Clinical trial NCT03418922
Conditions: Carcinoma, Hepatocellular
Sponsor: Eisai Co., Ltd.
Start date: 2018-01-16; Completion date: 2022-12-28
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The primary objective of this study is to evaluate the tolerability and safety of a combination of lenvatinib plus nivolumab in participants with hepatocellular carcinoma (HCC).

Detailed description:

Arms: arm 1: Participants will receive specified doses of lenvatinib (oral) and nivolumab (intravenous) on specified days. arm 2: If tolerable in Part 1, participants will receive specified doses of lenvatinib and nivolumab on specified days until criteria for discontinuation are met.
Interventions: intervention 1: Lenvatinib intervention 2: Nivolumab
Intervention descriptions: intervention 1: Specified doses will be administered orally on specified days. intervention 2: Specified doses will be administered intravenously on specified days.

Protocol documents:
Prot_000.pdf: 
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1 
TITLE PAGE 
 
 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E7080-J081-117 
Study Protocol 
Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with 
Hepatocellular Carcinoma 
Sponsor: 
Eisai Co., Ltd.  
4-6-10 Koishikawa Bunkyo-Ku, Tokyo 112-8088 Japan 
 
Ono Pharmaceutical Co., Ltd. 
1-5 Doshomachi 2-chome, Chuo-ku, Osaka 541-8564 Japan 
 
Investigational 
Product Name: 
E7080/lenvatinib, ONO-4538/nivolumab 
Indication: 
Hepatocellular carcinoma 
Phase: 
1b 
Approval Date:  
V8 
05 Feb 2021 
 
 
GCP Statement: 
This study is to be performed in full compliance with 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 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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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E7080, ONO-4538 
Name of Active Ingredient:  Lenvatinib, Nivolumab 
Study Protocol Title 
An Open-Label Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular 
Carcinoma 
Study Regions (Country) or Sites 
Part 1: 1 center in Japan 
Part 2: TBD [multiple centers in Japan]) 
Study Period and Phase of Development 
Approximately 45 months 
Phase 1b 
Objectives 
Primary Objective 
・ To evaluate the tolerability and safety for combination of lenvatinib plus nivolumab in subjects 
with hepatocellular carcinoma (HCC) 
Secondary Objectives 
・ To evaluate the following efficacy endpoints based on investigator review in subjects with 
HCC: 
- 
Objective response rate (ORR) 
・ To assess the pharmacokinetic (PK) profile of lenvatinib and nivolumab  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Study Design 
Overall Design 
This study will be conducted in 2 parts (Part 1 and Part 2). Part 1 will assess the tolerability of 
lenvatinib in combination with nivolumab in subjects with HCC for which no other appropriate 
therapy is available. Part 2 is to further characterize the safety and to assess preliminary efficacy of 
the combination therapy in subjects with HCC with no prior systemic therapy.  Part 1 and Part 2 will 
consist of a Pretreatment Phase, a Treatment Phase, and a Follow-up Phase. The Pretreatment Phase 
will involve obtaining informed consent, a screening test, and a baseline assessment.  The Treatment 
CCI


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Phase will start on Cycle 1 Day 1 (C1D1).  Each cycle is 4 weeks long and subjects will continue 
treatment until they meet any of the criteria in “Discontinuation Criteria by Subject”.  The Follow-
up Phase will consist of the examinations at study discontinuation and the final observation 30 days 
after the final treatment.  
 
Part 1 
Study treatment and starting dose are as follows. 
 
Lenvatinib: 12 mg (Body weight [BW] ≥60 kg) or 8 mg (BW <60 kg) once daily orally. 
Nivolumab: 240 mg (every 2 weeks [Q2W], intravenous [IV]) (Days 1 and 15 of each cycle) 
 
The tolerability will be reviewed based on dose limiting toxicity (DLT) of Cycle 1 (4 weeks) 
according to the following procedures and criteria. 
First, 3 subjects will be enrolled. 
(1)DLT occurs in 0 or 1 of 3 subjects. 
Add 3 more subjects and assess in a total of 6 subjects.  
1)DLT occurs in 0 or 1 of 6 subjects. 
This dose level is judged to be tolerable. 
2)DLT occurs in 2 or more of 6 subjects. 
The tolerability with this dose level will be discussed by the sponsor, sponsor’s responsible 
medical officer, and investigator.  
(2)DLT occurs in 2 or more of 3 subjects. 
The tolerability with this dose level and appropriateness of additional enrollment will be 
discussed by the sponsor, sponsor’s responsible medical officer, and investigators.  
 
In this dose level, at least 3 subjects treated with lenvatinib 12 mg (BW ≥60 kg) and nivolumab 
need to be included in the 6 subjects for DLT evaluation.  If this dose level is not tolerable, upon 
discussions among the sponsor, sponsor’s responsible medical officer, and investigator, the lower 
dose level of cohort will be considered or the study will be discontinued, and the protocol will be 
amended as necessary. An efficacy and safety evaluation advisor may be consulted for the 
consideration as needed. 
 
A DLT is defined as any of the events noted in the table below considered to be at least possibly 
related to lenvatinib and/or nivolumab occurring during Cycle 1. 
Hematologic 
Toxicity 
• 
Febrile neutropenia 
• 
Grade 4 neutropenia lasting >7 days 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 thrombocytopenia lasting > 7 days or associated with 
bleeding 
• 
Grade 4 anemia 
Nonhematologic 
Toxicity 
(Hepatotoxicity) 
• 
Clinical deterioration manifested by drug-related hepatic 
decompensation (eg, encephalopathy etc.) 
• 
AST or ALT > 15×ULN 
• 
AST/ALT >10.0×ULN lasting > 7 days or associated with clinical 
symptom 
• 
Total bilirubin > 5×ULN (for subjects with increased bilirubin at 
baseline, total bilirubin > 8×ULN) 


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Nonhematologic 
Toxicity 
(General) 
• 
Grade 4 nonhematologic toxicity (excluding laboratory 
abnormalities with no clinical significance) 
• 
Grade 3 gastrointestinal perforation, thromboembolic event, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reaction, infusion 
reaction, or wound dehiscence requiring treatment 
• 
Grade 3 toxicities lasting >3 days despite optimal supportive 
therapies (excluding abnormal laboratory values with no clinical 
significance or controllable hypertension) 
• 
Grade 2 uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 within the re-
treatment period or requires systemic treatment 
• 
Eight or more days of dose interruption of lenvatinib as a result of 
lenvatinib or nivolumab treatment-related toxicity during Cycle 1* 
 
* For reasons other than toxicity, this will not be considered as a DLT. In this situation, the relevant subject 
will be excluded from assessments of DLT and new subject will be added.  DLT was determined after 
discussions among the sponsor, the investigator, and the sponsor’s responsible medical officer.  An 
efficacy and safety evaluation advisor may be consulted for the consideration as needed.  
 
Part 2 
If the dose level is confirmed to be tolerable in Part 1, an additional 20 HCC subjects with no prior 
systemic therapy will be enrolled. At least 5 subjects (BW ≥60 kg) treated with lenvatinib 12 mg QD 
and at least 5 subjects (BW <60 kg) treated with lenvatinib 8 mg QD will be included. 
Number of Subjects 
This study will enroll approximately 26 subjects with HCC (6 in Part 1, 20 in Part 2).   
Inclusion Criteria 
1. Subjects must have confirmed diagnosis of HCC with any of the following criteria:  
• 
Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, 
sarcomatoid or mixed cholangio-HCC tumors 
• 
Clinically confirmed diagnosis of HCC according to American Association for the Study 
of Liver Diseases (AASLD) criteria, including cirrhosis of any etiology and/or chronic 
hepatitis B or C infection 
2. Part 1: HCC for which no other appropriate therapy is available 
Part 2:  No prior systemic therapy for advanced/unresectable HCC 
3. Subjects categorized to stage B (not applicable for transarterial chemoembolization [TACE]), or 
stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system. 
4. At least 1 measurable target lesion according to mRECIST meeting the following criteria 
(Lesions previously treated with radiotherapy or locoregional therapy must show radiographic 
evidence of disease progression to be deemed a target lesion).  
• 
Hepatic lesion 
i. 
The lesion can be accurately measured in at least 1 dimension as ≥1.0 cm (viable 
tumor for typical; and longest diameter for atypical) 
• 
Nonhepatic lesion 


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i. 
Lymph node (LN) lesion that measures at least 1 dimension ≥1.5 cm in the short 
axis, except for porta hepatis LN that measures ≥2.0 cm in the short axis. 
ii. 
Non-nodal lesion that measures ≥1.0 cm in the longest diameter 
5. Child-Pugh score A 
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 
of 0 to 1 
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive medications 
within 1 week prior to the C1D1 
8. 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 
9. Adequate bone marrow function:  
• 
Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5×103/μL) 
• 
Platelets ≥75,000/mm3 (≥75×109/L) 
• 
Hemoglobin ≥8.5 g/dL 
10. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) 
≤2.3 
11. Adequate liver function, defined as:  
• 
Bilirubin ≤2.0 mg/dL 
• 
Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine 
aminotransferase (ALT) ≤5×ULN 
12. Age ≥20 years at the time of informed consent   
13. Life expectancy of 12 weeks or more 
14. Voluntary agreement to provide written informed consent and the willingness and ability to 
comply with all aspects of the protocol.  
15. Meet the following criteria. 
(1) If patients have an archival tumor sample, they have to agree to submit it to sponsor.  
(2) (Part 2 only) Patients who agree to submit tumor sample obtained by fresh biopsy prior to 
the first dose of study drug (excluding patients with archival tumor sample or patients with 
inaccessible tumors of safety concern) 
Exclusion Criteria 
1. Imaging findings for HCC corresponding to any of the following (Part 1 only): 
• 
HCC with ≥50% liver occupation 
• 
Clear invasion into the bile duct 
• 
Portal vein invasion with Vp4 
2. Prior anticancer treatment within 28 days (or within 14 days in case of sorafenib and 
regorafenib) or any investigational agent within 28 days prior to the first dose of study drugs.  
3. All toxicities related to prior treatments have not resolved to Grade ≤1 (except alopecia and 
controlled stable cases).  
4. Any blood enhancing treatment (including blood transfusion, blood products, or agents that 
stimulate blood cell production, eg, granulocyte colony-stimulating factor [G-CSF]) within 28 
days prior to the first dose of study drugs 


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5. Prior treatment with lenvatinib, ONO-4538 (MDX-1106 or BMS-936558), any anti-PD-1, anti-
PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug 
specifically targeting T-cell regulation, or cancer vaccine therapy 
6. Subjects who have not recovered adequately from any complications from major surgery prior 
to starting therapy 
7. Subjects having ≥2+ proteinuria on urinalysis (subjects with Grade ≤1 confirmed by 
quantitative assessment will be eligible).  
8. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might 
affect the absorption of lenvatinib 
9. 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 
10. Prolongation of QTc (Fridericia formula) interval to >480 ms 
11. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 teaspoon) 
within 3 weeks prior to the first dose of study drug 
12. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR 
monitoring, eg, warfarin or similar agents.  Treatment with low molecular weight heparin and 
factor X inhibitors which do not require INR monitoring is permitted.  Antiplatelet agents are 
prohibited throughout the study.  
13. Gastric or esophageal varices that require interventional treatment within 28 days prior to first 
dose of study drug are excluded.  Prophylaxis with pharmacologic therapy (eg, nonselective 
beta-blocker) is permitted.  
14. Surgical arterial-portal venous shunt or arterial-venous shunt 
15. Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix, or carcinoma in situ 
including early gastric cancer) within the past 36 months 
16. Active infection (any infection requiring systemic treatment).  Hepatitis B and C [HBV/HCV] 
allowed (subjects with chronic HBV infection must have HBV DNA < 100 IU/mL and must be 
on antiviral therapy.) 
17. Active co-infection with: 
1)Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV DNA and HCV 
RNA, OR 
2)Hepatitis D infection in subjects with hepatitis B 
18. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the normal 
range with medication. 
19. Subjects with any active, known, or suspected autoimmune disease, with the following 
exceptions: 
1)Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy are 
permitted to enroll. 
2)Subjects with suspected autoimmune thyroid disorders may be enrolled if they are currently 
euthyroid or with residual hypothyroidism requiring only hormone replacement. 
3)Subjects with psoriasis requiring systemic therapy must be excluded from enrollment 
20. Any history of interstitial lung disease, and interstitial lung disease that is symptomatic or may 
interfere with the detection and management of suspected drug-related pulmonary toxicity 


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21. Subjects with a condition requiring systemic treatment with either corticosteroids (>10 mg/day 
prednisone equivalent) or other immunosuppressive medications within 14 days of study 
administration.  Inhaled or topical steroids and adrenal replacement doses >10 mg/day 
prednisone equivalents are permitted in the absence of active autoimmune disease. 
22. Subjects with meningeal carcinomatosis 
23. Subjects with any current brain or subdural metastases 
24. Subjects who are known to be positive for Human Immunodeficiency Virus (HIV).  
25. History of clinically significant hepatic encephalopathy 
26. Serious nonhealing wound, ulcer, or bone fracture 
27. Any subject who cannot be evaluated by either triphasic liver computed tomography (CT) or 
triphasic liver magnetic resonance imaging (MRI) because of allergy or other contraindication 
to both CT and MRI contrast agents 
28. Subjects being treated with drugs that strongly inhibit or induce CYP3A4 and that may be 
possibly used during this study.  
29. Any medical or other condition which, in the opinion of the investigator or subinvestigator, 
would preclude participation in a clinical trial 
30. 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).  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 (females who discontinued 
breastfeeding will be eligible). 
31. Women of childbearing potential or men of impregnate potential who don’t agree that both the 
subject and her partner will use the following methods of contraception for periods from before 
informed consent to during the clinical study and 5 months later (for male subjects 30 days) 
from last administration of study drug.  For contraception method, subject must agree to use 
any 2 of the following methods: vasectomy or condom for a male subject or partner, bilateral 
tubal ligation, diaphragm, intrauterine device, or use of oral contraception from at least 28 days 
before starting the study treatment for a female subject or partner. 
32. Participants who have received a live/attenuated vaccine within 28 days of first dose of study drugs 
Study Treatments 
Study drug in the study defines as E7080/lenvatinib and ONO-4538/nivolumab. 
 
Lenvatinib 
Lenvatinib is provided as 4-mg capsule.  Lenvatinib will be administered once a day (with or without 
food) in 4-week cycles at approximately the same time each day.  On Day 1 and Day 15 of each 
cycle, in case concomitantly administered, it will be administered immediately after completion of 
nivolumab administration. 
Starting dose of lenvatinib will be based on baseline BW as follows: 
・ 
BW ≥60 kg — 12 mg QD.  Study subjects will be orally administered lenvatinib as three 4-mg capsules. 
・ 
BW <60 kg — 8 mg QD.  Study subjects will be orally administered lenvatinib as two 4-mg capsules. 
Nivolumab 
Nivolumab is a clear to opalescent, colorless to pale-yellow liquid. Nivolumab injection for 
intravenous infusion is supplied as vials. Nivolumab will be administered as a dose of 240 mg as a 
30-minute IV infusion, Q2W. 
 
Study Treatment Dose Modification 


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1. Cycle 1 (Part 1 only)  
a. If DLT occurs:  
Relationship to lenvatinib and/or nivolumab will be evaluated, then lenvatinib and/or infusion of 
nivolumab should be interrupted or discontinued immediately.  Treatment may be resumed at same 
dose level of nivolumab and at 1 lower dose level of lenvatinib if toxicity is resolved to Grade 0–1 
(or tolerable Grade 2 for hematologic toxicities and proteinuria in case of lenvatinib) or baseline, 
when investigator or subinvestigator decides to continue the study.   
b. No DLT 
Relationship to lenvatinib and/or nivolumab will be evaluated, then lenvatinib and/or nivolumab 
will be interrupted.  Dose adjustments for management of intolerable toxicities will be made 
according to the guidelines provided in the table below.  Lenvatinib and nivolumab should be 
resumed at the same dose level, and dose reduction is not allowed.   
2. Cycle 2 and onward (and applies to Cycle 1 and onward of part 2) 
Relationship to lenvatinib and/or nivolumab will be evaluated, then necessity of dose modification 
(either or both drugs) will be determined.  Dose adjustment for management of intolerable 
toxicities will be made according to the guidelines provided in the table below. 
Lenvatinib 
Treatment-Related Toxicitya,b 
Dose Adjustment 
Hematologic 
Toxicities 
and Proteinuria 
Grade 3 c 
Interrupt until resolved to Grade 0-2 or baseline. In the first 
occurrence, dose should not be changed. In the second 
occurrence or later, reduce lenvatinib by 1 dose level.  
Grade 4 
Interrupt until resolved to Grade 0-2 or baseline. Reduce 
lenvatinib by 1 more dose level.  
Nonhematologic 
Toxicities 
Intolerable 
Grade 2d 
Dose of lenvatinib will be reduced by 1 dose level with or 
without dose interruption. 
Grade 3c,e,f 
Interrupt until resolved to Grade 0-1 or baseline. Reduce 
lenvatinib by 1 dose level. 
Grade 4f, g 
Discontinue lenvatinib 
a:  An interruption of lenvatinib for more than 28 days (due to treatment-related toxicities) will require discussion with 
the sponsor before treatment can be resumed.  During treatment interruption, repeat AEs assessment about every 7 days 
(until restarting administration).  
b:  Initiate optimal medical management for nausea, vomiting, diarrhea, and/or hypothyroidism prior to interruption or 
dose reduction of lenvatinib.  
c:  Not applicable to abnormal clinical laboratory values that are not clinically significant based on the judgment of the 
investigator or subinvestigator. 
d:  Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and investigator or 
subinvestigator.   
e:  Obese subjects with weight loss do not need to return to baseline or Grade 1 weight loss to restart lenvatinib.  There 
should be no weight loss for at least 1 week, and subjects should be started at the lower dose.  
f:  For asymptomatic Grade ≥3 elevations of amylase and lipase, sponsor should be consulted to obtain permission to 
continue treatment. 
g:  Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3.  
 
For management of hypertension, refer to the main protocol text for instructions without applying 
the table above. 
Initial Lenvatinib Dose (mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
Reduction 1 
Reduction 2 
Reduction 3 
12 
8 
4 
4 QODa  
8 
4 
4 QODa 
 


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a:  4 mg every other day [QOD].  Any dose reduction below 4 mg every other day must be discussed with the sponsor. 
Nivolumab 
Treatment-Related 
Toxicitya 
Dose Delay Criteria 
Criteria to Resume Dosing 
Skin-related adverse 
event 
Grade 3 
Grade ≤ 1 or baseline value 
Fatigue 
Grade 3 
Grade ≤2 
Laboratory abnormality 
(except for AST/ALT) 
Grade 3 (except for amylase or lipase 
abnormalities that are not associated 
with symptoms or clinical 
manifestations of pancreatitis) 
Grade ≤ 1 or baseline value 
(T-Bil: baseline CTCAE Grade or 
normal) 
AST/ALT 
Baseline AST/ALT is within normal 
limits: Grade ≥2.  
Baseline AST/ALT is Grade 1: Grade 
≥3. 
Baseline AST/ALT is Grade 2: ≥two-
fold of baseline value or ≥8x ULN  
Baseline CTCAE Grade or normal 
Pulmonary toxicity, 
diarrhea, or colitis 
Grade≥2 
Baseline 
Others 
Grade ≥2 
Grade ≤ 1 or baseline value 
(Endocrinopathies adequately 
controlled with only physiologic 
hormone replacement may resume 
treatment.) 
a:  A delay of nivolumab for more than 6 weeks will require sponsor’s approval before treatment can be resumed. 
 
Discontinuation Criteria of Nivolumab 
Nivolumab treatment should be discontinued for the following AEs related to nivolumab: 
・ Any Grade 2 uveitis, eye pain or blurred vision that does not respond to topical therapy and 
does not improve to Grade 1 severity within the re-treatment period or requires systemic 
treatment 
・ Any Grade 3 uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or infusion 
reaction 
・ Any Grade 3 thrombocytopenia lasting >7 days or associated with bleeding 
・ Any Grade 3 AE lasting >7 days, with the exceptions of skin, laboratory abnormalities, 
endocrinopathies adequately controlled with only physiologic hormone replacement 
・ Any hepatotoxicity as below: 
- 
AST or ALT >10×ULN lasting >2 weeks 
- 
AST or ALT >15×ULN 
- 
For subjects with total bilirubin ≤ULN at baseline:  total bilirubin > 5×ULN 
- 
For subjects with increased bilirubin at baseline:  total bilirubin > 8×ULN 
・ Any Grade 4 AE or laboratory abnormality, except for the following 
- 
Neutropenia <7 days 
- 
Lymphopenia or leukopenia 
- 
Amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis  


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- 
Isolated electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 
hours of their onset 
- 
Endocrinopathy adverse events that are adequately controlled with physiologic 
hormone replacement 
Duration of Treatment 
Treatment will be continued until the criteria for discontinuation is met. 
Criteria for discontinuation: 
1. The subject refuses to continue participation in the study or wishes to withdraw consent. 
2. Major violations of inclusion or exclusion criteria in the protocol are found after study 
enrollment. 
3. Subject is unable to continue the study due to an adverse event, in the opinion of the 
investigator or subinvestigator. 
4. The subject becomes pregnant. 
5. Progressive disease (when the principal investigator or subinvestigator and sponsor judges 
clinical benefit of lenvatinib plus nivolumab is maintained, it can be continued).  
6. The investigator or subinvestigator determines that discontinuation in the study is appropriate. 
Concomitant Drug/Therapy 
Prohibited Concomitant Medications/Therapies 
Subjects should not receive other antitumor therapies while on study.  If a subject receives 
additional antitumor therapies other than the study drug, 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.  
Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and measles, 
mumps, rubella [MMR]) are prohibited during treatment and until 30 days post last dose.  
The following medications are prohibited during the study.  During DLT evaluation in Part 1, 
preventive administration or changes in dose or medication should be prohibited until occurrence 
of a DLT. 
• Antiplatelet agents and anticoagulants that require INR monitoring, such as warfarin (treatments 
that do not require INR monitoring, such as low molecular weight heparin and certain factor X 
inhibitors are permitted). 
• Immunosuppressive agents (except to treat a drug-related adverse event) 
• Systemic corticosteroids > 10 mg daily prednisone equivalent (see the note below) 
 
Note: Following corticosteroids are allowed to use during the study. 
• Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption)  
• Adrenal replacement steroid doses >10 mg daily prednisone equivalent in the absence of active 
autoimmune disease. 
• Immunosuppressive doses of corticosteroids to treat adverse events (> 10 mg daily prednisone 
equivalent)  
• A brief course of corticosteroids (<3 weeks) for prophylaxis (eg, contrast agent allergy) or 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by 


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contact allergen) 
Assessments 
Efficacy 
All efficacy endpoints will be based on tumor assessments performed by the investigators using 
mRECIST. If necessary, independent review using mRECIST and RECIST1.1 will be performed 
(Part 2 only).  
 
Pharmacokinetic 
Plasma concentrations of lenvatinib and serum concentrations of nivolumab will be measured.   
Immunogenicity 
Anti-nivolumab antibody will also be measured. 
 
Pharmacodynamic/Pharmacogenomic 
Blood sample 
All subjects must provide blood sample for exploratory biomarker analysis.  
 
Tumor sample 
Archival tumor tissue must be provided for exploratory biomarker analysis and development of 
diagnostic product if available (Part 1 and Part 2). If not available, a newly obtained biopsy must be 
available prior to the first dose of study drug for biomarker analysis. Patients without archival tumor 
tissue and with inaccessible tumors for biopsy specimens can be enrolled without a biopsy (Part 2 
only).  
 
Safety 
Safety assessments will consist of monitoring and recording all 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, electrocardiograms (ECGs);  
echocardiograms or multigated acquisition (MUGA) scans including left ventricular ejection fraction 
(LVEF); and ECOG-PS. 
Bioanalytical Methods 
Validated methods will be used to measure plasma concentration of lenvatinib and serum 
concentration of nivolumab. In addition, ADA of nivolumab in serum and neutralizing antibody will 
be detected using validated methods. 
Statistical Methods 
Study Endpoints  
The following endpoints will be defined based on mRECIST (and RECIST 1.1; optional) except 
for OS.   
ORR is defined as the proportion of subjects who have BOR of CR or PR. 
DCR is defined as the proportion of subjects who have BOR of CR or PR or SD (duration from 
C1D1 to SD has to be ≥7 weeks). 
CBR is defined as the proportion of subjects who have BOR of CR or PR or durable SD (duration 
of SD ≥23 weeks). 
PFS is defined as the time from the first study dose date to the date of first documentation of 
disease progression or death (whichever occurs first) (Part 2 only). 


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TTP is defined as the time from the first study dose date to the date of first documentation of 
disease progression (Part 2 only). 
DOR is defined as the time from the first documentation of CR or PR to the date of first 
documentation of disease progression or death (whichever occurs first) (Part 2 only). 
TTR is defined as the time from the date of first study dose to the date of first documentation of 
CR or PR. (Part 2 only). 
OS is defined as the time from the date of first study dose to the date of death from any cause.  
Subjects who are lost to follow-up and the subjects who are alive at the date of data cutoff will be 
censored at the date the subject was last known alive or the cut-off date, whichever comes earlier 
(Part 2 only). 
Analysis Sets 
DLT Analysis Set will include all subjects (Part 1 only) who have completed Cycle 1 without 
major protocol deviation with at least 75% of lenvatinib compliance and at least 2 doses of 
nivolumab and are assessed for DLT, and subjects who have experienced DLT during Cycle 1.  
This will be the analysis set to determine tolerability. 
Safety Analysis Set will include all subjects who received at least 1 dose of lenvatinib or 
nivolumab. 
PK Analysis Set will include all subjects who have received at least 1 dose of lenvatinib and 
nivolumab, and have evaluable concentration data. 
The Efficacy Analysis Set will include all subjects who received at least 1 dose of lenvatinib and 
nivolumab. 
The Pharmacodynamic and PGx Analysis Set is the group of subjects who received at least 1 
dose of lenvatinib and nivolumab and had at least 1 postdose pharmacodynamic or PGx data. 
 
Efficacy Analyses 
Efficacy analyses will be conducted by part based on the Efficacy Analysis Set.  Tumor assessment 
will be analyzed based on the investigator’s assessment. If needed, the analysis based on 
independent review will be conducted.   
Part 1:  BOR will be summarized, and ORR and their corresponding exact 2-sided 95% 
confidence interval (CI) will be calculated.  DCR and CBR will be summarized in a same manner. 
 
Part 2:  In addition to the same analysis as above for Part 1, PFS will be summarized and plotted 
over time by Kaplan-Meier method.  TTP, DOR, TTR, and OS will be summarized similarly.  A 
waterfall plot will be presented for the percent changes from baseline in the sum of the diameters 
of target lesions at post-baseline nadir (ie, maximum tumor shrinkage).  A spider plot will be 
presented for the percent changes from baseline in the sum of the diameters of target lesions. 
 
Pharmacokinetic and/or Pharmacodynamic Analyses 
Pharmacokinetic 
The primary PK parameters of lenvatinib in the combination will be calculated by 
noncompartmental analysis using the PK analysis set (Part 1 only).  If warranted, additional 
analyses may be performed.  PK data for lenvatinib and nivolumab is planned to be analyzed using 
nonlinear mixed effects modeling.  PK data for lenvatinib and nivolumab may also be used to 
explore the exposure-response relationships for antitumor activity/efficacy as well as biomarkers 
and safety, if feasible.  The results of these analyses, if performed, will be reported separately.  


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Immunogenicity 
All immunogenicity analyses will be performed using the Safety Analysis Set.  The percentage and 
frequency of expression will be calculated for serum anti-nivolumab antibodies.  If anti-nivolumab 
antibody develops, presence of neutralizing antibody will be summarized using the frequency and 
percentage. 
Pharmacodynamic and Pharmacogenomics 
The effect of lenvatinib-nivolumab combination therapy on soluble and/or tissue biomarkers will 
be summarized using descriptive statistics.   
Tolerability/Safety Analyses 
All DLT analyses will be performed on the DLT Analysis Set.  The number and percentage of 
subjects with DLT will be calculated.  DLT will also be calculated by type. Safety analyses other 
than DLTs will be performed on the Safety Analysis Set.  All other safety analyses will be 
performed on the Safety Analysis Set by part.  The number and percentage of subjects with 
treatment-emergent AEs (TEAEs) and treatment-emergent SAEs will be summarized by system 
organ class (SOC) and preferred term (PT).  Safety data will be summarized using descriptive 
statistics (eg, n, mean, standard deviation, median, minimum, maximum for continuous variables; n 
[%] for categorical variables). 
Sample Size Rationale 
A sample size of approximately 26 subjects will be enrolled in this study, 6 patients for Part 1 and 
20 patients for Part 2.  Six subjects in Part 1 was deemed appropriate to evaluate the tolerability of 
the dose and perform preliminary safety assessment.  Twenty subjects in Part 2 was determined to 
further evaluate the safety and preliminary efficacy.  The probability to detect at least 1 
development of intolerable treatment-related AEs with a incidence of 10%, 15% or 20% in 20 
subjects was 87.8%, 96.1%, or 98.8%, respectively.  Therefore, the sample size is determined to be 
approximately 20 subjects. 
 
