A Trial of Lenvatinib Plus Pembrolizumab in Participants With Hepatocellular Carcinoma

• Sponsor: Eisai Co., Ltd. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03006926
• Collaborator: Merck Sharp & Dohme LLC (Industry)
• Enrollment: 104
• Locations: 26
• Arm: 1
• Anticipated Duration (Months): 69.5
• Patients Per Site: 4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is an open-label Phase 1b study designed to evaluate the tolerability and safety of lenvatinib in combination with pembrolizumab in participants with hepatocellular carcinoma (HCC). The study will evaluate objective response rate and duration of response by modified Response Evaluation Criteria In Solid Tumors (mRECIST) for HCC and Response Evaluation Criteria In Solid Tumors (RECIST 1.1) based on independent imaging review (IIR).

Condition or Disease	Intervention/Treatment	Phase
Hepatocellular Carcinoma	Drug: lenvatinib; Drug: pembrolizumab (200 mg)	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 104 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label Phase 1b Trial of Lenvatinib Plus Pembrolizumab in Subjects With Hepatocellular Carcinoma
• Actual Study Start Date: Feb 13, 2017
• Actual Primary Completion Date: Oct 31, 2019
• Anticipated Study Completion Date: Nov 30, 2022

Arms and Interventions

Arm

Intervention/Treatment

Experimental: lenvatinib 8 or 12 mg plus pembrolizumab 200 mg Participants will receive oral lenvatinib at a starting dose of 8 or 12 milligrams (mg) once a day (QD) in combination with intravenous pembrolizumab 200 mg every 3 weeks (Q3W) on a 21-day treatment cycle. The starting dose of lenvatinib will be based on Baseline body weight. Participants weighing greater than or equal to 60 kilograms (kg) will receive 12 mg QD; participants weighing less than 60 kg will receive 8 mg QD.

Drug: lenvatinib; 4 mg capsules; Drug: pembrolizumab (200 mg); 30-minute intravenous infusion

Outcome Measures

Primary Outcome Measures

1. DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From first dose until 30 days after the last dose (up to approximately 2 years 9 months)]

2. Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From first dose until 30 days after the last dose (up to approximately 2 years 9 months)]

3. DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs) [From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days)]

   DLT was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). DLT was defined as any of the following: (1) any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; (2) failure to >=75 percent (%) of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; (3) participants who discontinue treatment due to treatment-related toxicity in Cycle 1; (4) >2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria.

4. DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST 1.1 Assessed by Independent Imaging Review (IIR) [From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first (up to approximately 2 years and 9 months)]

   ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by IIR analysis. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 millimeter [mm] if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the long diameter (LD) (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.

5. DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR [From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months)]

   DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on mRECIST assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).

6. DLT+Expansion Part: Duration of Response (DOR) Based on RECIST 1.1 Assessed by IIR [From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months)]

   DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on RECIST 1.1 assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).

Secondary Outcome Measures

1. DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review [From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first (up to approximately 2 years and 9 months)]

   ORR was defined as the percentage of participants who had BOR of CR or PR based on mRECIST assessed by investigator review. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

2. DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review [From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months)]

   DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) based on mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).

3. DLT+Expansion Part: Progression-free Survival (PFS) Based on mRECIST and RECIST 1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review [From the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) (up to approximately 2 years 9 months)]

   PFS was defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) based on mRECIST and RECIST 1.1 assessed by IIR, and mRECIST assessed by investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).

4. DLT+Expansion Part: Time-to Progression (TTP) Based on mRECIST and RECIST 1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review [From date of first dose of study drug until disease progression (up to approximately 2 years 9 months)]

   TTP was defined as the time from the first study dose date to the date of first documentation of PD, based on mRECIST and RECIST 1.1 assessed by IIR and mRECIST assessed by an investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).

5. DLT+Expansion Part: Time-to Response (TTR) Based on mRECIST Assessed by IIR [From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months)]

   TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

6. DLT+Expansion Part: Time-to Response (TTR) Based on RECIST 1.1 Assessed by IIR [From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months)]

   TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to RECIST 1.1 assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

7. DLT+Expansion Part: Time-to Response (TTR) Based on mRECIST Assessed by Investigator Review [From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months)]

   TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.

8. DLT+Expansion Part: Overall Survival (OS) [From the date of first dose of study drug until date of death from any cause (up to approximately 2 years 9 months)]

   OS was measured from the date of first dose of study drug until date of death from any cause. Participants who were lost to follow-up and the participants who were alive at the date of data cutoff was censored at the date the participant was last known alive, whichever came earlier.

