Trial Outcomes & Findings for A Study of Lenvatinib Plus Nivolumab in Participants With Hepatocellular Carcinoma (NCT NCT03418922)

Last Updated: 2024-06-20

Results Overview

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 hematological or non-hematological toxicities considered to be at least possibly related to lenvatinib and/or nivolumab occurring during Cycle 1: 1) Febrile neutropenia or Grade 4 neutropenia for \>7 days; 2) Grade 4 thrombocytopenia and Grade 3 thrombocytopenia with bleeding; 3) Grade 4 anemia; 4) Clinical deterioration manifested by drug-related hepatic decompensation; 5) \>=Grade 3 non-hematological laboratory abnormalities with clinical symptoms that persisted; 6) Other Grade 3 toxicity lasting \>3 days or Grade 4 non-hematological toxicity of any duration; 7) Grade 2 uveitis, eye pain, or blurred vision that did not respond to topical therapy; 8) Failure to administer 8 or more dose of the planned administration number of study drug in Cycle 1 as a result of treatment-related toxicity.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

30 participants

Primary outcome timeframe

Cycle 1 (Cycle length = 28 days)

Results posted on

2024-06-20

Participant Flow

The study was conducted in two parts (Part 1 and Part 2) between 16 January 2018 and 28 December 2022 at 1 site for Part 1 and 6 sites for Part 2 in Japan.

A total of 30 participants were enrolled and received treatment. Of these, 6 participants were enrolled in Part 1 and 24 were enrolled in the Part 2.

Participant milestones

Participant milestones
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight greater than or equal to (\>=) 60 kg received lenvatinib 12 mg and participants with body weight less than (\<) 60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Overall Study STARTED	6	24
Overall Study COMPLETED	4	18
Overall Study NOT COMPLETED	2	6

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight greater than or equal to (\>=) 60 kg received lenvatinib 12 mg and participants with body weight less than (\<) 60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Overall Study Withdrawal by Subject	0	2
Overall Study Adverse Event	2	2
Overall Study Death	0	1
Overall Study Physician Decision	0	1

Baseline Characteristics

A Study of Lenvatinib Plus Nivolumab in Participants With Hepatocellular Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=24 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.	Total n=30 Participants Total of all reporting groups
Age, Continuous	73.5 Years STANDARD_DEVIATION 1.87 • n=5 Participants	67.1 Years STANDARD_DEVIATION 10.74 • n=7 Participants	68.4 Years STANDARD_DEVIATION 9.94 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	5 Participants n=7 Participants	6 Participants n=5 Participants
Sex: Female, Male Male	5 Participants n=5 Participants	19 Participants n=7 Participants	24 Participants n=5 Participants
Race/Ethnicity, Customized Japanese	6 Participants n=5 Participants	23 Participants n=7 Participants	29 Participants n=5 Participants
Race/Ethnicity, Customized Chinese	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: Cycle 1 (Cycle length = 28 days)

Population: The DLT analysis set included all participants who had completed Cycle 1 without major protocol deviation with at least 75 percent (%) of study drug compliance and at least 2 doses of nivolumab and were assessed for DLT, and participants who had experienced DLT during Cycle 1.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs)	0 Participants	—

PRIMARY outcome

Timeframe: From the first dose of study drug until 30 days after the last dose (up to 53 months)

Population: Safety analysis set included all participants who received at least 1 dose of lenvatinib or nivolumab.

A TEAE was defined as an adverse event (AE) that emerged during treatment and until the 30 days after the last dose or until the participants initiated new anticancer therapy, whichever was earlier, was absent at pretreatment (Baseline) or reemerged during treatment, was present at pretreatment (Baseline) but stopped before treatment, or worsened in severity during treatment relative to the pretreatment state, when the AE was continuous. An SAE was any untoward medical occurrence that at any dose: resulted in death, was life-threatening (that is, participant was at immediate risk of death from AE as it occurred; this did not include an event that, had it occurred in a more severe form or was allowed to continue, might have caused death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect (in the child of a participant who was exposed to the study drug).