 


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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................14 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................19 
5 
ETHICS............................................................................................................................22 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................22 
5.2 
Ethical Conduct of the Study .................................................................................22 
5.3 
Subject Information and Informed Consent ...........................................................22 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................23 
7 
INTRODUCTION ...........................................................................................................23 
8 
STUDY OBJECTIVES ....................................................................................................24 
8.1 
Primary Objective ..................................................................................................24 
8.2 
Secondary Objectives.............................................................................................24 
8.3 
Exploratory Objective(s) ........................................................................................24 
9 
INVESTIGATIONAL PLAN ..........................................................................................25 
9.1 
Overall Study Design and Plan ..............................................................................25 
9.1.1 
Part 1 ............................................................................................................25 
9.1.2 
Part 2 ............................................................................................................26 
9.1.3 
Study Design ................................................................................................27 
9.1.3.1 
Pretreatment Phase ...............................................................................27 
9.1.3.2 
Treatment Phase ...................................................................................28 
9.1.3.3 
Follow-up Phase...................................................................................28 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................28 
9.3 
Selection of Study Population ................................................................................28 
9.3.1 
Inclusion Criteria .........................................................................................28 
9.3.2 
Exclusion Criteria ........................................................................................30 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................32 
9.3.3.1 
Discontinuation Criteria by Subject .....................................................32 
9.4 
Treatments..............................................................................................................33 
9.4.1 
Treatments Administered .............................................................................33 
9.4.1.1 
Lenvatinib ............................................................................................33 
9.4.1.2 
Nivolumab............................................................................................33 
9.4.1.3 
Criteria for Interruption of Treatment, Dose Reduction and 
Discontinuation of Treatment ..............................................................33 
9.4.1.3.1 
Cycle 1 (Part 1 only) ......................................................................33 
9.4.1.3.2 
Cycle 2 and onward (and applies to Cycle 1 and onward of Part 
2) ....................................................................................................34 


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9.4.1.4 
Management of Hypertension ..............................................................36 
9.4.1.5 
Management of Proteinuria ..................................................................37 
9.4.1.6 
Management Algorithms for Immuno-Oncology Agents ....................37 
9.4.2 
Identity of Investigational Products .............................................................38 
9.4.2.1 
Chemical Name, Structural Formula of Lenvatinib .............................38 
9.4.2.2 
Chemical Name, Structural Formula of Nivolumab ............................38 
9.4.2.3 
Comparator Drug .................................................................................39 
9.4.2.4 
Labeling for Study Drug ......................................................................39 
9.4.2.5 
Storage Conditions ...............................................................................39 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................39 
9.4.4 
Selection of Doses in the Study ...................................................................39 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................41 
9.4.6 
Blinding........................................................................................................41 
9.4.7 
Prior and Concomitant Therapy ...................................................................41 
9.4.7.1 
Drug-Drug Interactions ........................................................................41 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs .....................................41 
9.4.8 
Treatment Compliance .................................................................................42 
9.4.9 
Drug Supplies and Accountability ...............................................................42 
9.5 
Study Assessments .................................................................................................43 
9.5.1 
Assessments .................................................................................................43 
9.5.1.1 
Demography .........................................................................................43 
9.5.1.2 
Pretreatment Assessments ....................................................................43 
9.5.1.2.1 
Medical History and Current medical conditions ..........................43 
9.5.1.2.2 
Primary disease and Prior therapies for primary disease ...............43 
9.5.1.2.3 
Gastroenterological Endoscopy .....................................................44 
9.5.1.3 
Efficacy Assessments...........................................................................44 
9.5.1.3.1 
Tumor Assessments .......................................................................44 
9.5.1.3.2 
Tumor Marker ................................................................................45 
9.5.1.3.3 
Survival Follow-up ........................................................................45 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Assessments .............................................................45 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................45 
9.5.1.4.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments ...................................................................................46 
9.5.1.4.3 
Anti-nivolumab antibodies.............................................................48 
9.5.1.5 
Safety Assessments ..............................................................................49 
9.5.1.5.1 
Adverse Events ..............................................................................49 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................51 


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9.5.1.5.3 
Laboratory Measurements .............................................................51 
9.5.1.5.4 
Vital Signs and Weight Measurements ..........................................52 
9.5.1.5.5 
Physical Examinations ...................................................................53 
9.5.1.5.6 
Electrocardiograms ........................................................................53 
9.5.1.5.7 
ECHOCARDIOGRAM OR MULTIPLE GATED 
ACQUISITION SCAN ..................................................................53 
9.5.1.5.8 
ECOG PS .......................................................................................53 
9.5.1.5.9 
Other Safety Assessments ..............................................................53 
9.5.2 
Schedule of Procedures/Assessments ..........................................................54 
9.5.2.1 
Schedule of Procedures/Assessments ..................................................54 
9.5.3 
Appropriateness of Measurements ...............................................................57 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................57 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................57 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................57 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................58 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................58 
9.5.4.4 
Expedited Reporting ............................................................................59 
9.5.4.5 
Breaking the Blind ...............................................................................59 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................59 
9.5.5 
Completion/Discontinuation of Subjects .....................................................59 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................59 
9.5.7 
Confirmation of Medical Care by Another Physician .................................60 
9.6 
Data Quality Assurance .........................................................................................60 
9.6.1 
Data Collection ............................................................................................60 
9.6.2 
Clinical Data Management ..........................................................................60 
9.7 
Statistical Methods .................................................................................................60 
9.7.1 
Statistical and Analytical Plans ....................................................................61 
9.7.1.1 
Study Endpoints ...................................................................................61 
9.7.1.1.1 
Primary Endpoints .........................................................................61 
9.7.1.1.2 
Secondary Endpoints .....................................................................61 
9.7.1.1.3 
Exploratory Endpoints ...................................................................61 
9.7.1.2 
Definitions of Analysis Sets.................................................................62 
9.7.1.3 
Subject Disposition ..............................................................................62 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................63 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................63 
9.7.1.6 
Efficacy Analyses ................................................................................63 


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9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................64 
9.7.1.7.1 
Pharmacokinetic Analyses .............................................................64 
9.7.1.7.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses .........................................................................................64 
9.7.1.8 
Safety/Tolerability Analyses ................................................................64 
9.7.1.8.1 
Extent of Exposure .........................................................................64 
9.7.1.8.2 
Adverse Events ..............................................................................64 
9.7.1.8.3 
Laboratory Values ..........................................................................65 
9.7.1.8.4 
Vital Signs ......................................................................................66 
9.7.1.8.5 
Electrocardiograms ........................................................................66 
9.7.1.8.6 
Other Safety Analyses....................................................................66 
9.7.1.9 
Immunogenicity ...................................................................................66 
9.7.2 
Determination of Sample Size .....................................................................66 
9.7.3 
Interim Analysis ...........................................................................................67 
9.7.4 
Other Statistical/Analytical Issues ...............................................................67 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................67 
10 REFERENCE LIST .........................................................................................................68 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......69 
11.1 
Changes to the Protocol .........................................................................................69 
11.2 
Adherence to the Protocol ......................................................................................69 
11.3 
Monitoring Procedures...........................................................................................69 
11.4 
Recording of Data ..................................................................................................70 
11.5 
Identification of Source Data .................................................................................70 
11.6 
Retention of Records..............................................................................................71 
11.7 
Auditing Procedures and Inspection ......................................................................71 
11.8 
Handling of Study Drug .........................................................................................71 
11.9 
Publication of Results ............................................................................................72 
11.10 Disclosure and Confidentiality ..............................................................................72 
11.11 Discontinuation of Study .......................................................................................72 
11.12 Subject Insurance and Indemnity ...........................................................................73 
12 APPENDICES .................................................................................................................74 
 
LIST OF IN-TEXT TABLES 
Table 1 
Dose Limiting Toxicities ...........................................................................26 
Table 2 
Dose Adjustments of Lenvatinib ...............................................................34 
Table 3 
Dose Reduction Recommendations for Lenvatinib ...................................34 
Table 4 
Dose Delay and Resuming Dosing of Nivolumab .....................................35 


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Table 5  Blood Sampling Schedule for Pharmacokinetic Assessment of Lenvatinib........45 
Table 6 Blood Sampling Schedule for Pharmacokinetic Assessment of Nivolumab ........46 
Table 7  Blood Sampling Schedule for Anti-nivolumab Antibodies .................................48 
Table 8 
Clinical Laboratory Tests ...........................................................................52 
Table 9 
Schedule of Procedures/Assessments in Study E7080-J081-117 (for 
Part 1 and Part 2)........................................................................................55 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................27 
 
LIST OF APPENDICES 
Appendix 1 
American Association for the Study of Liver Diseases (AASLD) 
Criteria .......................................................................................................75 
Appendix 2 
Modified Response Evaluation Criteria in Solid Tumors (mRECIST) .....76 
Appendix 3 
Barcelona Clinic Liver Cancer (BCLC) Staging System ..........................79 
Appendix 4 
Child-Pugh Classification ..........................................................................80 
Appendix 5 
Eastern Cooperative Oncology Group Performance Status (ECOG-PS) ..81 
Appendix 6 
New York Heart Association (NYHA) Cardiac Disease Classification ....82 
Appendix 7 
Tumor, Node, and Metastasis (TNM) Staging of Hepatocellular 
Carcinoma ..................................................................................................83 
 


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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
AASLD 
American Association for the Study of Liver Diseases 
AFP 
α-fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
AUC(0-inf) 
area under the concentration-time curve from zero time 
extrapolated to infinite time 
AUC(0-t) 
area under the concentration-time curve from zero time to time 
of last quantifiable concentration 
BOR 
best overall response 
BUN 
blood urea nitrogen 
βhCG 
beta human chorionic gonadotropin 
CBR 
clinical benefit rate 
CL 
total clearance 
Cavgss 
average steady-state plasma concentration 
Cmax 
maximum observed concentration 
Cpeak 
concentration at end of infusion 
Ctrough 
trough drug concentration at steady-state 
CR 
complete response 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
C#D# 
Cycle# Day# 
DNA 
deoxyribonucleic acid 
DCR 
disease control rate 
DOR 
Duration of response 
DLT 
dose limiting toxicity 
ECOG 
Eastern Cooperative Oncology Group 
 


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FDA 
United States Food and Drug Administration 
FFPE 
formalin fixed, paraffin-embedded 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
γ-GTP 
gamma glutamyl transferase 
HBc 
hepatitis B virus core 
HBs 
hepatitis B virus surface 
HBV 
hepatitis B virus 
hCG 
human chorionic gonadotropin 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonization 
LDH 
lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition technique 
mRECIST 
modified Response Evaluation Criteria in Solid Tumor 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PD-1 
Programmed cell death-1 
PDGF 
platelet derived growth factor 
PDGFRα 
platelet derived growth factor receptor α 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PR  
partial response 


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PS 
performance status 
PT 
preferred term 
QOL 
quality of life 
QT 
QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RNA 
ribonucleic acid 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SD 
stable disease 
SOC 
system organ class 
SOP 
standard operating procedure 
SPO2 
percutaneous oxygen saturation 
t½ 
terminal elimination phase half-life 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment emergent markedly abnormal laboratory values 
tmax 
time at which the highest drug concentration occurs 
TNM 
tumor, nodes, metastasis 
ULN 
upper limit of normal 
VEGF 
vascular endothelial growth factor 
VEGFR 
vascular endothelial growth factor receptor 
Vss 
volume of distribution at steady-state 
WHO DD 
World Health Organization Drug Dictionary 
 


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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with 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 of telephone numbers).  
Documentation of IRB compliance with 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 GCP.  The investigator or the sponsor will 
submit, depending on local regulations, periodic reports and inform the investigator, the head 
of the medical institution, and the relevant IRB via the head of the medical institution of any 
reportable adverse events (AEs) per GCP guidelines and local IRB standards of practice.  
Upon completion of the study, the investigator will provide the IRB and sponsor via the head 
of the medical institution 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 GCP guidelines as required 
by the following: 
• 
Principles of the World Medical Association Declaration of Helsinki 
• 
GCP 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator or subinvestigator 
must explain to each subject the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved, any potential discomfort, 
potential alternative procedure(s) or course(s) of treatment available to the subject, and the 
extent of maintaining confidentiality of the subject’s records.  Each subject must be informed 
that participation in the study is voluntary, that he/she may withdraw from the study at any 
time, and that withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. 


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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 are 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 by the investigator in 
accordance with GCP and all applicable local regulations in collaboration with the sponsor.  
Each subject must sign an approved ICF before study participation.  The form must be signed 
and dated by the investigator or subinvestigator (and clinical research coordinator, if needed).  
The original, signed ICF for each subject will be verified by the sponsor and kept on file 
according to local procedures at the site.   
The subject should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the study.  The 
communication of this information should be documented. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators under the sponsor in Japan (1 site for 
Part 1, not determined for Part 2). 
The name and telephone and fax numbers of the contact personnel at the sponsor are listed in 
the Attachment. 
7 
INTRODUCTION 
Primary liver cancer is the 6th most common cancer and is the 2nd most common cause of 
cancer-related death worldwide.  Hepatocellular carcinoma (HCC) represents more than 90% 
of primary liver cancer.  The majority of HCC occurs in Asia or Africa, however, the 
incidence has been rising in a number of low-rate areas including Europe and the United 
States. 
The prognosis for advanced HCC is very poor.  Although therapies including arterial infusion 
and radiation therapy have been tried, none has proven highly successful.  Sorafenib is the 
current standard of therapy for advanced HCC patients following clinical results from the 2 
pivotal trials in Western and Asian patients.  Regorafenib was approved for the second-line 
treatment of patients with unresectable hepatocellular carcinoma who have progressed after 
treatment with cancer chemotherapy. 
E7080/lenvatinib was developed at Eisai Tsukuba Research Laboratories.  Lenvatinib 
selectively inhibits VEGF receptors, KDR (VEGFR2), and is being developed as a novel 


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anticancer therapy through inhibition of angiogenesis.  A multinational Phase 3 study in 
subjects with HCC demonstrated noninferiority of lenvatinib to sorafenib for overall survival 
(OS).  
ONO-4538/nivolumab is a human anti-human programmed death-1 (PD-1, also known as 
CD279) monoclonal antibody, developed by Ono Pharmaceutical and Medarex (current 
Bristol-Myers Squibb).  Clinical development program of nivolumab is currently underway 
by Ono Pharmaceutical and Bristol-Myers Squibb.  Nivolumab is approved in many 
countries including the United States, European Union, and Japan. Nivolumab monotherapy 
has shown clinical benefit in HCC patients who have previously been treated with sorafenib 
and has been approved for use in the United States and elsewhere.  In addition, an 
international phase 3 study comparing nivolumab and sorafenib in progressed HCC patients 
who have not been treated with systemic chemotherapy (ONO-4538-35 / CA209459), and an 
international phase 3 study comparing the combination of nivolumab and ipilimumab with 
sorafenib or lenvatinib in progressed HCC patients who have not been treated 
(ONO-4538-92/CA2099DW) is currently ongoing. 
Unmet medical needs in the treatment of HCC still exist, and nivolumab is effective across a 
broad range of tumor types.  The current study is designed to evaluate the safety and efficacy 
of a combination of lenvatinib plus nivolumab in subjects with HCC. 
8 
STUDY OBJECTIVES 
8.1 
Primary Objective 
• 
To evaluate the tolerability and safety for combination of lenvatinib plus nivolumab in 
subjects with hepatocellular carcinoma (HCC) 
 
8.2 
Secondary Objectives 
• 
To evaluate the following efficacy endpoints based on investigator review in subjects 
with HCC: 
- 
Objective response rate (ORR) 
• 
To assess the pharmacokinetic (PK) profile of lenvatinib and nivolumab  
 
8.3 
Exploratory Objective(s) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


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9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study will be conducted in 2 parts (Part 1 and Part 2).  Part 1 will assess the tolerability 
of lenvatinib in combination with nivolumab in subjects with HCC for which no other 
appropriate therapy is available.  Part 2 is to further characterize the safety and to assess 
preliminary efficacy of the combination therapy in subjects with HCC with no prior systemic 
therapy.  
9.1.1 
Part 1 
In Part 1, the tolerability review of Cycle 1 (4 weeks) will be conducted by dose limiting 
toxicities (DLTs).  Study treatment and starting dose are as follows: 
Lenvatinib: 12 mg (Body weight [BW] ≥60 kg) or 8 mg (BW <60 kg) once daily orally 
Nivolumab: 240 mg (every 2 weeks [Q2W], intravenous [IV]) (Days 1 and 15 of each cycle) 
The tolerability will be reviewed based on dose limiting toxicity (DLT) of Cycle 1 (4 weeks) 
according to the following procedures and criteria. 
First, 3 subjects will be enrolled. 
7. DLT occurs in 0 or 1 of 3 subjects. 
Add 3 more subjects and assess in a total of 6 subjects.  
1. DLT occurs in 0 or 1 of 6 subjects. 
This dose level is judged to be tolerable. 
2. DLT occurs in 2 or more of 6 subjects. 
The tolerability with this dose level will be discussed by the sponsor, sponsor’s 
responsible medical officer, and investigator.  
8. DLT occurs in 2 or more of 3 subjects. 
The tolerability with this dose level and appropriateness of additional enrollment will 
be discussed by the sponsor, sponsor’s responsible medical officer, and investigator.  
In this dose level, at least 3 subjects treated with lenvatinib 12 mg (BW ≥60 kg) and 
nivolumab need to be included in the 6 subjects for DLT evaluation. If this dose level is not 
tolerable, upon discussions between the sponsor, sponsor’s responsible medical officer, and 
CCI


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investigator, the lower dose level of cohort will be considered or the study will be 
discontinued, and the protocol will be amended as necessary. An efficacy and safety 
evaluation advisor may be consulted for the consideration as needed. 
 
A DLT is defined as any of the events noted in the table below considered to be at least possibly related 
to lenvatinib and/or nivolumab occurring during Cycle 1. 
 
Table 1 
Dose Limiting Toxicities 
Hematologic 
toxicity 
• 
Febrile neutropenia 
• 
Grade 4 neutropenia lasting >7 days 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 thrombocytopenia lasting >7 days or associated with 
bleeding 
• 
Grade 4 anemia 
Nonhematologic 
Toxicity 
(Hepatotoxicity) 
• 
Clinical deterioration manifested by drug-related hepatic 
decompensation (eg, encephalopathy etc.) 
• 
AST or ALT > 15×ULN 
• 
AST/ALT >10.0×ULN lasting > 7 days or associated with clinical 
symptom 
• 
Total bilirubin > 5×ULN (for subjects with increased bilirubin at 
baseline, total bilirubin > 8×ULN) 
Nonhematologic 
Toxicity (General) 
• 
Grade 4 nonhematologic toxicity (excluding laboratory 
abnormalities with no clinical significance) 
• 
Grade 3 gastrointestinal perforation, thromboembolic event, uveitis, 
pneumonitis, bronchospasm, hypersensitivity reaction, infusion 
reaction, or wound dehiscence requiring treatment 
• 
Grade 3 toxicities lasting >3 days despite optimal supportive 
therapies (excluding abnormal laboratory values with no clinical 
significance or controllable hypertension) 
• 
Grade 2 uveitis, eye pain, or blurred vision that does not respond to 
topical therapy and does not improve to Grade 1 within the re-
treatment period or requires systemic treatment 
• 
Eight or more days of dose interruption of lenvatinib as a result of 
lenvatinib or nivolumab treatment-related toxicity during Cycle 1* 
* For reasons other than toxicity, this will not be considered as a DLT. In this situation, the relevant subject 
will be excluded from assessments of DLT and new subject will be added.  DLT was determined after 
discussions among the sponsor, the investigator, and the sponsor’s responsible medical officer.  An 
efficacy and safety evaluation advisor may be consulted for the consideration as needed. 
9.1.2 
Part 2 
If the dose level is confirmed to be tolerable in Part 1, an additional 20 HCC subjects with no 
prior systemic therapy will be enrolled. At least 5 subjects (BW ≥60 kg) treated with 


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lenvatinib 12 mg QD and at least 5 subjects (BW <60 kg) treated with lenvatinib 8 mg QD 
will be included. 
9.1.3 
Study Design 
An overview of the study design is presented in Figure 1.  Part 1 and Part 2 will consist of a 
Pretreatment Phase, a Treatment Phase, and a Follow-up Phase. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 
Study Design 
DLT = dose limiting toxicity. 
a:  Screening assessment should be performed within 14 days of first dose. (Informed consent can be obtained 
within 28 days of first dose.)  
9.1.3.1 
Pretreatment Phase 
The Pretreatment Phase will involve obtaining informed consent, a screening assessment, and 
a baseline assessment.  Screening will occur within 14 days before starting study drug 
administration after obtaining written informed consent.  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 (informed consent can be obtained within 28 days of 
first dose).  After screening assessments, the sponsor will be informed of eligibility of the 
patient by the investigator or subinvestigator.  The baseline assessment will be conducted 
within 4 days before starting study drug administration in order to confirm that the patient 
meet the eligibility requirement before moving to the Treatment Phase. 
Survival follow-up 
every 12±2 weeks 
(Part 2 only) 
Pretreatment Phase 
Treatment Phase 
Screening 
Baseline 
Cycle 2 and later 
Cycle 1 
Informed consent 
Treatment initiation 
Eligibility confirmation 
28-days cycles 
Last dose 
Discontinuation 
Within 
4 days 
DLT evaluation 
(Part 1 only) 
Within 14 daysa 
Follow-up Phase 
Last observation 
30 days (+7 days) after 
last dose 
Screening assessment 
Baseline assessment 


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9.1.3.2 
Treatment Phase 
In the Treatment Phase, subjects will receive lenvatinib in combination with nivolumab.  The 
Treatment Phase will begin with the first dose of study drug administration on Cycle 1 Day 
1.  Each cycle is 4 weeks long and subjects will continue treatment until they meet any of the 
criteria in “Discontinuation Criteria by Subject (see Section 9.3.3.1)”.   
In Part 1, subjects will be hospitalized during the Cycle 1, however, outpatient is allowed 
after Cycle 1 Day 15, when the investigator or subinvestigator judges that the subject’s safety 
is ensured.   
9.1.3.3 
Follow-up Phase 
The Follow-up Phase will consist of the examination at study discontinuation and the last 
observation visit which occurs 30 days after final administration of study drug.  The subject 
who discontinues study will have a discontinuation visit and last observation which occurs 30 
days after final administration of study drug.  If a new anticancer agent needs to be 
immediately started due to deterioration in the subject’s condition, the final observation visit 
can be conducted before 30 days after the last dose of the study drug has passed but prior to 
starting a new anticancer agent.  If the last observation visit occurs within 7 days after study 
drug discontinuation, discontinuation data can be used as the last observation data.   
In Part 2, all subjects will be followed for survival until death every 12 weeks (±2 week) 
from the date of discontinuation, except where a subject withdraws consent or the sponsor 
chooses to halt survival follow-up.  The survival follow-up will be continued until 
discontinuation of the last subject or for up to 2 years after Cycle 1 Day 1 of the last subject 
enrolled in Part 2, whichever occurs later.  
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is the study to evaluate the tolerability and safety and to explore the efficacy of a 
combination of lenvatinib plus nivolumab in subjects with HCC.  In view of seriousness in 
targeted subjects and ethical conduct of the study, placebo group will not be employed and 
open design will be used.   This study was designed according to “The Guidelines for 
Clinical Evaluation of Anti-Cancer Drugs in Japan (Notification No. 1101001 issued on 
November 1, 2005).” 
9.3 
Selection of Study Population 
Approximately 26 subjects (6 in Part 1, 20 in Part 2) will be enrolled at sites in Japan (1 site 
for Part 1, TBD for Part 2).  Subjects who do not meet all of the inclusion criteria or who 
meet any of the exclusion criteria will not be eligible to receive study drug. 
9.3.1 
Inclusion Criteria 
1. Subjects must have confirmed diagnosis of HCC with any of the following criteria:  
• Histologically or cytologically confirmed diagnosis of HCC, excluding 
fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors 


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• Clinically confirmed diagnosis of HCC according to American Association for the 
Study of Liver Diseases (AASLD) criteria (Appendix 1), including cirrhosis of any 
etiology and/or chronic hepatitis B or C infection 
2. Part 1:  HCC for which no other appropriate therapy is available 
Part 2:  No prior systemic therapy for advanced/unresectable HCC 
3. Subjects categorized to stage B (not applicable for transarterial chemoembolization 
[TACE]), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system 
(Appendix 3) 
4. At least 1 measurable target lesion according to mRECIST meeting the following criteria 
(Lesions previously treated with radiotherapy or locoregional therapy must show 
radiographic evidence of disease progression to be deemed a target lesion).  
• Hepatic lesion 
i. 
The lesion can be accurately measured in at least 1 dimension as ≥1.0 cm 
(viable tumor for typical; and longest diameter for atypical) 
• Nonhepatic lesion 
i. 
Lymph node (LN) lesion that measures at least 1 dimension ≥1.5 cm in the 
short axis, except for porta hepatis LN that measures ≥2.0 cm in the short axis 
ii. 
Non-nodal lesion that measures ≥1.0 cm in the longest diameter 
5. Child-Pugh score A 
6. Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status 
(PS) of 0 to 1 
7. Adequately controlled blood pressure (BP) with or without antihypertensive medications, 
defined as BP ≤150/90 mmHg at Screening and no change in antihypertensive 
medications within 1 week prior to the C1D1  
8. 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 
9. Adequate bone marrow function:  
• Absolute neutrophil count (ANC) ≥1500/mm3 (≥1.5×103/μL) 
• Platelets ≥75,000/mm3 (≥75×109/L) 
• Hemoglobin ≥8.5 g/dL 
10. Adequate blood coagulation function as evidenced by an International Normalized Ratio 
(INR) ≤2.3 
11. Adequate liver function, defined as:  
• Bilirubin ≤2.0 mg/dL 
• Aspartate aminotransferase (AST), alkaline phosphatase (ALP), and alanine 
aminotransferase (ALT) ≤5×ULN 
12. Age ≥20 years at the time of informed consent   
13. Life expectancy of 12 weeks or more 
14. Voluntary agreement to provide written informed consent and the willingness and ability 
to comply with all aspects of the protocol  
15. Meet the following criteria 


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(1) If patients have an archival tumor sample, they have to agree to submit it to sponsor.  
(2) (Part 2 only) Patients who agree to submit tumor sample obtained by fresh biopsy 
prior to the first dose of study drug (excluding patients with archival tumor sample or 
with inaccessible tumors of safety concern) 
9.3.2 
Exclusion Criteria 
1. Imaging findings for HCC corresponding to any of the following (Part 1 only): 
• 
HCC with ≥50% liver occupation 
• 
Clear invasion into the bile duct 
• 
Portal vein invasion with Vp4 
2. Prior anticancer treatment within 28 days (or within 14 days in case of sorafenib and 
regorafenib) or any investigational agent within 28 days prior to the first dose of study 
drugs.  
3.  All toxicities related to prior treatments have not resolved to Grade ≤1 (except alopecia 
and controlled stable cases).  
4. Any blood enhancing treatment (including blood transfusion, blood products, or agents 
that stimulate blood cell production, eg, granulocyte colony-stimulating factor [G-CSF]) 
within 28 days prior to the first dose of study drugs  
5. Prior treatment with lenvatinib, ONO-4538 (MDX-1106 or BMS-936558), any anti-PD-
1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody 
or drug specifically targeting T-cell regulation, or cancer vaccine therapy 
6. Subjects who has not recovered adequately from any complications from major surgery 
prior to starting therapy.  
7. Subjects having ≥2+ proteinuria on urinalysis (subjects with Grade ≤1 confirmed by 
quantitative assessment will be eligible).  
8. Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that 
might affect the absorption of lenvatinib. 
9. New York Heart Association (Appendix 6) 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. 
10. Prolongation of QTc (Fridericia formula) interval to >480 ms 
11. Gastrointestinal bleeding event or active hemoptysis (bright red blood of at least 0.5 
teaspoon) within 3 weeks prior to the first dose of study drug 
12. Bleeding or thrombotic disorders or use of anticoagulants requiring therapeutic INR 
monitoring, eg, warfarin or similar agents.  Treatment with low molecular weight heparin 
and factor X inhibitors which do not require INR monitoring is permitted.  Antiplatelet 
agents are prohibited throughout the study.  
13. Gastric or esophageal varices that require interventional treatment within 28 days prior to 
first dose of study drug are excluded.  Prophylaxis with pharmacologic therapy (eg, 
nonselective beta-blocker) is permitted.  
14. Surgical arterial-portal venous shunt or arterial-venous shunt 


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15. Active malignancy (except for HCC or definitively treated melanoma in-situ, basal or 
squamous cell carcinoma of the skin, or carcinoma in-situ of the cervix, or carcinoma in 
situ including early gastric cancer) within the past 36 months 
16. Active infection (any infection requiring systemic treatment).  Hepatitis B and C 
[HBV/HCV] allowed (subjects with chronic HBV infection must have HBV DNA < 100 
IU/mL and must be on antiviral therapy.) 
17. Active co-infection with: 
4)Both hepatitis B and C as evidenced by detectable HBV surface antigen or HBV DNA 
and HCV RNA, OR 
5)Hepatitis D infection in subjects with hepatitis B 
18. Pre-existing thyroid abnormality with thyroid function that cannot be maintained in the 
normal range with medication. 
19. Subjects with any active, known, or suspected autoimmune disease, with the following 
exceptions: 
1)Subjects with vitiligo, type 1 diabetes mellitus, resolved childhood asthma or atopy are 
permitted to enroll. 
2)Subjects with suspected autoimmune thyroid disorders may be enrolled if they are 
currently euthyroid or with residual hypothyroidism requiring only hormone 
replacement. 
3)Subjects with psoriasis requiring systemic therapy must be excluded from enrollment 
20. Any history of interstitial lung disease, and interstitial lung disease that is symptomatic or 
may interfere with the detection and management of suspected drug-related pulmonary 
toxicity 
21. Subjects with a condition requiring systemic treatment with either corticosteroids 
(>10 mg/day prednisone equivalent) or other immunosuppressive medications within 
14 days of study administration.  Inhaled or topical steroids and adrenal replacement 
doses >10 mg/day prednisone equivalents are permitted in the absence of active 
autoimmune disease. 
22. Subjects with meningeal carcinomatosis 
23. Subjects with any current brain or subdural metastases 
24. Subjects who are known to be positive for Human Immunodeficiency Virus (HIV).  
25. History of clinically significant hepatic encephalopathy 
26. Serious nonhealing wound, ulcer, or bone fracture 
27. Any subject who cannot be evaluated by either triphasic liver computed tomography (CT) 
or triphasic liver magnetic resonance imaging (MRI) because of allergy or other 
contraindication to both CT and MRI contrast agents 
28. Subjects being treated with drugs that strongly inhibit or induce CYP3A4 and that may be 
possibly used during this study.  
29. Any medical or other condition which, in the opinion of the investigator, would preclude 
participation in a clinical trial 
30. 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).  A separate baseline assessment is required if a negative screening pregnancy 


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test was obtained more than 72 hours before the first dose of study drug (females who 
discontinued breastfeeding will be eligible) 
31. Women of childbearing potential or man of impregnate potential who don’t agree that 
both the subject and her partner will use the following methods of contraception for 
periods from before informed consent to during the clinical study and 5 months later (for 
male subjects 30 days) from last administration of study drug.  For contraception method, 
subject must agree to use any 2 of the following methods: vasectomy or condom for a 
male subject or partner, bilateral tubal ligation, diaphragm, intrauterine device, or use of 
oral contraception from at least 28 days before starting the study treatment for a female 
subject or partner. 
32. Participants who have received a live/attenuated vaccine within 28 days of first dose of 
study drugs 
 
9.3.3 
Removal of Subjects From Therapy or Assessment 
The investigator or subinvestigator 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 complete protocol-specified discontinuation visits and 
procedures and survival follow-up unless the subject withdraws consent.  If a subject 
withdraws consent, the date will be documented in the source documents.   
In Part 2, all subjects will be followed for survival until death every 12 weeks (±2 week) 
from the date of discontinuation, except where a subject withdraws consent or the sponsor 
chooses to halt survival follow-up.  The survival follow-up will be continued until 
discontinuation of the last subject or for up to 2 years after Cycle 1 Day 1 of the last subject 
enrolled in Part 2, whichever occurs later. 
9.3.3.1 
Discontinuation Criteria by Subject 
If a subject meets any of the following criteria, the investigator will discontinue treating a 
subject with study treatment. 
1. The subject refuses to continue participation in the study or wishes to withdraw consent. 
2. Major violations of inclusion or exclusion criteria in the protocol are found after study 
enrollment. 
3. Subject is unable to continue the study due to an adverse event, in the opinion of the 
investigator or subinvestigator. 
4. The subject becomes pregnant. 
5. Progressive disease (when the investigator or subinvestigator judges clinical benefit of 
lenvatinib plus nivolumab is maintained, it can be continued).  
6. The investigator or subinvestigator determines that discontinuation in the study is 
appropriate. 
 


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9.4 
Treatments 
For this study, the study drugs are E7080/lenvatinib and ONO-4538/nivolumab.  
9.4.1 
Treatments Administered 
9.4.1.1 
Lenvatinib 
Lenvatinib is provided as 4-mg capsule.  Lenvatinib will be administered once a day (with or 
without food) in 4-week cycles at approximately the same time each day.  On Day 1 and Day 
15 of each cycle, in case concomitantly administered, it will be administered immediately 
after completion of nivolumab administration. 
Starting dose of lenvatinib will be based on baseline BW as follows: 
• 
BW ≥60 kg — 12 mg QD.  Study subjects will be orally administered lenvatinib as three 
4-mg capsules. 
• 
BW <60 kg — 8 mg QD.  Study subjects will be orally administered lenvatinib as two 4-
mg capsules. 
 
9.4.1.2 
Nivolumab 
Nivolumab injection for intravenous infusion contains 100 mg/10 mL of nivolumab in each 
vial.  Nivolumab will be administered at a dose of 240 mg as an IV infusion over 30 minutes, 
Q2W (Day 1 and Day 15 of each cycle).  Please refer to the current version of the 
Investigator’s Brochure (IB) and instructions for handling of investigational products for 
complete storage, preparation and administration information for nivolumab. 
9.4.1.3 
Criteria for Interruption of Treatment, Dose Reduction and Discontinuation of 
Treatment 
9.4.1.3.1 CYCLE 1 (PART 1 ONLY) 
1. If DLT occurs:  
Relationship of the DLT to lenvatinib and/or nivolumab will be evaluated, then lenvatinib 
and/or infusion of nivolumab should be interrupted or discontinued immediately.  Treatment 
may be resumed at the same dose level of nivolumab and at 1 lower dose level of lenvatinib 
if toxicity is resolved to Grade 0–1 (or tolerable Grade 2 for hematologic toxicities and 
proteinuria in case of lenvatinib) or baseline, when investigator or subinvestigator decides to 
continue the study.  
2. No DLT occurs: 
Relationship of the DLT to lenvatinib and/or nivolumab will be evaluated, then lenvatinib 
and/or nivolumab will be interrupted.  Dose adjustments for management of intolerable 
toxicities will be made according to the guidelines provided in the table below.  Lenvatinib 
and nivolumab should be resumed at the same dose level, and dose reduction is not allowed.   


