based on statistical power 
considerations.  
9.7.3
Interim Analysis
9.7.4
No interim analysis is planned for this study. Other Statistical/Analytical 
Issues
Not applicable.
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9.7.5
Procedure for Revising the Statistical Analysis Plan
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report.
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Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity.  
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Hamid O, Carvajal RD. Anti-programmed death-1 and anti-programmed death-ligand 1 
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Hattori K, Heissig B, Wu Y, Dias S, Tejada R, Ferris B, et al., Placental growth factor 
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microenvironment. Nat Med. 2002;8:841-9.
Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-
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Kato Y, Matsui J. Effects of Lenvatinib on Tumor-Associated Macrophages Enhance 
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pharmacokinetics of lenvatinib in healthy adults. Clin Drug Investig. 2014;34:651-9. 
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Stagg J, Allard B. Immunotherapeutic approaches in triple-negative breast cancer: latest 
research and clinical prospects. Ther Adv Med Oncol. 2013;5(3):169-81.
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as molecular targets in thyroid carcinoma. Endocrinology. 2005;146:1145-53.
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and immune correlates of anti–PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.
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KEYTRUDA Package Insert 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125514lbl.pdf
LENVIMA Package Insert 
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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 additional approval by the applicable IRB.  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 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 the IRB.  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 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 Japan’s 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 Japan’s GCP.  All 
records at the site are subject to inspection by the local auditing agency and to IRB review.
In accordance with Japan’s GCP, source documents include, but are not limited to, the 
following:

Clinic, office, or hospital charts

Copies or transcribed health care provider notes that have been certified for accuracy 
after production

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
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
Pain, quality of life, or medical history questionnaires completed by subjects

Records of telephone contacts

Diaries or evaluation checklists

Drug distribution and accountability logs maintained in pharmacies or by research 
personnel

Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks)

Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs

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 consented subject by qualified and 
authorized personnel.  All data on the CRF must reflect the corresponding source document, 
except when a section of the CRF itself is used as the source document.  Any correction to 
entries made on the CRF must be documented in a valid audit trail where the correction is
dated, the individual making the correct is identified, the reason for the change is stated, and 
the original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected.
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs.
11.5
Identification of Source Data
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items that are not included in any medical records (eg, hospital records, 
worksheets), the data recorded directly on the CRF are to be considered source data:  

Demographic data (race, ethnicity)

NYHA cardiac function classification:  date of evaluation, NYHA class

Prior therapy:  name, starting and ending date of the medication, starting dose, and 
reason for discontinuation 

ECG results:  normal/abnormal

Results of follow-up evaluation in subject who discontinued – in all categories

Tumor diagnosis:  TNM classification

Tumor assessment: presence or absence of target and non-target lesion

Target lesion: location, size in diameter, evaluation date and time

Non-target lesion: location, result of evaluation, evaluation date and time

New lesion: presence or absence, location, and date of confirmation, if present

Dose and dosing date of lenvatinib and pembrolizumab
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
Drug concentration measurement: dates and time of dosing, blood sampling, and food 
consumptions

Discontinuation:  reason for discontinuation

Information concerning AEs: CTCAE Grade (for items not specified in CTCAE), 
outcome, causal relationship to lenvatinib and/or pembrolizumab, severity of the AE, 
relation to overdose

Concomitant drug: reason for administration

Concomitant therapy: type of therapy, reason for use

Other relevant information
For the items excluding the following items (1 to 6), hospital records will be the source data 
in principle; however, other appropriate records, if any, may be used as source data.
1. Source data for informed consent
Informed consent form
2. Source data for tests and examinations
Test results sheet (and/or electronic data)
3. Source data for pathological assessment
Test results sheet, medical records provided by other hospital (and/or electronic data)
4. Source data for tumor assessment
Imaging record (and/or electronic form).  CRF is to be considered source data for 
assessment if it includes measured values
5. Source data for ECG recordings
Recorded ECG charts (and/or electronic data)
6. Shipping record of samples to outside laboratories
Shipping slip
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 correspondence).  The site should plan to retain study documents until the 
approval of a marketing application, until at least 3 years have elapsed since the formal 
discontinuation of clinical development of the investigational product as directed by the 
sponsor, or until at least 3 years have elapsed since the discontinuation or completion of this
clinical study, whichever comes later.  
Pembrolizumab is expected to be designated as a biologic product.  The site will retain and 
control the sources to identify the name and address of subject, the dosing date, and lot 
number of study drug for 10 years from the date of last dose (or shipment) for the purpose of 
traceability.  
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It is requested that at the completion of the required retention period the site contact the 
sponsor, allowing the sponsor the option of permanently retaining the study records.
11.7
Auditing Procedures and Inspection
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of Japan’s GCP and all applicable local 
regulations.  A government regulatory authority may request an inspection during the study 
or after its completion.
11.8
Handling of Study Drug
All study drugs will be supplied to the pharmacist or its designee 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 pharmacist or its designee must maintain 
an accurate record of the shipment and dispensing of the study drug in a drug accountability 
ledger.  An accurate record of the date and amount of study drug dispensed to each subject 
must be available for inspection at any time.  The CRA will visit the site and review these 
documents along with all other study conduct documents at appropriate intervals once study 
drug has been received by the site.
All drug supplies are to be used only for this study and not for any other purpose.  The 
pharmacist or its designee 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 pharmacist or its designee will return all used and unused 
drug containers, drug labels, and a copy of the completed drug disposition form (upon 
request) to the sponsor.
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 and the head of the medical institution.  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 head of the medical institution and the sponsor, 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 and will 
not be disclosed in whole or in part to others, or used for any purpose other than reviewing or 
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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 the Clinical Trial Agreement executed between the 
sponsor and the head of the medical institution.
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in the Clinical Trial Agreement executed between the 
head of the medical institution and the sponsor.
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 will also be 
informed promptly and provided the reason(s) for the termination or suspension by the 
sponsor or by the investigator/institution, as specified by the applicable regulatory 
requirement(s).
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the institution where applicable, and the 
investigator/institution should promptly inform the sponsor and the IRB and provide the 
sponsor and the IRB with a detailed written explanation of the termination or suspension.  
Study records must be retained as noted above.
11.12 Subject Insurance and Indemnity
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations.
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12 APPENDICES
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Appendix 1
Immune-related Response Evaluation Criteria in Solid 
Tumors
Investigators should follow the guidelines provided here which are an adaptation of RECIST 
1.1 and immune-related response criteria (irRC). The following guide represents a summary 
of irRECIST and is meant to help investigators in providing more objective and reproducible 
immune therapy related tumor response assessments in solid tumors.
The key changes for irRECIST are:
IrRECIST allows the site to select up to ten (10) target lesions at baseline, five (5) per 
organ, if clinically relevant via CT/MRI scans or by electronic calipers for skin
lesions. The ability to continue treatment, if clinically stable, until repeat imaging 
scans ≥4 weeks later (in most cases at the next scanning time point 6 weeks later) to 
confirm Progressive Disease (irPD)
irRECIST Lexicon
1.  Baseline Assessments
Measurable 
(Target) lesions
Measurable lesions must be accurately measured in at least one 
dimension with a minimum size of:
10 mm in the longest diameter (LDi) by CT or MRI scan (or no less 
than double the slice thickness) for non-nodal lesions and ≥15 mm in 
short axis (SDi) for nodal lesions
10 mm in LDi for clinical lesions (must be measured using electronic 
calipers)
Identify up to 10 lesions, not more than 5 from one organ system.  
Lymph nodes are considered one organ system
Likely to be reproducible across all time points
Representative of tumor burden
May include lesions in previously irradiated areas ONLY if there is 
demonstrated progression in that lesion after irradiation
Sum of diameters (SOD) of all target lesions including nodal and 
non-nodal are reported as baseline SOD, which is used for assessing 
tumor response at follow-up time points
Bone lesions
Regardless of the imaging modality, blastic bone lesions will not be
selected as target lesions.  Lytic or mixed lytic-blastic lesions with a 
measurable soft tissue component ≥10 mm can be selected as target 
lesions.
Cystic and 
Necrotic 
Lesions as 
Target Lesions
Lesions that are partially cystic or necrotic can be selected as target 
lesions.  The longest diameter of such a lesion will be added to the SOD 
of all target lesions at baseline.  If other lesions with a 
nonliquid/nonnecrotic component are present, those should be preferred.
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Lesions with 
Prior Local 
Treatment
During target lesion selection the radiologist will consider information on 
the anatomical sites of previous intervention (eg, previous irradiation, 
RF-ablation, TACE, surgery).  Lesions undergoing prior intervention will 
not be selected as target lesions unless there has been a demonstration of 
progression in the lesion.
Nonmeasurable 
(Nontarget) 
lesions
Nontarget lesions will include:
Measurable lesions not selected as target lesions.  There is no limit to 
the number of nontarget lesions that can be recorded at baseline
Other types of lesions that are confidently felt to represent neoplastic 
tissue, but are difficult to measure in a reproducible manner.  These 
include bone metastases, leptomeningeal metastases, malignant 
ascites, pleural or pericardial effusions, ascites, inflammatory breast 
disease, lymphangitis cutis/pulmonis, cystic lesions, ill-defined 
abdominal masses, etc.
Multiple non target lesions from the same organ may be captured as 
a single item on the eCRF (eg, multiple liver metastases)
Nontarget lesions should be reported as present at baseline
SODbaseline
Sum of diameters at baseline = LDi of all non-nodal + SDi of all nodal 
target lesions
2.  Time point Assessments After Baseline
Target lesion 
measurements
Locate image that optimizes the LDi of the non-nodal target lesion or 
short axis of target node(s).  There is no need to go to an identical slice 
from baseline.
Measure the respective LDi and SDi for all target lesions and calculate 
time point SOD (SOD timepoint).
Special consideration for target lesions:

If target lesion is too small to measure, a default value of 5 mm 
should be entered on eCRF.

If target lesion is 5-10 mm, actual diameter should be entered in the 
eCRF.  

If target lesion splits into 2 or more lesion then the LDi of split 
lesions will be added and entered in place of that lesion.