9. Cmax: Maximum Observed Plasma Concentration for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

   Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

10. Tmax: Time to Reach the Cmax for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

11. AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

12. AUC(0-ti): Area Under The Plasma Concentration-time Curve From Zero (Pre-Dose) to a Given Sampling Time (ti) for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

13. AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

14. t1/2: Terminal Elimination Phase Half-Life for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

15. CL/F: Apparent Total Clearance for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

16. Vz/F: Apparent Volume of Distribution at Terminal Phase for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

17. Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

18. Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

19. Tss,Max: Time to Maximum Concentration at Steady State For Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

20. AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

21. Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

22. Css,Av: Average Steady State Plasma Concentration for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

23. Rac (Cmax): Accumulation Index of Cmax for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Rac (Cmax) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

24. Rac (AUC): Accumulation Index of AUC for Lenvatinib and Pembrolizumab [Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)]

    Rac (AUC) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

25. Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status for Pembrolizumab [Cycles 1 and 6 Day 1: Pre-dose (cycle length=21 days)]

    Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of hepatocellular carcinoma (HCC)

• HCC for which no other appropriate therapy is available. Note: Expansion Part: No prior systemic therapy for advanced/unresectable HCC

• Stage B (not applicable for transarterial chemoembolization [TACE]), or stage C based on Barcelona Clinic Liver Cancer (BCLC) staging system

• At least 1 measurable target lesion according to modified Response Evaluation Criteria in Solid Tumors (mRECIST)

• Child-Pugh score A

• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 to 1

• Total triiodothyronine (T3) or free T3 and free thyroxine (T4) are within normal limits. (control by thyroid replacement therapy is acceptable.) Participants with T3, free T3 or free T4 abnormalities at screening who are asymptomatic can be eligible

• Adequately controlled blood pressure

• Adequate renal function

• Adequate bone marrow function

• Adequate blood coagulation function

• Adequate liver function

• Males or females age ≥ 18 years at the time of informed consent

• Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol

Exclusion Criteria:

• Prior treatment with lenvatinib or any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent

• 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) within the past 36 months

• Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical trial

• Active infection (any infection requiring systemic treatment). Hepatitis B or C [HBV/HCV] is allowed

• Participants with CNS metastases are not eligible, unless they have completed local therapy (eg, whole brain radiation therapy [WBRT], surgery or radiosurgery) and have discontinued the use of corticosteroids for this indication for at least 4 weeks before starting treatment in this study. Any signs (eg, radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	California Pacific Medical Center (CPMC)	San Francisco	California	United States	94115
2	Ronald Reagan UCLA Medical Center	Santa Monica	California	United States	90095
3	Mercy Medical Center	Baltimore	Maryland	United States	21202
4	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
5	Icahn School of Medicine Mount Sinai	New York	New York	United States	10029
6	BRCR Global Texas	Edinburg	Texas	United States	78539
7	Hôpital Haut-Levêque Centre médico-chirurgical Magellan	Pessac	Bordeaux	France	33604
8	Centre Eugène Marquis de Rennes	Rennes	Brittany	France	35042
9	CHU Toulouse	Toulouse	Occitanie	France	31059
10	Hôpital Timone	Marseille	Provence-Alpes-Côte d'Azur	France	13005
11	IRCCS Istituto Clinico Humanitas	Milan	Lombardy	Italy	20089
12	Azienda Ospedaliera Universitaria Policlinico Sant'Orsola Malpighi	Bologna	Province Of Bologna	Italy	15-40138
13	Eisai Trial Site 2	Kashiwa	Chiba	Japan
14	Eisai Trial Site 4	Kawasaki	Kanagawa	Japan
15	Eisai Trial Site 3	Sayama	Osaka	Japan
16	Eisai Trial Site 1	Chuo-ku	Tokyo	Japan
17	Republican Clinical Oncology Dispensary	Ufa	Bashkortostan	Russian Federation
18	St. Petersburg City Clinical Oncology Dispansery	Saint Petersburg	Leningrad Oblast	Russian Federation
19	S.I. Russian Oncological Research Center n.a. N. N. Blokhin RAMS	Moscow	Moscow Oblast	Russian Federation
20	Altay Regional Oncology Dispensary	Barnaul		Russian Federation
21	Hospital Universitario Marqués de Valdecilla	Santander	Cantabria	Spain	39008
22	Hospital General Universitario Gregorio Marañón	Madrid	Community Of Madrid	Spain	28007
23	Hospital Universitario 12 de Octubre	Madrid	Community Of Madrid	Spain	28041
24	Hospital Infanta Cristina de Badajoz	Badajoz	Province Of Badajoz	Spain	06080
25	Hospital Universitario de Salamanca	Salamanca	Province Of Salamanca	Spain	37007
26	Royal Free Hospital	London	Greater London	United Kingdom	NW3 2QG

Sponsors and Collaborators

• Eisai Co., Ltd.
• Merck Sharp & Dohme LLC

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jan 17, 2019
• Statistical Analysis Plan - Oct 22, 2019

More Information

Publications

None provided.

• Responsible Party: Eisai Co., Ltd.
• ClinicalTrials.gov Identifier: NCT03006926
• Other Study ID Numbers: E7080-J081-116; KEYNOTE 524; 2018-000522-55
• First Posted: Dec 30, 2016
• Last Update Posted: Mar 16, 2022
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Eisai Co., Ltd.: hepatocellular carcinoma; E7080; lenvatinib; pembrolizumab; Japan
• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Pembrolizumab; Lenvatinib

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 24 investigative sites in the United States, Japan, United Kingdom, France, Italy, Spain, and Russian Federation. Results in this summary are reported based on the primary completion date (31 October 2019) of study.
Pre-assignment Detail	A total of 104 participants were enrolled and received treatment. Of these, 6 participants were enrolled in DLT part and 98 were enrolled in the expansion part.