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=24 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) TEAEs	6 Participants	24 Participants
Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) SAEs	3 Participants	12 Participants

PRIMARY outcome

Timeframe: Baseline, up to Month 53

Population: Safety analysis set included all participants who received at least 1 dose of lenvatinib or nivolumab. Here, "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

Mean change from baseline in weight were evaluated.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=23 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Mean Change From Baseline in Vital Sign: Weight	2.82 kilogram Standard Deviation 3.931	-3.10 kilogram Standard Deviation 4.953

PRIMARY outcome

Timeframe: Baseline, up to Month 53

Mean change from baseline in body mass index were evaluated.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=23 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Mean Change From Baseline in Vital Sign: Body Mass Index	1.10 kilogram per square meter Standard Deviation 1.434	-1.12 kilogram per square meter Standard Deviation 1.811

PRIMARY outcome

Timeframe: Baseline, up to Month 53

Mean change from baseline in SpO2 were evaluated.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=23 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Mean Change From Baseline in Vital Sign: SpO2 (Oxygen Saturation)	0.2 percentage of blood oxygen saturation Standard Deviation 0.75	-0.6 percentage of blood oxygen saturation Standard Deviation 1.41

PRIMARY outcome

Timeframe: From the first dose of study drug until 30 days after the last dose (up to 53 months)

Population: Safety analysis set included all participants who received at least 1 dose of lenvatinib or nivolumab.

Treatment-emergent markedly abnormal laboratory value was defined as a postbaseline laboratory value with grade 3 or higher, and with a grade increase from baseline, (that is \[i.e.\] 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). Test abnormalities were graded by Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 as Grade 1 =mild; Grade 2 =moderate; Grade 3/Grade 4 =severe/life-threatening, Grade 5 =death.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=24 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Alkaline phosphatase: Markedly Abnormal High	0 Participants	1 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Hemoglobin: Markedly Abnormal Low	0 Participants	2 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Hemoglobin: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Platelets: Markedly Abnormal Low	2 Participants	1 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Leukocytes: Markedly Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Leukocytes: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Lymphocytes: Markedly Abnormal Low	2 Participants	4 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Lymphocytes: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Neutrophils: Markedly Abnormal Low	0 Participants	3 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Prothrombin international normalized ratio: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Aspartate aminotransferase: Markedly Abnormal High	0 Participants	6 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Alanine aminotransferase: Markedly Abnormal High	1 Participants	1 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Gamma-glutamyl transferase: Markedly Abnormal High	1 Participants	6 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Bilirubin: Markedly Abnormal High	0 Participants	3 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Creatinine: Markedly Abnormal High	1 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Glucose: Markedly Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Glucose: Markedly Abnormal High	0 Participants	4 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Albumin: Markedly Abnormal Low	1 Participants	2 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Cholesterol: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Triglycerides: Markedly Abnormal High	0 Participants	1 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Phosphate: Markedly Abnormal Low	0 Participants	3 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Sodium: Markedly Abnormal Low	0 Participants	3 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Sodium: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Potassium: Markedly Abnormal Low	0 Participants	3 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Potassium: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Calcium corrected: Markedly Abnormal Low	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Calcium corrected: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Magnesium: Markedly Abnormal Low	0 Participants	1 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Magnesium: Markedly Abnormal High	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Amylase: Markedly Abnormal High	1 Participants	1 Participants
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) Lipase: Markedly Abnormal High	3 Participants	5 Participants

PRIMARY outcome

Timeframe: Baseline, up to Month 53

Population: Safety analysis set included all participants who received at least 1 dose of lenvatinib or nivolumab.

Performance status assessments were based on 5-grade ECOG scale (from 0 to 4), where 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.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=24 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale Grade 0	0 Participants	15 Participants
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale Grade 1	5 Participants	6 Participants
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale Grade 2	0 Participants	1 Participants
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale Grade 3	1 Participants	2 Participants
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale Grade 4	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Baseline, up to Month 53

Change from baseline in left ventricular ejection fraction (LVEF) were evaluated by multigated acquisition scan (MUGA) or echocardiogram.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=5 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=19 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)	0.0 %LVEF Standard Deviation 2.00	0.4 %LVEF Standard Deviation 4.65

SECONDARY outcome

Timeframe: From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 52 months)

Population: Efficacy analysis set included all participants who received at least 1 dose of lenvatinib and nivolumab.