If two target lesion merged to form one lesion than LDi of one 
should be entered as “0 mm” while the other lesion should have the 
diameter of the merged lesion.
Nontarget 
Lesion 
Assessment
Nontarget lesions are evaluated qualitatively as present, absent, not 
evaluable (NE) or unequivocal progression.  The response of nontarget
lesions primarily contributes to the overall response assessments of irCR.  
Nontarget lesions do not affect irPR and irSD assessments.  Only a 
massive and unequivocal worsening of nontarget lesions alone, even in 
the presence of stable disease or a partial response in the target lesion is 
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indicative of irPD.  IrCR is not possible unless all nontarget lesions are 
absent.
Definition of 
New Lesion
Any lesion that was not recorded at baseline.  There is no minimum size 
criteria to identify a new lesion and clinical judgment must be used by 
the PI.

May include a lesion in an anatomical location that was not scanned 
at baseline (ie, brain)

Should be unequivocal and not due to differences in scanning 
technique

If equivocal, should be assessed at next time point; if present, irPD 
is the date the lesion was first seen (not the date confirmed)
3.  irRECIST Overall Tumor Assessment
irCR

Complete disappearance of all measurable and nonmeasurable 
lesions (from baseline) and there are no unequivocal new lesions 
(unconfirmed irCR).

Lymph nodes must decrease to <10 mm in short axis.

Confirmation of response is required ≥4 weeks later, preferably at 
next time point, to be considered a confirmed irCR.
irPR

If the SODtimepoint of TLs decreases by ≥30% compared to 
SODbaseline and there are no unequivocal new lesions, and no 
progression of nontarget disease, it is an irPR (unconfirmed).  

Confirmation is required ≥4 weeks later, preferably at next time 
point, to be considered a confirmed irPR.
irSD
Failure to meet criteria for irCR or irPR in the absence of irPD.

If the sum of the TLs and the status of the nontarget lesions do not 
reach the criteria to meet irPR or irPD (increase ≥20% and at least 
5 mm absolute increase in SOD compared to nadir†) the response is 
irSD.

irSD = neither 30% decrease compared to SODbaseline or 20% 
increase and at least 5 mm absolute change compared to nadir.

†SODnadir: Lowest measure SOD of TLs at any time point from 
baseline onward.
irPD
Minimum 20% increase and a minimum 5 mm absolute increase in SOD 
compared to nadir, or irPD for nontarget lesion(s) or unequivocal new 
lesion(s).

Confirmation of progression is recommended at a minimum of 4 
weeks after the first irPD assessment (preferably at next tumor 
assessment time point).
The decision to continue study treatment after the first evidence of PD is 
at the investigator’s discretion based on the clinical status of the subject 
as described in table below
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Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
1st radiologic 
evidence of PD
Repeat 
imaging at >4 
weeks (next 
TA time point) 
to confirm PD
May continue 
study treatment at 
the Investigator’s 
discretion while 
awaiting 
confirmatory scans 
Repeat 
imaging at >4 
weeks to 
confirm PD 
per physician 
discretion only
Discontinue 
treatment
Subsequent scan 
confirms PD
No additional 
imaging 
required
Discontinue 
treatment
No additional 
imaging 
required
N/A
Subsequent scan 
shows SD, PR or 
CR
Continue 
regularly 
scheduled 
imaging 
assessments 
Continue study 
treatment at the 
Investigator’s 
discretion
Continue 
regularly 
scheduled 
imaging 
assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion
Subjects may continue receiving study treatment while waiting for 
confirmation of irPD if they are clinically stable as defined by the 
following criteria:

Absence of signs and symptoms (including worsening of laboratory 
values) indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord 
compression) requiring urgent alternative medical intervention
If irPD is confirmed and the subject is experiencing extraordinary clinical 
benefit, site must contact Sponsor to discuss continuing treatment
irNE
Used in exceptional cases where insufficient data exists due to poor 
quality of scans or missed scans or procedure
Derivation of irRECIST overall responses
Measurable response 
Non-measureable response
Target Lesions
(% change in SOD)a
Nontarget Lesions 
Status
New Lesions 
Status
Overall Response 
(irRECIST)
100
Absent
Absent
irCRb
100
Present/NE
Absent
irPRb
≥30
Present/Absent/NE
Absent
irPRb
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<30 to <20
Present/Absent/NE
Absent
irSD
100
≥30
<30 to <20
NE
Present/Absent/NE
Present
irPDb
100
≥30
<30 to <20
NE
Unequivocal 
progression
Any
irPDb
≥20 from nadir
Any
Any
irPDb
NE
Present/Absent/NE
Absent
irNEb
irCR = immune-related complete response, irNE = immune-related not evaluable, irPD = immune-related progression 
disease, irPR = immune-related partial response, irSD = immune-related stable disease, NE = Not evaluable.
a: Decreases assessed relative to baseline, including measureable lesions only.
b: Assuming response (irCR or irPR) and progression (irPD) are confirmed by a second, consecutive assessment at least 4 
weeks apart.
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Appendix 2
Eastern Cooperative Oncology Group Performance 
Status (ECOG-PS)
Scale
Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature (eg, light house work, office work)
2
Ambulatory and capable of all self-care, but unable to carry out any work 
activities.  Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed 
or chair.
5
Dead
Adapted from Oken MM, et al. Am J Clin Oncol. 1982;5:649-55.
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Appendix 3
Common Terminology Criteria for Adverse Events 
(CTCAE) Version 4.03
The Common Terminology Criteria for Adverse Events (CTCAE v4.03, published 14 June 
2010) provides descriptive terminology to be used for adverse event reporting in clinical 
trials.  A brief definition is provided to clarify the meaning of each AE term.  To increase the 
accuracy of AE reporting, all adverse event terms in CTCAE v4.03 have been correlated with 
single-concept Medical Dictionary for Regulatory Activities (MedDRA) terms.
The Common Terminology Criteria for Adverse Events v4.03 grading refers to the severity 
of the AE.  The Common Terminology Criteria for Adverse Events grades 1 through 5, with 
unique clinical descriptions of severity for each AE, are based on this general guideline:
Grade
CTCAE Status
1
Mild:  asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
2
Moderate:  minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL)a
3
Severe or medically significant but not immediately life-threatening: 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADLb
4
Life-threatening consequences: urgent intervention indicated
5
Death related to adverse event
ADL = activities of daily living, CTCAE = Common Terminology Criteria for Adverse Events.
a:  Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
b:  Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
Adapted from the Cancer Therapy Evaluation Program, NCI.  CTCAE v4.03
For further details regarding MedDRA, refer to the MedDRA website at:  
http://www.meddra.org
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Appendix 4
New York Heart Association (NYHA) Cardiac Disease 
Classification
The New York Heart Association Cardiac Disease Classification provides a functional and 
therapeutic classification for the prescription of physical activity for cardiac subjects.  Based 
on NYHA definitions, subjects are to be classified as follows:
Class
NYHA Status
Class I:
Subjects with no limitation of activities; they suffer no symptoms from 
ordinary activities.
Class II:
Subjects with slight, mild limitation of activity; they are comfortable with rest 
or with mild exertion.
Class III:
Subjects with marked limitation of activity; they are comfortable only at rest.
Class IV:
Subjects who should be at complete rest, confined to bed or chair; any physical 
activity brings on discomfort and symptoms occur at rest.
NYHA = New York Heart Association.
Adapted from The Criteria Committee of the New York Heart Association.  Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels.  9th ed. New York: Little Brown; 1994. p.253-6.
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Appendix 5
Clinical Studies Evaluating Drug–Drug Interactions 
with Lenvatinib
Nonclinical studies identify CYP3A4 as a potentially important Cytochrome P450 isozyme
responsible for metabolism of lenvatinib.  Clinical studies were conducted to test these 
findings.  
Simultaneous CYP3A4/P-glycoprotein (P-gp) inhibition by ketoconazole slightly (15% to 
19%) increases systemic exposure to lenvatinib (Shumaker, et al., 2015).  Since no change 
was observed in half-life, tmax, or lag time (tlag), the slight increase in systemic exposure is 
probably related to a decrease in first pass metabolism.  However, since the magnitude of 
change is small, co-administration of lenvatinib with CYP3A4/P-gp inhibitors is not of 
clinical concern.  
The influence of P-gp inhibition on lenvatinib PK has been investigated.  P-gp inhibition was 
accomplished by co-administering a single dose of rifampin with a single dose of lenvatinib.  
Preliminary results suggest P-gp inhibition increases systemic exposure to lenvatinib 26% to 
32%.  Thus, co-administration of lenvatinib with P-gp inhibitors only causes a small increase 
in lenvatinib exposure.  
The influence of simultaneous P-gp and CYP3A4 induction on lenvatinib PK has been 
investigated.  Examination of simultaneous P-gp and CYP3A4 induction on lenvatinib PK 
was accomplished by administering rifampin QD for 21 days (Shumaker, et al., 2014).  A 
single dose of lenvatinib was co-administered with the 15th dose of rifampin.  Based on 
preliminary data, simultaneous P-gp and CYP3A4 induction minimally altered lenvatinib 
exposure as mean Cmax increased about 8% while AUC decreased about 7%.  Co-
administration of lenvatinib with CYP3A4/P-gp inducers is not of clinical concern.
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Appendix 6
Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Research
Subjects enrolled in this clinical study will have biologic samples collected for 
pharmacodynamic, pharmacogenomic, and other biomarker analysis. These samples may be 
used for discovery and validation to identify biomarkers that may be used for exploratory 
evaluation of response and/or safety-related outcomes as well as for use in diagnostic 
development.
The pharmacogenomicsamples may be used to identify genetic factors that may influence a 
subject’s exposure to the study drug, as well as genetic factors that may have an effect on 
clinical response or potential adverse events related to study treatment, and to explore the 
role of genetic variability in response.  Samples may be analyzed to determine a subject’s 
genotypes or sequence for a number of genes or non-coding regulatory regions.  The research 
may include the investigation of polymorphisms in genes that are likely to influence the 
study drug pharmacokinetics or therapeutic response.
Collection of the pharmacodynamic, pharmacogenomic, and other biomarker samples will be 
bound by the sample principles and processes outlined in the main study protocol.  Sample 
collection for pharmacodynamic, pharmacogenomic and other biomarker analysis is required 
as per the study protocol unless the collection and use of the samples is prohibited by specific 
country laws.
Sample Collection and Handling
The samples will be collected according to the study flow chart.  If, for operational or 
medical reasons, the genomic DNA blood sample cannot be obtained at the prespecified visit, 
the sample can be taken at any study center visit at the discretion of the investigator and site 
staff.
Security of the Samples, Use of the Samples, Retention of the Samples
Sample processing, for example DNA and/or RNA extraction, genotyping, sequencing, or 
other analysis will be performed by a laboratory under the direction of the sponsor.  
Processing, analysis, and storage will be performed at a secure laboratory facility to protect 
the validity of the data and maintain subject privacy.
Samples will only be used for the purposes described in this protocol.  Laboratories 
contracted to perform the analysis on behalf of the sponsor will not retain rights to the 
samples beyond those necessary to perform the specified analysis and will not transfer or sell 
those samples.  The sponsor will not sell the samples to a third party.
Samples will be stored for up to 15 years after the completion of the study (defined as 
submission of the clinical study report to the appropriate regulatory agencies).  At the end of 
the storage period, samples will be destroyed.  Samples may be stored longer if a health 
authority (or medicinal product approval agency) has active questions about the study.  In 
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this special circumstance, the samples will be stored until the questions have been adequately 
addressed.
It is possible that future research and technological advances may identify genomic variants 
of interest, or allow alternative types of genomic analysis not foreseen at this time.  Because 
it is not possible to prospectively define every avenue of future testing, all samples collected 
will be single or double coded (according to the ICH E15 guidelines) in order to maintain 
subject privacy.  
Right to Withdraw
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, Eisai will destroy the samples.  Information from 
any assays that have already been completed at the time of withdrawal of consent will 
continue to be used as necessary to protect the integrity of the research project.
Subject Privacy and Return of Data
No subject-identifying information (eg, initials, date of birth, government identifying 
number) will be associated with the sample.  All pharmacodynamic and other biomarker 
samples will be single coded.  Genomic DNA samples used to explore the effects on PK, 
treatment response, and safety will be single coded.  Genomic DNA samples that will be 
stored for long-term use (defined as 15 years after the completion of the study) will be double 
coded.  Double coding involves removing the initial code (subject ID) and replacing with 
another code such that the subject can be re-identified by use of 2 code keys.  The code keys 
are usually held by different parties.  The key linking the sample ID to the subject number 
will be maintained separately from the sample.  At this point, the samples will be double-
coded, the first code being the subject number.  Laboratory personnel performing genetic 
analysis will not have access to the “key.”  Clinical data collected as part of the clinical trial 
will be cleaned of subject identifying information and linked by use of the sample ID “key.”
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  Data from subjects enrolled in this study may be analyzed 
worldwide, regardless of location of collection.
The sponsor and its representatives and agents may share coded data with persons and 
organizations involved in the conduct or oversight of this research.  These include:

Clinical research organizations retained by the sponsor 

Independent ethics committees or institutional review boards that have responsibility for 
this research study 

National regulatory authorities or equivalent government agencies
At the end of the analysis, results may be presented in a final report which can include part or 
all of the coded data, in listing or summary format.  Other publication (eg, in peer-reviewed 
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scientific journals) or public presentation of the study results will only include summaries of 
the population in the study, and no identified individual results will be disclosed.
Given the research nature of the pharmacodynamic, pharmacogenomic, and other biomarker 
analysis, it will not be possible to return individual data to subjects.  The results that may be 
generated are not currently anticipated to have clinical relevance to the patients or their 
family members.  Therefore, these results will not be disclosed to the patients or their 
physicians.
If at any time, pharmacodynamic, pharmacogenomic, and/or other biomarker results are 
obtained that may have clinical relevance, IRB review and approval will be sought to 
determine the most appropriate manner of disclosure and to determine whether or not 
validation in a Clinical Laboratory Improvement Amendments (CLIA)-certified setting will 
be required.  Sharing of research data with individual patients should only occur when data 
have been validated by multiple studies and testing has been done in CLIA-approved 
laboratories.
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Appendix 7
KEYTRUDA® Package Insert
The latest KEYTRUDA Package Insert is available in the FDA website at:
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
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PROTOCOL SIGNATURE PAGE
Study Protocol Number:
E7080-J081-115
Study Protocol Title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subjects with Selected Solid Tumors
Investigational Product 
Name:
Lenvatinib (E7080/LENVIMA™) and Pembrolizumab (MK-
3475/KEYTRUDA®)
SIGNATURES
Authors:
 
OBG, Eisai Co., Ltd.
Date
.
 
OBG, Eisai Co., Ltd.
Date
 Eisai Co., Ltd.
Date
 Eisai Co., Ltd.
Date
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 1 of 9
Protocol Amendment
   Study Drug:
Lenvatinib (E7080)
   Study Protocol Number:
E7080-J081-115
Study title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subject with Selected Solid Tumors
  Protocol Amendment
   Number and Date:
Amendment 01: 16 Jun 2017
Original Text
Amended Text
Title Page: 
Approval Date
V1.0
14 Sep 2016 (Original Protocol)
V1.0
14 Sep 2016 (Original Protocol)
16 Jun 2017 (Amendment 01)
Reason of Amendment(s):
•
Protocol revision
Original Text
Amended Text
Clinical Protocol synopsis: 
Investigators
To be determined
Investigators
To be determined
Reason of Amendment(s):
•
No need to be included based on the protocol template.
Original Text
Amended Text
Clinical Protocol synopsis/ 9.3.2: 
Exclusion Criteria:
(Not included)
32. Has severe hypersensitivity (≥Grade
3) to pembrolizumab and/or any of its
excipients.
Reason of Amendment(s):
•
Updated based on the latest pembrolizumab protocol standard text provided by Merck.
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E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 2 of 9
Original Text
Amended Text
Clinical Protocol Synopsis: Dose Interval 
Modification Guidelines for Non-Hepatic 
Drug-Related Adverse Events (Table) /
9.4.1.3.2 Table 4:
Pneumonitis
3-4 : Permanently discontinue
Pneumonitis
3-4 or Recurrent 2 : Permanently
discontinue
Reason of Amendment(s):
•
Updated based on the latest pembrolizumab protocol standard text provided by Merck.
Original Text
Amended Text
7 INTRODUCTION
The goal of Study E7080-J081-115, which 
will be conducted in patients, is to confirm 
the tolerability and safety for combination 
of 
lenvatinib 
plus 
pembrolizumab 
in 
Japanese subjects with selected solid
tumors.
The goal of Study E7080-J081-115, which 
will be conducted in patients, is to confirm 
the tolerability and safety for combination 
of 
lenvatinib 
plus 
pembrolizumab 
in 
Japanese subjects with selected solid 
tumors: non-small cell lung cancer, 
predominantly 
clear 
cell 
renal 
cell 
carcinoma, 
endometrial 
carcinoma, 
urothelial 
carcinoma, 
squamous 
cell 
carcinoma of the head and neck, or 
melanoma (excluding uveal melanoma).
Reason of Amendment(s):
•
Description Adjustment.
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Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 3 of 9
Original Text
Amended Text
7.1.2
PD-1 Inhibitors and
Pembrolizumab:
Pembrolizumab [Keytruda (US)], a 
humanized monoclonal antibody against 
the programmed death receptor-1 (PD-1)
protein, has been developed by Merck &
Co for the treatment of patients with
cancer.   Pembrolizumab is approved for 
treatment of patients with melanoma in
several countries; in the US and European
Union (EU) it is approved for the 
treatment of patients with advanced
(unresectable or metastatic) melanoma in
adults.    Pembrolizumab has also been 
approved for treatment of patients with
NSCLC in several countries; in the US it is
indicated for the treatment of patients
with metastatic NSCLC whose tumors
express PD-L1 as determined by an FDA-
approved test and who have disease
progression on or after platinum-
containing chemotherapy.    Patients with
NSCLC and epidermal growth factor 
receptor (EGFR) or anaplastic lymphoma
kinase (ALK) genomic tumor aberrations
should also have disease progression on 
FDA approved therapy for these
aberrations prior to receiving 
pembrolizumab.
Pembrolizumab has demonstrated initial
clinical efficacy in single arm
monotherapy trials in subjects with
NSCLC, head and neck squamous cell 
carcinoma, urothelial cancer, gastric
cancer, triple negative breast cancer and
Hodgkin’s Lymphoma as determined by 
response rate.    Ongoing clinical trials are
being conducted in these tumor types as
well as a number of other advanced solid
tumor indications and hematologic 
malignancies.   For study details please 
refer to the Investigator’s Brochure.
Pembrolizumab is a potent humanized
immunoglobulin G4 (IgG4) monoclonal
antibody (mAb) with high specificity of
binding to the programmed cell death 1
(PD-1) receptor, thus inhibiting its 
interaction with programmed cell death
ligand 1 (PD-L1) and programmed cell
death ligand 2 (PD-L2).    Based on 
preclinical in vitro data, pembrolizumab
has high affinity and potent receptor
blocking activity for PD-1. Pembrolizumab 
has an acceptable preclinical safety profile 
and is in clinical development as an 
intravenous (IV) immunotherapy for 
advanced malignancies.   Keytruda™
(pembrolizumab) is indicated for the
treatment of patients across a number of 
indications.  For more details on specific
indications refer to the Investigator
brochure.
Page 116 of 128


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 4 of 9
Reason of Amendment(s):
•
Updated based on the latest pembrolizumab protocol standard text provided by Merck.
Original Text
Amended Text
7.2.2
Clinical Study (E7080-A001-111)
…
(Not included)
7.2.2
Clinical Studies
7.2.2.1
E7080-A001-111 (Phase 1b/2 of 
Lenvatinib Plus Pembrolizumab for 
Selected Solid Tumors in US)
…
7.2.2.2
E7080-J081-116 (Phase 1b of 
Lenvatinib Plus Pembrolizumab for 
Hepatocellular Carcinoma in Japan and 
US)
E7080-J081-116 (Study 116) is an open-
label, single arm, multicenter, Phase 1b 
study in subject with hepatocellular 
carcinoma, which is conducted in Japan 
and US.  Primary objective of this study is 
to evaluate the tolerability and safety of 
lenvatinib in combination with 
pembrolizumab in subjects with 
Hepatocellular Carcinoma.  This study is 
ongoing.
Reason of Amendment(s):
•
Updated that the study is ongoing.
Original Text
Amended Text
7.3 Study Rationale
…
(Not included)
The dose of pembrolizumab planned to be 
studied in this trial is 200 mg Q3W, which 
is the recommended dose of pembrolizumab 
based on the well-established safety and 
efficacy profile in solid tumors.
In KEYNOTE-001, an open-label Phase I 
study was conducted to evaluate the safety, 
tolerability, PK and pharmacodynamics, 
and anti-tumor activity of single agent 
pembrolizumab. 
Page 117 of 128