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9.4.1.3.2 CYCLE 2 AND ONWARD (AND APPLIES TO CYCLE 1 AND ONWARD OF PART 2) 
Relationship to lenvatinib and/or nivolumab will be evaluated, then necessity of dose 
modification (either or both drugs) will be determined.  Dose adjustments for management of 
intolerable toxicities will be made according to the guidelines provided in the table below. 
9.4.1.3.2.1 Criteria for Interruption of Treatment, Dose Reduction, and Discontinuation 
of Lenvatinib 
Dose adjustments for management of intolerable toxicities will be made according to the 
guidelines shown in Table 2.  Lenvatinib dose should be reduced as shown in Table 3.  For 
management of hypertension, refer to Section 9.4.1.4 without consulting the table below. 
Table 2 
Dose Adjustments of Lenvatinib 
Treatment-Related Toxicity a,b 
Dose Adjustment 
Hematologic Toxicities 
and Proteinuria 
Grade 3 c 
Interrupt until resolved to Grade 0-2 or baseline. In the first 
occurrence, dose should not be changed. In the second 
occurrence or later, reduce lenvatinib by 1 dose level.  
Grade 4 
Interrupt until resolved to Grade 0-2 or baseline. Reduce 
lenvatinib by 1 more dose level.  
Nonhematologic 
Toxicities 
Intolerable 
Grade 2d 
Dose of lenvatinib will be reduced by 1 dose level with or 
without dose interruption. 
Grade 3c,e,f 
Interrupt until resolved to Grade 0-1 or baseline. Reduce 
lenvatinib by 1 dose level. 
Grade 4 f, g 
Discontinue lenvatinib 
a:  An interruption of lenvatinib for more than 28 days (due to treatment-related toxicities) will require discussion with the 
sponsor before treatment can be resumed.  During treatment interruption, repeat AEs assessment about every 7 days (until 
restarting administration).  
b:  Initiate optimal medical management for nausea, vomiting, diarrhea, and/or hypothyroidism prior to interruption or dose 
reduction of lenvatinib.  
c:  Not applicable to abnormal clinical laboratory values that are not clinically significant based on the judgment of the 
investigator or subinvestigator. 
d:  Grade 2 toxicities will be determined to be tolerable or intolerable by both the subject and investigator or subinvestigator.   
e:  Obese subjects with weight loss do not need to return to baseline or Grade 1 weight loss to restart lenvatinib.  There 
should be no weight loss for at least 1 week, and subjects should be started at the lower dose.  
f:  For asymptomatic Grade ≥3 elevations of amylase and lipase, sponsor should be consulted to obtain permission to 
continue treatment. 
g:  Excluding laboratory abnormalities judged to be nonlife-threatening, which should be managed as Grade 3.  
 
Table 3 
Dose Reduction Recommendations for Lenvatinib 
Initial Lenvatinib Dose (mg, QD) 
Adjusted Dose To Be Administered (mg, QD) 
Reduction 1 
Reduction 2 
Reduction 3 
12 
8 
4 
4QODa  
8 
4 
4QODa 
 
a:  4 mg every other day [QOD].  Any dose reduction below 4 mg every other day must be discussed with the sponsor. 
 


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9.4.1.3.2.2 Criteria for Delay of Treatment, Resumption, and Discontinuation of 
Nivolumab 
9.4.1.3.2.2.1 Criteria for Delay of Treatment and Resumption of Nivolumab 
Dose adjustments for management of intolerable toxicities will be made according to the 
guidelines shown in Table 4. 
Table 4 
Dose Delay and Resuming Dosing of Nivolumab 
Treatment-Related 
Toxicitya 
Dose Delay Criteria 
Criteria to Resume Dosing 
Skin-related adverse 
event 
Grade 3 
Grade ≤ 1 or baseline value 
Fatigue 
Grade 3 
Grade ≤2 
Laboratory abnormality 
(except for AST/ALT) 
Grade 3 (except for amylase or lipase 
abnormalities that are not associated 
with symptoms or clinical 
manifestations of pancreatitis) 
Grade ≤ 1 or baseline value 
(T-Bil: baseline CTCAE Grade or 
normal) 
AST/ALT 
Baseline AST/ALT is within normal 
limits: Grade ≥2. 
Baseline AST/ALT is Grade 1: Grade 
≥3. 
Baseline AST/ALT is Grade 2: ≥two-
fold of baseline value or ≥8x ULN  
Baseline CTCAE Grade or normal 
Pulmonary toxicity, 
diarrhea, or colitis 
Grade≥2 
Baseline 
Others 
Grade ≥2 
Grade ≤ 1 or baseline value 
(Endocrinopathies adequately 
controlled with only physiologic 
hormone replacement may resume 
treatment.) 
ULN: upper limit of normal. 
a:  A delay of nivolumab for more than 6 weeks will require sponsor’s approval before treatment can be resumed.  
 
9.4.1.3.2.2.2 Discontinuation Criteria of Nivolumab 
Nivolumab treatment should be discontinued for the following AEs related to nivolumab: 
• 
Any Grade 2 uveitis, eye pain or blurred vision that does not respond to topical therapy 
and does not improve to Grade 1 severity within the re-treatment period or requires 
systemic treatment. 
• 
Any Grade 3 uveitis, pneumonitis, bronchospasm, hypersensitivity reaction, or infusion 
reaction. 
• 
Any Grade 3 thrombocytopenia lasting >7 days or associated with bleeding. 
• 
Any Grade 3 AE lasting >7 days, with the exceptions of skin, laboratory abnormalities, 
endocrinopathies adequately controlled with only physiologic hormone replacement. 
• 
Any hepatotoxicity as below: 


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- 
AST or ALT >10×ULN for >2 weeks 
- 
AST or ALT >15×ULN 
- 
For subjects with total bilirubin ≤ULN at baseline:  total bilirubin >5×ULN 
- 
For subjects with increased bilirubin at baseline:  total bilirubin >8×ULN 
• 
Any Grade 4 AE or laboratory abnormality, except for the following 
- 
Neutropenia <7 days 
- 
Lymphopenia or leukopenia 
- 
Amylase or lipase abnormalities that are not associated with symptoms or clinical 
manifestations of pancreatitis.  
- 
Isolated electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 
72 hours of their onset. 
- 
Endocrinopathy adverse events that are adequately controlled with physiologic 
hormone replacement. 
 
9.4.1.4 
Management of Hypertension 
Guidelines for assessment and management of hypertension are summarized as follows. 
CTCAE v4.03 grading for hypertension will be based on BP measurements only (and not on the 
number of antihypertensive medications). 
1. When blood pressure (BP) is elevated (systolic BP ≥140 mmHg or diastolic BP ≥90 
mmHg), BP measurement should be repeated at least 5 min apart.  In this case, BP 
assessment is defined as the mean value of two measurements at least 5 minutes apart. 
2. When systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg is observed in the 1st BP 
assessment, the 2nd BP assessment should be repeated at least 30 min apart.  The 2nd BP 
assessment is defined as the mean value of two measurements at least 5 minutes apart. 
For previously normotensive subjects, monotherapy with one of the classes of 
antihypertensives should be started when systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg 
is firstly observed on the 2nd BP assessment.  For those subjects already on 
antihypertensive medication, the dose of the current agent may be increased, if 
appropriate, or one or more agents of a different class of antihypertensives should be 
added.  
3. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg continues despite optimal 
management of hypertension, lenvatinib should be interrupted and resumed according to 
Table 3 at a dose of one-dose level reduction only when systolic BP ≤150 mmHg and 
diastolic BP ≤95 mmHg and the subject has been on a stable dose of antihypertensive 
medication for at least 48 hours.   
4. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg recurs despite the optimal 
management of hypertension, one-dose level reduction should be attempted. 
5. Discontinue lenvatinib administration when Grade 4 hypertension (life-threatening) is 
present. 
 


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9.4.1.5 
Management of Proteinuria 
Guidelines for assessment and management of proteinuria are summarized as follows. 
• 
Initial episode of proteinuria: if proteinuria ≥2+ is detected on urinalysis, lenvatinib and 
nivolumab will be continued and a 24-hour urine collection for total protein or a spot 
urine protein/creatinine ratio will be obtained as soon as possible to verify the grade of 
proteinuria.  Grading according to the National Cancer Institute’s (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE v4.03) will be based on the 24-hour 
urinary protein result or urine protein/creatinine ratio.  Management of lenvatinib 
administration will be based on the grade of proteinuria according to the Dose 
Adjustment provided in Table 2. 
• 
Recurrence or deterioration of proteinuria: if proteinuria 3+ or 4+ on urine dipstick is 
detected, lenvatinib and nivolumab will be continued and a 24-hour urine collection for 
total protein or a spot urine protein/creatinine ratio will be obtained as soon as possible to 
verify the grade of proteinuria.  Management of study drug administration will be based 
on the grade of proteinuria according to the Dose Adjustment provided in Table 2. 
• 
If an event of proteinuria ≥2 occurs, the subject must undergo urine dipstick testing (on 
Day 15 or more frequently if clinically indicated) until results are 1+ or negative for 3 
consecutive months. 
 
9.4.1.6 
Management Algorithms for Immuno-Oncology Agents 
The following groups of AEs will be managed by “Appendix 3 Management Algorithms” 
found in the current nivolumab IB: 
• 
Gastrointestinal 
• 
Renal 
• 
Pulmonary 
• 
Endocrinopathy 
• 
Skin 
• 
Neurological 
 
Please note that management algorithms of this protocol for the hepatic AEs are changed as 
below: 
• 
If AST or ALT elevation does not improve in 3 to 5 days of dose delay or worsen, 
methylprednisolone 0.5 to 2 mg/kg or oral steroids equivalent will start. 
• 
If AST or ALT >8×ULN occurs, methylprednisolone 1 to 2 mg/kg or oral steroids 
equivalent will start immediately. 
• 
Subjects who started steroids should be consulted with the sponsor within 24 hours of 
corticosteroids initiation.  Consultation with gastroenterologist will be recommended. 
• 
If AST or ALT elevation does not improve in 3 to 5 days or worsen, addition of 
mycophenolate mofetil 1 g twice daily should be considered with the sponsor. 




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9.4.2.3 
Comparator Drug 
Not applicable. 
9.4.2.4 
Labeling for Study Drug 
The following information is provided on the study drug labeling.  Details on labeling and 
package are shown in the Attachment.  
• 
For clinical study use only 
• 
Name and address of the sponsor 
• 
Chemical name/drug identifier 
• 
Lot number/batch number 
• 
Storage conditions/expiration date 
9.4.2.5 
Storage Conditions 
Study drug will be stored in accordance with the labeled storage conditions.  The assigned 
pharmacist or designee is responsible for ensuring that the study drug is maintained within an 
established temperature range.  The head of the medical institution is responsible for ensuring 
that records are maintained and the temperature should be monitored continuously by using 
either an in-house 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 nivolumab.  There is no randomization in this study. 
9.4.4 
Selection of Doses in the Study 
The starting dose of lenvatinib is selected as 12 mg (BW ≥60 kg) or 8 mg (BW <60 kg).  
This dose setting was used in the Phase 3 study of lenvatinib monotherapy versus sorafenib 
in subjects with unresectable HCC (E7080-G000-304 [Study 304]).  This is based on the 
review of the safety and pharmacokinetic data derived from the Phase 1/2 study of lenvatinib 
in subjects with HCC (E7080-J081-202).  Based on the results of Phase 1, the recommended 
dose for Phase 2 was determined to be 12 mg QD for HCC subjects with Child-Pugh class A 
(score 5–6).  Most toxicities were manageable by dose interruption and dose reduction, 
however, majority of subjects with higher lenvatinib exposure or a low body weight required 
a dose reduction.  Subsequently, population pharmacokinetic (PPK) analyses were performed 
to further explore the starting dose.  In order to reduce the number of dose reductions and 
withdrawals due to AEs, a weight-based dosing schedule has been established with the 2 
categories of 12 mg QD (BW ≥60 kg) and 8 mg QD (BW <60 kg).  Study 304 demonstrated 
the noninferiority of lenvatinib to sorafenib in these starting doses setting. 


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The dose of nivolumab is selected as 240 mg administered as an intravenous (IV) infusion 
every 2 weeks.  In a multiple-dose Phase 1 study of nivolumab conducted overseas (Study 
CA209003), nivolumab IV at doses from 0.1 to 10 mg/kg was administered every 2 weeks in 
subjects with malignant tumors.  A total of 306 subjects with tumor types including mainly 
non-small cell lung cancer (NSCLC), malignant melanoma, and renal cell carcinoma (RCC) 
were enrolled into this study and ONO-4538 demonstrated high antitumor activity at 3 mg/kg 
or higher.  With regard to safety, Phase 1 studies in and outside Japan showed ONO-4538 IV 
every 2 weeks was well tolerated at doses up to 20 mg/kg in Japan and 10 mg/kg outside 
Japan (ONO-4538-01 and CA209003).   
Based on these efficacy and safety data, ONO-4538 3 mg/kg IV every 2 weeks is being 
studied in clinical studies in subjects with multiple tumor types.  Recently, the use of flat 
dosing of ONO-4538, without body-weight normalizing, is being investigated to improve 
ease of administration.  Clinical studies in subjects with multiple tumor types are ongoing at 
a flat dose of 240 mg every 2 weeks and 480 mg every 4 weeks.   
To optimize dosing, PPK analyses were performed.  ONO-4538 demonstrated linear 
pharmacokinetics, with a dose-proportional increase in exposure across a dose range of 
0.1 mg/kg to 10 mg/kg and no differences were found across tumor types.  While both the 
ONO-4538 clearance and the volume of distribution increased with body weight, the 
magnitude of the increase was smaller than that of body weight.  A previously developed 
PPK model using data from subjects with NSCLC was further used for 1544 subjects from 
the 7 studies for malignant melanoma, NSCLC, and RCC.  Since the median body weight 
among these population dataset was 77 kg (range:  35, 160 kg), a flat dose of 240 mg every 2 
weeks, the corresponding dose to the 3 mg/kg dose at the body weight of 80 kg, was selected.  
A PPK model-based simulation was conducted to predict the exposure of ONO-4538 
administered 240 mg every 2 weeks.  The simulation result was evaluated by comparing 
simulated exposures at ONO-4538 3 mg/kg and ONO-4538 240 mg every 2 weeks.  The data 
used for simulation were based on randomly selected 1000 subjects from above cancer 
subjects for each dose setting.  No differences have been found in pharmacokinetics across 
ethnicity and tumor types, suggesting these results based on subjects with malignant 
melanoma, NSCLC, and RCC could be extrapolated to other tumor types.  The time-
averaged steady-state concentration (Cavgss) produced by 240 mg administered every 2 weeks 
was expected to be similar to that produced by 3 mg/kg every 2 week at the representative 
body weight of 80 kg.  
ONO-4538 is safe and well tolerated at doses up to 10 mg/kg every 2 weeks. The relationship 
of exposure and response seems to be flat at doses of 3 mg/kg or more. Based on the above 
pharmacokinetic, safety, and efficacy analysis data, the safety and efficacy profile of 
nivolumab 240 mg every 2 weeks was comparable to 3 mg/kg every 2 weeks. Nivolumab is a 
human monoclonal antibody; possibility of drug-concomitant chemotherapy interactions is 
extremely low.  Based on the above reasons, the flat dose of 240 mg IV every 2 weeks was 
chosen for this study. 


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9.4.5 
Selection and Timing of Dose for Each Subject 
The selection and timing of the lenvatinib and nivolumab for each subject are provided in 
Section 9.4.1.  Lenvatinib will be administered in a fasting state or after a meal.  The food 
effect study of lenvatinib indicated that lenvatinib exposure is not significantly affected by 
food intake. 
9.4.6 
Blinding 
The study will not be blinded.   
9.4.7 
Prior and Concomitant Therapy 
Any medication (including over-the-counter medications) or therapy administered to the 
subject during the study (starting at the date of informed consent and until 30 days after the 
final dose of study drug or until the subject initiates new anticancer therapy, whichever is 
earlier) will be recorded on the CRF.  For all drugs, the name, treatment start dates (or timing 
of starting treatment), treatment end dates, and reason for use will be recorded on the CRF.  
Concomitant drugs such as premedication, diagnostic agents, solutions, or fluid transfusions 
provided for surgery, medical examinations, or administrations will be excepted.  For 
concomitant therapy, the name, treatment start dates (or timing of starting treatment), 
treatment end dates, and reason for use will be recorded on the CRF.  Prior therapies on HCC 
are provided in Section 9.5.1.2.2. 
Treatment of complications or AEs, or therapy to ameliorate symptoms (including G-CSF, 
blood products, blood transfusions, fluid transfusions, antibiotics, steroids, antidiarrheal 
drugs, or tranquilizers) may be given at the discretion of the investigator or subinvestigator 
but these therapies or drugs should be used in caution. 
9.4.7.1 
Drug-Drug Interactions 
Lenvatinib’s weak in vitro inhibitory and induction potential on cytochrome P450 (CYP) 
enzymes suggests a low risk of lenvatinib interference with the PK of other drugs 
metabolized by CYP enzymes.  Nonclinical studies identify CYP3A as an important enzyme 
responsible for human hepatic metabolism of lenvatinib.  However, drug-drug interaction 
clinical studies conducted to test these findings showed that co-administration of lenvatinib 
with CYP3A/P-glycoprotein (P-gp) inhibitors or inducers is not of clinical concern.  
Nivolumab is a human monoclonal antibody; possibility of drug-concomitant chemotherapy 
interactions is extremely low.  Also, pharmacokinetic interactions of nivolumab with 
lenvatinib are not expected because nivolumab has low possibility to affect CYP expression 
indirectly via cytokine.    
9.4.7.2 
Prohibited Concomitant Therapies and Drugs 
Subjects should not receive other antitumor therapies while on study. If a subject receives 
additional antitumor therapies, 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. 


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Any live/attenuated vaccine (eg, varicella, zoster, yellow fever, rotavirus, oral polio and 
measles, mumps, rubella [MMR]) are prohibited during treatment and until 30 days post last 
dose. 
The following medications are prohibited during the study.  During DLT evaluation in Part 1, 
preventive administration or changes in dose or medication should be prohibited until 
occurrence of a DLT. 
• Antiplatelet agents and anticoagulants that require INR monitoring, such as warfarin 
(treatments that do not require INR monitoring, such as low molecular weight heparin and 
certain factor X inhibitors are permitted). 
• Immunosuppressive agents (except to treat a drug-related adverse event) 
• Systemic corticosteroids > 10 mg daily prednisone equivalent. 
 
Note: Following corticosteroids are allowed to use during the study. 
• Topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal 
systemic absorption)  
• Adrenal replacement steroid doses >10 mg daily prednisone equivalent in the absence of 
active autoimmune disease. 
• Immunosuppressive doses of corticosteroids to treat adverse events (> 10 mg daily 
prednisone equivalent)  
• A brief course of corticosteroids (<3 weeks) for prophylaxis (e.g., contrast dye allergy) or 
treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction 
caused by contact allergen) 
 
9.4.8 
Treatment Compliance 
The investigator or subinvestigator will record the treatment compliance.  The CRA will 
review the treatment compliance during site visits and at the completion of the study.   
9.4.9 
Drug Supplies and Accountability 
The assigned pharmacist (or the designee) will be responsible for the accountability of all 
study drugs (dispensing, inventory, and record keeping) following the sponsor’s instructions 
and adherence to GCP guidelines as well as local or regional requirements. 
Under no circumstances will the investigator or subinvestigator allow the study drugs to be 
used other than as directed by this protocol.  Study drugs will not be dispensed to any 
individual who is not enrolled in the study.  
The assigned pharmacist (or the designee) must maintain an accurate and timely record of the 
following:  receipt of all study drugs, dispensing of study drugs the subject, unused study 
drugs that are returned by the subjects (unused study drug-1), unused study drugs that are 
shipped to site but not dispensed to subjects (unused study drug-2), and return of reconciled 
study drugs to the sponsor or (a sum of unused study drugs 1 and 2).  This includes, but may 
not be limited to: (a) documentation of receipt of study drugs, (b) study drugs 


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dispensing/return reconciliation log, (c) study drugs accountability log, (d) documentation of 
returns to the sponsor.   
The study drugs and inventory records must be made available, upon request, for inspection 
by a CRA or a representative of a health authority.  Upon completion of unused drug 
accountability procedures and documentation of study drugs return by the assigned 
pharmacist (or designee), all unused study drugs are to be returned to the sponsor.  Unused 
study drugs that are returned from the site are hand-delivered to CRAs and to be returned to 
the sponsor’s designated depot. 
Drug accountability will be reviewed by the CRA during site visits and at the completion of 
the study, and throughout 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 Subject ID Number, date of informed consent, age, sex, and 
race/ethnicity. 
9.5.1.2 
Pretreatment Assessments 
9.5.1.2.1 MEDICAL HISTORY AND CURRENT MEDICAL CONDITIONS 
Medical and surgical history and current medical conditions will be recorded at the Screening 
Visit.  All medical history that is considered to have effects on safety, efficacy, or PK by the 
investigator or subinvestigator and medical conditions that are identified at Screening must 
be noted on the CRF.  NYHA Cardiac Disease Classification will be reported on the CRF. 
9.5.1.2.2 PRIMARY DISEASE AND PRIOR THERAPIES FOR PRIMARY DISEASE 
The following information on primary disease and its prior therapies will be collected at 
Screening and noted on the CRF. 
1. Cause of HCC (hepatitis B, C, alcohol, other, unknown) 
2. BCLC staging (Appendix 3) 
3. Specify whether disease is confined to liver or metastatic, and if metastatic, to which 
organs. 
4. Detailed medical history of HCC, pathology, if available, Date of diagnosis, TNM 
staging (Appendix 7) 
5. Child-Pugh category (Appendix 4) 
6. Prior therapies for primary disease 
- 
Any surgical procedures 
- 
Systemic anticancer therapy 


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- 
Hepatic intra-arterial chemotherapy 
- 
Transarterial [chemo] embolization 
- 
Radiofrequency ablation 
- 
Cryoablation 
- 
Percutaneous ethanol injection 
- 
Other treatments 
 
9.5.1.2.3 
GASTROENTEROLOGICAL ENDOSCOPY 
Gastroenterological endoscopy will be performed at Screening only.  Data within 3 months 
before the first dose can be used (data before obtaining informed consent can be used). 
9.5.1.3 
Efficacy Assessments 
9.5.1.3.1 TUMOR ASSESSMENTS 
All efficacy endpoints will be based on tumor assessments performed by the investigators 
using mRECIST (Appendix 2).  If necessary, independent review using mRECIST and 
RECIST1.1 will be performed (Part 2 only).  
Tumor assessments will be carried out at Screening and then every 8 weeks (Day 1 [±7 days] 
in odd number cycle) from Day 1 of Cycle 1, or more frequently if disease progression is 
clinically indicated.  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 can be acceptable). 
Screening tumor assessments using triphasic liver CT/MRI (optimized for pre-contrast, 
arterial, and portal venous phase), contrast-enhanced CT of the chest, and contrast-enhanced 
CT or MRI of abdomen, pelvis, and other areas of known disease plus suspected disease 
should be performed within 28 days prior to C1D1. CT or MRI will be performed using 
contrast media unless there is an allergy to contrast media.  If there is known allergy to 
contrast media, non-contrast CT or MRI will be used. 
Screening CT of the brain with contrast or MRI of the brain pre- and post-gadolinium should 
be performed within 28 days prior to C1D1. During the Treatment Phase, CT/MRI of the 
brain should be performed if clinically indicated. The same methodology and scan 
acquisition techniques used at Screening should be used throughout the study to ensure 
comparability. 
During the Treatment Phase, tumor assessments of the chest, abdomen, pelvis, and other 
areas of known disease at Screening plus newly suspected disease should be performed every 
8 weeks (Day 1 [±7 days] in odd number cycle) or more frequently, if clinically indicated. 
The same methodology (CT or MRI) and scan acquisition techniques including use and 
timing of IV contrast should be used as for the screening assessments.  Tumor assessment at 
the discontinuation visit is only necessary if more than 4 weeks have passed since the 


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previous assessment (window for these assessments is within 1 week of discontinuation 
visit). 
9.5.1.3.2 TUMOR MARKER 
The investigator or subinvestigator will measure α-fetoprotein (AFP) level.  Tumor marker 
will be tested at Screening and every 8 weeks (Day 1 [±7 days] in odd number cycle), or 
more frequently if clinically indicated.  Tumor marker will be measured at the same time 
point as tumor assessments.  If the data within 28 days prior to dosing are available (data 
before informed consent can be used). 
9.5.1.3.3 SURVIVAL FOLLOW-UP 
Subjects will be followed for survival until death every 12 weeks (±2 weeks) from the date of 
last observation, except where a subject withdraws consent or the sponsor chooses to halt 
survival follow-up.  The survival follow-up will be continued until discontinuation of the last 
subject or for up to 2 years after Cycle 1 Day 1 of the last subject enrolled in Part 2, 
whichever occurs later. 
9.5.1.4 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Assessments 
A schedule of lenvatinib and nivolumab PK, pharmacodynamic, and pharmacogenomics 
sampling is shown in the Schedule of Procedures/Assessments (Table 9).  
9.5.1.4.1 PHARMACOKINETIC ASSESSMENTS 
Table 5 and Table 6 present the detailed blood sampling schedule for pharmacokinetic 
assessments.  Lenvatinib in plasma and nivolumab in serum will be quantified using a 
validated method.  See the Laboratory Manual for a description of collection, handling, and 
shipping procedures for samples. 
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 the day and the day before of 
pharmacokinetic assessments will be recorded in the CRF. The actual start/stop time of 
infusion, date, and dose of nivolumab administered will be recorded in the CRF.  
Table 5  Blood Sampling Schedule for Pharmacokinetic Assessment of 
Lenvatinib 
Day (Part 1) 
Sampling Time 
Allowance (as a Target) 
Cycle 1 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
1 hour postdose of lenvatinib 
±15 minutes 
2 hours postdose of lenvatinib 
±15 minutes 
4 hours postdose of lenvatinib 
±15 minutes 
8 hours postdose of lenvatinib 
±60 minutes 
Cycle 1 Day 2 
Predose of lenvatinib 
(24 hours postdose) 
Within –60 minutes before dosing 
Cycle 1 Day 15 
Predose of lenvatinib 
Within –60 minutes before dosing 


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1 hour postdose of lenvatinib 
±15 minutes 
2 hours postdose of lenvatinib 
±15 minutes 
4 hours postdose of lenvatinib 
±15 minutes 
8 hours postdose of lenvatinib 
±60 minutes 
Cycle 1 Day 16 
Predose of lenvatinib 
(24 hours postdose) 
Within –60 minutes before dosing 
Thereafter Day 1 of 
every  Cycle a 
Predose of lenvatinib 
 
– 
a: Blood collection is not required after the 24th cycle [Added in Version 7] 
 
Day  (Part 2) 
Sampling Time 
Allowance (as a Target) 
Cycle 1 Day 1 
0.5 – 4 hour postdose of 
lenvatinib 
– 
Cycle 1 Day 15 
Predose of lenvatinib 
– 
0.5 – 4 hour postdose of 
lenvatinib 
– 
Day 1 of Cycles 2, 4, 
6 
Predose of lenvatinib 
– 
 
Table 6 Blood Sampling Schedule for Pharmacokinetic Assessment of 
Nivolumab 
Day 
Sampling Time 
Allowance (as a Target) 
Cycle 1 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Just before completion of 
nivolumab administration 
Within –2 minutes before dosing 
Cycle 1 Day 15 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 2 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 3 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 4 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 5 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Just before completion of 
nivolumab administration 
Within –5 minutes before dosing 
Cycle 5 Day 15 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 9 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 13 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Thereafter Day 1 of 
every 4 cycles 
Predose of nivolumab 
Within –60 minutes before dosing 
 
9.5.1.4.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ASSESSMENTS 
Blood samples, archived tumor tissue samples, and fresh tumor tissue by biopsy will be 
collected for pharmacodynamic and pharmacogenomic assessment.  PD-1 and other relevant 
biomarkers identified by the new perception or progress of science will be assessed, if 
needed.  Biomarker discovery will be performed to identify pharmacological effect and to 
predict subject response to lenvatinib and nivolumab as well as for potential use in diagnostic 
development. 


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9.5.1.4.2.1 Blood Biomarker 
Blood samples for the development of exploratory biomarkers will be collected from all 
consented subjects at designated time points as specified in the Schedule of 
Procedures/Assessments (Table 9) (blood samples for nivolumab will be collected in Part 2 
only).  Instructions for the processing, storage, and shipping of samples will be provided 
separately in the Laboratory Manual. 
9.5.1.4.2.2 Tissue Biomarker 
Archival tumor tissue must be provided for biomarker analysis as well as for potential use in 
diagnostic development if available (Part 1 and Part 2).  
In Part 2, if archival tumor tissue is not available, a newly obtained tumor tissue by fresh 
biopsy must be available prior to the first dose of study drug for biomarker analysis (fresh 
biopsy is not mandatory for the subject with previous tumor tissue or with inaccessible 
tumors of safety concern). Instructions for the processing, storage, and shipping of samples 
will be provided separately in the Laboratory Manual. 
Security of the samples, use of the samples, retention of the samples, and subject privacy are 
provided below. 
Security of the Samples, Use of the Samples, and Retention of the Samples  
Sample processing, for example DNA 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. At the end of the 
storage period, samples will be destroyed. Samples may be stored longer if a Heath Authority 
(or medicinal product approval agency) has active questions about the study. In this special 
circumstance, samples will be stored until the questions have been adequately addressed.   
Right to Withdraw 
If, during the time the samples are stored, a participant would like to withdraw his/her 
consent for participation in this research, the sponsor 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 the results of the research project. 


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Subject Privacy and Disclosure  of Data 
Samples will be single coded (Subject ID number).  No subject-identifying information (eg, 
initials, date of birth, government identifying number) will be associated with the sample. 
The sponsor will take steps to ensure that data are protected accordingly and confidentiality 
is maintained as far as possible.  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: 
• Medical institutions 
• 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 the clinical study report or a separate 
report which can include part or all of the coded data, in listing or summary format.  Other 
publication (eg, in peer-reviewed scientific journals) or public presentation of the study 
results will only include summaries of the population in the study, and no identified 
individual results will be disclosed. 
9.5.1.4.3 
ANTI-NIVOLUMAB ANTIBODIES 
Table 7 presents the detailed blood sampling schedule for anti-nivolumab antibodies.  Anti-
nivolumab antibodies will be quantified using a validated method.  If an anti-nivolumab 
antibody develops, presence of neutralizing antibody will be detected.  See the Laboratory 
Manual for a description of collection, handling, and shipping procedures for samples. 
Table 7  Blood Sampling Schedule for Anti-nivolumab Antibodies 
Day 
Sampling Time 
Allowance (As a Target) 
Cycle 1 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 1 Day 15 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 2 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 3 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 5 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 9 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Cycle 13 Day 1 
Predose of nivolumab 
Within –60 minutes before dosing 
Thereafter Day 1 of 
every 4 cycles 
Predose of nivolumab 
Within –60 minutes before dosing 
 


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9.5.1.5 
Safety Assessments 
Safety assessments include monitoring and recording all AEs, including all grading of 
CTCAE v4.03, and SAEs; regular laboratory evaluation for hematology, blood chemistry, 
and urine values; physical examinations; periodic measurement of vital signs; ECGs; and 
echocardiograms/MUGA scans to assess LVEF.  
9.5.1.5.1 ADVERSE EVENTS 
An AE is any untoward medical occurrence in a subject.  An AE does not necessarily have a 
causal relationship with the medicinal product.  For this study, the study drugs are lenvatinib 
and nivolumab.  
The criteria for identifying AEs in this study are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease found after the time of informed consent, whether or not considered 
related to the investigational product (Note:  Every sign or symptom should not be listed 
as a separate AE if the applicable disease [diagnosis] is being reported as an AE) 
• 
Any new disease or exacerbation of an existing disease.  However, worsening of the 
primary disease should be captured under efficacy assessments as disease progression 
rather than as an AE. 
• 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
All AEs, regardless of relationship to study drug or procedure, should be collected beginning 
from the time the subject signs the study ICF through the 30 days after the last dose or until 
the subject initiates new anticancer therapy, whichever is earlier.  SAEs will also be collected 
for 30 days after the last dose or until the subject initiates new anticancer therapy, whichever 
is earlier.   
Any laboratory abnormality considered to constitute an AE should be reported on the CRF.  
Abnormal laboratory values should not be listed as separate AEs if they are considered to be 
part of the clinical syndrome that is being reported as an AE.  It is the responsibility of the 
investigator to review all laboratory findings in all subjects and determine if they constitute 
an AE.  Medical and scientific judgment should be exercised in deciding whether an isolated 
laboratory abnormality should be classified as an AE.   
Abnormal ECG (QTcF) results, if not otherwise considered part of a clinical symptom that is 
being reported as an AE, should be considered an AE if the QTcF interval is more than 


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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 until 30 days after the 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 or subinvestigator to categorize each AE 
according to its severity and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to CTCAE v 4.03.  Investigators 
will report CTCAE grades for all AEs (for both increasing and decreasing severity).  
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
The relationship of each AE to the study drug will be recorded on the CRF in response to the 
following question: 
Is there a reasonable possibility that the study drug caused the AE? 
Yes (related) 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
No (not related) A causal relationship between the study drug and the AE is not a 
reasonable possibility. 