ORR was defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) based on mRECIST assessed by investigator review. CR defined as disappearance of all target lesions and non-target lesions (a short diameter is less than 10 millimeters \[mm\] if it exists in a lymph node). PR defined as at least 30% decrease in the sum of diameter of all target lesions without unequivocal progression of all non-target lesions, as compared with Baseline.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=24 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1 and Part 2: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Assessed by Investigator Review	66.7 percentage of participants Interval 22.3 to 95.7	79.2 percentage of participants Interval 57.8 to 92.9

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

Population: Pharmacokinetic (PK) analysis set included all participants who had received at least 1 dose of lenvatinib and nivolumab, and had evaluable concentration data.

Cmax was defined as the maximum plasma concentration for lenvatinib. Cmax was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=4 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Cmax: Maximum Observed Plasma Concentration for Lenvatinib	93.3 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 16.8	122 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 46.3

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

Population: PK analysis set included all participants who had received at least 1 dose of lenvatinib and nivolumab and had evaluable concentration data.

Tmax was defined as the time to reach maximum observed plasma concentration (Cmax) for lenvatinib. Tmax was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=4 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Tmax: Time to Reach the Cmax for Lenvatinib	1.45 hours Interval 0.87 to 2.02	3.97 hours Interval 1.8 to 7.52

SECONDARY outcome

Timeframe: Cycle 1 Day 1 and Day 15: 0-24 hours post-dose (Cycle length=28 days)

Population: PK analysis set included all participants who had received at least 1 dose of lenvatinib and nivolumab and had evaluable concentration data. Here, "number analyzed" signifies participants who were evaluable for specified timepoints.

AUC(0-t) was defined as the area under the plasma concentration-time curve from 0 time to last measurable point for lenvatinib. AUC(0-t) was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=4 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib Cycle 1 Day 1	882 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 0.0801	1380 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 36.0
Part 1, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib Cycle 1 Day 15	1410 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 16.7	1920 nanogramhour per milliliter (ngh/mL) Geometric Coefficient of Variation 17.2

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

Population: PK analysis set included all participants who had received at least 1 dose of lenvatinib and nivolumab and had evaluable concentration data. Here, "Overall number of participants analyzed" signifies participants who were evaluable for this outcome measure.

AUC(0-Inf) was defined as the area under the plasma concentration-time curve from 0 to infinity for lenvatinib. AUC(0-Inf) was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=1 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib	987 ng*h/mL Geometric Coefficient of Variation 6.10	1630 ng*h/mL Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

t1/2 was defined as the terminal elimination phase half-life for lenvatinib. t1/2 was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=1 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib	6.77 hours Geometric Coefficient of Variation 27.1	8.95 hours Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as (Dose/AUC(0-inf))/F. Where AUC(0-inf) is the area under the plasma concentration-time curve from zero to infinity and F is the bioavailability of the drug.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=1 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, CL/F: Apparent Total Clearance for Lenvatinib	8.09 liter per hour (L/h) Geometric Coefficient of Variation 6.30	7.37 liter per hour (L/h) Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/F was calculated as (CL/F)/Lambda Z. Where, CL/F is the apparent total clearance and lambda Z is the apparent terminal elimination rate constant.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=1 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib	79.0 liter Geometric Coefficient of Variation 20.4	95.1 liter Geometric Coefficient of Variation NA Geometric Coefficient of Variation could not be calculated for a single participant.