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 5 of 9
The dose escalation portion of this trial 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg 
and 10 mg/kg, administered every 2 
weeks (Q2W) and dose expansion 
cohorts evaluated 2 mg/kg Q3W and 10 
mg/kg Q3W in subjects with advanced 
solid tumors.  All dose levels were well 
tolerated and no dose-limiting toxicities 
were observed.  This first-in-human 
study of pembrolizumab showed 
evidence of target engagement and 
objective evidence of tumor size 
reduction at all dose levels.  No 
maximum tolerated dose has been 
identified.  In addition, 2 randomized 
cohort evaluations of melanoma subjects 
receiving pembrolizumab at a dose of 2 
mg/kg versus 10 mg/kg Q3W have been 
completed, and 1 randomized cohort 
evaluating 10 mg/kg Q3W versus 10 
mg/kg Q2W has also been completed.  
The clinical efficacy and safety data 
demonstrate a lack of important 
differences in efficacy or safety profile 
across doses.
An integrated body of evidence suggests 
that 200 mg Q3W is expected to provide 
similar response to 2 mg/kg Q3W, 10 
mg/kg Q3W and 10 mg/kg Q2W.  
Previously, a flat pembrolizumab 
exposure-response relationship for 
efficacy and safety has been found in 
subjects with melanoma in the range of 
doses between 2 mg/kg and 10 mg/kg.  
Exposures for 200 mg Q3W are expected 
to lie within this range and will be close 
to those obtained with 2 mg/kg Q3W 
dose.
A population PK model, which 
characterized the influence of body 
weight and other patient covariates on 
exposure, has been developed.  The PK 
profile of pembrolizumab is consistent 
with that of other humanized 
monoclonal antibodies, which typically 
have a low clearance and a limited
Page 118 of 128


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 6 of 9
volume of distribution.  The distribution 
of exposures from the 200 mg fixed dose 
are predicted to considerably overlap 
those obtained with the 2 mg/kg dose and 
importantly will maintain individual 
patient exposures within the exposure 
range established in melanoma as 
associated with maximal clinical response.  
PK properties of pembrolizumab, and 
specifically the weight-dependency in 
clearance and volume of distribution are 
consistent with no meaningful advantage 
to weight-based dosing relative to fixed 
dosing.
In translating to other tumor indications, 
similarly flat exposure-response 
relationships for efficacy and safety as 
observed in subjects with melanoma can 
be expected, as the anti-tumor effect of 
pembrolizumab is driven through 
immune system activation rather than 
through a direct interaction with tumor 
cells, rendering it independent of the 
specific tumor type.  In addition, available 
PK results in subjects with melanoma, 
NSCLC, and other tumor types support a 
lack of meaningful difference in 
pharmacokinetic exposures obtained at 
tested doses among tumor types.  Thus the 
200 mg Q3W fixed-dose regimen is 
considered an appropriate fixed dose for 
other tumor indications as well.
There has been no significant difference 
in tolerability and PK profile noted 
between Japanese and non-Japanese 
patients.
The pembrolizumab 200 mg Q3W fixed-
dose regimen is considered an 
appropriate fixed dose for other tumor 
indications as above.
Reason of Amendment(s):
•
Updated based on the latest pembrolizumab protocol standard text provided by Merck.
Page 119 of 128


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 7 of 9
Original Text
Amended Text
9.3.3
Removal of Subjects From
Therapy or Assessment:
…The Discontinuation From Treatment CRF
page will be completed indicating the 
primary reason for discontinuation and all
other reason(s) contributing to the 
subject’s discontinuation from treatment. 
In addition, the date of last dose of study 
drug(s) will be recorded on the Study Drug 
Dosing CRF page.
…The Discontinuation From Treatment CRF
page will be completed indicating the 
primary reason for discontinuation from 
treatment.
In addition, the date of last dose 
of study drug(s) will be recorded on the 
Study Drug Dosing CRF page.
Reason of Amendment(s):
•
Updated based on the latest protocol standard text of Eisai.
Original Text
Amended Text
9.4.1.5
Supportive Care Guidelines for 
Pembrolizumab
Pneumonitis: 
For Grade 3-4 events, immediately treat with 
intravenous steroids.
For Grade 3-4 events or recurrent Grade 
2, immediately treat with intravenous 
steroids.
Reason of Amendment(s):
•
Updated based on the latest pembrolizumab protocol standard text provided by Merck.
Original Text
Amended Text
9.5.1.5.1
ADVERSE EVENTS AND 
EVENTS ASSOCIATED WITH 
SPECIAL SITUATIONS:
All AEs observed during the study will be 
reported on the CRF.
All AEs, regardless 
of relationship to study drug or procedure, 
should be collected beginning from the time 
the subject signs the study ICF and for 30 
days after the last dose of study treatment.
Subjects who fail screening primarily due 
to AE(s) must have the AE(s) leading to 
screen failure reported.
All AEs observed during the study will be 
reported on the CRF.
All AEs, regardless 
of relationship to study drug or procedure, 
should be collected beginning from the time 
the subject signs the study ICF and for 30 
days after the last dose of study treatment.
Reason of Amendment(s):
•
Updated based on the latest protocol standard text of Eisai.
Page 120 of 128


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 8 of 9
Original Text
Amended Text
9.5.2.1 Schedule of Procedures/ 
Assessments:
Table 9
Schedule of
Procedures/Assessments in the
Pretreatment, Treatment, and Extension
Phases
Medical/surgical history
Baselinea
X
Tumor assessments: CT (MRI)n
Off-Treatment Visitv
X
(unless done within previous 4 weeks or 
subject discontinued for PD)
CT or MRI of the braino
Off-Treatment Visitv
X
(unless done within 4 weeks)
Medical/surgical history
Baselinea
Tumor assessments: CT (MRI)n
Off-Treatment Visitv
X
(unless done within previous 4 weeks or 
subject discontinued for PD and clinically 
stable)
CT or MRI of the braino
Off-Treatment Visitv
X
(unless done within 4 weeks and as 
needed)
Reason of Amendment(s):
•
Description Adjustment.
Original Text
Amended Text
9.5.4.2
Reporting of Pregnancy and 
Exposure to Study Drug Through 
Breastfeeding:
Any pregnancy in which the estimated date 
of conception is either before the last visit or 
within 120 days of the last study treatment, 
or 30 days following last study treatment 
if the subject initiates new anticancer 
therapy, whichever is earlier, must be 
reported.  Also, any exposure to study drug 
through breastfeeding during study 
treatment or within 120 days of the last 
study treatment, or 30 days following the 
last study treatment if the subject initiates 
a new anticancer therapy, whichever is 
earlier, must be reported.
Any pregnancy in which the estimated 
date of conception and exposure to study 
drug through breastfeeding must be 
reported until 30 days after the subject’s 
last dose.  From 30 days after the last 
dose, any pregnancy in which the estimated 
date of conception is either before the last 
visit or within 120 days of the last study 
treatment, or until the subject initiates new 
anticancer therapy, whichever is earlier, 
must be reported.  Also, from 30 days after
the last dose, any exposure to study drug 
through breastfeeding during study 
treatment or within 120 days of the last 
study treatment, or until the subject initiates 
a new anticancer therapy, whichever is
Page 121 of 128


E7080-J081-115
Amendment 01
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 9 of 9
earlier, must be reported
Reason of Amendment(s):
•
Changed to revise operational discrepancy.
Original Text
Amended Text
9.5.5
Completion/Discontinuation of
Subjects:
Subjects who discontinue early from the 
study will be discontinued for 1 of these 
primary reasons.
In addition to the 
primary reason, the subject may indicate 1
or more secondary reason(s) for 
discontinuation.    Study disposition
information will be collected on the
Subject Disposition CRF.
Subjects who discontinue early from the 
study will be discontinued for 1 of these 
primary reasons.
Reason of Amendment(s):
•
Updated based on the latest protocol standard text of Eisai.
Page 122 of 128


E7080-J081-115
Amendment 02
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 1 of 1
Protocol Amendment
   Study Drug:
Lenvatinib (E7080)
   
    Study Protocol Number:
E7080-J081-115
   
      Study title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subject with Selected Solid Tumors
  
    Protocol Amendment
   Number and Date:
Amendment 02: 10 Apr 2018
Original Text
Amended Text
Title Page: 
Approval Date
V1.0
14 Sep 2016 (Original Protocol)
            16 Jun 2017 (Amendment 01)
V1.0
14 Sep 2016 (Original Protocol)
           16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
Reason of Amendment(s):
•
Protocol revision
Original Text
Amended Text
Clinical Protocol synopsis: 
Study Period and Phase of 
Development
Approximately 18 months
30 months (plan)
Reason of Amendment(s):
•
Updated for extending study period.
Page 123 of 128


E7080-J081-115
Amendment 03
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 1 of 1
Protocol Amendment
   Study Drug:
Lenvatinib (E7080)
   
    Study Protocol Number:
E7080-J081-115
   
      Study title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subject with Selected Solid Tumors
  
    Protocol Amendment
   Number and Date:
Amendment 03: 05 Apr 2019
Original Text
Amended Text
Title Page: 
Approval Date
V1.0
14 Sep 2016 (Original Protocol)
            16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
V1.0
14 Sep 2016 (Original Protocol)
           16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
            05 Apr 2019 (Amendment 03)
Reason of Amendment(s):
•
Protocol revision
Original Text
Amended Text
Clinical Protocol synopsis: 
Study Period and Phase of 
Development
30 months (plan)
42 months (plan)
Reason of Amendment(s):
•
Updated for extending study period.
Page 124 of 128