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9.5.1.5.2 SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An 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) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error (see Section 9.5.4.2 and 9.5.4.3).  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” 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 8.  The Schedule of Procedures/Assessments (Table 9) 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 at each site.  


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Table 8 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
RBC count, hemoglobin, hematocrit, platelets, and WBC count 
with differential (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils) 
Anticoagulant test 
INRa 
Chemistry 
 
 Liver function tests 
Alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, gamma glutamyl transpeptidase, total bilirubin, 
direct bilirubin 
 Renal function tests 
Blood urea nitrogen, creatinine 
 Other 
Glucose, albumin, total cholesterol, triglycerides, phosphorus, 
lactate dehydrogenase, total protein, sodium, potassium, chloride, 
calcium, magnesium, ammoniab, amylasec, lipasec , ACTHe, 
cortisole 
Tumor marker 
AFP 
Thyroid function tests 
TSH, FT4 
Virus testsb 
HIV antibody,  HCV antibody, HBs antigen, HBs antibody, HBc 
antibody, HBV DNA, HCV RNA, HDV antibody or HDV RNAd 
Urinalysis 
pH, protein, glucose, ketones, RBCs, specific gravity 
AFP = α-fetoprotein, INR = International Normalized Ratio 
a: INR will be assessed on C2D1 and every cycle thereafter. 
b: Screening only.  Data within 28 days before the first dose can be used. 
c: Amylase and lipase will be measured at Screening, C2D1 and every cycle thereafter. 
d: Subjects with hepatitis B only 
e: If necessary, appropriate laboratory tests such as adrenal cortical function test (ACTH, cortisol) to be added. 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1).  In these instances, the AE corresponding to the laboratory 
abnormality will be recorded on the CRF.  If AEs were assessed during unscheduled visits, 
all the data corresponding to the laboratory abnormality will also 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], 
body temperature [in centigrade]), and weight (kg) and percutaneous oxygen saturation 
(SPO2) will be obtained at the visits designated in the Schedule of Procedures/Assessments 
(Table 9) by a validated method.  BP and pulse will be measured sitting after the subject has 
been resting.  All BP measurements should be performed on the same arm, preferably by the 
same person.   
Height will be measured at the Screening Visit only. 


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9.5.1.5.5 PHYSICAL EXAMINATIONS 
Physical examinations will be performed as designated in the Schedule of 
Procedures/Assessments (Table 9).  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 CRF. 
9.5.1.5.6 ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained as designated in the Schedule of 
Procedures/Assessments (Table 9).  Standardized, 12-lead ECG recordings that permit all 12 
leads to be displayed on a single page with an accompanying lead II rhythm strip below the 
customary 3×4 lead format may also be used.  In addition to a rhythm strip, a minimum of 3 
full complexes should be recorded from each lead simultaneously.  Subjects must be in the 
recumbent position for a period of 5 minutes prior to the ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol (see 
Section 9.5.1.5.1).  In these instances, the AE corresponding to the ECG abnormality will be 
recorded on the CRF. 
9.5.1.5.7 ECHOCARDIOGRAM OR MULTIPLE GATED ACQUISITION SCAN 
An echocardiogram or a MUGA scan (using technetium-99m-pertechnetate) to assess LVEF 
will be performed at Screening and at discontinuation visit.  Echocardiograms or MUGA 
scans should be performed locally in accordance with the institution’s standard practice.  
Either an echocardiogram or a MUGA scan which 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.  
9.5.1.5.8 ECOG PS 
An ECOG performance status should be done at each visit as designated in the Schedule of 
Procedures/Assessments (Table 9). 
9.5.1.5.9 OTHER SAFETY ASSESSMENTS 
9.5.1.5.9.1 Pregnancy Test 
An hCG or β-hCG test will be performed for women of childbearing potential.  A serum or 
urine sample will be taken at visits as designated in the Schedule of Procedures/Assessments 
(Table 9). 
All females will be considered to be of childbearing potential except: 
• 
Females who are postmenopausal (amenorrheic for at least 12 consecutive months 
without other known or suspected cause)  
• 
Females who have been sterilized surgically (ie, bilateral tubal ligation, total 
hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing) 


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• 
Females who have no possibility to be pregnant due to medical reasons 
 
9.5.1.5.9.2 Viral Tests 
Hepatitis B surface (HBs) antigen, HBs antibody, hepatitis B virus core (HBc) antibody, 
hepatitis C virus (HCV) antibody, HBV-DNA, HCV-RNA, HDV antibody or HDV RNA 
(hepatitis B only), and HIV antibody tests will be performed at Screening.  Data within 28 
days before the first dose can be used.    
9.5.2 
Schedule of Procedures/Assessments  
9.5.2.1 
Schedule of Procedures/Assessments 
Table 9 presents the schedule of procedures/assessments for the study. 




 
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Table 9 
Schedule of Procedures/Assessments in Study E7080-J081-117 (for Part 1 and Part 2) 
Concomitant 
medications/therapies 
Throughout 
C#D# = Cycle#/Day#, ECOG-PS = Eastern Cooperative Oncology Group performance status, INR= international normalized ratio, MUGA= multiple gated acquisition scan.   
a: 
Screening assessment should be initiated after obtaining informed consent (Informed consent can be obtained within 28 days of first dose).  
b: 
Height (Screening only) 
c: 
Virus test (Screening only, Data within 28 days before the first dose can be used), Ammonia test (Screening only), Hematology, blood chemistry, urinalysis, blood coagulation tests, thyroid function 
test. If necessary, appropriate laboratory tests such as adrenal cortical function test (ACTH, cortisol) to be added. 
d: 
Effort should be made to obtain during study. Exclude subjects without available archival tissues. 
e: 
Only in Part 2. Exclude subjects with inaccessible tumors for biopsy of safety concern.  
f: 
Data within 3 months before the first dose can be used (data before obtaining informed consent can also be used). 
g: 
Data within 28 days before the first dose can be used (data before obtaining informed consent can also be used). 
h: 
Regarding tests which are performed in both screening and baseline, if screening test is done 4 days before first dose, baseline tests are not required. 
i: 
For Part 1, blood collection at predose, 1, 2, 4, 8, 24 hours postdose of Cycle 1 Day1 and Day 15, and predose of Day 1 of every cycle thereafter. However, blood collection is not required after Cycle 
24. For Part 2, blood collection at 0.5 - 4 hours postdose of Cycle1 Day1, pre and 0.5 - 4 hours postdose of Cycle1 Day15 and predose of Cycles 2, 4, 6 
j: 
CT assessments (including tumor marker assessment) will be performed every 8 weeks (Day 1 [±7 days] in odd number cycle) from Day 1 of Cycle 1, or more frequently if disease progression is 
clinically indicated.  
k: 
Subjects will be hospitalized until completion of Cycle 1 in Part 1. Outpatient is allowed after C1D15 when investigator or subinvestigator judges that the subject’s safety is ensured.  
l: 
+3 days in C2D1 (Part 1 only) 
m: 
Cycle 3 or later, test items can be omitted only when investigator or subinvestigator judges that that the subject’s safety is ensured.  
n: 
Predose 
o: 
Data within 7 days before discontinuation, if available, can be used as the discontinuation data.  
p: 
Data within 28 days before off treatment, if available, can be used as the discontinuation data.  
q: 
If a new anticancer agent needs to be immediately started due to deterioration in the subject’s condition, the last observation visit can be conducted before 30 days after the last dose of the study drug 
has passed but prior to starting the new anticancer agent. If the last observation visit occurs within 7 days after study drug discontinuation, discontinuation data can be used as the last observation 
data. 
r: 
Only in Part 2. Every 12 weeks (±2 weeks) from last observation visit  
s: 
Predose and just before completion of nivolumab administration 
t: 
Predose of Cycles 2, 3, 4, 5, 9, 13 (thereafter every 4 cycles) and just before completion of nivolumab administration in Cycle 5 
u: 
Predose of Cycle 5 
v: 
Predose of Cycles 2, 3, 5, 9, 13 (thereafter every 4 cycles) 
w: 
Part 2 only. Predose of Cycles 1 and 3. When the subject discontinues the study before sampling of Cycle 3, the sampling at discontinuation visit should be done. 
 


 
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9.5.3 
Appropriateness of Measurements 
All clinical assessments are standard measurements commonly used in studies involving 
subjects with HCC. 
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 SAEs, regardless of their relationship to study treatment, must be reported on a 
completed SAE form as soon as possible but no later than 1 business day from the date the 
investigator becomes aware of the event. 
SAEs, regardless of causality assessment, must be collected through 30 days after 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 drug 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. 
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 or subinvestigator’s assessment of 
causality. 
Any follow-up information received on SAEs should be forwarded from the investigator to 
the sponsor 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 if requested 
by the sponsor. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 5 months of last study treatment or 30 days following the last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, and any partner’s pregnancy of 
male subjects in which the estimated date of conception is either before the last visit or 
within 30 days of last study treatment or 30 days following the last study treatment if the 


 
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subject initiates new anticancer therapy, whichever is earlier must be reported.  Also, any 
exposure to study drug through breastfeeding during study treatment or within 5 months of 
last study treatment or 30 days following the last study treatment if the subject initiates 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 or breastfeeding.  The contact information for the reporting 
of pregnancies and exposure to study drug through breastfeeding is provided in the 
Attachment.  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 
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.   


 
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All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the 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 CRF. 
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigator, 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 the 
investigator 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 
local and regional law and established guidance.  The format of these reports will be dictated 
by the local and regional requirements. 
9.5.5 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Table 9). 
The investigator or subinvestigator 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 recorded on the CRF with the reason 
of discontinuation.  Study disposition information will be collected on the Subject 
Disposition CRF. 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 


 
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9.5.7 
 Confirmation of Medical Care by Another Physician 
The investigator, subinvestigator, or clinical research coordinator will instruct subjects to 
inform site personnel when they are planning to receive medical care by another physician.  
At each visit, the investigator, subinvestigator, or clinical research coordinator 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 or subinvestigator, with the consent of the subject, will 
inform the other physician that the subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.  Site audits 
will be made periodically by the sponsor’s 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.  As defined by GCP, 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 the sponsor and should not be made 
available in any form to third parties without written permission from the sponsor, except for 
authorized representatives of the sponsor 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. 
9.7 
Statistical Methods 
All statistical analyses will be performed after the data cutoff for primary analysis or the 
study is completed, and 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). 






 
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9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set will be 
summarized for each part.  Continuous demographic and baseline variables include age, 
height, and weight; categorical variables include sex, age group (<65 years, ≥65 years), race, 
ethnics, ECOG-PS, and primary disease characteristics and prior therapies for primary 
disease.   
9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the Safety Analysis Set by part.  Anatomical Therapeutic Chemical (ATC) class (eg, 
anatomical class, therapeutic class, pharmacologic class, chemical class, if feasible), and 
WHO DD preferred term.  Prior medications will be defined as medications that stopped 
before the first dose of study drug.  Concomitant medications will be defined as medications 
that (1) started before the first dose of study drug and were continuing at the time of the first 
dose of study drug, or (2) or, started at the time of or after 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 conducted by part based on the Efficacy Analysis Set.  Tumor 
assessment will be analyzed based on the investigator’s assessment. If needed, the analysis 
based on independent review will be conducted.   
Part 1 
BOR will be summarized based on mRECIST, and ORR and their corresponding exact 2-
sided 95% confidence interval (CI) will be calculated.  DCR and CBR will be summarized in 
a same manner. 
Part 2 
In addition to the same analysis as above for Part 1, PFS will be summarized and plotted over 
time by Kaplan-Meier method.  The median, first and third quartiles (Q1 and Q3) of PFS rate 
and the cumulative probability of PFS rate at selected time points with 2-sided 95% CI will 
be calculated, but not limited to.  PFS censoring rules will be defined in the SAP and 
followed FDA guidance (2007).  TTP, DOR, TTR, and OS will be summarized similarly.  A 
waterfall plot will be presented for the percent changes from baseline in the sum of the 
diameters of target lesions at post-baseline nadir (ie, maximum tumor shrinkage).  A spider 
plot will be presented for the percent changes from baseline in the sum of the diameters of 
target lesions. 
 


 
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9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 PHARMACOKINETIC ANALYSES 
The primary PK parameters of lenvatinib in the combination will be calculated by 
noncompartmental analysis using the PK analysis set (Part 1 only).  If warranted, additional 
analyses may be performed.  PK data for lenvatinib and nivolumab is planned to be analyzed 
using nonlinear mixed effects modeling.  PK data for lenvatinib and nivolumab may also be 
used to explore the exposure-response relationships for antitumor activity/efficacy as well as 
biomarkers and safety, if feasible.  The results of these analyses, if performed, will be 
reported separately. 
9.7.1.7.2 PHARMACODYNAMIC, PHARMACOGENOMIC, AND OTHER BIOMARKER ANALYSES 
The effect of lenvatinib-nivolumab combination therapy on soluble and/or tissue biomarkers 
will be summarized using descriptive statistics.   
9.7.1.8 
Safety/Tolerability Analyses 
All DLT analyses will be performed on the DLT Analysis Set.  The number and percentage 
of subjects with DLT will be calculated.  DLT will also be summarized per type of toxicity.  
All other safety analyses will be performed on the Safety Analysis Set by part.  Safety data 
will be summarized using descriptive statistics (eg, n, mean, standard deviation, median, 
minimum, maximum for continuous variables; n [%] for categorical variables).   
9.7.1.8.1 EXTENT OF EXPOSURE 
The number of cycles/days on treatment, sum of subject-time, number of administration, total 
amount of study drug administered, dose intensity, and relative dose intensity (actual 
dose/planned dose) will be summarized for lenvatinib and nivolumab separately. 
9.7.1.8.2 ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using 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 
treatment and until the 30 days after the last dose or until the subject initiates new anticancer 
therapy, whichever is earlier, having been absent at pretreatment (Baseline) or  
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 


 
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Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The incidence of TEAEs will be reported as the number (percentage) of subjects with TEAEs 
by MedDRA SOC and PT.  A subject will be counted only once within 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 of study drug, 
study drug dose reduction, and study drug interruption will be summarized by MedDRA 
SOC and PT.  A subject data listing of all AEs leading to discontinuation of study drug, study 
drug dose reduction, and study drug interruption will be provided. 
9.7.1.8.3 LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units.  For all 
quantitative parameters listed in Section 9.5.1.5.3, the actual value and the change from 
baseline to each postbaseline visit will be summarized by visit using descriptive statistics.  
Qualitative parameters will be summarized using frequencies (number and percentage of 
subjects), and changes from baseline to each postbaseline visit will be reported using shift 
tables.  Percentages will be based on the number of subjects with both nonmissing baseline 
and relevant postbaseline results. 
Laboratory parameters will be categorized according to CTCAE v4.03 grades by visit and 
maximum postbaseline grades will be summarized.  Shifts from Baseline CTCAE v4.03 
grades to postbaseline grades will be presented.   
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s 
reference range. They will be shown in subject data listing. 
CTCAE v4.03 will be used to identify subjects with treatment-emergent markedly abnormal 
laboratory values (TEMAVs), if necessary. 


 
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9.7.1.8.4 VITAL SIGNS 
Descriptive statistics for vital signs parameters (ie, systolic and diastolic BP, pulse, 
temperature), weight, and SPO2 and changes from baseline will be presented by visit. 
9.7.1.8.5 ELECTROCARDIOGRAMS 
ECG assessments performed at each visit will be used for evaluation.  Shift tables will 
present changes from baseline in ECG interpretation (categorized as normal; abnormal, not 
clinically significant; and abnormal, clinically significant) to each visit.  Descriptive statistics 
for ECG parameters and changes from baseline will be presented by visit. 
In addition, the number (percentage) of subjects with at least 1 postbaseline abnormal ECG 
result in QTc Fridericia (QTcF) will be summarized.  Clinically abnormal ECG results in 
QTcF will be categorized as follows: 
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 
9.7.1.8.6 OTHER SAFETY ANALYSES 
Descriptive statistics for LVEF and LVEF changes from baseline assessed by MUGA scans 
or echocardiograms will be summarized by visit. 
ECOG-PS will be summarized by scale at each visit and by highest postbaseline scale. 
9.7.1.9 
Immunogenicity 
All immunogenicity analyses will be performed using the Safety Analysis Set.  The 
percentage and frequency of expression will be calculated for serum anti-nivolumab 
antibodies.  If anti-nivolumab antibody develops, frequency and percentage for presence of 
neutralizing antibody will be summarized. 
9.7.2 
Determination of Sample Size 
A sample size of approximately 26 subjects will be enrolled in this study; 6 patients for Part 
1 and 20 patients for Part 2.  Six subjects in Part 1 was deemed appropriate to evaluate the 
tolerability of the dose and perform preliminary safety assessment.  Twenty subjects in Part 2 
was determined to further evaluate the safety and preliminary efficacy.  The probability to 
detect at least 1 development of intolerable treatment-related AEs with an incidence of 10%, 


 
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15% or 20% in 20 subjects was 87.8%, 96.1%, or 98.8%, respectively.  Therefore, the sample 
size is determined to be approximately 20 subjects.  
9.7.3 
Interim Analysis 
No interim analysis is planned for this study.  
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 


 
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10 REFERENCE LIST 
El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in 
patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-
comparative, phase 1/2 dose escalation and expansion trial. Lancet. 2017;389(10088):2492-
502. 
RECIST Reference 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al.  New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009;45(2):228-47. 


 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved in writing 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 IRBs.  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 or subinvestigator 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 or subinvestigator will conduct the study in strict accordance with the 
protocol. 
11.3 Monitoring Procedures 
The CRA will maintain contact with the investigator and designated staff by telephone, letter, 
or email between study visits.  Monitoring visits to each site will be conducted by the 
assigned CRA as described in the monitoring plan.  The head of the medical institution will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with GCP.  All records at the site are 
subject to inspection by the local auditing agency and to IRB review. 
In accordance with GCP, source documents include, but are not limited to, the following: 
• 
Clinic, office, or hospital charts 
• 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
• 
Recorded data from automated instruments  
• 
Pain, quality of life, or medical history questionnaires completed by subjects 


 
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• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs  
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs 
• 
CRF components that are completed directly by subjects and serve as their own source 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correction is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded on the CRF must reflect the corresponding source documents.  For 
the following items, the data recorded directly on the CRF are to be considered source data: 
- 
Study drug administration (reason for treatment discontinuation, reason for dose 
modification. or others) 
- 
Reasons for prior and concomitant therapy (including medications and therapies) 
- 
Discontinuation (reason for discontinuation, or others) 
- 
Sampling date and time for PK analysis 
- 
Sampling date for clinical laboratory tests 
- 
AEs (grade, relationship to study drug, outcome or others) 
- 
Outcome of Follow-up when a subject stop visiting the site 
- 
Race, ethnicity 
 
For items except (1) to (6) below, the source documents are considered to be source data, but 
any appropriate document instead of source documents can be used as source data: 
 
(1)Source data of informed consent 


 
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- 
Signed ICF 
(2)Source data of histopathology 
- 
Histopathology chart, patient referral document including electronic data  
(3)Source data of tumor assessment 
- 
Films including electronic data  
Note that findings and measurement recorded on the CRF are source data. 
(4)Source data of ECGs 
- 
ECG charts including electronic data  
Note that normal or abnormal findings recorded on the CRF are source data. 
(5)Record of sample shipment to external vender 
- 
Sample shipment slip 
(6)Source data of relevant tests 
- 
Clinical laboratory test chart including electronic data  
 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, 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, as directed by the sponsor, for at least 2 years 
after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or at least 3 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. 
It is requested that at the completion of the required retention period the medical institution 
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 GCP and all applicable local regulations.  Government 
regulatory authority may request an inspection. 
11.8 Handling of Study Drug 
All study drugs will be supplied to the assigned pharmacist (or 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 assigned pharmacist (or 
designee) must maintain an accurate record of the shipment and dispensing of the study drug 


 
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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 
assigned pharmacist (or designee) must not destroy any drug labels or discard 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 assigned pharmacist (or designee) will return 
all used study drugs and a copy of the completed drug disposition form to the sponsor, if 
required. 
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.  
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. 
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 
performing the study, without the written consent of the sponsor.  No data collected as part of 
this study will be used in any written work, including publications, without the written 
consent of the sponsor.  These obligations of confidentiality and non-use shall in no way 
diminish such obligations as set forth in either the Confidentiality Agreement or Clinical 
Trial Agreement executed between the sponsor 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 either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the sponsor and the head of the medical institution. 
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/the head of the medical institution 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 


 
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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/the head of medical 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 in 11.6 Retention of Records 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 
American Association for the Study of Liver Diseases 
(AASLD) Criteria 
Diagnosis of hepatocellular carcinoma is to be clinically confirmed according to AASLD 
practice guidelines as described in:  Bruix J, Sherman M; American Association for the Study 
of Liver Diseases.  Management of hepatocellular carcinoma: an update. Hepatology. 
2011;53(3):1020-2.  Available from:  http://www.aasld.org/practiceguidelines. 
The diagnostic algorithm is shown below. 
 
 


 
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Appendix 2 
Modified Response Evaluation Criteria in Solid Tumors 
(mRECIST) 
Tumor response assessments in this clinical trial will use modified Response Evaluation 
Criteria in Solid Tumors (mRECIST) based on Lencioni and Llovet (2010) and incorporating 
elements of RECIST 1.1 based on Eisenhauer, et al.(2009) 
QUANTITATIVE AND QUALITATIVE ASSESSMENTS OF TUMOR BURDEN 
The disease burden at Baseline will be categorized into target and nontarget lesions.  The target 
and nontarget categories are classified into typical hepatic lesions, atypical hepatic lesions, and 
nonhepatic lesions. 
• 
Typical hepatic lesions are lesions that display hypervascularity in the arterial 
phase and “wash-out” in the portal venous phase of contrast-enhanced CT or MRI 
imaging. 
• 
Atypical hepatic lesions are lesions that are not showing the distinctive 
enhancement pattern but are considered to be malignant. 
• 
Nonhepatic lesions are all nodal and non-nodal lesions outside of the liver. 
SELECTION AND MEASUREMENT OF TARGET LESIONS  
A maximum of 2 target lesions per organ and 5 target lesions in total, representative of all 
involved organs, may be selected.  Target lesions are lesions that can be accurately measured 
in at least one dimension and whose minimum lesion size is as follows: 
• 
Typical hepatic target lesions:  The longest diameter of the viable tumor must 
measure ≥ 1 cm or ≥ two times the slice thickness/reconstruction interval (if the 
slice thickness/reconstruction interval is >5 mm). 
• 
Atypical hepatic target lesions:  The longest diameter must measure ≥ 1 cm or ≥ two 
times 
the 
slice 
thickness/reconstruction 
interval 
(if 
the 
slice 
thickness/reconstruction interval is >5 mm).  
• 
Nonhepatic non-nodal target lesions:  The longest diameter must measure ≥ 1 cm 
or ≥ two times the slice thickness/reconstruction interval (if the slice 
thickness/reconstruction interval is >5 mm).  
• 
Nonhepatic nodal target lesions (lymph nodes):  The short axis must measure 
≥ 1.5 cm with exception of porta hepatis lymph nodes that need to be ≥ 2.0 cm in 
the 
short 
axis 
(regardless 
of 
modality/scanner 
type 
and 
slice 
thickness/reconstruction interval). 


 
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If typical and atypical liver lesions are present, preference should be given to typical liver 
lesions when selecting targets.  Target lesions are measured at every time point and a single 
Sum of Diameters (SOD) will be determined by adding the longest diameters of all non-nodal 
lesions and short axes (i.e., widest dimensions perpendicular to the long axis) of nodal 
nonhepatic lesions.  For typical hepatic lesions the longest diameters will include only the 
viable tissue, while for all other target lesions all tumor tissue (whether necrotic or not) will be 
included in the SOD.  Note that hypovascular tissue should not be considered as necrotic 
(nonviable) tissue. While hypovascular tissue will still show contrast uptake (although less 
than what would be observed in a hypervascular lesion), necrotic tissue will show complete 
absence of any contrast enhancement. Quantitative determinations of average Hounsfield Units 
(HU) in the tissue of interest both pre-contrast and post-contrast may be used, if needed, to 
support the subjective assessment: necrotic (nonviable) tissue will show no change in HU 
between the phases, while hypovascular tissue will yield an increase in HU (although less than 
what would be observed in a hypervascular lesion) between pre-contrast and post-contrast 
images of the same region.  Please refer to the Image Interpretation Guidance Manual for the 
use of mRECIST for HCC for further details regarding differentiating hypovascular from 
necrotic (nonviable) tissue. 
 
Target lesions are assessed as CR, PR, SD, PD, or NE at every time point based on the SOD. 
SELECTION AND ASSESSMENT OF NONTARGET LESIONS   
Nontarget lesions are all other lesions, including malignant portal vein thrombosis, infiltrative 
type, and diffuse type HCC with ill-defined lesion borders and truly nonmeasurable lesions.  
Nontarget lesions will be assessed qualitatively, and the possible assessments are CR, Non-
CR/Non-PD (NN), and PD.  
If a hepatic nontarget lesion exhibits an enhancement pattern that is consistent with HCC, the 
determination of CR, NN, PD, or NE will be dependent on the enhancing portion of the lesion.  
All other nontarget lesions will be assessed following the conventional RECIST 1.1 criteria. 
If pleural effusions or ascites selected as nontarget lesions at Baseline are stable in size or 
minimally enlarging, they will be assessed as NN.  A cytopathological confirmation of any 
effusion that appears or worsens on treatment is required when the measurable tumor has met 
criteria for response or SD. 
NEW LESIONS 
New lesions are defined as: 
• 
Unequivocally new nonhepatic lesions seen at follow-up, without a corresponding 
lesion on the baseline imaging. 
• 
 New typical hepatic lesions displaying intratumoral arterial enhancement 
(hypervascularization in the arterial phase and washout in the portal venous phase 
on contrast-enhanced CT or MRI) that measure ≥ 1 cm in the longest diameter. 


 
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• 
New atypical hepatic lesions ≥ 1 cm in the longest diameter that show interval 
growth in subsequent scans of at least 1 cm. 
Any lesion that meets the requirements for unequivocal new lesions will trigger PD.  Any 
lesion that does not meet the above criteria (e.g., < 1 cm in longest diameter and/or does not 
show typical HCC vascular enhancement pattern) should be considered an equivocal new 
lesion.  If an equivocal lesion is later determined to be unequivocal, the time point of 
progression will be the time point the lesion was first noted as equivocal. 
OVERALL RESPONSE ASSESSMENTS 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Time Point Response 
CR 
CR 
No 
CR 
CR 
NN 
No 
PR 
CR 
NE 
No 
PR 
PR 
NE 
No 
PR 
PR 
CR 
No 
PR 
PR 
NN 
No 
PR 
SD 
NE 
No 
SD 
SD 
CR 
No 
SD 
SD 
NN 
No 
SD 
PD 
Any 
Yes/No 
PD 
Any 
PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
NE 
Non-PD 
No 
NE 
CR 
No nontarget lesions 
identified 
No 
CR 
PR 
No nontarget lesions 
identified 
No 
PR 
SD 
No nontarget lesions 
identified 
No 
SD 
CR = complete response, NE = not evaluable, NN = Non-CR/Non-PD, PD = progressive disease, PR = partial response, 
SD = stable disease 


 
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Appendix 3 
Barcelona Clinic Liver Cancer (BCLC) Staging System 
 
 
European Association For The Study Of The Liver; European Organisation For Research And Treatment Of 
Cancer.  EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma.  J Hepatol. 2012 
Apr;56(4):908-43.  Erratum to: ‘‘EASL–EORTC Clinical Practice Guidelines: Management of hepatocellular 
carcinoma’’ [J Hepatol 2012;56:908-43]. J Hepatol. 2012.  In press.  http://www.easl.eu/_clinical-practice-
guideline/issue-7-April-2012-management-of-hepatocellular-carcinoma 


 
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Appendix 4 
Child-Pugh Classification 
Parameter 
Scorea 
1 
2 
3 
Ascites 
Absent 
Mild 
(Respond to treatment) 
Moderate 
(Refractory) 
Serum bilirubin (mg/dL) 
<2.0 
2.0 – 3.0 
>3.0 
Serum albumin (g/dL) 
>3.5 
2.8 – 3.5 
<2.8 
INR  
<1.7 
1.7 – 2.30 
>2.30 
Encephalopathyb 
0 
1 – 2 
3 – 4 
INR = international normalized ratio. 
a:  Child-Pugh A: 5 or 6 points; Child-Pugh B: 7 – 9 points; Child-Pugh C: >9 points. 
b:  Encephalopathy grades defined as follows: 
Grade 0:  normal consciousness, personality, neurological examination, electroencephalogram  
Grade 1:  restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps (cycles per second) waves 
Grade 2:  lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves  
Grade 3:  somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
Grade 4:  unrousable, coma, no personality/behavior, decerebrate, slow 2–3 cps delta activity 
 
 


 
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Appendix 5 
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 (e.g., 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 6 
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. 
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 7 
Tumor, Node, and Metastasis (TNM) Staging of 
Hepatocellular Carcinoma 
The TNM classification for staging of hepatocellular carcinoma per the American Joint 
Committee on Cancer (AJCC) is provided below: 
Primary tumor (T) 
TX Primary tumor cannot be assessed. 
T0 No evidence of primary tumor 
T1 Solitary tumor without vascular invasion 
T2 Solitary tumor with vascular invasion or multiple tumors, none > 5 cm 
T3a Multiple tumors > 5 cm 
T3b Single tumor or multiple tumors of any size involving a major branch of the portal or 
hepatic vein 
T4 Tumor(s) with direct invasion of adjacent organs other than gallbladder or with visceral 
peritoneum 
Regional lymph nodes (N) 
NX Regional lymph nodes cannot be assessed. 
N0 No regional lymph node metastasis 
N1 Regional lymph node metastasis 
Distant metastasis (M) 
M0 No distant metastasis 
M1 Distant metastasis 
 
Anatomic stage/prognostic groups 
Stage 
T 
N 
M 
I 
T1 
N0 
M0 
II 
T2 
N0 
M0 
IIIA 
T3a 
N0 
M0 
IIIB 
T3b 
N0 
M0 
IIIC 
T4 
N0 
M0 
IVA 
Any T N1 
M0 
IVB 
Any T Any N M1 


 
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Source:  Cheng CH, Lee CF, Wu TH, Chan KM, Chou HS, Wu TJ, et al.  Evaluation of the 
new AJCC staging system for resectable hepatocellular carcinoma.  World J Surg Oncol. 
2011;9:114.   