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=28 days)

Css,max was defined as the maximum plasma concentration at steady state for lenvatinib. Css,max was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=3 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib	139 ng/mL Geometric Coefficient of Variation 29.5	164 ng/mL Geometric Coefficient of Variation 9.93

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=28 days)

Css,min is the minimum plasma concentration at steady state for lenvatinib. Css,min was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=3 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib	13.5 ng/mL Geometric Coefficient of Variation 15.8	28.2 ng/mL Geometric Coefficient of Variation 48.7

SECONDARY outcome

Timeframe: Cycle 1 Day 15: 0-24 hours post-dose (Cycle length=28 days)

Tss,Max was defined as the time to reach maximum observed plasma concentration of lenvatinib at steady state. Tss,Max was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=3 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib	3.94 hours Interval 3.85 to 4.02	3.93 hours Interval 3.92 to 7.98

SECONDARY outcome

Timeframe: Cycle 1 Day 1 and Day 15: 0-24 hours post-dose (Cycle length=28 days)

Rac(Cmax) was calculated as Css,max at Cycle 1 Day 15/Cmax at Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=3 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib	1.48 ratio Geometric Coefficient of Variation 12.4	1.28 ratio Geometric Coefficient of Variation 62.4

SECONDARY outcome

Timeframe: Cycle 1 Day 1 and Day 15: 0-24 hours post-dose (Cycle length=28 days)

Rac(AUC) was calculated as AUC(0-t) at Cycle 1 Day 15/AUC(0-t) at Cycle 1 Day 1.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=3 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, Rac (AUC0-t): Accumulation Ratio of AUC(0-t) for Lenvatinib	1.59 ratio Geometric Coefficient of Variation 17.0	1.38 ratio Geometric Coefficient of Variation 47.1

SECONDARY outcome

Timeframe: Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days)

MRT was derived by non-compartmental analysis using lenvatinib plasma concentrations.

Outcome measures

Outcome measures
Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=2 Participants In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=1 Participants In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Part 1, MRT: Mean Residence Time for Lenvatinib	10.9 hours Interval 9.35 to 12.4	13.7 hours Interval 13.7 to 13.7

Adverse Events

Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg

Serious events: 3 serious events

Other events: 6 other events

Deaths: 1 deaths

Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg

Serious events: 12 serious events

Other events: 24 other events

Deaths: 18 deaths

Serious adverse events

Other adverse events

Additional Information

Eisai Inquiry Service

Eisai Co., Ltd.

Phone: none

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=6 participants at risk In Part 1, Participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg.	Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg n=24 participants at risk In Part 2, participants received lenvatinib 12 mg or 8 mg capsules, orally, once daily, in combination with nivolumab 240 mg, infusion, intravenously, Q2W on Days 1 and 15 of each 28 days Cycle. Participants with body weight \>=60 kg received lenvatinib 12 mg, participants with body weight \<60 kg, received lenvatinib 8 mg.
Blood and lymphatic system disorders Lymphadenitis	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Endocrine disorders Adrenal insufficiency	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Endocrine disorders Adrenocorticotropic hormone deficiency	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Endocrine disorders Hyperthyroidism	16.7% 1/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	0.00% 0/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Gastrointestinal disorders Diarrhoea	16.7% 1/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	0.00% 0/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
General disorders Oedema	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
General disorders Oedema peripheral	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
General disorders Pyrexia	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Hepatobiliary disorders Hepatic failure	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Hepatobiliary disorders Jaundice cholestatic	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Hepatobiliary disorders Portal vein thrombosis	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Infections and infestations Bronchitis	16.7% 1/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	0.00% 0/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Infections and infestations Liver abscess	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Injury, poisoning and procedural complications Head injury	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Injury, poisoning and procedural complications Spinal compression fracture	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Investigations C-reactive protein increased	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Metabolism and nutrition disorders Hyperammonaemia	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Nervous system disorders Hepatic encephalopathy	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	8.3% 2/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Nervous system disorders Depressed level of consciousness	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Nervous system disorders Presyncope	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Psychiatric disorders Delirium	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Renal and urinary disorders Acute kidney injury	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Respiratory, thoracic and mediastinal disorders Interstitial lung disease	16.7% 1/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	0.00% 0/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Skin and subcutaneous tissue disorders Stevens-Johnson syndrome	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.
Vascular disorders Aortic dissection	0.00% 0/6 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.	4.2% 1/24 • From the first dose of study drug until 30 days after the last dose (up to 53 months) The safety analysis set included all participants who had received at least 1 dose of study drug.