E7080-J081-115
Amendment 04
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 1 of 3
Protocol Amendment
   Study Drug:
Lenvatinib (E7080)
   
    Study Protocol Number:
E7080-J081-115
   
      Study title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subject with Selected Solid Tumors
  
    Protocol Amendment
   Number and Date:
Amendment 04: 14 Feb 2020
Original Text
Amended Text
Title Page: 
Approval Date
V1.0
14 Sep 2016 (Original Protocol)
            16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
           05 Apr 2019 (Amendment 03)
V1.0
14 Sep 2016 (Original Protocol)
           16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
           05 Apr 2019 (Amendment 03)
            14 Feb 2020 (Amendment 04)
Reason of Amendment(s):
•
Protocol revision
Original Text
Amended Text
Clinical Protocol synopsis: 
Assessments
Efficacy
Subjects going off treatment without disease 
progression will also undergo tumor 
assessments per the Schedule of 
Procedures/Assessments until disease 
progression is documented or another 
anticancer therapy is initiated.
Subjects going off treatment without disease 
progression (excluding the subject with CR 
at off-treatment visit) will also undergo 
tumor assessments per the Schedule of 
Procedures/Assessments until disease 
progression is documented or another 
anticancer therapy is initiated.
Reason of Amendment(s):
•
Changed to revise operational discrepancy.
Page 125 of 128


E7080-J081-115
Amendment 04
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 2 of 3
Original Text
Amended Text
9.3.3 
Removal of Subjects From 
Therapy or Assessment
During the Follow-up Period, subjects who 
have discontinued study treatment without 
progression should have disease assessments 
until disease progression is documented or 
another anticancer therapy is initiated.
During the Follow-up Period, subjects who 
have discontinued study treatment without 
progression (excluding the subject with CR 
at off-treatment visit) should have disease 
assessments until disease progression is 
documented or another anticancer therapy is 
initiated.
Reason of Amendment(s):
•
Changed to revise operational discrepancy.
Original Text
Amended Text
9.5.1.3 
Efficacy Assessments
Subjects going off treatment without disease 
progression will also undergo tumor 
assessments per the Schedule of 
Procedures/Assessments until disease 
progression is documented or another 
anticancer therapy is initiated.
Subjects going off treatment without disease 
progression (excluding the subject with CR 
at off-treatment visit) will also undergo 
tumor assessments per the Schedule of 
Procedures/Assessments until disease 
progression is documented or another 
anticancer therapy is initiated.
Reason of Amendment(s):
•
Changed to revise operational discrepancy.
Page 126 of 128


E7080-J081-115
Amendment 04
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 3 of 3
Original Text
Amended Text
Table 10
AssessmentsSchedule of 
Procedures/Assessments in 
the Pretreatment, 
Treatment, and Extension 
Phases
n: During the Follow-up Period, subjects who 
have discontinued study treatment without 
progression should have disease assessments 
until disease progression is documented or 
another anticancer therapy is initiated
n: During the Follow-up Period, subjects who 
have discontinued study treatment without 
progression (excluding the subject with CR 
at off-treatment visit) should have disease 
assessments until disease progression is 
documented or another anticancer therapy is 
initiated
Reason of Amendment(s):
•
Changed to revise operational discrepancy.
Page 127 of 128


E7080-J081-115
Amendment 04
Eisai Co., Ltd.
Eisai Inc.
CONFIDENTIAL
Page 1 of 3
Protocol Amendment
   Study Drug:
Lenvatinib (E7080)
   
    Study Protocol Number:
E7080-J081-115
   
      Study title:
An Open-Label Phase 1b Trial of Lenvatinib Plus 
Pembrolizumab in Subject with Selected Solid Tumors
  
    Protocol Amendment
   Number and Date:
Amendment 05: 7 Apr 2020
Original Text
Amended Text
Title Page: 
Approval Date
V1.0
14 Sep 2016 (Original Protocol)
           16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
           05 Apr 2019 (Amendment 03)
            14 Feb 2020 (Amendment 04)
V1.0
14 Sep 2016 (Original Protocol)
           16 Jun 2017 (Amendment 01)
            10 Apr 2018 (Amendment 02)
           05 Apr 2019 (Amendment 03)
            14 Feb 2020 (Amendment 04)
              7 Apr 2020 (Amendment 05)
Reason of Amendment(s):
•
Protocol revision
Original Text
Amended Text
Clinical Protocol synopsis: 
Study Period and Phase of 
Development
42 months (plan)
54 months (plan)
Reason of Amendment(s):
•
Updated for extending study period.
Page 128 of 128

SAP_001.pdf: 
Statistical Analysis Plan 
E7080-J081-115 
 
 
 
Eisai 
Version3.0: 11 Oct 2019 
Confidential 
Page 1 of 30 
 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7080-J081-115 
Study Protocol 
Title: 
An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in 
Subjects with Selected Solid Tumors 
Date: 
11 Oct 2019 
Version: 
Version 3.0 


Statistical Analysis Plan 
E7080-J081-115 
 
 
 
Eisai 
Version3.0: 11 Oct 2019 
Confidential 
Page 2 of 30 
 
 
1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS .................................................................................................. 2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................... 4 
3 
INTRODUCTION ............................................................................................................ 6 
3.1 
Study Objectives ..................................................................................................... 6 
3.1.1 
Primary Objective ......................................................................................... 6 
3.1.2 
Secondary Objectives .................................................................................... 6 
3.1.3 
Exploratory Objective ................................................................................... 6 
3.2 
Overall Study Design and Plan ............................................................................... 7 
4 
DETERMINATION OF SAMPLE SIZE ......................................................................... 8 
5 
STATISTICAL METHODS ............................................................................................. 9 
5.1 
Study Endpoints ...................................................................................................... 9 
5.1.1 
Primary Endpoint .......................................................................................... 9 
5.1.2 
Secondary Endpoints .................................................................................... 9 
5.1.2.1 
Pharmacokinetic (PK) Endpoints ........................................................ 9 
5.1.3 
Exploratory 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 ..................................................................................... 11 
5.2.4 
Demographic and Other Baseline Characteristics ...................................... 11 
5.2.5 
Prior and Concomitant Therapy .................................................................. 13 
5.2.6 
Treatment Compliance ................................................................................ 13 
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 .......................................................................... 14 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .................................... 14 
5.3.6 
Other Considerations .................................................................................. 14 
5.4 
Efficacy Analyses ................................................................................................. 14 
5.4.1 
Efficacy Analyses ....................................................................................... 14 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses .............................................................................................. 15 
5.5.1 
Pharmacokinetic Analyses .......................................................................... 15 
5.5.1.1 
Plasma or serum Concentration and its PK Parameter Analysis ...... 15 
5.5.1.2 
Pharmacokinetic Data Figures .......................................................... 16 


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5.6 
Safety Analyses ..................................................................................................... 16 
5.6.1 
Extent of Exposure ...................................................................................... 16 
5.6.2 
Dose Limiting Toxicity ............................................................................... 18 
5.6.3 
Adverse Events ........................................................................................... 18 
5.6.4 
Laboratory Values ....................................................................................... 19 
5.6.5 
Vital Signs ................................................................................................... 20 
5.6.6 
Electrocardiograms ..................................................................................... 20 
5.6.7 
Other Safety Analyses ................................................................................. 20 
5.7 
Other Analyses ...................................................................................................... 21 
5.8 
Exploratory Analyses ............................................................................................ 21 
6 
INTERIM ANALYSES .................................................................................................. 21 
7 
CHANGES IN THE PLANNED ANALYSES .............................................................. 22 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING .............................. 23 
8.1 
General Data Handling ......................................................................................... 23 
8.2 
Efficacy Data Handling ......................................................................................... 23 
8.3 
Safety Data Handling ............................................................................................ 25 
8.4 
Pharmacokinetic Data Handling ........................................................................... 26 
8.4.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Everolimus Blood and Concentration ......................................................... 26 
8.4.2 
BLQ Handling for Calculation of PK Parameters ...................................... 26 
8.4.3 
BLQ Handling for Developing Concentration-Time Profiles .................... 26 
8.4.4 
Handling of Anomalous Concentration Values .......................................... 26 
8.4.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters ................................................................................................... 26 
9 
PROGRAMMING SPECIFICATIONS ......................................................................... 28 
10 STATISTICAL SOFTWARE ......................................................................................... 28 
11 MOCK TABLES, LISTINGS, AND GRAPHS ............................................................. 28 
12 REFERENCES ............................................................................................................... 28 
13 APPENDICES ................................................................................................................ 29 
13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 ............................................................................. 29 
 


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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AE 
adverse event 
ATC 
anatomical therapeutic chemical 
BOR 
best overall response 
BTC 
biliary tract cancer 
CI 
confidence interval 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
common toxicity criteria for adverse events 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
LLT 
lower level term 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamics 
PD 
progressive disease 
PFS 
progression free survival 
PK 
pharmacokinetics 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
QT 
QT interval 
RECIST 
response evaluation criteria in solid tumor 
SAP 
statistical analysis plan 
SD 
stable disease 
SI 
système international 
SOC 
system organ class 


Statistical Analysis Plan 
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Abbreviation 
Term 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TLG 
tables, listings, and graphs 
WHO DD 
World Health Organization drug dictionary 
 


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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E7080-
J081-115 (Amendment 02). 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
To confirm the tolerability and safety for combination of lenvatinib plus pembrolizumab in 
subjects with selected solid tumors. 
3.1.2 
Secondary Objectives 
To evaluate the following efficacy endpoints by Immune-related Response Evaluation 
Criteria In Solid Tumors (irRECIST) and modified RECIST 1.1: 
- 
Objective response rate (ORR) 
- 
Duration of response (DOR) 
To assess the pharmacokinetic (PK) profile of lenvatinib and pembrolizumab 
To detect anti-drug antibodies for pembrolizumab (ADA) 
3.1.3 
Exploratory Objective 
・ To evaluate the following efficacy endpoints by irRECIST and modified RECIST 1.1: 
- Progression-free survival (PFS) 
- Time to response (TTR) 
- Disease control rate (DCR) 
- Clinical benefit rate (CBR) 
・ To investigate the relationship between candidate biomarkers and anti-tumor activity of 
lenvatinib in combination with pembrolizumab: 
・ To explore blood and tumor markers (such as programmed cell death protein 1 ligand 1 
[PD L1] expression levels, cytokine and angiogenic factor profiling), and immune cell 
profiling and evaluate their relationship with clinical outcomes including anti-tumor 
activity of lenvatinib in combination with pembrolizumab. 