 
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Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 7.0, 14 Feb 2020) 
Amended Text (Version 8.0, 05 Feb 2021) 
Reason of 
Amendment(s) 
2 
Exclusion Criteria 
31. Women of childbearing potential or men of impregnate 
potential who don’t agree that both the subject and her 
partner will use the following methods of contraception for 
periods from before informed consent to during the clinical 
study and 5 months later (for male subjects 7 months) from 
last administration of study drug. 
Exclusion Criteria 
31. Women of childbearing potential or men of impregnate 
potential who don’t agree that both the subject and her 
partner will use the following methods of contraception for 
periods from before informed consent to during the clinical 
study and 5 months later (for male subjects 30 days) from 
last administration of study drug. 
Amendment 
according to the 
change of 
addendum of 
nivolumab 
investigator’s 
brochure 
9.1.3.3 
(omission) 
In Part 2, all subjects will be followed for survival until 
death every 12 weeks (±2 week) from the date of 
discontinuation, except where a subject withdraws consent 
or the sponsor chooses to halt survival follow-up.  The 
survival follow-up will be continued for up to 2 years after 
Cycle 1 Day 1 of the last subject enrolled in Part 2. 
(omission) 
In Part 2, all subjects will be followed for survival until 
death every 12 weeks (±2 week) from the date of 
discontinuation, except where a subject withdraws consent 
or the sponsor chooses to halt survival follow-up.  The 
survival follow-up will be continued until discontinuation of 
the last subject or for up to 2 years after Cycle 1 Day 1 of 
the last subject enrolled in Part 2, whichever occurs later. 
Change of 
survival 
follow-up 
duration 
9.3.2 
31. Women of childbearing potential or men of impregnate 
potential who don’t agree that both the subject and her 
partner will use the following methods of contraception for 
periods from before informed consent to during the clinical 
study and 5 months later (for male subjects 7 months) from 
last administration of study drug. 
31. Women of childbearing potential or men of impregnate 
potential who don’t agree that both the subject and her 
partner will use the following methods of contraception for 
periods from before informed consent to during the clinical 
study and 5 months later (for male subjects 30 days) from 
last administration of study drug. 
Amendment 
according to the 
change of 
addendum of 
nivolumab 
investigator’s 
brochure 


 
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Page 2 of 3 
 
Section 
Original Text (Version 7.0, 14 Feb 2020) 
Amended Text (Version 8.0, 05 Feb 2021) 
Reason of 
Amendment(s) 
9.3.3 
(omission) 
In Part 2, all subjects will be followed for survival until 
death every 12 weeks (±2 week) from the date of 
discontinuation, except where a subject withdraws consent 
or the sponsor chooses to halt survival follow-up.  The 
survival follow-up will be continued for up to 2 years after 
Cycle 1 Day 1 of the last subject enrolled in Part 2. 
(omission) 
In Part 2, all subjects will be followed for survival until 
death every 12 weeks (±2 week) from the date of 
discontinuation, except where a subject withdraws consent 
or the sponsor chooses to halt survival follow-up.  The 
survival follow-up will be continued until discontinuation of 
the last subject or for up to 2 years after Cycle 1 Day 1 of 
the last subject enrolled in Part 2, whichever occurs later. 
Change of 
survival follow-
up duration 
9.5.1.3.3 
Subjects will be followed for survival until death every 
12 weeks (±2 week) from the date of last observation, except 
where a subject withdraws consent or the sponsor chooses to 
halt survival follow-up.  The survival follow-up will be 
continued for up to 2 years after Cycle 1 Day 1 of the last 
subject enrolled in Part 2. 
Subjects will be followed for survival until death every 
12 weeks (±2 weeks) from the date of last observation, 
except where a subject withdraws consent or the sponsor 
chooses to halt survival follow-up.  The survival follow-up 
will be continued until discontinuation of the last subject or 
for up to 2 years after Cycle 1 Day 1 of the last subject 
enrolled in Part 2, whichever occurs later. 
Change of 
survival 
follow-up 
duration 
9.5.1.4.2.2 
(omission) 
At the end of the analysis, results may be presented in the 
clinical study report which can include part or all of the 
coded data, in listing or summary format.  Other publication 
(eg, in peer-reviewed scientific journals) or public 
presentation of the study results will only include summaries 
of the population in the study, and no identified individual 
results will be disclosed. 
(omission) 
At the end of the analysis, results may be presented in the 
clinical study report or a separate report which can include 
part or all of the coded data, in listing or summary format.  
Other publication (eg, in peer-reviewed scientific journals) 
or public presentation of the study results will only include 
summaries of the population in the study, and no identified 
individual results will be disclosed. 
To adjust the 
description. 


 
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Section 
Original Text (Version 7.0, 14 Feb 2020) 
Amended Text (Version 8.0, 05 Feb 2021) 
Reason of 
Amendment(s) 
9.5.4.2 
Any pregnancy in which the estimated date of conception is 
either before the last visit or within 5 months of last study 
treatment or 30 days following the last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, 
and any partner’s pregnancy of male subjects in which the 
estimated date of conception is either before the last visit or 
within 7 months of last study treatment or 30 days following 
the 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 5 months of last study treatment or 30 
days following the last study treatment if the subject initiates 
new anticancer therapy, whichever is earlier, must be 
reported. 
Any pregnancy in which the estimated date of conception is 
either before the last visit or within 5 months of last study 
treatment or 30 days following the last study treatment if the 
subject initiates new anticancer therapy, whichever is earlier, 
and any partner’s pregnancy of male subjects in which the 
estimated date of conception is either before the last visit or 
within 30 days of last study treatment or 30 days following 
the 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 5 months of last study treatment or 30 
days following the last study treatment if the subject initiates 
new anticancer therapy, whichever is earlier, must be 
reported. 
Amendment 
according to the 
change of 
addendum of 
nivolumab 
investigator’s 
brochure 
9.7 
All statistical analyses will be performed 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). 
All statistical analyses will be performed after the data 
cutoff for primary analysis or the study is completed, and 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). 
To adjust the 
description. 
 


 
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Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 6.0, 22 Nov 2019) 
Amended Text (Version 7.0, 14 Feb 2020) 
Reason of 
Amendment(s) 
2 
Study Period and Phase of Development  
Approximately 30 months  
Phase 1b 
Study Period and Phase of Development 
Approximately 45 months 
Phase 1b 
Because it is 
expected that 
there will be 
subjects who 
continue to 
receive the study 
treatment at 
“approximately 
30 months” after 
the start of the 
study. 
7 
ONO-4538/nivolumab is a human anti-human programmed 
death-1 (PD-1, also known as CD279) monoclonal antibody, 
developed by Ono Pharmaceutical and Medarex (current 
Bristol-Myers Squibb).  Clinical development program of 
nivolumab is currently underway by Ono Pharmaceutical 
and Bristol-Myers Squibb.  Nivolumab is approved in many 
countries including the United States, European Union, and 
Japan.  However, nivolumab is not approved in subjects with 
HCC anywhere in the world.  The preliminary results from 
the multinational Phase 1/2 study (CA209040 study) for 
HCC subjects showed favorable efficacy and safety profile 
(El-Khoueiry AB, et al., 2017).  A phase 3 randomized study 
of nivolumab compared with sorafenib in the first-line 
treatment of subjects with advanced HCC (ONO-4538-
35/CA209459) is ongoing. 
ONO-4538/nivolumab is a human anti-human programmed 
death-1 (PD-1, also known as CD279) monoclonal antibody, 
developed by Ono Pharmaceutical and Medarex (current 
Bristol-Myers Squibb).  Clinical development program of 
nivolumab is currently underway by Ono Pharmaceutical 
and Bristol-Myers Squibb.  Nivolumab is approved in many 
countries including the United States, European Union, and 
Japan.  Nivolumab monotherapy has shown clinical benefit 
in HCC patients who have previously been treated with 
sorafenib and has been approved for use in the United States 
and elsewhere.  In addition, an international phase 3 study 
comparing nivolumab and sorafenib in progressed HCC 
patients who have not been treated with systemic 
chemotherapy (ONO-4538-35 / CA209459), and an 
international phase 3 study comparing the combination of 
To reflect the 
latest information 
on nivolumab. 


 
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Section 
Original Text (Version 6.0, 22 Nov 2019) 
Amended Text (Version 7.0, 14 Feb 2020) 
Reason of 
Amendment(s) 
nivolumab and ipilimumab with sorafenib or lenvatinib in 
progressed HCC patients who have not been treated (ONO 
4538-92/CA2099DW) is currently ongoing. 
9.4.4 
Based on these efficacy and safety data, ONO-4538 3 mg/kg 
IV every 2 weeks is being studied in clinical studies in 
subjects with melanoma, NSCLC, RCC, classical Hodgkin's 
lymphoma, and head and neck cancer.  Recently, the use of 
flat dosing of ONO-4538, without body-weight normalizing, 
is being investigated to improve ease of administration.  
Clinical studies in subjects with ovarian cancer, esophageal 
cancer, and HCC are ongoing at a flat dose of 240 mg every 
2 weeks. 
Based on these efficacy and safety data, ONO-4538 3 mg/kg 
IV every 2 weeks is being studied in clinical studies in 
subjects with multiple tumor types.  Recently, the use of flat 
dosing of ONO-4538, without body-weight normalizing, is 
being investigated to improve ease of administration.  
Clinical studies in subjects with multiple tumor types are 
ongoing at a flat dose of 240 mg every 2 weeks and 480 mg 
every 4 weeks. 
To reflect the 
latest information 
on nivolumab. 
9.5.1.4.1 
Blood Sampling Day (Part 1)  
Thereafter Day 1 of every Cycle 
Blood Sampling Day (Part 1)  
Thereafter Day 1 of every Cycle a 
 
a: Blood collection is not required after the 24th cycle 
[Added in Version 7.0] 
It was 
determined that 
the drug 
concentration 
data obtained so 
far for Part 1 
subjects allow for 
sufficient 
evaluation of 
trough value 
fluctuations 
during long-term 
administration. 
9.5.2.1 
i: For Part 1, blood collection at predose, 1, 2, 4, 8, 24 hours 
postdose of Cycle 1 Day1 and Day 15, and predose of Day 1 
of every cycle thereafter.  For Part 2, blood collection at 0.5 
- 4 hours postdose of Cycle1 Day1, pre and 0.5 - 4 hours 
postdose of Cycle1 Day15 and predose of Cycles 2, 4, 6 
i: For Part 1, blood collection at predose, 1, 2, 4, 8, 24 hours 
postdose of Cycle 1 Day1 and Day 15, and predose of Day 1 
of every cycle thereafter.  However, blood collection is not 
required after Cycle 24.  For Part 2, blood collection at 0.5 - 
4 hours postdose of Cycle1 Day1, pre and 0.5 - 4 hours 
postdose of Cycle1 Day15 and predose of Cycles 2, 4, 6 
It was 
determined that 
the drug 
concentration 
data obtained so 
far for Part 1 
subjects allow for 


 
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Section 
Original Text (Version 6.0, 22 Nov 2019) 
Amended Text (Version 7.0, 14 Feb 2020) 
Reason of 
Amendment(s) 
sufficient 
evaluation of 
trough value 
fluctuations 
during long-term 
administration. 
9.7.1.1.2 
• 
ORR is defined as the proportion of subjects who have 
BOR of CR or PR 
• 
Pharmacokinetic parameters of lenvatinib 
 
• 
ORR is defined as the proportion of subjects who have 
BOR of CR or PR 
• 
Pharmacokinetic parameters of lenvatinib and 
nivolumab 
 
Correction of 
errors 
 


 
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Page 1 of 1 
 
Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 5.0, 19 Jul 2019) 
Amended Text (Version 6.0, 22 Nov 2019) 
Reason of 
Amendment(s) 
2 
Exclusion Criteria  
(Not stated) 
Exclusion Criteria 
32. Participants who have received a live/attenuated vaccine 
within 28 days of first dose of study drugs 
To consider the 
possibility to 
affect the safety 
assessments of 
nivolumab. 
Prohibited Concomitant Medications/Therapies 
(Not stated) 
Prohibited Concomitant Medications/Therapies 
Any live/attenuated vaccine (eg, varicella, zoster, yellow 
fever, rotavirus, oral polio and measles, mumps, rubella 
[MMR]) are prohibited during treatment and until 30 days 
post last dose. 
9.3.2 
Exclusion Criteria  
(Not stated) 
Exclusion Criteria 
32. Participants who have received a live/attenuated vaccine 
within 28 days of first dose of study drugs 
9.4.7.2 
Prohibited Concomitant Therapies and Drugs  
(Not stated) 
Prohibited Concomitant Therapies and Drugs  
Any live/attenuated vaccine (eg, varicella, zoster, yellow 
fever, rotavirus, oral polio and measles, mumps, rubella 
[MMR]) are prohibited during treatment and until 30 days 
post last dose. 
 


 
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Page 1 of 1 
 
Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 4.0, 27 Aug 2018) 
Amended Text (Version 5.0, 19 Jul 2019) 
Reason of 
Amendment(s) 
9.5.1.5.3 
Table 8 Clinical Laboratory Tests  
 
Chemistry: Other 
Glucose, albumin, total cholesterol, triglycerides, 
phosphorus, lactate dehydrogenase, total protein, sodium, 
potassium, chloride, calcium, magnesium, ammoniab, 
amylasec, lipasec 
 
Table 8 Clinical Laboratory Tests 
 
Chemistry: Other 
Glucose, albumin, total cholesterol, triglycerides, 
phosphorus, lactate dehydrogenase, total protein, sodium, 
potassium, chloride, calcium, magnesium, ammoniab, 
amylasec, lipasec, ACTHe, cortisole  
 
e:  If necessary, appropriate laboratory tests such as adrenal 
cortical function test (ACTH, cortisol) to be added. 
To reflect the 
revision* of 
nivolumab 
package insert as 
of 09 May 2019.  
 
 
* Hepatic failure 
and pituitary 
dysfunction were 
added to the 
section of 
“Clinically 
Significant 
Adverse 
Reactions” of the 
package insert. 
9.5.2.1 
Table 9 Schedule of Procedures/Assessments in Study 
E7080-J081-117 (for Part 1 and Part 2) 
 
c: Virus test (Screening only, Data within 28 days before the 
first dose can be used), Ammonia test (Screening only), 
Hematology, blood chemistry, urinalysis, blood coagulation 
tests, thyroid function test. 
Table 9 Schedule of Procedures/Assessments in Study 
E7080-J081-117 (for Part 1 and Part 2) 
 
c: Virus test (Screening only, Data within 28 days before the 
first dose can be used), Ammonia test (Screening only), 
Hematology, blood chemistry, urinalysis, blood coagulation 
tests, thyroid function test.  If necessary, appropriate 
laboratory tests such as adrenal cortical function test 
(ACTH, cortisol) to be added. 
 


 
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Page 1 of 2 
 
Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 3.0, 07 May 2018) 
Amended Text (Version 4.0, 27 Aug 2018) 
Reason of 
Amendment(s) 
2 
 
9.3.2 
Exclusion Criteria 
1. Imaging findings for HCC corresponding to any of the 
following: 
• 
HCC with ≥50% liver occupation 
• 
Clear invasion into the bile duct 
• 
Portal vein invasion with Vp4 
Exclusion Criteria 
1. Imaging findings for HCC corresponding to any of the 
following (Part 1 only): 
• 
HCC with ≥50% liver occupation 
• 
Clear invasion into the bile duct 
• 
Portal vein invasion with Vp4 
To confirm the 
safety/efficacy in 
the subject group 
in the left 
column.  It was 
determined that 
the criteria have 
no significant 
impact on subject 
safety because it 
is used to ensure 
uniformity of 
subject 
backgrounds. 
2 
2. Cycle 2 and onward (and applies to Cycle 1 and 
onward of part 2) 
Relationship to lenvatinib and/or nivolumab will be 
evaluated, then necessity of dose modification (either or 
both drugs) will be determined.  Dose adjustment for 
management of intolerable toxicities will be made according 
to the guidelines provided in the table below. 
 
a:  An interruption of lenvatinib for more than 28 days (due 
to treatment-related toxicities) will require discussion with 
the sponsor before treatment can be resumed.  During 
treatment interruption, repeat AEs assessment at least every 
2. Cycle 2 and onward (and applies to Cycle 1 and 
onward of part 2) 
Relationship to lenvatinib and/or nivolumab will be 
evaluated, then necessity of dose modification (either or 
both drugs) will be determined.  Dose adjustment for 
management of intolerable toxicities will be made according 
to the guidelines provided in the table below. 
 
a:  An interruption of lenvatinib for more than 28 days (due 
to treatment-related toxicities) will require discussion with 
the sponsor before treatment can be resumed.  During 
treatment interruption, repeat AEs assessment about every 
To review the 
assessment 
period during the 
interruption of 
lenvatinib. 


 
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Section 
Original Text (Version 3.0, 07 May 2018) 
Amended Text (Version 4.0, 27 Aug 2018) 
Reason of 
Amendment(s) 
7 days (until restarting administration). 
7 days (until restarting administration). 
9.4.1.3.2.1 
Table 2 Dose Adjustments of Lenvatinib 
 
a:  An interruption of lenvatinib for more than 28 days (due 
to treatment-related toxicities) will require discussion with 
the sponsor before treatment can be resumed.  During 
treatment interruption, repeat AEs assessment at least every 
7 days (until restarting administration). 
Table 2 Dose Adjustments of Lenvatinib 
 
a:  An interruption of lenvatinib for more than 28 days (due 
to treatment-related toxicities) will require discussion with 
the sponsor before treatment can be resumed.  During 
treatment interruption, repeat AEs assessment about every 
7 days (until restarting administration). 
Table 9 
[Footnote] 
w: Predose of Cycles 1 and 3. When the subject 
discontinues the study before sampling of Cycle 3, the 
sampling at discontinuation visit should be done. 
[Footnote] 
w: Part 2 only. Predose of Cycles 1 and 3. When the 
subject discontinues the study before sampling of Cycle 
3, the sampling at discontinuation visit should be done. 
To clarify the 
description. 
 


 
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Page 1 of 4 
 
Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 2.0, 09 Jan 2018) 
Amended Text (Version 3.0, 07 May 2018) 
Reason of 
Amendment(s) 
2 
 
9.7.1.7.1 
The primary PK parameters of lenvatinib in the combination 
will be calculated by noncompartmental analysis using the 
PK analysis set. 
The primary PK parameters of lenvatinib in the combination 
will be calculated by noncompartmental analysis using the 
PK analysis set (Part 1 only). 
To review the 
analysis in Part 2 
according to the 
accumulation of 
pharmacokinetic 
information on 
lenvatinib. 
 
9.5.1.4.1 
Table 5 Blood Sampling Schedule for Pharmacokinetic 
Assessment of Lenvatinib 
Day 
Sampling Time 
Allowance (as a Target) 
Cycle 1 Day 
1 
Predose of nivolumab 
Within –60 minutes before 
dosing 
1 hour postdose of 
lenvatinib 
±15 minutes 
2 hours postdose of 
lenvatinib 
±15 minutes 
4 hours postdose of 
lenvatinib 
±15 minutes 
8 hours postdose of 
lenvatinib 
±60 minutes 
Cycle 1 Day 
2 
Predose of lenvatinib 
(24 hours postdose) 
Within –60 minutes before 
dosing 
Cycle 1 Day 
15 
Predose of lenvatinib 
Within –60 minutes before 
dosing 
1 hour postdose of 
lenvatinib 
±15 minutes 
2 hours postdose of 
lenvatinib 
±15 minutes 
4 hours postdose of 
lenvatinib 
±15 minutes 
8 hours postdose of 
lenvatinib 
±60 minutes 
Cycle 1 Day 
16 
Predose of lenvatinib 
(24 hours postdose) 
Within –60 minutes before 
dosing 
Table 5 Blood Sampling Schedule for Pharmacokinetic 
Assessment of Lenvatinib 
Day (Part 1) 
Sampling Time 
Allowance (as a Target) 
Cycle 1 Day 
1 
Predose of nivolumab 
Within –60 minutes before 
dosing 
1 hour postdose of 
lenvatinib 
±15 minutes 
2 hours postdose of 
lenvatinib 
±15 minutes 
4 hours postdose of 
lenvatinib 
±15 minutes 
8 hours postdose of 
lenvatinib 
±60 minutes 
Cycle 1 Day 
2 
Predose of lenvatinib 
(24 hours postdose) 
Within –60 minutes before 
dosing 
Cycle 1 Day 
15 
Predose of lenvatinib 
Within –60 minutes before 
dosing 
1 hour postdose of 
lenvatinib 
±15 minutes 
2 hours postdose of 
lenvatinib 
±15 minutes 
4 hours postdose of 
lenvatinib 
±15 minutes 
8 hours postdose of 
lenvatinib 
±60 minutes 


 
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Section 
Original Text (Version 2.0, 09 Jan 2018) 
Amended Text (Version 3.0, 07 May 2018) 
Reason of 
Amendment(s) 
Thereafter 
Day 1 of 
every  Cycle 
Predose of lenvatinib 
 
– 
 
Cycle 1 Day 
16 
Predose of lenvatinib 
(24 hours postdose) 
Within –60 minutes before 
dosing 
Thereafter 
Day 1 of 
every  Cycle 
Predose of lenvatinib 
 
– 
 
Day (Part 2) 
Sampling Time 
Allowance (as a 
Target) 
Cycle 1 Day 1 
0.5 – 4 hour postdose 
of lenvatinib 
– 
Cycle 1 Day 15 
Predose of lenvatinib 
– 
0.5 – 4 hour postdose 
of lenvatinib 
– 
Day 1 of Cycles 
2, 4, 6 
Predose of lenvatinib 
– 
9.5.1.4.2.1 
Blood samples for the development of exploratory 
biomarkers will be collected from all consented subjects at 
designated time points as specified in the Schedule of 
Procedures/Assessments (Table 9). 
Blood samples for the development of exploratory 
biomarkers will be collected from all consented subjects at 
designated time points as specified in the Schedule of 
Procedures/Assessments (Table 9) (blood samples for 
nivolumab will be collected in Part 2 only). 
To review the 
biomarker blood 
sampling 
schedule. 
9.5.1.5.3 
Virus testsb in Table 8 
b:  Screening only. 
Virus testsb in Table 8 
b:  Screening only.  Data within 28 days before the first dose 
can be used. 
It was reviewed 
based on 
turnaround time 
of clinical 
laboratory 
results.  
9.5.1.5.9.2 
Hepatitis B surface (HBs) antigen, HBs antibody, hepatitis B 
virus core (HBc) antibody, hepatitis C virus (HCV) 
antibody, HBV-DNA, HCV-RNA, HDV antibody or HDV 
RNA (hepatitis B only), and HIV antibody tests will be 
performed at Screening. 
Hepatitis B surface (HBs) antigen, HBs antibody, hepatitis B 
virus core (HBc) antibody, hepatitis C virus (HCV) 
antibody, HBV-DNA, HCV-RNA, HDV antibody or HDV 
RNA (hepatitis B only), and HIV antibody tests will be 
performed at Screening.  Data within 28 days before the first 
dose can be used. 


 
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Section 
Original Text (Version 2.0, 09 Jan 2018) 
Amended Text (Version 3.0, 07 May 2018) 
Reason of 
Amendment(s) 
9.5.1.5.4 
Vital sign measurements (ie, systolic and diastolic BP 
[mmHg], pulse [beats per minute], body temperature [in 
centigrade]), and weight (kg) and percutaneous oxygen 
saturation (SPO2) will be obtained at the visits designated in 
the Schedule of Procedures/Assessments (Table 9) by a 
validated method.  BP and pulse will be measured sitting 
after the subject has been resting.  All BP measurements 
should be performed on the same arm, preferably by the 
same person.  One BP assessment is defined as the mean 
value of 3 measurements at least 5 minutes apart.  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 1-hour apart. 
Vital sign measurements (ie, systolic and diastolic BP 
[mmHg], pulse [beats per minute], body temperature [in 
centigrade]), and weight (kg) and percutaneous oxygen 
saturation (SPO2) will be obtained at the visits designated in 
the Schedule of Procedures/Assessments (Table 9) by a 
validated method.  BP and pulse will be measured sitting 
after the subject has been resting.  All BP measurements 
should be performed on the same arm, preferably by the 
same person. 
To adjust the 
description 
according to the 
protocol revision 
(Ver. 2.0). 
Table 9 
[Endpoints] 
Lenvatinib PK blood sampling: 
PD biomarker blood sampling: 
 
 
 
 
 
 
[Footnotes] 
c: 
Virus test (Screening only), Ammonia test (Screening 
only), hematology, blood chemistry, urinalysis, blood 
coagulation tests, thyroid function test.   
i: 
Blood collection at pre, 1, 2, 4, 8, 24 hours post-dose 
l: 
+3 days in C2D1 
[Endpoints] 
Lenvatinib PK blood sampling:  Change its footnote for 
Cycle 2 or later from n to i. 
Lenvatinib PD biomarker blood sampling:  Eliminate Day 
15 assessment in Cycle 2 or later. 
Nivolumab PD biomarker blood sampling:  Add assessments 
to Day 1 in Cycle 1, Day 1 in Cycle 2 or later, and 
Discontinuation. 
 
[Footnotes] 
c: 
Virus test (Screening only, Data within 28 days before 
the first dose can be used), Ammonia test (Screening only), 
hematology, blood chemistry, urinalysis, blood coagulation 
tests, thyroid function test.   
i: 
For Part 1, blood collection at predose, 1, 2, 4, 8, 24 
hours postdose of Cycle 1 Day1 and Day 15, and predose of 
Day 1 of every cycle thereafter.  For Part 2, blood collection 
at 0.5 – 4 hours postdose of Cycle 1 Day1, pre and 0.5 – 4 
hours postdose of Cycle 1 Day 15 and predose of Cycles 2, 
4, 6. 
l: 
+3 days in C2D1 (Part 1 only) 
Due to review 
based on 
turnaround time 
of in-site clinical 
laboratory 
results, review of 
pharmacokinetic 
analysis on 
lenvatinib, and 
reconsideration 
of the biomarker 
blood sampling 
schedule, etc. 


 
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Section 
Original Text (Version 2.0, 09 Jan 2018) 
Amended Text (Version 3.0, 07 May 2018) 
Reason of 
Amendment(s) 
w: Predose of Cycles 1 and 3.  When the subject 
discontinues the study before sampling of Cycle 3, the 
sampling at discontinuation visit should be done. 
 


 
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Protocol Change Tracking 
Study Protocol Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with Hepatocellular Carcinoma 
Study Protocol Number: 
E7080-J081-117 
 
Section 
Original Text (Version 1.0, 26 Sep 2017) 
Amended Text (Version 2.0, 09 Jan 2018) 
Reason of 
Amendment(s) 
2 
 
9.3.2 
18. Subjects with a history of coinfection with both hepatitis 
B and C, including, but not limited to: 
1)HBV DNA positive or HBV surface antigen positive 
subjects with detectable HCV antibody, OR 
2)HCV RNA positive subjects with resolved HBV infection 
as evidenced by detectable HBV surface antibody, 
detectable HBV core antibody, undetectable HBV DNA, and 
undetectable HBV surface antigen, OR 
3)Any positive test for HBV excluding HBV surface 
antibody indicating chronic or resolved HBV infection 
(positive HBV core antibody, positive HBV surface antigen, 
or detectable HBV DNA) and any positive test for HCV 
indicating chronic or resolved infection (positive HCV 
antibody or detectable HCV RNA) 
(Not stated) 
Amendment due 
to feedback from 
the investigator 
or 
subinvestigator 
and accumulation 
of experience to 
administer 
nivolumab 
2 
 
9.4.7.2 
Antiplatelet agents 
Antiplatelet agents and anticoagulants that require INR 
monitoring, such as warfarin (treatments that do not require 
INR monitoring, such as low molecular weight heparin and 
certain factor X inhibitors are permitted). 
To ensure the 
consistency with 
No. 12 of the 
exclusion 
criteria, and other 
studies of 
lenvatinib for 
HCC.  
9.4.1.4 
Guidelines for assessment and management of hypertension 
are summarized as follows. 
Guidelines for assessment and management of hypertension 
are summarized as follows. CTCAE v4.03 grading for 
Amendment 
according to 


 
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Section 
Original Text (Version 1.0, 26 Sep 2017) 
Amended Text (Version 2.0, 09 Jan 2018) 
Reason of 
Amendment(s) 
1. One blood pressure (BP) assessment is defined as the 
mean value of three measurements at least 5 minutes 
apart. 
2. For previously normotensive subjects, monotherapy 
with one of the classes of antihypertensives should be 
started when systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg is firstly observed  on 2 measurements 1 
hour apart.  For those subjects already on 
antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or one or more 
agents of a different class of antihypertensives should be 
added. 
3. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
continues despite optimal management of hypertension, 
lenvatinib should be interrupted and resumed according 
to Table 3 at a dose of one-dose level reduction only 
when systolic BP ≤150 mmHg and diastolic BP ≤95 
mmHg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours. 
4. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
recurs despite the optimal management of hypertension, 
one-dose level reduction should be attempted. 
5. Discontinue lenvatinib administration when Grade 4 
hypertension (life-threatening) is present 
hypertension will be based on BP measurements only (and 
not on the number of antihypertensive medications). 
1. When blood pressure (BP) is elevated (systolic BP 
≥140 mmHg or diastolic BP ≥90 mmHg), BP 
measurement should be repeated at least 5 min apart.  In 
this case, BP assessment is defined as the mean value of 
two measurements at least 5 minutes apart. 
2. When systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg is observed in the 1st BP assessment, the 
2nd BP assessment should be repeated at least 30 min 
apart.  The 2nd BP assessment is defined as the mean 
value of two measurements at least 5 minutes apart. For 
previously normotensive subjects, monotherapy with 
one of the classes of antihypertensives should be started 
when systolic BP ≥140 mmHg or diastolic BP 
≥90 mmHg is firstly observed on the 2nd BP 
assessment.  For those subjects already on 
antihypertensive medication, the dose of the current 
agent may be increased, if appropriate, or one or more 
agents of a different class of antihypertensives should be 
added.  
3. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
continues despite optimal management of hypertension, 
lenvatinib should be interrupted and resumed according 
to Table 3 at a dose of one-dose level reduction only 
when systolic BP ≤150 mmHg and diastolic BP 
≤95 mmHg and the subject has been on a stable dose of 
antihypertensive medication for at least 48 hours.   
4. If systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg 
recurs despite the optimal management of hypertension, 
one-dose level reduction should be attempted. 
5. Discontinue lenvatinib administration when Grade 4 
hypertension (life-threatening) is present. 
review of 
management of 
hypertension 
based on the 
accumulation of 
experience with 
lenvatinib 
administration. 


 
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Section 
Original Text (Version 1.0, 26 Sep 2017) 
Amended Text (Version 2.0, 09 Jan 2018) 
Reason of 
Amendment(s) 
9.5.1.4.2.2 
Security of the Samples, Use of the Samples, and 
Retention of the Samples  
Samples will be stored until the finalization of the analytical 
report at the central laboratory.  At the end of the storage 
period, samples will be destroyed. 
Security of the Samples, Use of the Samples, and 
Retention of the Samples  
Samples will be stored for up to 15 years after the 
completion of the study.  At the end of the storage period, 
samples will be destroyed.  Samples may be stored longer if 
a Heath Authority (or medicinal product approval agency) 
has active questions about the study.  In this special 
circumstance, samples will be stored until the questions have 
been adequately addressed. 
To allow 
long-term sample 
retention, 
considering 
responses to 
authorities in the 
future.  
 