Arm/Group Title	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg	Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	In DLT part, participants received lenvatinib 12 milligram (mg) or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with body weight greater than or equal to (>=) 60 kilogram (kg) received lenvatinib 12 mg, participants with body weight less than (<) 60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow-up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until progressive disease (PD), development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Upon confirmation of the tolerability of the tested combination regimen of lenvatinib plus pembrolizumab in in Cycle 1, expansion part was opened for participant's enrollment.	In the Expansion part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Period Title: Overall Study
STARTED	6	98
COMPLETED	6	0
NOT COMPLETED	0	98

Baseline Characteristics

Arm/Group Title	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg	Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg	Total
Arm/Group Description	In DLT part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow-up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Upon confirmation of the tolerability of the tested combination regimen of lenvatinib plus pembrolizumab in in Cycle 1, expansion part was opened for participant's enrolment.	In the Expansion part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.	Total of all reporting groups
Overall Participants	6	98	104
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	65.2 (10.11)	66.2 (8.16)	66.1 (8.23)
Sex: Female, Male (Count of Participants)
Female	1 16.7%	19 19.4%	20 19.2%
Male	5 83.3%	79 80.6%	84 80.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	3 3.1%	3 2.9%
Not Hispanic or Latino	6 100%	78 79.6%	84 80.8%
Unknown or Not Reported	0 0%	17 17.3%	17 16.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	6 100%	26 26.5%	32 30.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	2 2%	2 1.9%
White	0 0%	51 52%	51 49%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	19 19.4%	19 18.3%

Outcome Measures

1. Primary Outcome

Title	DLT Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame	From first dose until 30 days after the last dose (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of study drug.

Arm/Group Title	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg
Arm/Group Description	In DLT part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with Body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.
Measure Participants	6
TEAEs	6 100%
SAEs	3 50%

2. Primary Outcome

Title	Expansion Part: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame	From first dose until 30 days after the last dose (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who had received at least 1 dose of study drug.

Arm/Group Title	Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	In the Expansion part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, in 21-day treatment cycles until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	98
TEAEs	97 1616.7%
SAEs	64 1066.7%

3. Primary Outcome

Title	DLT Part: Number of Participants With Dose Limiting Toxicities (DLTs)
Description	DLT was graded according to Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). DLT was defined as any of the following: (1) any of the hematological or nonhematological toxicities considered to be at least possibly related to lenvatinib and/or pembrolizumab occurring during Cycle 1; (2) failure to >=75 percent (%) of the planned dosage of lenvatinib as a result of treatment-related toxicity during Cycle 1; (3) participants who discontinue treatment due to treatment-related toxicity in Cycle 1; (4) >2 week delay in starting pembrolizumab in Cycle 2 because of a treatment-related toxicity, even if the toxicity does not meet DLT criteria.
Time Frame	From first dose of study drug up to Cycle 1 Day 21 (Cycle length= 21 days)

Outcome Measure Data

Analysis Population Description

The DLT analysis set included all participants (except for the Expansion part) who had completed Cycle 1 without major protocol deviation with at least 75% of study drug compliance and assessed for DLT, and participants who had experienced DLT during Cycle 1.

Arm/Group Title	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg
Arm/Group Description	In DLT part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with Body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor.
Measure Participants	6
Count of Participants [Participants]	0 0%

4. Primary Outcome

Title	DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST and RECIST 1.1 Assessed by Independent Imaging Review (IIR)
Description	ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 assessed by IIR analysis. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 millimeter [mm] if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the long diameter (LD) (hereafter referred to as sum of LD) of all target lesions, as compared with Baseline summed LD.
Time Frame	From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first (up to approximately 2 years and 9 months)

Outcome Measure Data

Analysis Population Description

All participants with hepatocellular carcinoma (HCC) who had received at least 1 dose of combination of lenvatinib and pembrolizumab,as first line (1L) therapy, with no prior systemic therapy. In DLT part, 4 participants had received prior systemic therapy with sorafenib, therefore, they were excluded from analysis for this measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	100
RECIST 1.1	36.0 600%
mRECIST	46.0 766.7%

5. Primary Outcome

Title	DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by IIR
Description	DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on mRECIST assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).
Time Frame	From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. In DLT part, 4 participants who received prior systemic therapy with sorafenib, were excluded from analysis for this measure. Overall number analyzed are the participants who were evaluable for this outcome measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	46
Median (95% Confidence Interval) [months]	8.6

6. Primary Outcome

Title	DLT+Expansion Part: Duration of Response (DOR) Based on RECIST 1.1 Assessed by IIR
Description	DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on RECIST 1.1 assessed by IIR analysis. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).
Time Frame	From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. In DLT part, 4 participants who received prior systemic therapy with sorafenib, were excluded from analysis for this measure. Overall number analyzed are the participants who were evaluable for this outcome measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	36
Median (95% Confidence Interval) [months]	12.6

7. Secondary Outcome

Title	DLT+Expansion Part: Objective Response Rate (ORR) Based on mRECIST Assessed by Investigator Review
Description	ORR was defined as the percentage of participants who had BOR of CR or PR based on mRECIST assessed by investigator review. Responses (PR or CR) were confirmed no less than 4 weeks after the initial response. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.
Time Frame	From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first (up to approximately 2 years and 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as first line therapy, with no prior systemic therapy. In DLT part of the study, 4 participants had received prior sorafenib, therefore, they were excluded from analysis for this measure.