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3.2 
Overall Study Design and Plan 
This is an open-label Phase 1b study.  This study will confirm the tolerability and safety of 
lenvatinib in combination with pembrolizumab in subjects with selected solid tumors.  
Subjects in this study will have one of the following tumors:  non-small cell lung cancer, 
predominantly clear cell renal cell carcinoma, endometrial carcinoma, urothelial carcinoma, 
squamous cell carcinoma of the head and neck, or melanoma (excluding uveal melanoma).   
This study will begin with lenvatinib 20 mg/day orally and pembrolizumab 200 mg (every 3 
weeks [Q3W], intravenous [IV]) in subjects with selected solid tumors on a 21-day treatment 
cycle.  For the confirmation of the tolerability of the dose level, dose limiting toxicities 
(DLTs) will be evaluated during the first cycle (21 days).   
If 0 or 1of 6 subjects in a given dose level cohort experiences a DLT, the dose level will be 
considered tolerable.   
Enrollement will be interrupted if 2 or more DLTs are observed at any dose level, and after 
sponsor and investigators’ review, enrollment may continue for up to 6 subjects based on the 
nature and severity of the DLTs.  Once 6 subjects are enrolled, then, 4 additional subjects (10 
subjects in total) will be added and that dose level will be considered tolerable if DLT is 
observed in 3 or less of the10 subjects in total.  An independent medical advisor as third 
party should be consulted for the review as needed. 
A lower dose level of lenvatinib of 14 mg once daily (QD) in combination with 200 mg 
pembrolizumab Q3W or study discontinuation will be considered, if 20 mg lenvatinib plus 
200 mg pembrolizumab dose level is not tolerable, upon discussions between the sponsor and 
investigators, and the protocol will be amended as necessary.  An independent medical 
advisor as third party should be consulted for the consideration as needed. 
If there is a potential subject who is not evaluable for DLT (eg, subject who fails to 
administer ≥75% of the planned dosage of lenvatinib due to a reason other than treatment 
related toxicity during Cycle 1), the investigator and sponsor will discuss whether or not to 
include the subject in the DLT Analysis Set.  If subject is not evaluable for DLT then the 
subject will be replaced. 
The study will be conducted in 3 phases:  a Pretreatment Phase, a Treatment Phase, and an 
Extension Phase (Figure 1). 
・ The Pretreatment Phase will last no longer than 28 days and will include a Screening 
Period and a Baseline Period. 
・ The Treatment Phase consists of the first cycle (21 days) for each subject.  The 
Treatment Phase for each subject ends after they complete Cycle 1 of treatment or if they 
discontinue early.  Those subjects who discontinue study treatment in Cycle 1 transition 
to the Off Treatment (Off-Tx) Visit of the Follow-up Period of the Extension Phase.  
Those who complete Cycle 1 transition to the Treatment Period of the Extension Phase.   


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・ The Extension Phase begins after a subject completes Cycle 1 and ends when the 
subject completes the Off-Tx Visit.  Subjects will continue to receive study treatment 
until disease progression, development of unacceptable toxicity, withdrawal of consent, 
or sponsor termination of the study.  The Extension Phase consists of 2 periods, the 
Treatment Period and the Follow-up Period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLT = dose limiting toxicity, IV = intravenous, Q3W = every 3 weeks.   
Figure 1 Study Design 
4 
DETERMINATION OF SAMPLE SIZE 
A sample size of 6 to 10 subjects in this study.  This is not based on statistical power 
considerations. 
 
 
21 days per cycle 
Pretreatment 
Treatment 
Extension 
Screening 
Informed consent 
Enrollment 
Baseline 
First dose 
≤28 days 
≤3 days 
Final dose 
Off-Treatment Visit 
Follow-up 
Cycle 1 
Treatment (Cycle 2 & onward) 
≤30 days 
DLT observation 
Administer lenvatinib 20 mg/day 
or 14 mg/day orally and 
pembrolizub 200 mg Q3W IV 


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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. 
5.1 
Study Endpoints 
The efficacy endpoints based on irRECIST and ORR (Week 24) were defined in protocol but 
excluded from the analyses. According to ongoing clinical data, analyses based on irRECIST 
were almost same as ones based on mRECIST. ORR (Week 24) is to be same as ORR. 
5.1.1 
Primary Endpoint 
The primary objective is to confirm the tolerability and safety for combination of lenvatinib 
plus pembrolizumab in subjects with selected solid tumors.  Thus, the primary endpoints will 
be safety related endpoints including DLT. 
5.1.2 
Secondary Endpoints 
The secondary endpoints related to the efficacy endpoints will be ORR and DOR by 
modified RECIST 1.1.  These efficacy endpoints are defined as follows.   
・ ORR is defined as the proportion of subjects who have BOR of CR or PR at the time of 
data cutoff. 
・ DOR is defined as the time from the first documentation of CR or PR to the date of first 
documentation of disease progression (based on modified RECIST 1.1) or death 
(whichever occurs first).  
Determination of the PK profile of lenvatinib and pembrolizumab while subjects are 
receiving combination therapy.  
Serum ADA will be also measured. 
5.1.2.1 
Pharmacokinetic (PK) Endpoints 
PK parameters derived by non-compartmental analysis using plasma concentrations of 
lenvatinib 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 


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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 
MRT 
mean residence time 
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 
 
5.1.3 
Exploratory Endpoints  
The exploratory endpoints related to the efficacy endpoints will be PFS, TTR, DCR, and 
CBR by modified RECIST 1.1.  These efficacy endpoints are defined as follows. 
・ PFS is defined as the time from the first study dose date to the date of first 
documentation of disease progression (based on modified RECIST 1.1) or death 
(whichever occurs first).  If a subject has not experienced disease progression or death, 
then the subject’s data will be censored at the date of the last available tumor assessment.   
・ TTR is defined as the time from the date of first study dose to the date of first 
documentation of CR or PR. 
・ DCR is defined as the proportion of subjects who have BOR of CR or PR or SD 
(minimum duration from C1D1 to SD ≥5 weeks). 
・ CBR is defined as the proportion of subjects who have BOR of CR or PR or durable SD 
(duration of SD ≥23 weeks).   
The exploratory objective is to investigate the relationship between candidate biomarkers and 
anti-tumor activity of lenvatinib in combination with pembrolizumab.  Exploratory endpoints 
will be blood and tumor markers (such as PD-L1 expression levels, cytokine and angiogenic 
factor profiling), and immune cell profiling.   


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5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
DLT Analysis Set will include all subjects who have completed Cycle 1 without major 
protocol deviation with at least 75% of study drug compliance and are assessed for DLT, and 
subjects who have experienced DLT during Cycle 1.  This will be the analysis set to confirm 
tolerability. 
Safety Analysis Set / Efficacy Analysis Set will include all subjects who received at least 1 
dose of study drug. 
Pharmacokinetic Analysis Set includes all subjects who have received at least 1 dose of 
lenvatinib and pembrolizumab, and have evaluable concentration data. 
The number of subjects enrolled, the number (percentage) of subjects included in each 
analysis set will be presented for overall subjects.  Subject data listings will be provided. 
5.2.2 
Subject Disposition 
For the summary table of screening subjects, the number (percentage) of subjects who were 
enrolled (i.e., subjects who signed informed consent), continued in the study after screening, 
failed screening, and the primary reason for screen failures will be presented.  
For the summary of the subject disposition, the number (percentage) of subjects who were 
treated/not treated, completed/discontinued the study treatment, and the reason for the study 
treatment discontinuation. Subject disposition table will be presented for overall subjects. 
A subject who completed the study treatment in extension phase is defined as a subject who 
is still continuing study treatment at the time of study cut-off or discontinued treatment due 
to disease progression. 
Subject data listings will be provided. 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major and minor 
protocol deviations will be identified and documented before the database lock.  The protocol 
deviations identified according to the criteria at study entry and during treatment will be 
included in TLGs covered by SAP and presented in the clinical study report (CSR). 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized for overall subjects using 
descriptive statistics.  This summary table will be generated on the Safety Analysis Set, DLT 
Analysis Set and the PK Analysis Set. 
Continuous demographic and baseline variables include 


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・ age 
・ height 
・ weight 
Categorical demographic and baseline variables include 
・ age group (<65 years, ≥65 to <75 years, ≥75 years) 
・ sex 
・ race 
・ ethnicity 
・ country 
・ ECOG-PS 
・ NYHA (I, II, III, IV and NA for Heart failure) 
Disease history and characteristics at study entry will also be summarized by: 
・ Primary tumor 
・ Diagnostic information 
 TNM staging 
・ Time since original diagnosis to the first dose 
・ Time since last disease progression to the first dose 
・ Known mutation status (EGFR, KRAS, NRAS, BRAF) 
Prior anticancer therapies will be summarized by: 
・ Number of prior regimen 
・ Type of previous therapy (adjuvant, neoadjuvant, metastatic, locally advanced, 
maintenance, unknown) 
・ Best response for last anti-cancer therapy (CR, PR, SD, PD, NE, NA, unknown) 
・ Duration of last therapy (months) 
・ Time from end of last therapy to study entry (months) 
Prior radiotherapy will be summarized by: 
・ Subjects with any prior radiotherapy 
・ Tumor lesion at the site progressed since radiotherapy (yes, no, not evaluated) 
・ Time from last radiotherapy to date of treatment (months). 
Prior anticancer procedure will be presented in subject data listing. 