SAP_001.pdf: 
Clinical Study Report
E7080-J081-117
16.1.9
Documentation of Statistical Methods
Listed below are all versions of the Statistical Analysis Plan for this study. The corresponding 
documents are provided on the following pages.
Statistical Analysis Plan
Version
Date
Revised original
V2.0
21 Apr 2023
Original 
V1.0
17 Jan 2018
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7080-J081-117 
Study Protocol 
Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with 
Hepatocellular Carcinoma 
Date: 
21 Apr 2023 
Version: 
Version 2.0 
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1 
TABLE OF CONTENTS 
 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................7 
3.1 
Study Objectives ......................................................................................................7 
3.1.1 
Primary Objective ..........................................................................................7 
3.1.2 
Secondary Objectives .....................................................................................7 
3.1.3 
Exploratory Objective ....................................................................................7 
3.2 
Overall Study Design and Plan ................................................................................7 
3.2.1 
Part 1 ..............................................................................................................8 
3.2.2 
Part 2 ..............................................................................................................8 
3.2.3 
Study Design ..................................................................................................9 
3.2.3.1 
Pretreatment Period ..............................................................................9 
3.2.3.2 
Treatment Period ..................................................................................9 
3.2.3.3 
Follow-up Period ...............................................................................10 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................11 
5 
STATISTICAL METHODS ............................................................................................12 
5.1 
Study Endpoints .....................................................................................................12 
5.1.1 
Primary Endpoints .......................................................................................12 
5.1.2 
Secondary Endpoints ...................................................................................12 
5.1.2.1 
Pharmacokinetic (PK) Endpoints .......................................................12 
5.1.3 
Exploratory Endpoints .................................................................................13 
5.2 
Study Subjects ........................................................................................................14 
5.2.1 
Definitions of Analysis Sets.........................................................................14 
5.2.2 
Subject Disposition ......................................................................................14 
5.2.3 
Protocol Deviations ......................................................................................15 
5.2.4 
Demographic and Other Baseline Characteristics .......................................15 
5.2.5 
Prior and Concomitant Therapy ...................................................................16 
5.2.6 
Treatment Compliance .................................................................................17 
5.3 
Data Analysis General Considerations ..................................................................17 
5.3.1 
Pooling of Centers........................................................................................17 
5.3.2 
Adjustments for Covariates..........................................................................17 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................17 
5.3.4 
Examination of Subgroups ...........................................................................17 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................17 
5.3.6 
Other Considerations ...................................................................................17 
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5.4 
Efficacy Analyses ..................................................................................................18 
5.4.1 
Efficacy Analyses ........................................................................................18 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................23 
5.5.1 
Pharmacokinetic Analyses ...........................................................................23 
5.5.1.1 
Plasma or serum Concentration and its PK Parameter Analysis .......23 
5.5.1.2 
Pharmacokinetic Data Figures ...........................................................23 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....24 
5.6 
Safety Analyses ......................................................................................................25 
5.6.1 
Extent of Exposure .......................................................................................25 
5.6.2 
Dose Limiting Toxicity ................................................................................27 
5.6.3 
Adverse Events ............................................................................................27 
5.6.4 
Laboratory Values ........................................................................................29 
5.6.5 
Vital Signs ....................................................................................................29 
5.6.6 
Electrocardiograms ......................................................................................29 
5.6.7 
Other Safety Analyses ..................................................................................30 
5.7 
Other Analyses .......................................................................................................30 
5.8 
Exploratory Analyses .............................................................................................31 
6 
INTERIM ANALYSES ...................................................................................................32 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................32 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING ...............................33 
8.1 
General Data Handling ..........................................................................................33 
8.2 
Efficacy Data Handling ..........................................................................................33 
8.3 
Safety Data Handling .............................................................................................34 
8.4 
Pharmacokinetic Data Handling ............................................................................37 
8.4.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Nivolumab Serum Concentration ................................................................37 
8.4.2 
BLQ Handling for Calculation of PK Parameters .......................................37 
8.4.3 
BLQ Handling for Developing Concentration-Time Profiles .....................37 
8.4.4 
Handling of Anomalous Concentration Values ...........................................37 
8.4.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters ....................................................................................................38 
8.4.6 
Handling of Individual Data ........................................................................39 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................40 
10 STATISTICAL SOFTWARE ..........................................................................................40 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................40 
12 REFERENCES ................................................................................................................40 
13 APPENDICES .................................................................................................................41 
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13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 ..............................................................................41 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
anti-drug antibody 
AE 
adverse event 
AFP 
α-fetoprotein 
ATC 
anatomical therapeutic chemical 
BCLC 
Barcelona Clinic Liver Cancer 
BLQ 
below lower quantification 
BMI 
body mass index 
BOR 
best overall response 
BW 
body weight 
CBR 
clinical benefit rate 
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 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
HCC 
hepatocellular carcinoma 
IV 
Intravenous 
LLOQ 
lower limit of quantification 
LLT 
lower level term 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
multiple-gated acquisition technique 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamics 
PD 
progressive disease 
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Abbreviation 
Term 
PFS 
progression free survival 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
QD 
every day 
QOD 
every other day 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Q2W 
every 2 weeks 
RECIST 
response evaluation criteria in solid tumor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SD 
standard deviation 
SI 
système international 
SOC 
system organ class 
SpO2 
percutaneous oxygen saturation 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TLG 
tables, listings, and graphs 
TNM 
tumor, nodes, metastasis 
TTP 
time to progression 
TTR 
time to response 
WHO DD 
World Health Organization drug dictionary 
 
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is available. Part 2 is to further characterize the safety and tolerability and to assess 
preliminary efficacy of the combination therapy in HCC with no prior systemic therapy. 
3.2.1 
 Part 1 
In Part 1, the tolerability review of Cycle 1 (4 weeks) will be conducted by dose limiting 
toxicities (DLTs). Study treatment and starting dose is as follows: 
Lenvatinib: 12 mg (Body Weight [BW] ≥60 kg) or 8 mg (BW <60 kg) once daily orally 
Nivolumab: 240 mg (every 2 weeks [Q2W], intravenous [IV]) 
The tolerability will be reviewed based on Dose Limiting Toxicity (DLT) of Cycle 1 (4 
weeks) according to the following procedures. 
First, 3 subjects will be enrolled. 
(1) DLT occurs in 0 or 1 of 3 subjects 
Add 3 more subjects and assess in a total of 6 subjects. 
1) DLT occurs in 0 or 1 of 6 subjects 
This dose level is judged to be tolerable. 
2) DLT occurs in 2 or more of 6 subjects 
The tolerability with this dose level will be discussed by the sponsor, sponsor’s 
responsible medical officer, and investigators. 
(2) DLT occurs in 2 or more of 3 subjects 
The tolerability with this dose level and appropriateness of additional enrollment will be 
discussed by the sponsor, sponsor’s responsible medical officer, and investigators. 
In this dose level, at least 3 subjects treated with lenvatinib 12 mg (BW ≥60 kg) and 
nivolumab need to be included in the 6 subjects for DLT evaluation. If this dose level is not 
tolerable, upon discussions between the sponsor, sponsor’s responsible medical officer, and 
investigators, the lower dose level of cohort will be considered or the study will be 
discontinued, and the protocol will be amended as necessary. An efficacy and safety 
evaluation advisor maybe consulted for the consideration as needed. 
3.2.2 
Part 2 
If the dose level is confirmed to be tolerable, an additional 20 HCC subjects with no prior 
systemic therapy will be enrolled. At least 5 subjects (BW ≥60 kg) treated with Lenvatinib 12 
mg QD and at least 5 subjects (BW <60 kg) treated with Lenvatinib 8 mg QD will be 
included. 
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3.2.3 
Study Design 
An overview of the study design is presented in Figure 1. Part 1 and Part 2 will consist of a 
pretreatment period, a treatment period, and a follow-up period. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
DLT = dose limiting toxicity. 
a: Screening assessment should be performed within 14 days of first dose. (Informed consent can be obtained 
within 28 days of first dose.)  
Figure 1 Study Design 
 
3.2.3.1 
Pretreatment Period 
The pretreatment period will involve obtaining informed consent, a screening assessment, 
and a baseline assessment.  Screening will occur within 14 days before starting study drug 
administration after obtaining written informed consent.  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 (informed consent can be obtained within 28 days of 
first dose).  After screening assessments, the sponsor will be informed of eligibility of the 
patient by the investigator or subinvestigator.  The baseline assessment will be conducted 
within 4 days before starting study drug administration in order to confirm that the patient 
meet the eligibility requirement before moving to the Treatment Period. 
3.2.3.2 
Treatment Period 
In the Treatment Period, subjects will receive lenvatinib in combination with nivolumab.  
The Treatment Period will begin with the first dose of study drug administration on Cycle 1 
Survival follow-up 
every 12±2 weeks 
Part 2 only 
Pretreatment Period 
Treatment Period 
Screening 
Baseline 
Cycle 2 and later 
Cycle 1 
Informed consent 
Treatment initiated 
Eligibility confirmation 
28-days cycles 
Last dose 
Discontinuation 
Within 
4 days 
DLT evaluation 
(Part 1 only) 
Within 14 daysa 
Follow-up Period 
Last observation 
30 days (+7 days) after 
last dose 
Screening assessment 
Baseline assessment 
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Day 1.  Each cycle is 28 days long and subjects continue treatment until they meet any of the 
criteria in “Discontinuation Criteria by Subject (see Protocol Section 9.3.3.1)”.   
Subjects will be hospitalized during the Cycle 1, however, outpatient is allowed after Cycle 1 
Day 15, when investigator or subinvestigator judges that that the subject’s safety is ensured. 
3.2.3.3 
Follow-up Period 
The follow-up period will consist of the examination at study discontinuation and the last 
observation visit which occurs 30 days after final administration of study drug.  If the last 
observation visit occurs within 7 days after study drug discontinuation, discontinuation data 
can be used as the last observation data.  The subject who discontinues study will have a 
discontinuation visit and last observation which occurs 30 days after final administration of 
study drug.  If a new anticancer agent needs to be immediately started due to deterioration in 
the subject’s condition, the final observation visit can be conducted before 30 days after the 
last dose of the study drug has passed but prior to starting the new anticancer agent. 
In Part 2, all subjects will be followed for survival until death every 12 weeks (±2 week) 
from the date of discontinuation, except where a subject withdraws consent or the sponsor 
chooses to halt survival follow-up.  The survival follow-up will be continued for up to 2 
years after Cycle 1 Day 1 of the last subject enrolled in Part 2. 
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4 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 26 subjects will be enrolled in this study, 6 subjects for Part 
1 and 20 patients for Part 2.  Six subjects in Part 1 was deemed appropriate to evaluate the 
tolerability of the dose and perform preliminary safety assessment.  Twenty subjects in Part 2 
was determined to further evaluate the safety and preliminary efficacy.  The probability to 
detect at least 1 development of intolerable treatment-related AEs with a true incidence of 
10%, 15% or 20% in 20 subjects was 87.8%, 96.1%, or 98.8%, respectively.  Therefore, the 
sample size is determined to be approximately 20 subjects. 
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5 
STATISTICAL METHODS 
All statistical analyses will be performed by the sponsor or designee after the data cutoff for 
analysis or the study is completed and the database is locked.  Statistical analyses will be 
performed using SAS software or other validated statistical software as required.   
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. 
All statistical analysis will be performed by part separately. Summarization for lenvatinib 8 
mg group, 12 mg group and total subjects will be presented. 
5.1 
Study Endpoints 
The endpoints of this study are shown below.  All efficacy endpoints will be assessed using 
mRECIST.  If necessary, RECIST1.1 will also be performed and used for analysis. 
5.1.1 
Primary Endpoints 
• 
DLTs (Part 1 only) 
• 
Safety endpoints including AEs, laboratory tests, vital signs, ECG, ECOG-PS, and 
LVEF 
 
5.1.2 
Secondary Endpoints 
• 
ORR is defined as the proportion of subjects who have BOR of CR or PR 
• 
Pharmacokinetic parameters of lenvatinib 
  
5.1.2.1 
Pharmacokinetic (PK) Endpoints 
PK parameters derived by non-compartmental analysis using plasma concentrations of 
lenvatinib (Part 1) which include, but are not limited to, are shown as below: 
 
Cmax 
maximum observed concentration 
tmax 
time at which the highest drug concentration occurs 
AUC(0-t) 
area under the concentration-time curve from zero time to time of last quantifiable 
concentration 
AUC(0-inf) 
area under the concentration-time curve from zero time extrapolated to infinite time 
t½ 
terminal elimination phase half-life 
CL/F 
apparent total clearance following oral dosing 
Vz/F 
apparent volume of distribution at terminal phase 
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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  
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In this protocol, subjects who completed the study are defined as subjects who completed the 
appropriate DLT evaluation in Part 1, or subjects who completed the discontinuation 
assessment or last observation assessment in Part 2.  Subjects who completed the study 
treatment are defined as who discontinued the treatment due to disease progression or 
subjects who are continuing the study treatment at the date of data cutoff. 
Subject data listings will be provided. 
5.2.3 
Protocol Deviations 
Important protocol deviation criteria will be established and subjects with important protocol 
deviations will be identified and documented before the database lock. Also, protocol 
deviations related to COVID-19 (coronavirus disease 2019) and subjects with the deviations 
will be identified and documented before database lock. 
Subject data listings will be provided. 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive 
statistics in Safety Analysis Set. 
Continuous demographic and baseline variables include 
• 
Age 
• 
Height 
• 
Weight 
• 
BMI 
 
Categorical demographic and baseline variables include 
• 
Age group (< 65 years, ≥ 65 to < 75 years, ≥ 75 years) 
• 
Weight group (< 60kg, ≥ 60 kg) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
ECOG-PS 
• 
NYHA (I, II, III, IV and NA for Heart failure) 
 
Disease history and characteristics at study entry will also be summarized by: 
• 
HCC type (Fibrolamellar, Scirrhous, Spindle cell variant, Pleomorphic type, Clear cell 
type, Trabecular, Multinodular differentiated, Moderately differentiated, Poorly 
differentiated, Well differentiated, Biopsy performed – HCC type unknown, Biopsy not 
performed, Other) 
• 
Child-Pugh score 
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• 
BCLC stage 
• 
AFP (as continuous variable) 
• 
AFP group (<200 ng/mL, ≥ 200 ng/mL) 
• 
Macroscopic portal vein invasion (Yes, No) 
• 
Portal vein involvement (Vp0, Vp1, Vp2, Vp3, Vp4) 
• 
Extrahepatic spread (Yes, No) 
• 
Involved disease organ 
• 
Number of involved disease organ per patient (1, 2, ≥3) 
• 
Diagnosis of HCC (Histological or cytological diagnosis of HCC, Clinically confirmed 
diagnosis of HCC) 
• 
Time from confirmed diagnosis of HCC to the date of first study treatment (months) (as 
continuous variable) 
 For patients who were “histologically or cytologically” and “clinically” confirmed, 
whichever earlier diagnosis date is used. 
• 
TNM classification at diagnosis 
• 
Tumor staging at diagnosis  
• 
Factor of Carcinogenesis (Hepatitis B, Hepatitis C, Alcohol, Unknown, Other) 
• 
Number of previous anticancer medication as regimen (0, 1, 2, ≥3) 
• 
Subjects with any previous radiotherapy 
 
Previous anticancer procedure will be summarized by: 
• 
Subjects with any previous anticancer procedure 
• 
Number of previous anticancer procedure (0, 1, 2, 3, 4, ≥5) 
• 
Previous procedure name (Hepatic intra-arterial chemotherapy, Transarterial [chemo] 
embolization, Radiofrequency ablation, Cryoablation, Percutaneous ethanol injection, 
Hepatectomy, Other) 
• 
Time from end of most recent procedure to the date of first study treatment (months) (as 
continuous variable) 
 
Subject data listings 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 started before the first dose of study treatment.  
Concomitant medications will be defined as medications that (1) started before the first dose 
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of study treatment 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 treatment up to 30 days after the subject’s last 
dose.  Medications received after 30 days of last dose will be considered as post treatment 
medications. 
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) class (anatomical class, 
pharmacological class), and WHO DD preferred term on the Safety Analysis Set. 
Non-pharmacological procedures will be classified into standardized medical terminology 
using the Medical Dictionary for Regulatory Activities (MedDRA version 20.1 or later). 
 
All medications and non-pharmacological procedures will be presented in subject data listings. 
5.2.6 
Treatment Compliance 
Treatment related protocol deviations will be presented in CSR as provided in the section 
5.2.3. 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers  
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
No adjustment for covariates will be performed. 
5.3.3 
Multiple Comparisons/Multiplicity 
No statistical comparison is planned in this study. 
5.3.4 
Examination of Subgroups 
No subgroup analysis will be performed.  
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
The details of handling of missing data will be described in the section 8. 
5.3.6 
Other Considerations 
Not applicable. 
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5.4 
Efficacy Analyses 
Efficacy analyses will be conducted on the Efficacy Analysis Set.  Tumor assessment will be 
analyzed base on the investigator’s assessment. If needed, the analysis based on independent 
review will be conducted.   
5.4.1 
Efficacy Analyses 
Part 1 
BOR will be summarized based on mRECIST, and ORR and its corresponding exact 2-sided 
95% confidence interval (CI) will be calculated.  DCR and CBR will be summarized in a 
same manner. 
Part 2 
In addition to the same analysis as above for Part 1, following analyses will be performed. 
PFS is defined as the time from the date of first dose to the date of first documented PD or 
death due to any cause (whichever occurs first) and calculated as below. For subjects who do 
not have an event, PFS will be censored. Censoring rules for PFS are shown in Table 1
 
Censoring rules for PFS. 
PFS (months) = (Date of first documented PD/ death/ censored date – Date of first dose + 1) / 
(365.25/12). 
The PFS rate will be calculated using Kaplan-Meier method. The median, Q1, and Q3 for 
PFS with their 95% CIs will be evaluated. The 95% CIs will be calculated based on 
Greenwood formula and a generalized Brookmeyer and Crowley method with log-log 
transformation. The number (percentage) of subjects with event/censored will be 
summarized. The PFS rate with its 95% CI at 2, 4, 6, 8, 10 and 12 months will also be 
calculated, but not limited to these time points. Kaplan-Meier plots with the number of 
subjects at risk will be presented. 
 
TTP is defined as the time from the date of first dose to the date of first documented PD and 
calculated as below. For subjects who do not have an event, TTP will be censored. Censoring 
rules for TTP are shown in Table 2 Censoring rules for TTP. TTP will also be summarized 
in the same manner as with PFS. 
TTP (months) = (Date of first documented PD/ censored date – Date of first dose + 1) / 
(365.25/12). 
 
DOR is defined as the time from the first documentation of CR or PR to the date of first 
documented PD or death (whichever occurs first) and calculated as below. DOR will be 
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calculated only for subjects having at least one CR or PR. Censoring rules for DOR is same 
as PFS. DOR will also be summarized in the same manner as with PFS. 
DOR (months) = (Date of first documented PD/ death/ censored date – Date of the first 
documentation of CR or PR + 1) / (365.25/12). 
 
TTR is defined as the time from the date of first study dose to the date of first documentation 
of CR or PR and calculated as below. TTR will be summarized in only subjects with CR or 
PR using summary statistics. 
TTR (months) = (Date of documentation of CR or PR – Date of first dose + 1) / (365.25/12). 
 
OS is defined as the time from the date of first study dose to the date of death due to any 
cause and calculated as below.  Subjects who are lost to follow-up and the subjects who are 
alive at the date of data cutoff will be censored at the date the subject was last known alive or 
the cut-off date, whichever comes earlier. Censoring rules for OS are shown in Table 3
 
Censoring rules for OS. OS will also be summarized in the same manner as with PFS. 
OS (months) = (Date of death/ censored date – Date of first dose + 1) / (365.25/12). 
 
A waterfall plot will be presented for the percent changes from baseline in the sum of the 
diameters of target lesions at post-baseline nadir (ie, maximum tumor shrinkage).  A spider 
plot will be presented for the percent changes from baseline in the sum of the diameters of 
target lesions. The diameters after subsequent anti-cancer treatment initiation are not 
included in the waterfall and spider plot. 
Summary statistics for tumor marker (AFP) the changes and percent changes from baseline 
will be presented by visit. Also, AFP will be categolized as >200 μg/L or <= 200 μg/L and 
presented by visit. 
Subject data listings will be provided. 
 
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Table 1 
Censoring rules for PFS 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose 
Censored 
2 
Progression documented at scheduled 
visit 
Date of first radiologic PD assessment Event 
3 
Progression documented between 
scheduled visits 
Date of first radiologic PD assessment Event 
4 
No progression nor death at the time of 
data cut-off or  discontinuation from study 
treatment 
Date 
of 
last 
adequate 
radiologic assessment* 
Censored 
5 
New anticancer treatment started 
Date of last adequate radiologic 
assessment* prior to or on date of 
new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date of death 
Event 
7 
Death between adequate assessment 
visits* 
Date of death 
Event 
8 
Death or progression after two or 
more 
consecutive 
missed 
visit/tumor assessment** 
Date of last adequate radiologic 
assessment* 
before 
missed 
tumor assessments 
Censored 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or 
PD as determined by investigators. 
** More than one missed visit is defined if the duration between the last tumor assessment and death or PD is 
longer than 126 days (ie. 8 weeks x 2 + 2 weeks [allowance of visit]) for subjects on the every 8 week scanning 
schedule 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 baseline tumor assessment (No. 1), the subject will be censored on date of first 
dose. However, if the subject died within 56 days (8 weeks) after the first dosing date and did not receive 
new anticancer treatment, the date of death will be the PFS event date (not censored).  
• 
If a subject had new anticancer treatment before PD or death (No. 5), 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 assessments consecutively before PD or death (No. 8), 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 criteria, the earliest censoring date will be 
used.  
• 
Otherwise, if a subject had an event (No. 2, 3, 6, 7), 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, 4, 5, 8).  
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Table 2 
Censoring rules for TTP 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose 
Censored 
2 
Progression documented at scheduled 
visit 
Date of first radiologic PD assessment Event 
3 
Progression documented between 
scheduled visits 
Date of first radiologic PD assessment Event 
4 
No progression at the time of data cut-off 
or  discontinuation from study treatment 
Date 
of 
last 
adequate 
radiologic assessment* 
Censored 
5 
New anticancer treatment started 
Date of last adequate radiologic 
assessment* prior to or on date of 
new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date 
of 
last 
adequate radiologic 
assessment* 
Censored 
7 
Death between adequate assessment 
visits* 
Date 
of 
last 
adequate radiologic 
assessment* 
Censored 
8 
PD after two or more consecutive 
missed visit/tumor assessment** 
Date of last adequate radiologic 
assessment* 
before 
missed 
tumor assessments 
Censored 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or 
PD as determined by investigators. 
** More than one missed visit is defined if the duration between the last tumor assessment and PD is longer 
than 126 days (ie. 8 weeks x 2 + 2 weeks [allowance of visit]) for subjects on the every 8 week scanning 
schedule in this study. 
The priority of the censoring rules is as follows:  
1. If the subject had PD, the following sequence will be applied:  
• 
If a subject did not have baseline tumor assessment (No. 1), the subject will be censored on date of first 
dose.  
• 
If a subject had new anticancer treatment before PD (No. 5), 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 assessments consecutively before PD (No. 8), the subject will be censored 
on the date of the last adequate tumor assessment before PD.  
• 
Otherwise, if a subject had an event (No. 2, 3), the earliest event date will be used.  
 
2. If a subject did not have PD, the censoring date will be the earliest censoring date if the subject met multiple 
censoring criteria (No. 1, 4, 5, 6, 7, 8). 
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Table 3 
Censoring rules for OS 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
Death before or on data cut off 
Date of Death 
Event 
2 
Death after data cut off 
Date of data cut off 
Censored 
3 
Subject still alive at data cut off 
Date of data cut off 
Censored 
4 
Subject lost to follow-up or 
withdraw of consent before data cut off 
Date last known to be alive 
Censored 
 
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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual lenvatinib plasma concentrations and 
nivolumab serum concentrations listings. The PK Analysis Set will be used for the summaries 
of lenvatinib plasma concentrations and nivolumab serum concentrations, for summaries and 
listings of PK parameters of lenvatinib.  The PK Analysis Set for lenbatinib and for novolumab 
will be used for each analysis. 
5.5.1.1 
Plasma or serum Concentration and its PK Parameter Analysis 
<Concentration> 
Plasma concentration values for lenvatinib and serum concentration values for nivolumab 
will be summarized by dose level using summary statistics (n, mean, standard deviation 
[SD], median, minimum [min] and maximum [max]) by Part and nominal time point. 
Plasma concentrations of lenvatinib, serum concentrations of nivolumab will be listed for 
each subject by actual sampling time. 
<PK Parameter (Lenvatinib only in Part 1)> 
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), t½, λz, CL/F, Vz/F, MRT, Css,max, Css,min, tss,max, AUC(0-τ), CLss/F, Css,av, 
Rac(Cmax), Rac(AUC), and PTF ratio. 
Rac(AUC) will be calculated based on AUC(0-t) not AUC(0-τ) of Cycle Day1 and Cycle Day 
15. 
Other PK parameters may be calculated as appropriate. 
Summary statistics will be tabulated for the PK parameters of lenvatinib by dose level.  
Summary statistics (n, mean, SD, median, min, and max) will be presented for all parameters 
(apart from tmax 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 versus actual time will be 
displayed by individual subjects in Part 1.  The actual time will be plotted on the X axis and 
the concentrations of lenvatinib will be plotted by dose level on the Y axis.The linear and semi-
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log mean (+SD) plots of lenvatinib plasma concentration versus nominal time will be displayed 
in Part 1.  The nominal time will be plotted on the X axis and the mean (+SD) will be plotted 
by dose level on the Y axis on the same graph by visit (Cycle 1 Day 1 and Cycle1 Day 15). 
The linear plots of individual and mean (±SD) pre-dose serum concentration for nivolumab 
will be displayed by Part.  For plots of individual concentrations, actual time will be used.  For 
plot of mean concentrations, the nominal time will be used. 
The linear mean (±SD) plots of nivolumab pre-dose serum concentration versus nominal time 
will be displayed by Part.  The nominal time will be plotted on the X axis and the mean (±SD) 
will be plotted on the Y axis.  
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
The effect of lenvatinib-nivolumab combination therapy on soluble and/or tissue biomarkers 
will be summarized using descriptive statistics. This analysis will be performed only when 
relavant biomarkers are evaluated and the analysis is deemed nesessary. 
 
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5.6 
Safety Analyses 
All DLT analyses will be performed on the DLT Analysis Set.  All other safety analyses will 
be performed on the Safety Analysis Set by part.  Safety data will be summarized using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables). 
5.6.1 
Extent of Exposure 
The parameters to be summarized are defined as follows. 
These parameters for extent of exposure will be computed and presented for lenvatinib alone 
and nivolumab alone, separately. 
For lenvatinib:   
• 
Number of cycles = The last cycle with at least one lenvatinib dosing 
• 
Duration of treatment (days) = Last dosing date – first dosing date + 1 
• 
Duration of treatment (months) = (Last dosing date – first dosing date + 1) / (365.25/12) 
• 
Number of subject-month with study drug dosing = Sum of duration of treatment 
(months) per subjects 
• 
Total number of doses = Sum of days with lenvatinib dosing 
• 
Total doses (mg) = Sum of all the actual dose 
• 
Dose intensity (mg / days) = Total doses / Duration of treatment (days) 
• 
Relative dose intensity (%) = 100 × Dose intensity / planned starting dose (8 or 12 mg) 
 
For nivolumab: 
• 
Number of cycles = The last cycle with at least one nivolumab dosing 
• 
Duration of treatment (days) = Last dosing date with nivolumab – first dosing date + 1 
• 
Duration of treatment (months) = (Last dosing date with nivolumab – first dosing date + 
1) / (365.25/12) 
• 
Number of subject-month with study drug dosing = Sum of duration of treatment 
(months) per subjects  
• 
Total number of doses = Sum of days with nivolumab dosing 
• 
Total doses (mg) = Sum of all the actual dose derived by [ 240 (mg) x (Actual volume 
infused (ml) / volume to be infused (ml))] 
• 
Dose intensity (mg / 2weeks) = Total doses / ((Last dosing date with nivolumab – first 
dosing date + 14) / 14)  
• 
Relative dose intensity (%) = 100 × Dose intensity / 240 (mg) 
 
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Number of cycles as combination therapy of lenvatinib and nivolumab will also be calculated 
and presented. The smaller number of cycles within a subject is defined as the number of 
cycle as combination therapy.  
Furthermore, the following information of administration will also be summarized for both 
lenvatinib and nivolumab based on study medication data.  
For lenvatinib, the number (percentage) of subjects who experienced a dose reduction and 
interruption will be summarized. For subjects who experienced a dose reduction, cycle of the 
first dose reduction will be summarized by descriptive statistics. Cycle of the first dose 
interruption will also be summarized in subjects who experienced a dose interruption. 
Frequency of dose reductions will be summarized by categories (1, 2, 3, ≥4). Frequency of 
dose interruptions will also be summarized by appropriate categories (e.g., 1, 2, 3, ≥4). 
The date of dose reduction (from XX mg to YY mg, XX > YY > 0) is defined as the first 
date of planned dose of 0 mg followed by YY mg. The first date of 0 mg has to follow 
planned dose of XX mg. If the starting dose of YY mg does not follow 0 mg but XX mg, the 
first date of planned dose of YY mg is regarded as the date of dose reduction.  Note that from 
4 mg QD to 4mg QOD is also dose reduction. 
The dose interruption is defined as the case where planned dose is 0 mg. The starting date of 
dose interruption is defined as the first date of planned dose of 0 mg following and followed 
by same dose level (> 0 mg). For example: 12 mg followed by 0 mg and followed by 12 mg; 
8 mg followed by 0 mg followed by 8 mg. Successive days with planned dose of 0 mg is 
counted as one dose interruption event. If after dose 0 mg, the subject discontinued from 
lenvatinib permanently, it is not regarded as a drug interruption (but as a drug 
discontinuation). 
An illustration for dose reduction and interruption in a subject is shown in Figure 2. 
 
Figure 2 Dose reduction and interruption for lenvatinib 
For nivolumab, the number (percentage) of subjects who experienced a dose interruption will 
be summarized. Cycle of first dose interruption will be summarized by descriptive statistics 
in subjects who experienced a dose interruption. Frequency of dose interruptions will be 
summarized by appropriate categories (e.g., 1, 2, 3, ≥4). 
The dose interruption is defined as the case where planned dose of 0 mg. Successive dates 
with planned dose of 0 mg is counted as one dose interruption event, and the first date with 
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planned dose of 0 mg is defined as the starting date of dose interruption. If after dose 0 mg, 
the subject discontinued from nivolumab permanently, it is not regarded as a drug 
interruption (but as a drug discontinuation). 
Subject data listings will be provided. 
5.6.2 Dose Limiting Toxicity 
The number and percentage of subjects with DLT will be calculated.  DLT will also be 
summarized per type of toxicity.   
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 20.1 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 the section 8.3, will be included in 
summary tables.  All AEs, treatment emergent or otherwise, will be presented in subject data 
listings. 
Treatment-related TEAEs include those events considered by the investigator to be related to 
study treatment. 
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.  
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 discontinuation of lenvatinib, discontinuation of nivolumab, 
dose reduction of lenvatinib, dose interruption of lenbatinib and dose interruption of nivolumab 
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 (any grade) 
• 
TEAEs by the highest CTCAE grade 
• 
TEAEs grade 3 or above 
• 
Treatment-emergent SAEs 
• 
Non-serious TEAEs 
• 
Treatment-related TEAEs 
• 
Treatment-related TEAEs by the highest CTCAE grade 
• 
Treatment-related TEAEs grade 3 or above 
• 
Treatment-related serious TEAEs 
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• 
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 nivolumab  
• 
TEAEs leading to dose interruption of nivolumab 
 
All deaths will also be summarized by primary reasons of deaths (progressive disease, AEs, 
others), deaths within 30 days of last dose of study drug, deaths >30 days of last dose of 
study drug, and treatment-related deaths. 
Subject data listings of all deaths, SAEs, AEs leading to death, discontinuation of lenvatinib, 
discontinuation of nivolumab, dose reduction of lenvatinib, dose interruption of lenbatinib 
and dose interruption of nivolumab will be provided. 
Select Adverse Events 
The select Adverse Events (select AEs) consist of a list of MedDRA PT grouped by specific 
category (e.g. endocrine events, and gastrointestinal events categories, etc.). AEs that may 
differ from or be more severe than AEs caused by non-immunotherapies and AEs whose 
early recognition and management may mitigate severe toxicity are included as select AEs. 
The select AEs and the categories/sub-categories are defined by the Sponsor and the list of 
PT used for the analyses will be prepared sepalately from SAP.  
Select AEs will be summarized by PT on each category/subcategory. The incidence of below 
events will be reported as the number (percentage) of subjects. 
• 
Select AEs (any grade) 
• 
Select AEs by the highest CTCAE grade 
• 
Select AEs grade 3 or above 
• 
Serious select AEs (any grade) 
• 
Serious select AEs grade 3 or above 
• 
Treatment-related select AEs (any grade) 
• 
Treatment-related select AEs by the highest CTCAE grade 
• 
Treatment-related select AEs grade 3 or above 
• 
Treatment-related serious select AEs (any grade) 
• 
Treatment-related serious select AEs grade 3 or above 
• 
Select AEs leading to discontinuation of nivolumab (any grade) 
• 
Select AEs grade 3 or above leading to discontinuation of nivolumab 
• 
Select AEs leading to dose interruption of nivolumab (any grade) 
• 
Select AEs grade 3 or above leading to dose interruption of nivolumab 
 
Subject data listings of the select AEs will be provided.  
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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 plot display 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. 
Laboratory parameters will be graded by CTCAE ver. 4.03 in the section 13.  Changes from 
CTCAE grade at baseline to each postbaseline visit and worst postbaseline will be reported 
using shift tables. CTCAE will also 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, 
and temperature), weight, and SPO2 and changes from baseline will be presented by visit. 
Box plot display 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: 
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• 
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 
Descriptive statistics for LVEF and LVEF changes from baseline assessed by MUGA scans 
or echocardiograms 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 
Immunogenicity 
Serum anti-nivolumab antibodies (ADA) will be summarised for subjects which meet all the 
following criteria. 
• 
Nivolumab is administered once or more. 
• 
It has measurements of ADA (note of, a subject with the sample which baseline result is 
potential positive but confirmatory result is not available will be excluded) at both 
baseline and at least one post-treatment anti-drug antibody assessment. 
 