Arm/Group Title	HCC 1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	100
Number (95% Confidence Interval) [percentage of participants]	41.0 683.3%

8. Secondary Outcome

Title	DLT+Expansion Part: Duration of Response (DOR) Based on mRECIST Assessed by Investigator Review
Description	DOR was defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) based on mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).
Time Frame	From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first (up to approximately 2 years and 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab,as first line therapy,with no prior systemic therapy. In DLT part of study, 4 participants had received prior sorafenib, therefore, they were excluded. "Overall Number of Participants Analyzed": participants evaluable for this measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	41
Median (95% Confidence Interval) [months]	12.6

9. Secondary Outcome

Title	DLT+Expansion Part: Progression-free Survival (PFS) Based on mRECIST and RECIST 1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review
Description	PFS was defined as the time from the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) based on mRECIST and RECIST 1.1 assessed by IIR, and mRECIST assessed by investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).
Time Frame	From the first study dose date to the date of first documentation of disease progression or death (whichever occurred first) (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab,as first line therapy, with no prior systemic therapy. In DLT part of the study, 4 participants had received prior systemic therapy with sorafenib, therefore, they were excluded from analysis for this measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	100
mRECIST: IIR	9.3
RECIST 1.1: IIR	8.6
mRECIST: Investigator Review	8.2

10. Secondary Outcome

Title	DLT+Expansion Part: Time-to Progression (TTP) Based on mRECIST and RECIST 1.1 Assessed by IIR and Based on mRECIST Assessed by Investigator Review
Description	TTP was defined as the time from the first study dose date to the date of first documentation of PD, based on mRECIST and RECIST 1.1 assessed by IIR and mRECIST assessed by an investigator review. PD was defined as at least a 20% increase in the sum of LD of target and non-target lesions as compared with the smallest sum of LD and the increase of LD was at least 5 mm (including new lesions).
Time Frame	From date of first dose of study drug until disease progression (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as first line therapy, with no prior systemic therapy. In DLT part of the study, 4 participants had received prior systemic therapy with sorafenib, therefore, they were excluded from analysis of this measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	100
mRECIST: IIR	9.7
RECIST 1.1: IIR	9.7
mRECIST: Investigator Review	9.7

11. Secondary Outcome

Title	DLT+Expansion Part: Time-to Response (TTR) Based on mRECIST Assessed by IIR
Description	TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.
Time Frame	From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. In DLT part, 4 participants who received prior systemic therapy with sorafenib, were excluded from analysis for this measure. Overall number analyzed are the participants who were evaluable for this outcome measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	46
Median (Full Range) [months]	1.9

12. Secondary Outcome

Title	DLT+Expansion Part: Time-to Response (TTR) Based on RECIST 1.1 Assessed by IIR
Description	TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to RECIST 1.1 assessed by IIR. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.
Time Frame	From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. In DLT part, 4 participants who received prior systemic therapy with sorafenib, were excluded from analysis for this measure. Overall number analyzed are the participants who were evaluable for this outcome measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	36
Median (Full Range) [months]	2.8

13. Secondary Outcome

Title	DLT+Expansion Part: Time-to Response (TTR) Based on mRECIST Assessed by Investigator Review
Description	TTR was defined as the time from the date of first study dose to the date of first documentation of CR or PR, in participants with confirmed CR or PR. It was evaluated according to mRECIST assessed by investigator review. CR defined as disappearance of all target and non-target lesions (a short diameter is <10 mm if it exists in a lymph node). PR defined as at least 30% decrease in the sum of the LD (hereafter referred to as sum of LD) of all target and non-target lesions, as compared with Baseline summed LD.
Time Frame	From date of first dose of study drug until CR or PR (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who received at least 1 dose of combination of lenvatinib and pembrolizumab as 1L therapy with no prior systemic therapy. In DLT part, 4 participants who received prior systemic therapy with sorafenib, were excluded from analysis for this measure. Overall number analyzed are the participants who were evaluable for this outcome measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	41
Median (Full Range) [months]	2.7

14. Secondary Outcome

Title	DLT+Expansion Part: Overall Survival (OS)
Description	OS was measured from the date of first dose of study drug until date of death from any cause. Participants who were lost to follow-up and the participants who were alive at the date of data cutoff was censored at the date the participant was last known alive, whichever came earlier.
Time Frame	From the date of first dose of study drug until date of death from any cause (up to approximately 2 years 9 months)

Outcome Measure Data

Analysis Population Description

All participants with HCC who had received at least 1 dose of combination of lenvatinib and pembrolizumab, as first line therapy, with no prior systemic therapy. In DLT part of study, 4 participants had received prior systemic therapy with sorafenib, therefore, they were excluded from analysis of this measure.