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Subject data listings for demographic and other baseline characteristics will be provided. 
MEDICAL HISTORY 
A subject data listing of medical history and current medical condition will be provided. 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD) drug codes.  Prior 
medications will be defined as medications that stopped before the first dose of study drug.  
Concomitant medications will be defined as medications that (1) started before the first dose 
of study drug and were continuing at the time of the first dose of study drug, or (2) started on 
or after the date of the first dose of study drug up to 30 days after the subject’s last dose or 
until the subject initiates new anticancer therapy, whichever is earlier. The other medications 
are defined as post-treatment medications.  
The following summary table will be presented for overall subjects on the Safety Analysis Set. 
The number (percentage) of subjects who took prior anti-cancer medications (ie., anti-cancer 
medications and anti-cancer procedures) will be summarized by Anatomical Therapeutic 
Chemical (ATC) class, and WHO DD preferred term for overall subjects. 
The number (percentage) of subjects who took prior and concomitant medications (ie., all 
medication and non-pharmacological procedure) will be summarized by Anatomical 
Therapeutic Chemical (ATC) class, and WHO DD preferred term for overall subjects. 
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 “ but will not be included in TLGs covered by SAP. 
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. 


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5.3.4 
Examination of Subgroups 
The subgroup analyses will be performed, if deemed appropriate.  The definition of 
subgroup will be determined and documented in SAP before database locked.  
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
The details of handling of missing data will be described in section 8. 
5.3.6 
Other Considerations 
Not applicable. 
5.4 
Efficacy Analyses 
All efficacy analyses will be summarized with available data in the clinical database at the 
data cutoff.  The efficacy analysis will be performed based on the Efficacy Analysis Set.  
Efficacy data will be presented for overall subjects. 
5.4.1 
Efficacy Analyses 
All efficacy endpoints will be based on the tumor assessments performed by the investigators 
using modified RECIST 1.1.  Based on the  tumor assessment criteria, BOR will be 
summarized, and ORR and its corresponding exact 2-sided 95% confidence interval (CI) will 
be calculated. Responses of PR or CR have to be confirmed no less than 4 weeks after the 
initial response in this study.  DOR will also be summarized and plotted over time by 
Kaplan-Meier method.  The analysis for DOR will be performed in the subjects whose 
response of PR or CR is confirmed. 
Likewise, PFS and TTR will be analyzed as needed.  If applicable, DCR, CBR, and their 
corresponding exact 2-sided 95% CI will also be calculated.  A waterfall plot will be 
presented for the percent changes from baseline in the sum of the diameters of target lesions 
at postbaseline nadir (ie, maximum tumor shrinkage). 
The percent changes from baseline over time in the sum of the diameters of target lesions 
will be presented using by spider plot.The definition of DOR, PFS, TTR and durable SD will 
be as follows: 
 DOR (days) = Date of first documented PD/ death/ censored date (whichever occurs 
first) – Date of first evaluation of PR or CR + 1. 
 PFS (days) = Date of first documented PD/ death/ censored date (whichever occurs 
first) – Date of first dose + 1. 
 TTR (days) = Date of first documented CR or PR (whichever occurs first) – Date of 
first dose + 1. 
 Durable SD = duration of SD ≥23 weeks 


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 Duration of SD is defined as the time from the date of first dose to the first 
documented PD or death, whichever occurs first.  
The censoring rules for DOR and PFS are detailed in section 8. 
Subject data listings will be provided. 
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, 
pembrolizumab serum concentrations and ADA levels listings. The PK Analysis Set will be 
used for the summaries of lenvatinib plasma concentrations and pembrolizumab serum 
concentrations and for summaries and listings of PK parameters of lenvatinib.  The data in 
patient with dose-reduction/interruption will not be included on calculation of summary 
statistics.  Analysis of pembrolizmab serum concentrations and ADA levels will be performed 
and detailed in a separate report by Merck & Co., Inc. 
5.5.1.1 
Plasma or serum Concentration and its PK Parameter Analysis 
<Concentration> 
Plasma concentration values for lenvatinib and serum concentration values for 
pembrolizumab 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, serum concentrations of pembrolizumab and ADA 
levels will be listed for each subject by actual sampling time. 
<PK Parameter (Lenvatinib Only)> 
PK parameters will be derived by non-compartmental analysis using WinNonlin software 
(version 6.2.1 or later) according to 302-104.01-MNL. 
The following pharmacokinetic parameters for lenvatinib will be calculated: Cmax, tmax, 
AUC(0-t), AUC(0-inf), t1/2, λz, CL/F, Vz/F, MRT, Css,max, Css,min, tss,max, AUC(0-τ), CLss/F, Css,av, 
Rac(Cmax), Rac(AUC), PTF. 
Other PK parameters may be calculated as appropriate. 
Rac(AUC) will be calculated based on AUC(0-t) not AUC(0-τ) of Cycle Day1 and Cycle Day 
15. 
Summary statistics will be tabulated for the PK parameters of lenvatinib.  Summary statistics 
(n, mean, SD, median, min, and max) will be presented for all parameters (apart from tmax 


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and tss,max where mean and SD are not required).  In addition, geometric mean and %CV will 
also be presented for all parameters apart from tmax and tss,max.  
PK parameters of lenvatinib 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 the linear plots of 
serum concentration for pembrolizumab 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 
pembrolizumab will be plotted on the Y axis. 
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 mean (+SD) plots of pembrolizumab serum 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. 
5.6 
Safety Analyses 
All tolerability analyses will be performed on the DLT Analysis Set.  Safety analyses will be 
performed on the Safety Analysis Set.  Tolerability and safety data will be presented for 
overall subjects as appropriate by using summary statistics (e.g., n, mean, standard deviation, 
median, Q1, Q3, minimum, maximum for continuous variables; number [percentage] for 
categorical variables). 
5.6.1 
Extent of Exposure 
The parameters to be summarized are defined as follows.  The parameters for extent of 
exposure will be computed for combination (lenvatinib plus pembrolizumab), lenvatinib 
alone and pembrolizumab alone, respectively.   
1. Number of cycles of Lenvatinib = Round down “(last dosing date – first dosing date) / 
21 + 1” to integer. 
2. Number of cycles of Pembrolizumab = Round “(last dosing date – first dosing date + 1) / 
21 + 1” to integer. 
3. Number of cycles of combination treatment = Larger number of cycle of each study 
drug. 
4. Duration of treatment (days) = Last dosing date – first dosing date + 1 
5. Duration of treatment (months) = (Last dosing date – first dosing date + 1) / (365.25/12) 
6. Total doses (mg) of Lenvatinib = Sum of all the actual dose 


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7. Total doses (mg) of Pembrolizumab = Sum of all the actual dose derived by [ Planned 
dose (mg) x (Actual volume infused (ml) / volume to be infused (ml))] 
8. Dose intensity of Lenvatinib (mg / (days)) = Total doses / Duration of treatment 
9. Dose intensity of Pembrolizumab (mg / (Q3W)) = Total doses / No. of cycles 
10. Relative dose intensity (%) = 100 × Dose intensity / starting planned dose 
The following tables will provide the parameters to be calculated for the study drug. 
Lenbatinib plus 
Pembrolizumab 
Lenvatinib 
Pembrolizumab 
3, 4*, 5* 
*: defined as the duration between 
the earliest first dose start date of 
either medication and the latest 
last dose end date of either 
medication 
1, 4, 5, 6, 8, 10 
2, 4, 5, 7, 9, 10 
 
Furthermore, the following information of administration will also be summarized for each 
drug, lenvatinib and pembrolizumab.  
The number (percentage) of subjects who experienced dose reductions and treatment 
interruptions will be summarized based on actual dose record from study medication data.  
The analysis for dose reduction will be performed only for lenvatinib. 
Time to first dose reduction of lenvatinib (weeks) and interruption of pembrolizumab 
(cycles) will be summarized by descriptive statistics for subjects with dose 
reduction/interruption event.  Summary for all subjects will also be provided using Kaplan-
Meier method. For subjects without dose reduction/interruption event, the time to dose 
reduction/interruption is censored at the last dosing date.  
Frequency of dose interruptions will also be summarized by appropriate categories (e.g., 1, 2, 
3, ≥4).  
Frequency of dose reductions will be summarized by categories (1, 2, 3, 4).   
・ Definition of Dose Reduction of Lenvatinib:  
 Dose level reduces from previous dose level after dose interruption period per 
Protocol. For example, 24 mg followed by 0 mg followed by 20 mg; 20 mg followed 
by 0 mg followed by 14 mg. 


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 If the reduced dose level starts without dose interruption period, that case is also 
counted as dose reduction event. 
・ Definition of Dose interruption of Lenvatinib:  
 Only include the scenario that the before and after dose 0 (interruption period), the 
dose levels are the same. For example: 24 mg followed by 0 mg and followed by 24 
mg; 20 mg followed by 0 mg followed by 20 mg.  
 If dose level reduces from previous dose level after dose interruption period (dose 0), 
it should be counted into dose reduction, but not dose interruption. For example, 24 
mg followed by 0 mg followed by 20 mg, the period with 0 mg should not be counted 
into dose interruption, but instead should be counted as a dose reduction.  
 If after dose 0 mg, the subject discontinued from treatment permanently, it should be 
counted as a treatment discontinuation instead of a dose interruption. 
・ Definition of Dose Interruption of Pembrolizumab:  
 The record of 0 mg dosed is counted as the dose interruption event. 
 
The actual dosing transition and duration of both study drug with tumor response is presented 
using swimmer plot. 
Subject data listings will be provided. 
5.6.2 Dose Limiting Toxicity 
The number (percentage) of subjects who experienced DLT will be summarized.  The 
category of DLT will also be summarized.   
Subject data listings will be provided. 
5.6.3 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA version 19.0 or later).  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) 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. 
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.  