Each sample from the subject is categorized based on the following definitions: 
Sample ADA Status: 
• 
Baseline ADA-positive sample: ADA is detected in the last sample before initiation of 
treatment 
• 
Baseline ADA-negative sample: ADA is not detected in the last sample before initiation 
of treatment 
• 
ADA-positive sample: After initiation of treatment, (1) an ADA detected (positive 
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seroconversion) sample in a subject for whom ADA is not detected at baseline, or (2) an 
ADA detected sample with ADA titer to be at least 4-fold or greater (≥) than baseline 
positive titer 
• 
ADA-negative sample: After initiation of treatment, ADA not positive sample relative to 
baseline (except missing data). 
 
Next, using the sample ADA status, subject ADA status is defined as follows: 
Subject ADA Status: 
• 
Baseline ADA-positive subject: A subject with baseline ADA-positive sample. Among 
the baseline ADA-positive subjects, the subject who has baseline ADA-positive sample 
with neutralizing antibodies detected will be defined as the baseline neutralizing 
positive. 
• 
ADA-positive subject: A subject with at least one ADA positive-sample relative to 
baseline at any time after initiation of treatment 
1) Persistent Positive (PP): ADA-positive sample at 2 or more consecutive time points, 
where the first and last ADA-positive samples are at least 15 weeks apart 
2) Not PP-Last Sample Positive: Not persistent positive with ADA-positive sample at 
the last sampling time point 
3) Other Positive: Not persistent positive but some ADA-positive samples with the last 
sample being negative 
4) Neutralizing Positive: At least one ADA-positive sample with neutralizing antibodies 
detected 
• 
ADA-negative subject: A subject with no ADA-positive sample after the initiation of 
treatment. 
 
The number (percentage) of subjects will be summarized by part for the following subject 
ADA status.  
• 
Baseline ADA-positive 
• 
ADA-positive 
 Persistent Positive (PP) 
 Not PP-Last Sample Positive 
 Other Positive 
• 
ADA-negative 
 
Subject data listing of all ADA assessments will be provided. 
For exploratory purpose,  the number (percentage) of subject with the baseline neutralizing 
positive/neutralizing positive may be summarized, if appropriate. Also, subject data listings 
of ADA assessments for subjects with neutralizing positive may be provided. 
 
5.8 
Exploratory Analyses 
No exploratory analyses are planned for this study. 
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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 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. 
8.2 
Efficacy Data Handling 
Handling of missing data for tumor assessment result 
For the analysis of ORR, DCR and CBR, subjects with missing response status (subjects whose 
baseline is missing and/or no adequate post-baseline tumor assessments result) will be coded 
as non-responders on Efficacy Analysis Set.   
Data of tumor assessment result after documented PD or discontinuation from treatment 
For the analysis of tumor assessment relevant efficacy endpoints, tumor assessment result 
after PD or final observation visit (for non-PD patients) are excluded from the analyses, but 
included in subject data listing. 
Visit Windows 
The purpose of visit windows is to provide a single record per subject per visit for the 
calculation of descriptive statistics for tumor marker per scheduled visit, and change from 
baseline per visit. 
The observation closest to the target date will be used in by visit summaries. If two or more 
observations have the same distance to the target visit day, the one that has the highest value 
will be used for summary tables.  If the multiple data in the same distance to the target date 
are same, the data measured at an earlier date will be used for summary tables. 
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The visit window is applied for tumor marker assessment summary. 
Analysis visit 
Target Day 
Analysis Window 
Start Day 
End Day 
Cycle 3 Day 1  
Cycle 3 Day 1  
Cycle 3 Day 1 - 7  
Cycle 3 Day 1 + 7  
Cycle 5 Day 1  
Cycle 5 Day 1  
Cycle 5 Day 1 - 7  
Cycle 5 Day 1 + 7  
Cycle n Day 1 (n ≥ 7 
and odd numbers) 
Cycle n Day 1  
Cycle n Day 1 - 7 
Cycle n Day 1 + 7 
 
 
8.3 
Safety Data Handling 
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. 
 
Adverse Events 
Adverse Events with incomplete start dates will be considered treatment emergent if: 
a. Day and month are missing and the year is equal to or after the year of the first dose 
date;  
b. Day is missing, and the year is after the year of the first dose;  
c. Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first dose date; 
d. Year is missing; 
e. Complete date is missing. 
 
Concomitant Medications 
Medications with incomplete end dates will be considered concomitant if: 
a. Day and month are missing and the year is equal to or after the year of the first dose 
date;  
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b. Day is missing, and the year is after the year of the first dose;  
c. Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first dose date; or 
d. Year is missing; 
e. Complete date is missing. 
OR; complete end dates is between the date of first study dose and date of last study dose 
even if the start date of medications is incomplete. 
TEMAV (Treatment-Emergent Markedly Abnormal Value) 
Treatment-emergent markedly abnormal laboratory value (TEMAV) is defined as a 
postbaseline laboratory value with grade 3 or higher, and with a grade increase from baseline.  
(ie., Increasing grade 0 to 3 or higher, grade 1 to 3 or higher, grade 2 to 3 or higher, grade 3 
to 4 or 5, grade 4 to 5.)  
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. 
Calculation of creatinine clearance 
To calculate a creatinine clearance (mL/min), the Cockcroft & Cault formula will be used. 
Males: ((140 – age (years)) × weight (kg)) / (Creatinine (serum:mg/dL) × 72) 
Females: ((140 – age (years)) × weight (kg) ×0.85) / (Creatinine (serum:mg/dL) × 72) 
Visit Windows 
The purpose of visit windows is to provide a single record per subject per visit for the 
calculation of descriptive statistics for safety parameters (e.g., laboratory values and vital 
signs, etc.) per scheduled visit, and change from baseline per visit. Other safety analyses 
(e.g., worst grade laboratory results) will include all observations. 
The observation closest to the target date will be used in by visit summaries. If two or more 
observations have the same distance to the target visit day, the one that has the highest 
CTCAE grade or is furthest away from the normal range will be used for summary tables.  If 
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the multiple data in the same distance to the target date are in the same range from normal 
value, the data measured at an earlier date will be used for summary tables. 
The visit window is applied for safety assessment item which is scheduled at each visit. 
Analysis visit 
Target Day 
Visit Window 
Start Day of Visit Window 
End Day of Visit Window 
Cycle 1 Day 8  
Cycle 1 Day 1 + 7  
Cycle 1 Day 1 + 5  
Cycle 1 Day 1 + 9  
Cycle 1 Day 15  
Cycle 1 Day 1 + 14  
Cycle 1 Day 1 + 12  
Cycle 1 Day 1 + 16  
Cycle 1 Day 22  
Cycle 1 Day 1 + 21  
Cycle 1 Day 1 + 19  
Cycle 1 Day 1 + 23  
Cycle 2 Day 1  
Cycle 1 Day 1 + 28  
Cycle 1 Day 1 + 28 
Cycle 1 Day 1 + 31 
Cycle 2 Day 8 
Cycle 1 Day 1 + 35  
Cycle 1 Day 1 + 32 
Cycle 1 Day 1 + 38 
Cycle 2 Day 15 
Cycle 1 Day 1 + 42  
Cycle 1 Day 1 + 39 
Cycle 1 Day 1 + 45 
Cycle 2 Day 22 
Cycle 1 Day 1 + 49  
Cycle 1 Day 1 + 46 
Cycle 1 Day 1 + 52 
Cycle n Day 1 (n ≥ 3) 
Cycle 1 Day 1 + 28 x (n-1) 
Cycle 1 Day 1 + 28 x (n-1) 
- 3 
Cycle 1 Day 1 + 28 x (n-1) 
+ 3 
Cycle n Day 8 (n ≥ 3) 
Cycle 1 Day 1 + 28 x (n-1) 
+ 7 
Cycle 1 Day 1 + 28 x (n-1) 
+ 4 
Cycle 1 Day 1 + 28 x (n-1) 
+ 10 
Cycle n Day 15 (n ≥ 3)  
Cycle 1 Day 1 + 28 x (n-1) 
+ 14 
Cycle 1 Day 1 + 28 x (n-1) 
+ 11 
Cycle 1 Day 1 + 28 x (n-1) 
+ 17 
Cycle n Day 22 (n ≥ 3)  
Cycle 1 Day 1 + 28 x (n-1) 
+ 21 
Cycle 1 Day 1 + 28 x (n-1) 
+ 18 
Cycle 1 Day 1 + 28 x (n-1) 
+ 24 
End of Treatment  
30 days after last dose  
Date of last dose  
Date of last dose + 37 
C1D1 is the day of first dosing.  
 
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8.4 
Pharmacokinetic Data Handling 
8.4.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Nivolumab Serum Concentration 
The LLOQ of lenvatinib plasma concentrations is 0.100 ng/mL 
The LLOQ of nivolumab serum concentrations is 0.200 μg/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). 
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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, Cmin, 
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 
(Listing only) 
- 
- 
- 
- 
t1/2(C1D1&D15) 
h 
X 
Significant digits 
3 
3 
3 
3 
3 
AUC(0-t), AUC(0-inf), 
AUC(0-ti), AUC(0-τ) 
ng•h/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
CL/F, CLss/F 
L/h 
X 
Significant digits 
3 
3 
3 
3 
3 
Vz/F(C1D1&D15) 
L 
X 
Significant digits 
3 
3 
3 
3 
3 
Rac 
 
X 
Significant digits 
3 
3 
3 
3 
3 
PTF ratio 
% 
X 
Significant digits 
3 
3 
3 
3 
3 
Mean, SD, geometric mean and CV will not be calculated for tmax, tss,max. 
CV(%)= sqrt(exp[SD**2 of log transformed data]-1)*100 
 
NOTE 
1. The following parameters are reported in the CSR, but appear in Listings only.  They are 
important information to confirm that individual t1/2 and its related parameters such 
asAUC(0-inf) are appropriately derived and allow those PK parameters to be reproduced 
when necessary. 
a. Time points used for estimation of λz (lower and upper) 
b. Number of the time points used for λz 
c. Adjusted regression coefficient (R2adj) 
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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8.4.6 
Handling of Individual Data 
The following cases will be excluded for the calculation of summary statistics. 
・Blood samples at predose are collected after administration 
・Overdose 
・Blood samples for nivolumab PK assessment are collected when the most recent dosing 
of nivolumab is interrupted. 
・Blood samples for lenvatinib PK assessment are collected when the most recent dosing 
of lenvatinib is reduced or interrupted. 
・Regarding lenvatinib PK assessment from Cycle 1 Day 1 to Cycle 1 Day 16 in Part 1, 
blood samples for lenvatinib PK assessment are collected after dose reduction or 
interruption of lenvatinib by Cycle 1 Day 15. 
・Dosing and/or sampling date/time are missing 
・Blood samples are not taken in the nominal time point 
・Concentration data collected at Discontinuation or Off-Treatment visit. 
 
The following case will be determined individually. 
・Significant deviation from the allowance of PK blood sampling schedule.  However, 
concentration data at predose will not be excluded when the blood sampling is collected at 
predose on the scheduled day. 
・There is discrepancy between planned and actual volume of nivolumab dosing. 
・Concentration data is not scientifically valid (e.g, concentration at predose on Cycle 1 
Day 1 is not BLQ and concentration at just completion of dosing is BLQ.) 
 
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9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be conducted by Takumi Information Technology, using 
validated standard programs or double programming.  For analyses needed in data review, 
single programming will be used. 
All statistical analyses will be performed using SAS (version 9.3 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, Dec 2018 [internet; cited on 3rd Apr 2023] Available from: 
https://www.fda.gov/media/71195/download  
 
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13 APPENDICES 
13.1 National Institute for Health: Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 
National Cancer Institute (NCI) Cancer therapy evaluation program Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 May 2009 (v4.03 June 2010) is available online at: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf 
CTCAE grades for selected laboratory parameters are listed in the table below, where ULN is the upper limit of normal and LLN is the 
lower limit of normal.  
Lab Parameter 
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hematology 
Hemoglobin (low) 
100 - <LLN (g/L) 
80 - <100 (g/L) 
<80 (g/L) 
__ 
Death 
Hemoglobin (high) 
Increase in >0 - 20 g/L 
above ULN (ie.., Increase 
in >0 - 2 gm/dL above 
ULN) or above baseline if 
baseline is above ULN 
Increase in >20 - 40 g/L 
above ULN (ie.., Increase 
in >2 - 4 gm/dL above 
ULN) or above baseline if 
baseline is above ULN 
Increase in >40 g/L above 
ULN (ie.., Increase in >4 
gm/dL  above ULN) or 
above baseline if baseline is 
above ULN 
__ 
__ 
Platelet Count (PLT) 
(low) 
75 - <LLN (x 10^9/L) 
50 - <75 (x 10^9/L) 
25 - <50 (x 10^9/L) 
<25 (x 10^9/L) 
__ 
White Blood Cell Count 
(WBC) (low) 
3 - <LLN (x 10^9/L) 
2 - <3 (x 10^9/L) 
1 - <2 (x 10^9/L) 
<1 (x 10^9/L) 
__ 
White Blood Cell Count 
(WBC) (high) 
__ 
__ 
>100 x 10^9/L (ie..,
>100,000/mm^3)
__ 
Death 
Lymphocytes (low) 
0.8 - <LLN (x 10^9/L) 
0.5 - <0.8 (x 10^9/L) 
0.2 - <0.5 (x 10^9/L) 
<0.2 (x 10^9/L) 
__ 
Lymphocytes (high) 
__ 
>4 - 20 (x 10^9/L) (ie..,
>4,000 - 20,000/mm^3)
>20 (x 10^9/L) (ie.., >
20,000/mm^3)
__ 
__ 
Neutrophils (low) 
1.5 - <LLN (x 10^9/L) 
1 - <1.5 (x 10^9/L) 
0.5 - <1 (x 10^9/L) 
<0.5 (x 10^9/L) 
__ 
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Lab Parameter  
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Blood Coagulation  
INR (high) 
>1 - 1.5 x ULN 
>1.5 - 2.5 x ULN 
>2.5 x ULN 
__ 
__ 
Blood Chemistry 
Albumin (low) 
30 - <LLN (g/L) 
20 - <30 (g/L) 
<20 (g/L) 
__ 
Death 
Alkaline Phosphatase 
(ALP) (high) 
>ULN - 2.5 x ULN 
>2.5 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
__ 
ALT (SGPT) (high)  
>ULN - 3 x ULN 
>3 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
__ 
AST (SGOT) (high) 
>ULN - 3 x ULN 
>3 - 5.0 x ULN 
>5.0 - 20.0 x ULN 
>20.0 x ULN 
__ 
Total Bilirubin (high) 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
__ 
Calcium, serum-low 
(hypocalcemia) 
2.0 - <LLN (mmol/L) (ie.., 
8.0 mg/dL - <LLN) * 
1.75 - <2 (mmol/L) (ie.., 
7.0 - <8.0 mg/dL) * 
1.5 - <1.75 (mmol/L) (ie.., 
6.0 - <7.0 mg/dL) * 
<1.5 (mmol/L) (ie.., <6.0 
mg/dL) * 
Death 
Calcium, serum-high 
(hypercalcemia) 
>ULN – 2.9 (mmol/L) (ie.., 
>ULN – 11.5 mg/dL) * 
>2.9 – 3.1 (mmol/L) (ie.., 
>11.5 – 12.5 mg/dL) * 
>3.1 – 3.4 (mmol/L) (ie.., 
>12.5 – 13.5 mg/dL) * 
>3.4 (mmol/L) (ie.., >13.5 
mg/dL) * 
Death 
Cholesterol (high) 
>ULN -7.75 mmol/L 
>7.75 -10.34 mmol/L 
>10.34 -12.92 mmol/L 
>12.92 mmol/L 
__ 
CPK (high) 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
__ 
Creatinine  (high) 
>1 – 1.5 x baseline; >ULN 
– 1.5 x ULN 
>1.5 – 3.0 x baseline; >1.5 
– 3.0 x ULN 
>3.0 x baseline; >3.0 – 6.0 
x ULN 
>6.0 x ULN 
__ 
GGT (gamma-
glutamyltransferase) 
(high) 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5.0 x ULN 
>5.0 x ULN – 20.0 x ULN 
>20.0 x ULN 
__ 
Glucose, serum-low 
(hypoglycemia)  
3 - <LLN (mmol/L) 
2.2 - <3 (mmol/L) 
1.7 - <2.2 (mmol/L) 
<1.7 (mmol/L) 
Death 
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Lab Parameter  
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Glucose, serum-high 
(hyperglycemia)  
ULN – 8.9 (mmol/L) 
>8.9 – 13.9 (mmol/L) 
>13.9 – 27.8 (mmol/L) 
>27.8 (mmol/L) 
Death 
Lipase (high) 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
__ 
Magnesium (low) 
<LLN – 0.5 (mmol/L) 
<0.5 – 0.4 (mmol/L) 
<0.4 – 0.3 (mmol/L) 
<0.3 (mmol/L) 
Death 
Magnesium (high) 
>ULN – 1.23 (mmol/L) 
__ 
>1.23 – 3.30 (mmol/L) 
>3.30 (mmol/L) 
Death 
Triglyceride 
(hypertriglyceridemia) 
(high) 
1.71 – 3.42 (mmol/L) 
>3.42 – 5.7 (mmol/L) 
>5.7 – 11.4 (mmol/L) 
>11.4 (mmol/L) 
Death 
Phosphate, serum-low 
(hypophosphatemia) 
0.8 - <LLN (mmol/L) 
0.6 - <0.8 (mmol/L) 
0.3 - <0.6 (mmol/L) 
<0.3 (mmol/L) 
Death 
Potassium, serum-low 
(hypokalemia) 
3.0 - <LLN (mmol/L) 
__ 
2.5 - <3.0 (mmol/L) 
<2.5 (mmol/L) 
Death 
Potassium, serum-high 
(hyperkalemia) 
>ULN – 5.5 (mmol/L)  
>5.5 – 6.0 (mmol/L) 
>6.0 – 7.0 (mmol/L)  
>7.0 (mmol/L) 
Death 
Uric Acid 
(hyperuricemia) (high) 
>ULN – 590 (umol/L) 
__ 
__ 
>590 (umol/L) 
__ 
Sodium, serum-low 
(hyponatremia) 
130 - <LLN (mmol/L) 
__ 
120 - <130 (mmol/L) 
<120 (mmol/L) 
Death 
Sodium, serum-high 
(hypernatremia) 
>ULN - 150 (mmol/L)  
>150 - 155 (mmol/L) 
>155 - 160 (mmol/L)  
>160 (mmol/L) 
Death 
Urinalysis 
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Lab Parameter  
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Proteinuria (high) 
1+ proteinuria;  urinary 
protein <1.0 g/24 hrs 
≥2+ proteinuria;  urinary 
protein 1.0 - 3.4 g/24 hrs 
urinary protein >=3.5 g/24 
hrs 
__ 
__ 
* Corrected serum calcium by albumin should be referred. If serum albumin is <4.0 g/dL, the corrected calcium will be calculated using the following formula: 
Corrected calcium (mg/dL) = Total calcium (mg/dL) – 0.8 x [Albumin (g/dL) – 4] 
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SIGNATURE PAGE 
Author:  
 
 
 
 
 
Electlonic signature in eDMS 
 
 
 
 
  
 DHBL 
 
 
Date 
Approval: 
 
 
 
 
 
Electlonic signature in eDMS 
 
 
 
 
 
 
 
 
 
 
 
 DHBL 
 
 
Electlonic signature in eDMS 
 
Date 
Study Director 
 
 
 DHBL 
 
 
Electlonic signature in eDMS 
Date 
 
 
 
 
Pharmacokinetic Analyst 
 
 
 DHBL 
 
Date 
 
 
 
 
 
 
 
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PPD
PPD
PPD
PPD
PPD
PPD
PPD
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E7080-J081-117 
Study Protocol 
Title: 
A Phase 1b Trial of Lenvatinib Plus Nivolumab in Subjects with 
Hepatocellular Carcinoma 
Date: 
17 Jan 2018 
Version: 
Version 1.0 
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Statistical Analysis Plan 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................4 
3 
INTRODUCTION .............................................................................................................6 
3.1 
Study Objectives ......................................................................................................6 
3.1.1 
Primary Objective ..........................................................................................6 
3.1.2 
Secondary Objectives.....................................................................................6 
3.1.3 
Exploratory Objective ....................................................................................6 
3.2 
Overall Study Design and Plan ................................................................................6 
3.2.1 
Part 1 ..............................................................................................................7 
3.2.2 
Part 2 ..............................................................................................................7 
3.2.3 
Study Design ..................................................................................................8 
3.2.3.1 
Pretreatment Period ..............................................................................8 
3.2.3.2 
Treatment Period ..................................................................................8 
3.2.3.3 
Follow-up Period .................................................................................9 
4 
DETERMINATION OF SAMPLE SIZE ........................................................................10 
5 
STATISTICAL METHODS ............................................................................................11 
5.1 
Study Endpoints .....................................................................................................11 
5.1.1 
Primary Endpoints .......................................................................................11 
5.1.2 
Secondary Endpoints ...................................................................................11 
5.1.2.1 
Pharmacokinetic (PK) Endpoints .......................................................11 
5.1.3 
Exploratory Endpoints .................................................................................12 
5.2 
Study Subjects ........................................................................................................13 
5.2.1 
Definitions of Analysis Sets.........................................................................13 
5.2.2 
Subject Disposition ......................................................................................13 
5.2.3 
Protocol Deviations ......................................................................................14 
5.2.4 
Demographic and Other Baseline Characteristics .......................................14 
5.2.5 
Prior and Concomitant Therapy ...................................................................15 
5.2.6 
Treatment Compliance .................................................................................16 
5.3 
Data Analysis General Considerations ..................................................................16 
5.3.1 
Pooling of Centers........................................................................................16 
5.3.2 
Adjustments for Covariates..........................................................................16 
5.3.3 
Multiple Comparisons/Multiplicity .............................................................16 
5.3.4 
Examination of Subgroups ...........................................................................16 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers .....................................16 
5.3.6 
Other Considerations ...................................................................................16 
5.4 
Efficacy Analyses ..................................................................................................17 
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5.4.1 
Efficacy Analyses ........................................................................................17 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................23 
5.5.1 
Pharmacokinetic Analyses ...........................................................................23 
5.5.1.1 
Plasma or serum Concentration and its PK Parameter Analysis .......23 
5.5.1.2 
Pharmacokinetic Data Figures ...........................................................23 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses ....24 
5.6 
Safety Analyses ......................................................................................................25 
5.6.1 
Extent of Exposure .......................................................................................25 
5.6.2 
Dose Limiting Toxicity ................................................................................27 
5.6.3 
Adverse Events ............................................................................................27 
5.6.4 
Laboratory Values ........................................................................................28 
5.6.5 
Vital Signs ....................................................................................................28 
5.6.6 
Electrocardiograms ......................................................................................29 
5.6.7 
Other Safety Analyses..................................................................................29 
5.7 
Other Analyses .......................................................................................................29 
5.8 
Exploratory Analyses .............................................................................................30 
6 
INTERIM ANALYSES ...................................................................................................31 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................31 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................32 
8.1 
General Data Handling ..........................................................................................32 
8.2 
Efficacy Data Handling..........................................................................................32 
8.3 
Safety Data Handling .............................................................................................32 
8.4 
Pharmacokinetic Data Handling ............................................................................36 
8.4.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Nivolumab Serum Concentration ................................................................36 
8.4.2 
BLQ Handling for Calculation of PK Parameters .......................................36 
8.4.3 
BLQ Handling for Developing Concentration-Time Profiles .....................36 
8.4.4 
Handling of Anomalous Concentration Values ...........................................36 
8.4.5 
General Rules for Presentation of Drug Concentrations and PK 
Parameters ....................................................................................................37 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................38 
10 STATISTICAL SOFTWARE ..........................................................................................38 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................38 
12 REFERENCES ................................................................................................................38 
13 APPENDICES .................................................................................................................39 
13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03 ..............................................................................39 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ADA 
anti-drug antibody 
AE 
adverse event 
AFP 
α-fetoprotein 
ATC 
anatomical therapeutic chemical 
BCLC 
Barcelona Clinic Liver Cancer 
BLQ 
below lower quantification 
BMI 
body mass index 
BOR 
best overall response 
BW 
body weight 
CBR 
clinical benefit rate 
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 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
HCC 
hepatocellular carcinoma 
IV 
Intravenous 
LLOQ 
lower limit of quantification 
LLT 
lower level term 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MUGA 
multiple-gated acquisition technique 
NE 
not evaluable 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
PD 
pharmacodynamics 
PD 
progressive disease 
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Abbreviation 
Term 
PFS 
progression free survival 
PGx 
pharmacogenomics 
PK 
pharmacokinetics 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
QD 
every day 
QOD 
every other day 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
Q2W 
every 2 weeks 
RECIST 
response evaluation criteria in solid tumor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SD 
standard deviation 
SI 
système international 
SOC 
system organ class 
SpO2 
percutaneous oxygen saturation 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TLG 
tables, listings, and graphs 
TNM 
tumor, nodes, metastasis 
TTP 
time to progression 
TTR 
time to response 
WHO DD 
World Health Organization drug dictionary 
 
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is available. Part 2 is to further characterize the safety and tolerability and to assess 
preliminary efficacy of the combination therapy in HCC with no prior systemic therapy. 
3.2.1 
 Part 1 
In Part 1, the tolerability review of Cycle 1 (4 weeks) will be conducted by dose limiting 
toxicities (DLTs). Study treatment and starting dose is as follows: 
Lenvatinib: 12 mg (Body Weight [BW] ≥60 kg) or 8 mg (BW <60 kg) once daily orally 
Nivolumab: 240 mg (every 2 weeks [Q2W], intravenous [IV]) 
The tolerability will be reviewed based on Dose Limiting Toxicity (DLT) of Cycle 1 (4 
weeks) according to the following procedures. 
First, 3 subjects will be enrolled. 
(1) DLT occurs in 0 or 1 of 3 subjects 
Add 3 more subjects and assess in a total of 6 subjects. 
1) DLT occurs in 0 or 1 of 6 subjects 
This dose level is judged to be tolerable. 
2) DLT occurs in 2 or more of 6 subjects 
The tolerability with this dose level will be discussed by the sponsor, sponsor’s 
responsible medical officer, and investigators. 
(2) DLT occurs in 2 or more of 3 subjects 
The tolerability with this dose level and appropriateness of additional enrollment will be 
discussed by the sponsor, sponsor’s responsible medical officer, and investigators. 
In this dose level, at least 3 subjects treated with lenvatinib 12 mg (BW ≥60 kg) and 
nivolumab need to be included in the 6 subjects for DLT evaluation. If this dose level is not 
tolerable, upon discussions between the sponsor, sponsor’s responsible medical officer, and 
investigators, the lower dose level of cohort will be considered or the study will be 
discontinued, and the protocol will be amended as necessary. An efficacy and safety 
evaluation advisor maybe consulted for the consideration as needed. 
3.2.2 
Part 2 
If the dose level is confirmed to be tolerable, an additional 20 HCC subjects with no prior 
systemic therapy will be enrolled. At least 5 subjects (BW ≥60 kg) treated with Lenvatinib 12 
mg QD and at least 5 subjects (BW <60 kg) treated with Lenvatinib 8 mg QD will be 
included. 
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3.2.3 
Study Design 
An overview of the study design is presented in Figure 1. Part 1 and Part 2 will consist of a 
pretreatment period, a treatment period, and a follow-up period. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
DLT = dose limiting toxicity. 
a: Screening assessment should be performed within 14 days of first dose. (Informed consent can be obtained 
within 28 days of first dose.)  
Figure 1 Study Design 
 
3.2.3.1 
Pretreatment Period 
The pretreatment period will involve obtaining informed consent, a screening assessment, 
and a baseline assessment.  Screening will occur within 14 days before starting study drug 
administration after obtaining written informed consent.  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 (informed consent can be obtained within 28 days of 
first dose).  After screening assessments, the sponsor will be informed of eligibility of the 
patient by the investigator or subinvestigator.  The baseline assessment will be conducted 
within 4 days before starting study drug administration in order to confirm that the patient 
meet the eligibility requirement before moving to the Treatment Period. 
3.2.3.2 
Treatment Period 
In the Treatment Period, subjects will receive lenvatinib in combination with nivolumab.  
The Treatment Period will begin with the first dose of study drug administration on Cycle 1 
Survival follow-up 
every 12±2 weeks 
Part 2 only 
Pretreatment Period 
Treatment Period 
Screening 
Baseline 
Cycle 2 and later 
Cycle 1 
Informed consent 
Treatment initiated 
Eligibility confirmation 
28-days cycles 
Last dose 
Discontinuation 
Within 
4 days 
DLT evaluation 
(Part 1 only) 
Within 14 daysa 
Follow-up Period 
Last observation 
30 days (+7 days) after 
last dose 
Screening assessment 
Baseline assessment 
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Day 1.  Each cycle is 28 days long and subjects continue treatment until they meet any of the 
criteria in “Discontinuation Criteria by Subject (see Protocol Section 9.3.3.1)”.   
Subjects will be hospitalized during the Cycle 1, however, outpatient is allowed after Cycle 1 
Day 15, when investigator or subinvestigator judges that that the subject’s safety is ensured. 
3.2.3.3 
Follow-up Period 
The follow-up period will consist of the examination at study discontinuation and the last 
observation visit which occurs 30 days after final administration of study drug.  If the last 
observation visit occurs within 7 days after study drug discontinuation, discontinuation data 
can be used as the last observation data.  The subject who discontinues study will have a 
discontinuation visit and last observation which occurs 30 days after final administration of 
study drug.  If a new anticancer agent needs to be immediately started due to deterioration in 
the subject’s condition, the final observation visit can be conducted before 30 days after the 
last dose of the study drug has passed but prior to starting the new anticancer agent. 
In Part 2, all subjects will be followed for survival until death every 12 weeks (±2 week) 
from the date of discontinuation, except where a subject withdraws consent or the sponsor 
chooses to halt survival follow-up.  The survival follow-up will be continued for up to 2 
years after Cycle 1 Day 1 of the last subject enrolled in Part 2. 
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4 
DETERMINATION OF SAMPLE SIZE 
A sample size of approximately 26 subjects will be enrolled in this study, 6 patients for Part 1 
and 20 patients for Part 2.  Six subjects in Part 1 was deemed appropriate to evaluate the 
tolerability of the dose and perform preliminary safety assessment.  Twenty subjects in Part 2 
was determined to further evaluate the safety and preliminary efficacy.  The probability to 
detect at least 1 development of intolerable treatment-related AEs with an incidence of 10%, 
15% or 20% in 20 subjects was 87.8%, 96.1%, or 98.8%, respectively.  Therefore, the sample 
size is determined to be approximately 20 subjects. 
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5 
STATISTICAL METHODS 
All statistical analyses will be performed by the sponsor or designee after the data cutoff for 
analysis or the study is completed and the database is locked.  Statistical analyses will be 
performed using SAS software or other validated statistical software as required.   
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. 
All statistical analysis will be performed by part separately. Summarization for lenvatinib 8 
mg group, 12 mg group and total subjects will be presented. 
5.1 
Study Endpoints 
The endpoints of this study are shown below.  All efficacy endpoints will be assessed using 
mRECIST.  If necessary, RECIST1.1 will also be performed and used for analysis. 
5.1.1 
Primary Endpoints 
• 
DLTs (Part 1 only) 
• 
Safety endpoints including AEs, laboratory tests, vital signs, ECG, ECOG-PS, and 
LVEF 
 
5.1.2 
Secondary Endpoints 
• 
ORR is defined as the proportion of subjects who have BOR of CR or PR 
• 
Pharmacokinetic parameters of lenvatinib 
  