Arm/Group Title	HCC-1L: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	Participants received lenvatinib 8 or 12 mg, capsules, orally, once daily in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles as first line therapy until disease progression, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
Measure Participants	100
Median (95% Confidence Interval) [months]	22.0

15. Secondary Outcome

Title	Cmax: Maximum Observed Plasma Concentration for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Tmax: Time to Reach the Cmax for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

17. Secondary Outcome

Title	AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

18. Secondary Outcome

Title	AUC(0-ti): Area Under The Plasma Concentration-time Curve From Zero (Pre-Dose) to a Given Sampling Time (ti) for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

19. Secondary Outcome

Title	AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

20. Secondary Outcome

Title	t1/2: Terminal Elimination Phase Half-Life for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

21. Secondary Outcome

Title	CL/F: Apparent Total Clearance for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

22. Secondary Outcome

Title	Vz/F: Apparent Volume of Distribution at Terminal Phase for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

23. Secondary Outcome

Title	Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

24. Secondary Outcome

Title	Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

25. Secondary Outcome

Title	Tss,Max: Time to Maximum Concentration at Steady State For Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

26. Secondary Outcome

Title	AUC(0-tau): Area Under the Plasma Concentration-time Curve Over the Dosing Interval for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

27. Secondary Outcome

Title	Clss/F: Apparent Total Clearance Following Oral Administration at Steady State for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

28. Secondary Outcome

Title	Css,Av: Average Steady State Plasma Concentration for Lenvatinib and Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

29. Secondary Outcome

Title	Rac (Cmax): Accumulation Index of Cmax for Lenvatinib and Pembrolizumab
Description	Rac (Cmax) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

30. Secondary Outcome

Title	Rac (AUC): Accumulation Index of AUC for Lenvatinib and Pembrolizumab
Description	Rac (AUC) was calculated as the ratio of drug concentrations observed during a dosing interval at steady state divided by drug concentrations seen during the dosing interval after a single (first) dose. Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Lenvatinib: Cycle 1 Days 1 and 15: 0-24 hours post-dose; Pembrolizumab: Cycles 1, 2, 4, 6, 8 Day 1: 0-24 hours post-infusion (each cycle length = 21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