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An overview table, including the incidence of and the number of subjects with TEAEs, 
Treatment-Related TEAEs, TEAEs with grade 3 or above, serious adverse events (SAEs), 
deaths, and TEAEs that led to treatment discontinuation, dose reduction, or dose interruption 
will be provided. 
The incidence of below events will be reported as the number (percentage) of subjects with 
TEAEs by MedDRA SOC and PT.  
・ TEAEs 
・ TEAEs by CTCAE grade 
・ TEAEs grade 3 or above 
・ Serious TEAEs 
・ Treatment-related TEAEs 
・ Treatment-related TEAEs by CTCAE grade 
・ Treatment-related TEAEs grade 3 or above 
・ Treatment-related serious TEAEs 
・ TEAEs leading to discontinuation of Lenvatinib  
・ TEAEs leading to dose reduction of Lenvatinib 
・ TEAEs leading to dose interruption of Lenvatinib 
・ TEAEs leading to discontinuation of Pembrolizumab  
・ TEAEs leading to dose interruption of Pembrolizumab 
・ TEAEs leading to discontinuation of Lenvatinib or Pembrolizumab 
・ TEAEs leading to dose interruption of Lenvatinib or Pembrolizumab 
 
The the number (percentage) of subjects with TEAEs will also be reported by MedDRA PT 
in descending order. 
Subject data listings of all deaths, SAEs, AEs leading to death, treatment discontinuation, 
dose reduction, or dose interruption will be provided. All AE regardless of treatment-
emergent or not will be included in the subject data listings. 
5.6.4 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units.  For all 
quantitative parameters, the actual value and the change from baseline to each postbaseline 
visit 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 will be reported using shift tables.  Percentages will be based on the 
number of subjects with both nonmissing baseline and relevant postbaseline results. 
Box and whisker plot will be used to show the longitudinal change of the parameters by visit. 
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 LNH classification will be provided in a subject data listing. 


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Laboratory parameters will be graded by CTCAE ver. 4.03.  Changes from CTCAE grade at 
baseline to each postbaseline visit and worst postbaseline will be reported using shift tables. 
CTCAE ver. 4.03 will be used to identify subjects with Treatment-emergent markedly 
abnormal laboratory value (TEMAV).   The number (percentage) of subjects with TEMAV 
(markedly abnormal high/low) will be summarized for each visit and overall study period. 
The TEMAV will be defined in the section 8.3. 
Subject data listings will be provided. 
5.6.5 
Vital Signs 
Summary statistics for vital signs parameters (diastolic and systolic blood pressure, pulse, 
respiratory rate, and temperature), and weight and changes from baseline will be presented 
by visit. 
Box and whisker plot will be used to show the longitudinal change of the parameters by visit. 
Subject data listings will be provided. 
5.6.6 
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 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: 
・ QTcF interval increases from baseline >30 ms 
・ QTcF interval increases from baseline >60 ms 
Subject data listings will be provided. 
5.6.7 
Other Safety Analyses 
LVEF 


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LVEF and change from baseline will be summarized by visit. 
Subject data listings will be provided. 
ECOG PS 
The number (percentage) of subjects for each category of ECOG PS will be summarized by 
visit. The highest postbaseline scale of ECOG PS for each subject will also be summarized.  
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 will be conducted. 


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7 
CHANGES IN THE PLANNED ANALYSES 
A summary of all major additions, changes and deletions in the planned analyses described in 
the protocol or previous version of SAP will be provided in this section. 
The efficacy endpoints based on irRECIST and ORR (Week 24) were defined in protocol but 
excluded from the analyses. According to ongoing clinical data, analyses based on irRECIST 
were almost same as ones based on mRECIST. ORR (Week 24) is to be same as ORR. 
The definition of concomitant medications are aligned with protocol’s assessment rule. 
 
Pharmacokinetic analysis: 
• Manual number of non-compartmental analysis was revised from 302-104.00 to 302-
104.01 
 
Section 5.5.1 
• “The data in patient with dose-reduction/interruption will not be included on calculation 
of summary statistics.” was added. 
• “Analysis of pembrolizmab serum concentrations and ADA levels will be performed 
and detailed in a separate report by Merck & Co., Inc.” was added. 
• PK parameter; Calculation of AUC(0-ti) was deleted. Calculation of λz and MRT was 
added. 
 
Section 8.4 
• The LLOQ of lenvatinib plasma concentration was revised from 0.250 to 0.100 ng/mL. 
• General Rules for Presentation of Drug Concentrations and PK Parameters was 
updated. 
 


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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 
Definition of Baseline data 
Baseline is defined as the last non-missing value observed on or prior to the first dose of study 
treatment for a given parameter. 
Definition of 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 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 were actually conducted after its administration. 
8.2 
Efficacy Data Handling 
Handling of missing data 
For the analysis of response rates (proportion of subjects whose best overall response on tumor 
assessment is PR, CR, SD or dSD), subjects with missing response status (subjects whose 
baseline or post-baseline tumor assessment is missing) will be coded as non-responders on 
Efficacy Analysis Set.   
Censoring rules for PFS 
The following table provides the censoring rules for PFS. 
No. 
Situation 
Date of Event (Progression/Death) or 
Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose 
Censored 


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2 
Progression 
documented 
between 
scheduled visits 
Date of first radiologic PD assessment 
Event 
3 
No progression at the time of data cut-offDate of last adequate radiologic 
assessment before or on date of 
data cut-off 
Censored 
4 
New anticancer treatment started 
Date of last adequate radiologic 
assessment prior to or on date of new 
anticancer treatment 
Censored 
5 
Death before first PD assessment 
Date of death 
Event 
6 
Death between adequate assessment
visits* 
Date of death 
Event 
7 
Death or progression after more 
than 
one 
missed 
visit/tumor 
assessment** 
Date of last adequate radiologic 
assessment before missed tumor 
assessments 
Censored 
CR = complete response, PD = progressive disease, PR = partial response, SD =stable disease, 
* Adequate tumor assessment is radiologic assessment of CR, PR, SD, non-CR/non-PD, or PD at 
regular interval as defined in the protocol. 
** More than one missed visit/adequate tumor assessment is defined as having either one of the following 
two durations being longer than 12 weeks + 2weeks (ie, the date of death or PD – the date of last adequate 
tumor assessment > 97 days) for subjects on the every 6 week tumor assessment schedule in the first 8 cycles of 
treatment and 18 weeks + 2 weeks  (ie, the date of death or PD – the date of last adequate tumor assessment > 
139 days) for subjects on the every 9 week tumor assessment schedule after Cycle 8 in this study. 
The priority of the censoring rules is as follows: 
1. If the subject had PD or death, the following sequence will be applied: 
• If a subject did not have a baseline tumor assessment (No. 1), the subject will be 
censored on the date of first dose.  However, if the subject died within 97 days (14 
weeks -1 day) after first dose and did not receive a new anticancer treatment, it will be 
counted as PFS event at the date of death. If a subject had new anticancer treatment 
before PD or death (No. 4), the subject will be censored on the date of the last adequate 
tumor assessment prior to or on the date of new anticancer treatment. 
• If a subject missed two or more tumor assessments before PD or death (No. 7), 
the subject will be censored on the date of the last adequate tumor assessment before 
PD or death.  Note that if a subject is censored by both this criterion and the anticancer 
treatment criterion (No.4), the earliest censoring date will be used. 
• Otherwise, if a subject had an event (No. 2, No. 5, or No. 6), the earliest event date will 
be used. 
2. If a subject did not have PD or death, the censoring date will be the earliest 
censoring date if the subject met multiple censoring criteria (No. 1, No. 3, No. 4, or 
No. 7). 
 
Censoring rules for DOR 


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The censoring rules for DOR will be employed same rule as PFS. 
8.3 
Safety Data Handling 
Definition of derived variables for extent of exposure 
The derivation rule will be presented in the section 5.6.1. 
Treatment-emergent adverse event 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during the 
time from the first dose of study drug to 30 days following the last dose of study drug, having 
been absent at pretreatment (Baseline) 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. 
TEMAV (Treatment-Emergent Markedly Abnormal Value) 
The treatment-emergent markedly abnormal laboratory values (TEMAV) will be summarized 
using CTCAE grade 3 and 4 postbaseline test results.  
Handling of below lower quantification values in laboratory results 
In the cases where laboratory result contains below lower quantification (BLQ) value, it will 
be replaced to the lower limit value of quantification (LLOQ) for summary tables. 
The priority of use for blood pressure 
For systolic and diastolic blood pressures, additional confirmatory assessment will be done 
more than 60 minutes after initial assessment, if necessary.  In the case where there are both 
the initial and confirmatory assessment results in a day, confirmatory one will be used. 
Visit Windows for Safety Analyses 
The analysis window for safety analysis is based on the visits recorded in CRF. In the 
calculation of descriptive statistics for safety parameters (eg, laboratory values and vital 
signs, etc.) per scheduled visit, and change from baseline per visit, if multiple observations 
fall in the same scheduled visit, the first record will be used for summary tables. Other safety 
analyses (eg, worst grade laboratory results) will include all observations until the date of 30 
days following the last dose of study drug. 


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8.4 
Pharmacokinetic Data Handling 
8.4.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Everolimus Blood and Concentration 
The LLOQ of lenvatinib plasma concentrations is 0.100 ng/mL 
The LLOQ of pembrolizumab serum concentrations is 25 ng/mL 
8.4.2 
BLQ Handling for Calculation of PK Parameters 
While calculating PK parameters in WinNonlin, BLQ values will be handled according to 
302-104.01-MNL, for non-compartmental pharmacokinetic analysis. 
8.4.3 
BLQ Handling for Developing Concentration-Time Profiles 
When developing individual concentration-time profiles, BLQ values will be handled 
according to 302-104.01-MNL for non-compartmental pharmacokinetic analysis. 
8.4.4 
Handling of Anomalous Concentration Values 
The handling of anomalous concentration values will follow the guidance in the SWP for 
non-compartmental pharmacokinetic analysis (302-104.01-MNL). 
8.4.5 
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 and tss,max, 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, Css,min, 
Css,av 
ng/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
tmax, tss,max 
h 
X 
Fixed decimal 
places 
2 
2 
- 
- 
- 
λz(C1D1&D15) 
1/h 
X 
Significant digits 
3 
3 
3 
3 
3 
t1/2(C1D1&D15) 
h 
X 
Significant digits 
3 
3 
3 
3 
3 
AUC(0-t), AUC(0-inf), 
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 
MRT 
h 
X 
Significant digits 
3 
3 
3 
3 
3 


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Rac 
 
X 
Significant digits 
3 
3 
3 
3 
3 
PTF 
% 
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 as 
AUC(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) 
d. Percentage of AUC(0-inf) obtained by extrapolation (%AUCex)  
e. The last time points used for calculation of AUC(0-t) (tlast) 
 
In Listings, a) and e) 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) and d), 
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 except pembrolizumab PK and ADA related ones 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 SAS (version 9.3 or later) and WinNonlin 
(version 6.2.4 or later).  As necessary, other validated statistical software will also be used. 
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: https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 


PPD
PPD
PPD