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 
AUC(0-ti) 
area under the concentration-time curve from zero (pre-dose) to a given sampling 
time (ti) 
AUC(0-inf) 
area under the concentration-time curve from zero time extrapolated to infinite time 
t½ 
terminal elimination phase half-life 
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CL/F 
apparent total clearance following oral dosing 
Vz/F 
apparent volume of distribution at terminal phase 
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  
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progression or death, whichever occurs first. For censored subjects before documentation of 
disease progression or death, duration of SD is defined as the time from the first study dose 
date to the censored date. The censoring rule is same as PFS. The duration of SD is used to 
define durable SD and it is calculated in patients whose BOR was SD. 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
DLT Analysis Set will include all subjects (Part 1 only) who have completed Cycle 1 
without major protocol deviation with at least 75% of lenvatinib compliance and at least 2 
doses of nivolumab and are assessed for DLT, and subjects who have experienced DLT 
during Cycle 1.  This will be the analysis set to determine tolerability. 
Safety Analysis Set will include all subjects who received at least 1 dose of lenvatinib or 
nivolumab. 
PK Analysis Set will include all subjects who have received at least 1 dose of lenvatinib and 
nivolumab, and have evaluable concentration data. 
The Efficacy Analysis Set will include all subjects who received at least 1 dose of lenvatinib 
and nivolumab. 
The Pharmacodynamic and PGx Analysis Set is the group of subjects who received at 
least 1 dose of lenvatinib and nivolumab and had at least 1 postdose pharmacodynamic or 
PGx data. 
The number of subjects enrolled, the number (percentage) of subjects included in each 
analysis set will be presented.  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 (ie, 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, and the reason for the study 
discontinuation will be presented. Similarly, the number (percentage) of subjects who 
completed/discontinued the study treatment, and the reason for the discontinuation from 
study treatment will also be summarized. The number (percentage) of subjects who 
discontinued either lenvatinib alone or nivolumab alone and the reason for discontinuation 
will be summarized.  
In this protocol, subjects who completed the study are defined as subjects who completed the 
appropriate DLT evaluation in Part 1 and subjects who completed the discontinuation 
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assessment or last observation assessment in Part 2.  Subjects who completed the study 
treatment are defined as who discontinued the treatment due to disease progression or 
subjects who are continuing the study treatment at the date of data cutoff. 
Subject data listings will be provided. 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock.  The protocol 
deviations identified according to the criteria at study entry and during treatment will not be 
included in TLGs covered by SAP, but will be presented in the clinical study report (CSR). 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized using descriptive 
statistics in Safety Analysis Set. 
Continuous demographic and baseline variables include 
• 
Age 
• 
Height 
• 
Weight 
• 
BMI 
 
Categorical demographic and baseline variables include 
• 
Age group (< 65 years, ≥ 65 to < 75 years, ≥ 75 years) 
• 
Weight group (< 60kg, ≥ 60 kg) 
• 
Sex 
• 
Race 
• 
Ethnicity 
• 
ECOG-PS 
• 
NYHA (I, II, III, IV and NA for Heart failure) 
 
Disease history and characteristics at study entry will also be summarized by: 
• 
HCC type (Fibrolamellar, Scirrhous, Spindle cell variant, Pleomorphic type, Clear cell 
type, Trabecular, Multinodular differentiated, Moderately differentiated, Poorly 
differentiated, Well differentiated, Biopsy performed – HCC type unknown, Biopsy not 
performed, Other) 
• 
Child-Pugh score 
• 
BCLC stage 
• 
AFP (as continuous variable) 
• 
AFP group (<200 ng/mL, ≥ 200 ng/mL) 
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• 
Macroscopic portal vein invasion (Yes, No) 
• 
Portal vein involvement (Vp0, Vp1, Vp2, Vp3, Vp4) 
• 
Extrahepatic spread (Yes, No) 
• 
Involved disease organ 
• 
Number of involved disease organ per patient (1, 2, ≥3) 
• 
Diagnosis of HCC (Histological or cytological diagnosis of HCC, Clinically confirmed 
diagnosis of HCC) 
• 
Time from confirmed diagnosis of HCC to the date of first study treatment (months) (as 
continuous variable) 
 For patients who were “histologically or cytologically” and “clinically” confirmed, 
whichever earlier diagnosis date is used. 
• 
TNM classification at diagnosis 
• 
Tumor staging at diagnosis  
• 
Factor of Carcinogenesis (Hepatitis B, Hepatitis C, Alcohol, Unknown, Other) 
• 
Number of previous anticancer medication as regimen (0, 1, 2, ≥3) 
• 
Subjects with any previous radiotherapy 
 
Previous anticancer procedure will be summarized by: 
• 
Subjects with any previous anticancer procedure 
• 
Number of previous anticancer procedure (0, 1, 2, 3, 4, ≥5) 
• 
Previous procedure name (Hepatic intra-arterial chemotherapy, Transarterial [chemo] 
embolization, Radiofrequency ablation, Cryoablation, Percutaneous ethanol injection, 
Hepatectomy, Other) 
• 
Time from end of most recent procedure to the date of first study treatment (months) (as 
continuous variable) 
 
Subject data listings 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 
treatment.  Concomitant medications will be defined as medications that (1) started before 
the first dose of study treatment and were continuing at the time of the first dose of study 
drug, or (2) started on or after the date of the first dose of study treatment up to 30 days after 
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the subject’s last dose.  Medications received after 30 days of last dose will be considered as 
post treatment medications. 
The number (percentage) of subjects who took prior and concomitant medications will be 
summarized by Anatomical Therapeutic Chemical (ATC) class (anatomical class, 
pharmacological class), and WHO DD preferred term on the Safety Analysis Set. 
Non-pharmacological procedures will be classified into standardized medical terminology 
using the Medical Dictionary for Regulatory Activities (MedDRA version 20.1 or later). 
All medications and non-pharmacological procedures will be presented in subject data 
listings. 
5.2.6 
Treatment Compliance 
Treatment related protocol deviations will be presented in CSR as provided in the section 
5.2.3. 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers 
Subjects from all centers will be pooled for all analyses. 
5.3.2 
Adjustments for Covariates 
No adjustment for covariates will be performed. 
5.3.3 
Multiple Comparisons/Multiplicity 
No statistical comparison is planned in this study. 
5.3.4 
Examination of Subgroups 
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 the section 8. 
5.3.6 
Other Considerations 
Not applicable. 
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5.4 
Efficacy Analyses 
Efficacy analyses will be conducted on the Efficacy Analysis Set.  Tumor assessment will be 
analyzed base on the investigator’s assessment. If needed, the analysis based on independent 
review will be conducted.   
5.4.1 
Efficacy Analyses 
Part 1 
BOR will be summarized based on mRECIST, and ORR and its corresponding exact 2-sided 
95% confidence interval (CI) will be calculated.  DCR and CBR will be summarized in a 
same manner. 
Part 2 
In addition to the same analysis as above for Part 1, following analyses will be performed. 
PFS is defined as the time from the date of first dose to the date of first documented PD or 
death due to any cause (whichever occurs first) and calculated as below. For subjects who do 
not have an event, PFS will be censored. Censoring rules for PFS are shown in Table 1. 
PFS (months) = (Date of first documented PD/ death/ censored date – Date of first dose + 1) / 
(365.25/12). 
The cumulative PFS rate will be calculated using Kaplan-Meier method. The median, Q1, 
and Q3 for PFS with their 95% CIs will be evaluated. The 95% CIs will be calculated based 
on Greenwood formula and log-log transformation. The number (percentage) of subjects with 
event/censored will be summarized. The PFS rate with its 95% CI at 2, 4, 6, 8, 10 and 12 
months will also be calculated, but not limited to these time points. Kaplan-Meier plots with 
the number of subjects at risk will be presented. 
 
TTP is defined as the time from the date of first dose to the date of first documented PD and 
calculated as below. For subjects who do not have an event, TTP will be censored. Censoring 
rules for TTP are shown in Table 2. TTP will also be summarized in the same manner as with 
PFS. 
TTP (months) = (Date of first documented PD/ censored date – Date of first dose + 1) / 
(365.25/12). 
 
DOR is defined as the time from the first documentation of CR or PR to the date of first 
documented PD or death (whichever occurs first) and calculated as below. DOR will be 
calculated only for subjects having at least one CR or PR. Censoring rules for DOR is same 
as PFS. 
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DOR (months) = (Date of first documented PD/ death/ censored date – Date of the first 
documentation of CR or PR + 1) / (365.25/12). 
 
TTR is defined as the time from the date of first study dose to the date of first documentation 
of CR or PR and calculated as below. TTR will be summarized in two populations (1) all 
subjects (2) only subjects having event. For subjects who do not have an event, TTR will be 
censored. Censoring rules for TTR are shown in Table 3. TTR will also be summarized in the 
same manner as with PFS, but the Kaplan-Meier plot will be described in bottom-up style 
and corresponding rates at each time point will be presented. 
TTR (months) = (Date of documentation of CR or PR / censored date – Date of first dose + 
1) / (365.25/12). 
 
OS is defined as the time from the date of first study dose to the date of death due to any 
cause and calculated as below.  Subjects who are lost to follow-up and the subjects who are 
alive at the date of data cutoff will be censored at the date the subject was last known alive or 
the cut-off date, whichever comes earlier. Censoring rules for OS are shown in Table 4. OS 
will also be summarized in the same manner as with PFS. 
OS (months) = (Date of death/ censored date – Date of first dose + 1) / (365.25/12). 
 
A waterfall plot will be presented for the percent changes from baseline in the sum of the 
diameters of target lesions at post-baseline nadir (ie, maximum tumor shrinkage).  A spider 
plot will be presented for the percent changes from baseline in the sum of the diameters of 
target lesions. The diameters after subsequent anti-cancer treatment initiation are not 
included in the waterfall and spider plot. 
Summary statistics for tumor marker (AFP) the changes and percent changes from baseline 
will be presented by visit. 
Subject data listings will be provided. 
 
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Table 1 
Censoring rules for PFS 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose 
Censored 
2 
Progression documented at scheduled 
visit 
Date of first radiologic PD assessment Event 
3 
Progression documented between 
scheduled visits 
Date of first radiologic PD assessment Event 
4 
No progression nor death at the time of 
data cut-off or  discontinuation from 
study treatment 
Date 
of 
last 
adequate 
radiologic assessment* 
Censored 
5 
New anticancer treatment started 
Date of last adequate radiologic 
assessment* prior to or on date of 
new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date of death 
Event 
7 
Death between adequate assessment 
visits* 
Date of death 
Event 
8 
Death or progression after two or 
more 
consecutive 
missed 
visit/tumor assessment** 
Date 
of 
last 
adequate 
radiologic assessment* before 
missed tumor assessments 
Censored 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or 
PD as determined by investigators. 
** More than one missed visit is defined if the duration between the last tumor assessment and death or PD 
is longer than 126 days (ie. 8 weeks x 2 + 2 weeks [allowance of visit]) for subjects on the every 8 week 
scanning schedule 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 baseline tumor assessment (No. 1), the subject will be censored on date of first 
dose. However, if the subject died within 56 days (8 weeks) after the first dosing date and did not receive 
new anticancer treatment, the date of death will be the PFS event date (not censored).  
• 
If a subject had new anticancer treatment before PD or death (No. 5), 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 assessments consecutively before PD or death (No. 8), 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 criteria, the earliest censoring date will be used.  
• 
Otherwise, if a subject had an event (No. 2, 3, 6, 7), 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, 4, 5, 8).  
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Table 2 
Censoring rules for TTP 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose 
Censored 
2 
Progression documented at scheduled 
visit 
Date of first radiologic PD assessment Event 
3 
Progression documented between 
scheduled visits 
Date of first radiologic PD assessment Event 
4 
No progression at the time of data cut-off 
or  discontinuation from study treatment 
Date 
of 
last 
adequate 
radiologic assessment* 
Censored 
5 
New anticancer treatment started 
Date of last adequate radiologic 
assessment* prior to or on date of 
new anticancer treatment 
Censored 
6 
Death before first PD assessment 
Date 
of 
last 
adequate radiologic 
assessment* 
Censored 
7 
Death between adequate assessment 
visits* 
Date 
of 
last 
adequate radiologic 
assessment* 
Censored 
8 
PD after two or more consecutive 
missed visit/tumor assessment** 
Date 
of 
last 
adequate 
radiologic assessment* before 
missed tumor assessments 
Censored 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or 
PD as determined by investigators. 
** More than one missed visit is defined if the duration between the last tumor assessment and PD is longer 
than 126 days (ie. 8 weeks x 2 + 2 weeks [allowance of visit]) for subjects on the every 8 week scanning 
schedule in this study. 
The priority of the censoring rules is as follows:  
1. If the subject had PD, the following sequence will be applied:  
• 
If a subject did not have baseline tumor assessment (No. 1), the subject will be censored on date of first 
dose.  
• 
If a subject had new anticancer treatment before PD (No. 5), 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 assessments consecutively before PD (No. 8), the subject will be censored 
on the date of the last adequate tumor assessment before PD.  
• 
Otherwise, if a subject had an event (No. 2, 3), the earliest event date will be used.  
 
2. If a subject did not have PD, the censoring date will be the earliest censoring date if the subject met multiple 
censoring criteria (No. 1, 4, 5, 6, 7, 8). 
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Table 3 
Censoring rules for TTR 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
No baseline tumor assessments 
Date of first dose 
Censored 
2 
CR or PR documented at scheduled 
visit 
Date of first CR or PR assessment 
Event 
3 
CR or PR documented between 
scheduled visits 
Date of first CR or PR assessment 
Event 
4 
No CR nor PR by the time of data cut-off 
or  discontinuation from study treatment 
Date 
of 
last 
adequate 
radiologic assessment* 
Censored 
5 
New anticancer treatment started 
Date of last adequate radiologic 
assessment* prior to or on date of 
new anticancer treatment 
Censored 
6 
Death before first CR or PR assessment 
Date 
of 
last 
adequate radiologic 
assessment* 
Censored 
7 
Death between adequate assessment 
visits* 
Date 
of 
last 
adequate radiologic 
assessment* 
Censored 
8 
CR or PR after two or more 
consecutive 
missed 
visit/tumor 
assessment** 
Date of first CR or PR 
assessment 
Event 
* Adequate tumor assessment is a radiologic assessment of CR, PR, SD, non-CR/non-PD or 
PD as determined by investigators. 
** More than one missed visit is defined if the duration between the last tumor assessment and CR or PR is 
longer than 126 days (ie. 8 weeks x 2 + 2 weeks [allowance of visit]) for subjects on the every 8 week 
scanning schedule in this study. 
The priority of the censoring rules is as follows:  
1. If the subject had CR or PR, the following sequence will be applied:  
• 
If a subject had new anticancer treatment before CR or PR (No. 5), the subject will be censored on the date 
of the last adequate tumor assessment prior to or on the date of new anticancer treatment. 
• 
Otherwise, if a subject had an event (No. 2, 3, 8), the earliest event date will be used. Even if a subject 
missed two or more assessments consecutively before CR or PR (No. 8), the subject will be counted as 
event case on the date of the tumor assessment with CR or PR. 
 
2. If a subject did not have CR or PR, the censoring date will be the earliest censoring date if the subject met 
multiple censoring criteria (No. 1, 4, 5, 6, 7). 
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Table 4 
Censoring rules for OS 
No. 
Situation 
Date of Event or Censoring 
Outcome 
1 
Death before or on data cut off 
Date of Death 
Event 
2 
Death after data cut off 
Date of data cut off 
Censored 
3 
Subject still alive at data cut off 
Date of data cut off 
Censored 
4 
Subject lost to follow-up or 
withdraw of consent before data cut off 
Date last known to be alive 
Censored 
 
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5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
The Safety Analysis Set will be used for individual lenvatinib plasma concentrations and 
nivolumab serum concentrations listings. The PK Analysis Set will be used for the 
summaries of lenvatinib plasma concentrations and nivolumab serum concentrations, for 
summaries and listings of PK parameters of lenvatinib. 
5.5.1.1 
Plasma or serum Concentration and its PK Parameter Analysis 
<Concentration> 
Plasma concentration values for lenvatinib and serum concentration values for nivolumab 
will be summarized by dose level 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 nivolumab will be listed for 
each subject by actual sampling time. 
<PK Parameter> 
PK parameters will be derived by non-compartmental analysis using WinNonlin software 
(version 6.2.1 or later) according to 302-104.00-MNL. 
The following pharmacokinetic parameters for lenvatinib will be calculated: Cmax ,tmax, 
AUC(0-t), AUC(0-ti), AUC(0-inf), t½, CL/F, Vz/F, Css,max, Css,min, tss,max, AUC(0-τ), CLss/F, Css,av, 
Rac(Cmax), Rac(AUC), PTF ratio and λz. 
Other PK parameters may be calculated as appropriate. 
Summary statistics will be tabulated for the PK parameters of lenvatinib by dose level.  
Summary statistics (n, mean, SD, median, min, and max) will be presented for all parameters 
(apart from tmax 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 serum concentration 
for nivolumab 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 nivolumab will be 
plotted by dose level 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) 
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will be plotted by dose level on the Y axis on the same graph by visit (Cycle 1 Day 1 and 
Cycle1 Day 15). 
The linear and semi-log mean (+SD) plots of nivolumab 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. 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker Analyses 
The effect of lenvatinib-nivolumab combination therapy on soluble and/or tissue biomarkers 
will be summarized using descriptive statistics. This analysis will be performed only when 
relavant biomarkers are evaluated and the analysis is deemed nesessary. 
 
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5.6 
Safety Analyses 
All DLT analyses will be performed on the DLT Analysis Set.  All other safety analyses will 
be performed on the Safety Analysis Set by part.  Safety data will be summarized using 
descriptive statistics (eg, n, mean, standard deviation, median, minimum, maximum for 
continuous variables; n [%] for categorical variables). 
5.6.1 
Extent of Exposure 
The parameters to be summarized are defined as follows. 
These parameters for extent of exposure will be computed and presented for lenvatinib alone 
and nivolumab alone, separately. 
For lenvatinib:   
• 
Number of cycles = The last cycle with at least one lenvatinib dosing 
• 
Duration of treatment (days) = Last dosing date – first dosing date + 1 
• 
Duration of treatment (months) = (Last dosing date – first dosing date + 1) / (365.25/12) 
• 
Number of subject-month with study drug dosing = Sum of duration of treatment 
(months) per subjects 
• 
Total number of doses = Sum of days with lenvatinib dosing 
• 
Total doses (mg) = Sum of all the actual dose 
• 
Dose intensity (mg / days) = Total doses / Duration of treatment (days) 
• 
Relative dose intensity (%) = 100 × Dose intensity / starting planned dose (8 or 12 mg) 
 
For nivolumab: 
• 
Number of cycles = The last cycle with at least one nivolumab dosing 
• 
Duration of treatment (days) = Last dosing date with nivolumab – first dosing date + 1 
• 
Duration of treatment (months) = (Last dosing date with nivolumab – first dosing date + 
1) / (365.25/12) 
• 
Number of subject-month with study drug dosing = Sum of duration of treatment 
(months) per subjects  
• 
Total number of doses = Sum of days with nivolumab dosing 
• 
Total doses (mg) = Sum of all the actual dose derived by [ 240 (mg) x (Actual volume 
infused (ml) / volume to be infused (ml))] 
• 
Dose intensity (mg / 2weeks) = Total doses / ((Last dosing date with nivolumab – first 
dosing date + 14) / 14)  
• 
Relative dose intensity (%) = 100 × Dose intensity / 240 (mg) 
 
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Number of cycles as combination therapy of lenvatinib and nivolumab will also be calculated 
and presented. The smaller number of cycles within a subject is defined as the number of 
cycle as combination therapy.  
Furthermore, the following information of administration will also be summarized for both 
lenvatinib and nivolumab based on study medication data.  
For lenvatinib, the number (percentage) of subjects who experienced a dose reduction and 
interruption will be summarized. For subjects who experienced a dose reduction, cycle of the 
first dose reduction will be summarized by descriptive statistics. Cycle of the first dose 
interruption will also be summarized in subjects who experienced a dose interruption. 
Frequency of dose reductions will be summarized by categories (1, 2, 3, ≥4). Frequency of 
dose interruptions will also be summarized by appropriate categories (e.g., 1, 2, 3, ≥4). 
The date of dose reduction (from XX mg to YY mg, XX > YY > 0) is defined as the first 
date of planned dose of 0 mg followed by YY mg. The first date of 0 mg has to follow 
planned dose of XX mg. If the starting dose of YY mg does not follow 0 mg but XX mg, the 
first date of planned dose of YY mg is regarded as the date of dose reduction.  Note that from 
4 mg QD to 4mg QOD is also dose reduction. 
The dose interruption is defined as the case where planned dose is 0 mg. The starting date of 
dose interruption is defined as the first date of planned dose of 0 mg following and followed 
by same dose level (> 0 mg). For example: 12 mg followed by 0 mg and followed by 12 mg; 
8 mg followed by 0 mg followed by 8 mg. Successive days with planned dose of 0 mg is 
counted as one dose interruption event. If after dose 0 mg, the subject discontinued from 
lenvatinib permanently, it is not regarded as a drug interruption (but as a drug 
discontinuation). 
An illustration for dose reduction and interruption in a subject is shown in Figure 2. 
 
Figure 2 Dose reduction and interruption for lenvatinib 
For nivolumab, the number (percentage) of subjects who experienced a dose interruption will 
be summarized. Cycle of first dose interruption will be summarized by descriptive statistics 
in subjects who experienced a dose interruption. Frequency of dose interruptions will be 
summarized by appropriate categories (e.g., 1, 2, 3, ≥4). 
The dose interruption is defined as the case where planned dose of 0 mg. Successive dates 
with planned dose of 0 mg is counted as one dose interruption event, and the first date with 
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planned dose of 0 mg is defined as the starting date of dose interruption. If after dose 0 mg, 
the subject discontinued from nivolumab permanently, it is not regarded as a drug 
interruption (but as a drug discontinuation). 
Subject data listings will be provided. 
5.6.2 Dose Limiting Toxicity 
The number and percentage of subjects with DLT will be calculated.  DLT will also be 
summarized per type of toxicity.   
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 20.1 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 the section 8.3, will be included in 
summary tables.  All AEs, treatment emergent or otherwise, will be presented in subject data 
listings. 
Treatment-related TEAEs include those events considered by the investigator to be related to 
study treatment. 
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.  
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 discontinuation of lenvatinib, discontinuation of nivolumab, 
dose reduction of lenvatinib, dose interruption of lenbatinib and dose interruption of 
nivolumab 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 the highest CTCAE grade 
• 
TEAEs grade 3 or above 
• 
Serious TEAEs 
• 
Treatment-related TEAEs 
• 
Treatment-related TEAEs by the highest CTCAE grade 
• 
Treatment-related TEAEs grade 3 or above 
• 
Treatment-related serious TEAEs 
• 
TEAEs leading to discontinuation of lenvatinib  
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• 
TEAEs leading to dose reduction of lenvatinib 
• 
TEAEs leading to dose interruption of lenvatinib 
• 
TEAEs leading to discontinuation of nivolumab  
• 
TEAEs leading to dose interruption of nivolumab 
 
All deaths will also be summarized by primary reasons of deaths (progressive disease, AEs, 
others), deaths within 30 days of last dose of study drug, deaths >30 days of last dose of 
study drug, and treatment-related deaths. 
Subject data listings of all deaths, SAEs, AEs leading to death, discontinuation of lenvatinib, 
discontinuation of nivolumab, dose reduction of lenvatinib, dose interruption of lenbatinib 
and dose interruption of nivolumab will be provided. 
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 plot display 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. 
Laboratory parameters will be graded by CTCAE ver. 4.03 in the section 13.  Changes from 
CTCAE grade at baseline to each postbaseline visit and worst postbaseline will be reported 
using shift tables. CTCAE will also 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 changes from baseline to each postbaseline visit and overall study period will 
also be reported using shift tables.  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, 
and temperature), weight, and SPO2 and changes from baseline will be presented by visit. 
Box plot display will be used to show the longitudinal change of the parameters by visit. 
Subject data listings will be provided. 
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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 
Descriptive statistics for LVEF and LVEF changes from baseline assessed by MUGA scans 
or echocardiograms 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 
Immunogenicity 
All immunogenicity analyses will be performed using the Safety Analysis Set.  The 
percentage and frequency of expression will be calculated for serum anti-nivolumab 
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antibodies (ADA).  If anti-nivolumab antibody develops, presence of neutralizing antibody 
will be summarized. 
Subject data listings will be provided. 
5.8 
Exploratory Analyses 
No exploratory analyses are planned for this study. 
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6 
INTERIM ANALYSES 
No interim analysis will be conducted. 
7 
CHANGES IN THE PLANNED ANALYSES 
A summary of all major additions, changes and deletions in the planned analyses described in 
the protocol will be provided in this section. 
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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 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. 
8.2 
Efficacy Data Handling 
Handling of missing data for tumor assessment result 
For the analysis of ORR, DCR and CBR, subjects with missing response status (subjects 
whose baseline is missing and/or no adequate post-baseline tumor assessments result) will be 
coded as non-responders on Efficacy Analysis Set.   
Rules for missing dates of tumor assessment or death 
In case of dates missing in adverse event and concomitant medication collection following 
rules will be followed. 
Data of tumor assessment result after documented PD or discontinuation from 
treatment 
For the analysis of tumor assessment relevant efficacy endpoints, tumor assessment result 
after PD or final observation visit (for non-PD patients) are excluded from the analyses, but 
included in subject data listing. 
8.3 
Safety Data Handling 
Treatment-emergent adverse event 
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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. 
 
Adverse Events 
Adverse Events with incomplete start dates will be considered treatment emergent if: 
a. Day and month are missing and the year is equal to or after the year of the first dose 
date;  
b. Day is missing, and the year is after the year of the first dose;  
c. Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first dose date; 
d. Year is missing; 
e. Complete date is missing. 
 
Concomitant Medications 
Medications will be considered concomitant if: 
a. Day and month are missing and the year is equal to or after the year of the first dose 
date;  
b. Day is missing, and the year is after the year of the first dose;  
c. Day is missing and the year is equal to the year of the first dose date and the month is 
equal to or after the month of the first dose date; or 
d. Year is missing; 
e. Complete date is missing. 
 
TEMAV (Treatment-Emergent Markedly Abnormal Value) 
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Treatment-emergent markedly abnormal laboratory value (TEMAV) is defined as a 
postbaseline laboratory value with grade 3 or higher, and with a grade increase from baseline.  
(ie., Increasing grade 0 to 3 or higher, grade 1 to 3 or higher, grade 2 to 3 or higher, grade 3 
to 4 or 5, grade 4 to 5.)  
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. 
Calculation of creatinine clearance 
To calculate a creatinine clearance (mL/min), the Cockcroft & Cault formula will be used. 
Males: ((140 – age (years)) × weight (kg)) / (Creatinine (serum:mg/dL) × 72) 
Females: ((140 – age (years)) × weight (kg) ×0.85) / (Creatinine (serum:mg/dL) × 72) 
Visit Windows 
The purpose of visit windows is to provide a single record per subject per visit for the 
calculation of descriptive statistics for safety parameters (e.g., laboratory values and vital 
signs, etc.) per scheduled visit, and change from baseline per visit. Other safety analyses (e.g., 
worst grade laboratory results) will include all observations. 
The observation closest to the target date will be used in by visit summaries. If two or more 
observations have the same distance to the target visit day, the one that has the highest 
CTCAE grade or is furthest away from the normal range will be used for summary tables.  If 
the multiple data in the same distance to the target date are in the same range from normal 
value, the data measured at an earlier date will be used for summary tables. 
The visit window is applied for safety assessment item which is scheduled at each visit. 
Analysis visit 
Target Day 
Visit Window 
Start Day of Visit Window 
End Day of Visit Window 
Cycle 1 Day 8  
Cycle 1 Day 1 + 7  
Cycle 1 Day 1 + 5  
Cycle 1 Day 1 + 9  
Cycle 1 Day 15  
Cycle 1 Day 1 + 14  
Cycle 1 Day 1 + 12  
Cycle 1 Day 1 + 16  
Cycle 1 Day 22  
Cycle 1 Day 1 + 21  
Cycle 1 Day 1 + 19  
Cycle 1 Day 1 + 23  
Cycle 2 Day 1  
Cycle 1 Day 1 + 28  
Cycle 1 Day 1 + 28 
Cycle 1 Day 1 + 31 
Cycle 2 Day 8 
Cycle 1 Day 1 + 35  
Cycle 1 Day 1 + 32 
Cycle 1 Day 1 + 38 
Cycle 2 Day 15 
Cycle 1 Day 1 + 42  
Cycle 1 Day 1 + 39 
Cycle 1 Day 1 + 45 
Cycle 2 Day 22 
Cycle 1 Day 1 + 49  
Cycle 1 Day 1 + 46 
Cycle 1 Day 1 + 52 
Cycle n Day 1 (n ≥ 3) 
Cycle n Day 1 + 28 x (n-1) 
Cycle n Day 1 + 28 x (n-1) 
- 3 
Cycle n Day 1 + 28 x (n-1) 
+ 3 
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Cycle n Day 8 (n ≥ 3) 
Cycle n Day 1 + 28 x (n-1) 
+ 7 
Cycle n Day 1 + 28 x (n-1) 
+ 4 
Cycle n Day 1 + 28 x (n-1) 
+ 10 
Cycle n Day 15 (n ≥ 3)  
Cycle n Day 1 + 28 x (n-1) 
+ 14 
Cycle n Day 1 + 28 x (n-1) 
+ 11 
Cycle n Day 1 + 28 x (n-1) 
+ 17 
Cycle n Day 22 (n ≥ 3)  
Cycle n Day 1 + 28 x (n-1) 
+ 21 
Cycle n Day 1 + 28 x (n-1) 
+ 18 
Cycle n Day 1 + 28 x (n-1) 
+ 24 
End of Treatment  
30 days after last dose  
Date of last dose  
Date of last dose + 37 
C1D1 is the day of first dosing.  
 
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8.4 
Pharmacokinetic Data Handling 
8.4.1 
Lower Limit of Quantification of lenvatinib Plasma Concentration and 
Nivolumab Serum Concentration 
The LLOQ of lenvatinib plasma concentrations is 0.250 ng/mL 
The LLOQ of nivolumab serum concentrations is 0.200 μg/mL 
8.4.2 
BLQ Handling for Calculation of PK Parameters 
While calculating PK parameters in WinNonlin, BLQ values will be handled according to 
302-104.00-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 302-104.00-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 (302-104.00-MNL). 
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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, Cmin, 
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 
(Listing only) 
- 
- 
- 
- 
t1/2(C1D1&D15) 
h 
X 
Significant digits 
3 
3 
3 
3 
3 
AUC(0-t), AUC(0-inf), 
AUC(0-ti), AUC(0-τ) 
ng•h/mL 
X 
Significant digits 
3 
3 
3 
3 
3 
CL/F, CLss/F 
L/h 
X 
Significant digits 
3 
3 
3 
3 
3 
Vz/F(C1D1&D15) 
L 
X 
Significant digits 
3 
3 
3 
3 
3 
Rac 
 
X 
Significant digits 
3 
3 
3 
3 
3 
PTF ratio 
% 
X 
Significant digits 
3 
3 
3 
3 
3 
Mean, SD, geometric mean and CV will not be calculated for tmax, tss,max. 
CV(%)= sqrt(exp[SD**2 of log transformed data]-1)*100 
 
NOTE 
1. The following parameters are reported in the CSR, but appear in Listings only.  They are 
important information to confirm that individual t1/2 and its related parameters such 
asAUC(0-inf) are appropriately derived and allow those PK parameters to be reproduced 
when necessary. 
a. Time points used for estimation of λz (lower and upper) 
b. Number of the time points used for λz 
c. Adjusted regression coefficient (R2adj) 
In Listings, a) are shown in same digits as actual sampling time after dosing used for 
calculation of PK parameters.  For b), integer number is used in Listings.  For c), significant 
3 digits are used in Listing. 
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Statistical Analysis Plan 
E7080-J081-117 
Eisai/Ono Pharmaceutical 
Version 1.0 
Confidential 
Page 38 of 43 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
10 STATISTICAL SOFTWARE 
All statistical analyses will be conducted by Takumi Information Technology, using 
validated standard programs or double programming.  For analyses needed in data review, 
single programming will be used. 
All statistical analyses will be performed using SAS (version 9.3 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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Statistical Analysis Plan 
E7080-J081-117 
Eisai/Ono Pharmaceutical 
Version 1.0 
Confidential 
Page 43 of 43 
SIGNATURE PAGE 
Author:  
 
  
Medicine Development Center 
Date 
Approval: 
 
 
 
 
Medical Development Center 
Date 
Study Director 
 
 
 Oncology Business Group 
Date 
Pharmacokinetic Analyst 
 
 
 Medicine Development Center 
Date 
Eisai
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