31. Secondary Outcome

Title	Number of Participants Positive for Serum Anti-drug Antibodies (ADA) Status for Pembrolizumab
Description	Data for this outcome measure will be reported after study completion (anticipated study completion date is August 2021).
Time Frame	Cycles 1 and 6 Day 1: Pre-dose (cycle length=21 days)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	From the date of administration of the first dose of the study drug up to 30 days after the last dose of study drug (up to approximately 2 years 9 months)
Arm/Group Title	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg		Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
Arm/Group Description	In DLT part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in Cycle 1 of a 21-day treatment cycle. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg. Participants who discontinued treatment in Cycle 1, entered the follow-up phase. Participants who were still receiving treatment at the end of Cycle 1, continued to receive same treatment until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Upon confirmation of the tolerability of the tested combination regimen of lenvatinib plus pembrolizumab in in Cycle 1, expansion part was opened for participant's enrolment.		In the Expansion part, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with pembrolizumab 200 mg, infusion, intravenously, every 3 weeks, in 21-day treatment cycles until PD, development of unacceptable toxicity, withdrawal of consent, or study termination by sponsor. Participants with body weight >=60 kg received lenvatinib 12 mg, participants with body weight <60 kg, received lenvatinib 8 mg.
All Cause Mortality
	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg		Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		33/98 (33.7%)
Serious Adverse Events
	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg		Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		64/98 (65.3%)
Blood and lymphatic system disorders
Neutropenia	0/6 (0%)	0	1/98 (1%)	1
Pancytopenia	0/6 (0%)	0	1/98 (1%)	1
Cardiac disorders
Acute coronary syndrome	0/6 (0%)	0	1/98 (1%)	1
Myocardial infarction	0/6 (0%)	0	1/98 (1%)	1
Endocrine disorders
Adrenal insufficiency	0/6 (0%)	0	2/98 (2%)	2
Hypophysitis	0/6 (0%)	0	1/98 (1%)	1
Gastrointestinal disorders
Abdominal pain	0/6 (0%)	0	3/98 (3.1%)	3
Diarrhoea	1/6 (16.7%)	1	2/98 (2%)	2
Oesophageal varices haemorrhage	0/6 (0%)	0	2/98 (2%)	2
Upper gastrointestinal haemorrhage	0/6 (0%)	0	2/98 (2%)	2
Ascites	0/6 (0%)	0	1/98 (1%)	1
Immune-mediated pancreatitis	0/6 (0%)	0	1/98 (1%)	1
Inguinal hernia	1/6 (16.7%)	1	0/98 (0%)	0
Intestinal perforation	0/6 (0%)	0	1/98 (1%)	2
Intra-abdominal fluid collection	0/6 (0%)	0	1/98 (1%)	1
Nausea	0/6 (0%)	0	1/98 (1%)	1
Odynophagia	0/6 (0%)	0	1/98 (1%)	1
Pancreatitis acute	0/6 (0%)	0	1/98 (1%)	1
Vomiting	0/6 (0%)	0	1/98 (1%)	1
General disorders
Pyrexia	0/6 (0%)	0	5/98 (5.1%)	6
Death	0/6 (0%)	0	2/98 (2%)	2
General physical health deterioration	0/6 (0%)	0	2/98 (2%)	3
Asthenia	0/6 (0%)	0	1/98 (1%)	1
Fatigue	0/6 (0%)	0	1/98 (1%)	1
Malaise	0/6 (0%)	0	1/98 (1%)	1
Peripheral swelling	0/6 (0%)	0	1/98 (1%)	1
Hepatobiliary disorders
Hepatic cirrhosis	0/6 (0%)	0	2/98 (2%)	3
Hepatic failure	0/6 (0%)	0	2/98 (2%)	2
Hepatic function abnormal	0/6 (0%)	0	2/98 (2%)	3
Biliary colic	0/6 (0%)	0	1/98 (1%)	1
Cholangitis	0/6 (0%)	0	1/98 (1%)	1
Hepatic pain	0/6 (0%)	0	1/98 (1%)	1
Hyperbilirubinaemia	0/6 (0%)	0	1/98 (1%)	1
Immune-mediated hepatitis	0/6 (0%)	0	1/98 (1%)	1
Jaundice cholestatic	0/6 (0%)	0	1/98 (1%)	1
Liver disorder	0/6 (0%)	0	1/98 (1%)	1
Portal vein thrombosis	0/6 (0%)	0	1/98 (1%)	1
Infections and infestations
Urinary tract infection	0/6 (0%)	0	4/98 (4.1%)	4
Pneumonia	0/6 (0%)	0	3/98 (3.1%)	4
Sepsis	0/6 (0%)	0	2/98 (2%)	3
Biliary sepsis	0/6 (0%)	0	1/98 (1%)	2
Clostridium difficile infection	0/6 (0%)	0	1/98 (1%)	1
