Carcinoma, Hepatocellular
Conditions
Brief summary
The primary objective of this study is to evaluate the tolerability and safety of a combination of lenvatinib plus nivolumab in participants with hepatocellular carcinoma (HCC).
Interventions
DRUGLenvatinib
Specified doses will be administered orally on specified days.
DRUGNivolumab
Specified doses will be administered intravenously on specified days.
Sponsors
Ono Pharmaceutical Co. Ltd
Eisai Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have confirmed diagnosis of hepatocellular carcinoma (HCC) with any of the following criteria: * Histologically or cytologically confirmed diagnosis of HCC, excluding fibrolamellar, sarcomatoid or mixed cholangio-HCC tumors * Clinically confirmed diagnosis of HCC according to American Association for the Study of Liver Diseases criteria, including cirrhosis of any etiology and/or chronic hepatitis B or C infection * Part 1: HCC for which no other appropriate therapy is available; Part 2: No prior systemic therapy for advanced/unresectable HCC * Participants categorized to stage B (not applicable for transarterial chemoembolization), or stage C based on Barcelona Clinic Liver Cancer staging system * Child-Pugh score A * Participants must have an Eastern Cooperative Oncology Group Performance Status of 0 to 1 * Age greater than or equal to (\>=) 20 years at the time of informed consent
Exclusion criteria
* Active co-infection with hepatitis B and hepatitis C * Participants with any active, known, or suspected autoimmune disease * Participants being treated with drugs that strongly inhibit or induce CYP3A4 and that may be possibly used during this study * Females who are breastfeeding or pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs) | Cycle 1 (Cycle length = 28 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 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. |
| Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From the first dose of study drug until 30 days after the last dose (up to 53 months) | 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). |
| Mean Change From Baseline in Vital Sign: Weight | Baseline, up to Month 53 | Mean change from baseline in weight were evaluated. |
| Mean Change From Baseline in Vital Sign: Body Mass Index | Baseline, up to Month 53 | Mean change from baseline in body mass index were evaluated. |
| Mean Change From Baseline in Vital Sign: SpO2 (Oxygen Saturation) | Baseline, up to Month 53 | Mean change from baseline in SpO2 were evaluated. |
| Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | From the first dose of study drug until 30 days after the last dose (up to 53 months) | 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. |
| Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Baseline, up to Month 53 | 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. |
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | Baseline, up to Month 53 | Change from baseline in left ventricular ejection fraction (LVEF) were evaluated by multigated acquisition scan (MUGA) or echocardiogram. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part 1, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 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. |
| Part 1, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 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. |
| Part 1, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 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. |
| Part 1 and Part 2: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Assessed by Investigator Review | From the first dose of study drug to the first date of documentation of PD or death, whichever occurred first (up to 52 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 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. |
| Part 1, Rac (AUC0-t): Accumulation Ratio of AUC(0-t) for Lenvatinib | 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. |
| Part 1, MRT: Mean Residence Time for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days) | MRT was derived by non-compartmental analysis using lenvatinib plasma concentrations. |
| Part 1, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 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. |
| Part 1, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days) | Cmax was defined as the maximum plasma concentration for lenvatinib. Cmax was derived by non-compartmental analysis using lenvatinib plasma concentrations. |
| Part 1, Tmax: Time to Reach the Cmax for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days) | 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. |
| 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 and Day 15: 0-24 hours post-dose (Cycle length=28 days) | 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. |
| Part 1, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib | Cycle 1 Day 1: 0-24 hours post-dose (Cycle length=28 days) | 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. |
| Part 1, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | 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. |
| Part 1, CL/F: Apparent Total Clearance for Lenvatinib | 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. |
| Part 1, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 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. |
Countries
Japan
Participant flow
Recruitment details
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.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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 \>=60 kg received lenvatinib 12 mg and participants with body weight less than \<60 kg, received lenvatinib 8 mg. | 6 |
| 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. | 24 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Total |
|---|---|---|---|
| Age, Continuous | 73.5 Years STANDARD_DEVIATION 1.87 | 67.1 Years STANDARD_DEVIATION 10.74 | 68.4 Years STANDARD_DEVIATION 9.94 |
| Race/Ethnicity, Customized Chinese | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Japanese | 6 Participants | 23 Participants | 29 Participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 19 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 6 | 18 / 24 |
| other Total, other adverse events | 6 / 6 | 24 / 24 |
| serious Total, serious adverse events | 3 / 6 | 12 / 24 |
Outcome results
Primary
Change From Baseline in Left Ventricular Ejection Fraction (LVEF)
Change from baseline in left ventricular ejection fraction (LVEF) were evaluated by multigated acquisition scan (MUGA) or echocardiogram.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 0.0 %LVEF | Standard Deviation 2 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Change From Baseline in Left Ventricular Ejection Fraction (LVEF) | 0.4 %LVEF | Standard Deviation 4.65 |