Lower respiratory tract infection	0/6 (0%)	0	1/98 (1%)	1
Peritonitis bacterial	0/6 (0%)	0	1/98 (1%)	3
Staphylococcal bacteraemia	0/6 (0%)	0	1/98 (1%)	1
Injury, poisoning and procedural complications
Fall	0/6 (0%)	0	1/98 (1%)	1
Hip fracture	0/6 (0%)	0	1/98 (1%)	1
Investigations
Blood bilirubin increased	0/6 (0%)	0	8/98 (8.2%)	12
Aspartate aminotransferase increased	1/6 (16.7%)	1	2/98 (2%)	3
Alanine aminotransferase increased	1/6 (16.7%)	1	1/98 (1%)	1
Blood lactate dehydrogenase increased	1/6 (16.7%)	1	0/98 (0%)	0
White blood cell count decreased	0/6 (0%)	0	1/98 (1%)	3
Metabolism and nutrition disorders
Dehydration	0/6 (0%)	0	2/98 (2%)	2
Failure to thrive	0/6 (0%)	0	1/98 (1%)	1
Hyperammonaemia	0/6 (0%)	0	1/98 (1%)	2
Hyperkalaemia	0/6 (0%)	0	1/98 (1%)	1
Hypernatraemia	0/6 (0%)	0	1/98 (1%)	1
Hyponatraemia	0/6 (0%)	0	1/98 (1%)	1
Musculoskeletal and connective tissue disorders
Muscular weakness	0/6 (0%)	0	1/98 (1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	0/6 (0%)	0	1/98 (1%)	1
Basal cell carcinoma	0/6 (0%)	0	1/98 (1%)	1
Metastases to central nervous system	0/6 (0%)	0	1/98 (1%)	1
Oesophageal squamous cell carcinoma	0/6 (0%)	0	1/98 (1%)	1
Pancreatic carcinoma	0/6 (0%)	0	1/98 (1%)	1
Nervous system disorders
Hepatic encephalopathy	0/6 (0%)	0	5/98 (5.1%)	6
Cerebrovascular accident	0/6 (0%)	0	1/98 (1%)	1
Dizziness	0/6 (0%)	0	1/98 (1%)	1
Facial paralysis	0/6 (0%)	0	1/98 (1%)	1
Nervous system disorder	0/6 (0%)	0	1/98 (1%)	1
Seizure	0/6 (0%)	0	1/98 (1%)	1
Subarachnoid haemorrhage	1/6 (16.7%)	1	0/98 (0%)	0
Transient ischaemic attack	0/6 (0%)	0	1/98 (1%)	1
Psychiatric disorders
Confusional state	0/6 (0%)	0	3/98 (3.1%)	3
Depression	0/6 (0%)	0	1/98 (1%)	3
Mental status changes	0/6 (0%)	0	1/98 (1%)	2
Renal and urinary disorders
Proteinuria	0/6 (0%)	0	1/98 (1%)	1
Renal failure	0/6 (0%)	0	1/98 (1%)	1
Renal impairment	0/6 (0%)	0	1/98 (1%)	1
Urinary retention	0/6 (0%)	0	1/98 (1%)	1
Reproductive system and breast disorders
Acquired hydrocele	0/6 (0%)	0	1/98 (1%)	1
Prostatic obstruction	0/6 (0%)	0	1/98 (1%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/6 (0%)	0	2/98 (2%)	2
Pulmonary embolism	0/6 (0%)	0	2/98 (2%)	2
Acute respiratory distress syndrome	0/6 (0%)	0	1/98 (1%)	1
Acute respiratory failure	0/6 (0%)	0	1/98 (1%)	2
Asthma	0/6 (0%)	0	1/98 (1%)	1
Chronic obstructive pulmonary disease	0/6 (0%)	0	1/98 (1%)	1
Epistaxis	0/6 (0%)	0	1/98 (1%)	1
Immune-mediated pneumonitis	0/6 (0%)	0	1/98 (1%)	1
Pneumonitis	0/6 (0%)	0	1/98 (1%)	1
Skin and subcutaneous tissue disorders
Erythema multiforme	0/6 (0%)	0	1/98 (1%)	1
Vascular disorders
Hypotension	0/6 (0%)	0	1/98 (1%)	1
Other (Not Including Serious) Adverse Events
	DLT Part: Lenvatinib 12 mg or 8 mg + Pembrolizumab 200 mg		Expansion Part: Lenvatinib 12 mg or 8 mg+ Pembrolizumab 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		97/98 (99%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)	3	19/98 (19.4%)	41
Neutropenia	0/6 (0%)	0	7/98 (7.1%)	14
Thrombocytopenia	0/6 (0%)	0	8/98 (8.2%)	13
Cardiac disorders
Cardiac failure	1/6 (16.7%)	1	2/98 (2%)	2
Ear and labyrinth disorders
Vertigo	1/6 (16.7%)	1	2/98 (2%)	2
Endocrine disorders
Hyperthyroidism	0/6 (0%)	0	7/98 (7.1%)	7
Hypothyroidism	4/6 (66.7%)	4	29/98 (29.6%)	34
Gastrointestinal disorders
Abdominal discomfort	1/6 (16.7%)	1	1/98 (1%)	1
Abdominal pain	1/6 (16.7%)	1	17/98 (17.3%)	25
Abdominal pain upper	0/6 (0%)	0	7/98 (7.1%)	9
Ascites	0/6 (0%)	0	10/98 (10.2%)	12
Cheilitis	1/6 (16.7%)	1	1/98 (1%)	1
Constipation	1/6 (16.7%)	1	13/98 (13.3%)	14
Dental caries	1/6 (16.7%)	1	1/98 (1%)	1
Diarrhoea	5/6 (83.3%)	15	48/98 (49%)	103
Dry mouth	0/6 (0%)	0	7/98 (7.1%)	7
Duodenal ulcer	1/6 (16.7%)	1	0/98 (0%)	0
Eructation	1/6 (16.7%)	1	0/98 (0%)	0
Gastritis	1/6 (16.7%)	1	1/98 (1%)	1
Haemorrhoids	1/6 (16.7%)	1	0/98 (0%)	0
Inguinal hernia	1/6 (16.7%)	1	0/98 (0%)	0
Nausea	3/6 (50%)	3	21/98 (21.4%)	31
Stomatitis	1/6 (16.7%)	1	14/98 (14.3%)	26
Vomiting	1/6 (16.7%)	2	18/98 (18.4%)	28
General disorders
Asthenia	0/6 (0%)	0	24/98 (24.5%)	49
Fatigue	2/6 (33.3%)	2	32/98 (32.7%)	59
Malaise	1/6 (16.7%)	1	5/98 (5.1%)	16
Oedema peripheral	3/6 (50%)	4	14/98 (14.3%)	20
Pyrexia	0/6 (0%)	0	10/98 (10.2%)	15
Hepatobiliary disorders
Hyperbilirubinaemia	0/6 (0%)	0	8/98 (8.2%)	24
Immune system disorders
Contrast media allergy	1/6 (16.7%)	1	1/98 (1%)	1
Contrast media reaction	1/6 (16.7%)	1	0/98 (0%)	0
Infections and infestations
Nasopharyngitis	1/6 (16.7%)	1	8/98 (8.2%)	10
Paronychia	1/6 (16.7%)	1	2/98 (2%)	2
Rash pustular	0/6 (0%)	0	5/98 (5.1%)	8
Rhinitis	1/6 (16.7%)	1	2/98 (2%)	2
Upper respiratory tract infection	1/6 (16.7%)	2	2/98 (2%)	3
Urinary tract infection	0/6 (0%)	0	6/98 (6.1%)	7
Injury, poisoning and procedural complications
Fall	1/6 (16.7%)	2	1/98 (1%)	3
Investigations
Alanine aminotransferase increased	2/6 (33.3%)	5	19/98 (19.4%)	36
Amylase increased	0/6 (0%)	0	11/98 (11.2%)	25
Aspartate aminotransferase increased	2/6 (33.3%)	9	30/98 (30.6%)	70
Blood albumin decreased	0/6 (0%)	0	5/98 (5.1%)	5
Blood alkaline phosphatase increased	0/6 (0%)	0	11/98 (11.2%)	19
Blood bilirubin increased	0/6 (0%)	0	19/98 (19.4%)	51
Blood creatinine increased	0/6 (0%)	0	10/98 (10.2%)	12
Blood lactate dehydrogenase increased	1/6 (16.7%)	1	5/98 (5.1%)	7
Blood pressure increased	0/6 (0%)	0	5/98 (5.1%)	8
Blood thyroid stimulating hormone decreased	1/6 (16.7%)	1	1/98 (1%)	1
Blood thyroid stimulating hormone increased	1/6 (16.7%)	2	7/98 (7.1%)	8
Blood urea increased	0/6 (0%)	0	6/98 (6.1%)	10
C-reactive protein increased	1/6 (16.7%)	1	1/98 (1%)	1
Electrocardiogram QT prolonged	0/6 (0%)	0	6/98 (6.1%)	10
Eosinophil count increased	1/6 (16.7%)	2	0/98 (0%)	0
Gamma-glutamyltransferase increased	0/6 (0%)	0	9/98 (9.2%)	16
Lipase increased	0/6 (0%)	0	20/98 (20.4%)	44
Neutrophil count decreased	3/6 (50%)	17	6/98 (6.1%)	39
Platelet count decreased	1/6 (16.7%)	3	12/98 (12.2%)	38
Weight decreased	4/6 (66.7%)	13	28/98 (28.6%)	58
White blood cell count decreased	1/6 (16.7%)	6	7/98 (7.1%)	39
Metabolism and nutrition disorders
Decreased appetite	6/6 (100%)	15	34/98 (34.7%)	65
Dehydration	0/6 (0%)	0	5/98 (5.1%)	5
Hyperglycaemia	1/6 (16.7%)	2	12/98 (12.2%)	43
Hyperkalaemia	0/6 (0%)	0	5/98 (5.1%)	6
Hypertriglyceridaemia	0/6 (0%)	0	6/98 (6.1%)	17
Hypoalbuminaemia	1/6 (16.7%)	2	14/98 (14.3%)	43
Hypomagnesaemia	0/6 (0%)	0	12/98 (12.2%)	20
Hyponatraemia	2/6 (33.3%)	7	13/98 (13.3%)	18
Hypophosphataemia	0/6 (0%)	0	8/98 (8.2%)	13
Musculoskeletal and connective tissue disorders
Arthralgia	1/6 (16.7%)	1	15/98 (15.3%)	20
Back pain	0/6 (0%)	0	6/98 (6.1%)	8
Groin pain	1/6 (16.7%)	1	0/98 (0%)	0
Muscle spasms	0/6 (0%)	0	5/98 (5.1%)	7
Musculoskeletal pain	1/6 (16.7%)	1	6/98 (6.1%)	9
Myalgia	0/6 (0%)	0	8/98 (8.2%)	11
Pain in extremity	1/6 (16.7%)	2	5/98 (5.1%)	8
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour pain	2/6 (33.3%)	2	0/98 (0%)	0
Nervous system disorders
Dysgeusia	1/6 (16.7%)	1	9/98 (9.2%)	10
Headache	0/6 (0%)	0	8/98 (8.2%)	8
Hepatic encephalopathy	0/6 (0%)	0	5/98 (5.1%)	8
Psychiatric disorders
Insomnia	2/6 (33.3%)	2	7/98 (7.1%)	8
Renal and urinary disorders
Haematuria	0/6 (0%)	0	8/98 (8.2%)	13
Proteinuria	2/6 (33.3%)	16	24/98 (24.5%)	54
Respiratory, thoracic and mediastinal disorders
Cough	1/6 (16.7%)	2	4/98 (4.1%)	5
Dysphonia	2/6 (33.3%)	2	22/98 (22.4%)	29
Dyspnoea	0/6 (0%)	0	7/98 (7.1%)	11
Skin and subcutaneous tissue disorders
Dermatitis bullous	1/6 (16.7%)	1	0/98 (0%)	0
Dry skin	0/6 (0%)	0	5/98 (5.1%)	6
Erythema	1/6 (16.7%)	1	0/98 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	1/6 (16.7%)	1	22/98 (22.4%)	38
Pruritus	2/6 (33.3%)	3	17/98 (17.3%)	20
Rash	2/6 (33.3%)	6	16/98 (16.3%)	24
Skin erosion	1/6 (16.7%)	1	0/98 (0%)	0
Vascular disorders
Hypertension	4/6 (66.7%)	17	37/98 (37.8%)	85

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.