Primary
Mean Change From Baseline in Vital Sign: Body Mass Index
Mean change from baseline in body mass index were evaluated.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Mean Change From Baseline in Vital Sign: Body Mass Index | 1.10 kilogram per square meter | Standard Deviation 1.434 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Mean Change From Baseline in Vital Sign: Body Mass Index | -1.12 kilogram per square meter | Standard Deviation 1.811 |
Primary
Mean Change From Baseline in Vital Sign: SpO2 (Oxygen Saturation)
Mean change from baseline in SpO2 were evaluated.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Mean Change From Baseline in Vital Sign: SpO2 (Oxygen Saturation) | 0.2 percentage of blood oxygen saturation | Standard Deviation 0.75 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Mean Change From Baseline in Vital Sign: SpO2 (Oxygen Saturation) | -0.6 percentage of blood oxygen saturation | Standard Deviation 1.41 |
Primary
Mean Change From Baseline in Vital Sign: Weight
Mean change from baseline in weight were evaluated.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Mean Change From Baseline in Vital Sign: Weight | 2.82 kilogram | Standard Deviation 3.931 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Mean Change From Baseline in Vital Sign: Weight | -3.10 kilogram | Standard Deviation 4.953 |
Primary
Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale
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.
Time frame: Baseline, up to Month 53
Population: Safety analysis set included all participants who received at least 1 dose of lenvatinib or nivolumab.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 0 | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 1 | 5 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 2 | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 3 | 1 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 4 | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 2 | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 0 | 15 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 4 | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 1 | 6 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Highest Post-Baseline Values for Eastern Cooperative Oncology Group Performance Status (ECOG-PS) Scale | Grade 3 | 2 Participants |
Primary
Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs)
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Potassium: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Glucose: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Potassium: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Neutrophils: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Calcium corrected: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Glucose: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Calcium corrected: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Hemoglobin: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Magnesium: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Albumin: Markedly Abnormal Low | 1 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Magnesium: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Prothrombin international normalized ratio: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Amylase: Markedly Abnormal High | 1 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Cholesterol: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Lipase: Markedly Abnormal High | 3 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Triglycerides: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Leukocytes: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Leukocytes: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Phosphate: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Lymphocytes: Markedly Abnormal Low | 2 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Alkaline phosphatase: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Aspartate aminotransferase: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Sodium: Markedly Abnormal Low | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Alanine aminotransferase: Markedly Abnormal High | 1 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Lymphocytes: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Gamma-glutamyl transferase: Markedly Abnormal High | 1 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Sodium: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Bilirubin: Markedly Abnormal High | 0 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Platelets: Markedly Abnormal Low | 2 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Creatinine: Markedly Abnormal High | 1 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Hemoglobin: Markedly Abnormal Low | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Cholesterol: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Hemoglobin: Markedly Abnormal Low | 2 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Hemoglobin: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Platelets: Markedly Abnormal Low | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Lymphocytes: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Neutrophils: Markedly Abnormal Low | 3 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Prothrombin international normalized ratio: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Alkaline phosphatase: Markedly Abnormal High | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Creatinine: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Glucose: Markedly Abnormal Low | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Glucose: Markedly Abnormal High | 4 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Albumin: Markedly Abnormal Low | 2 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Triglycerides: Markedly Abnormal High | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Phosphate: Markedly Abnormal Low | 3 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Sodium: Markedly Abnormal Low | 3 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Sodium: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Potassium: Markedly Abnormal Low | 3 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Potassium: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Calcium corrected: Markedly Abnormal Low | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Calcium corrected: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Magnesium: Markedly Abnormal Low | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Magnesium: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Amylase: Markedly Abnormal High | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Lipase: Markedly Abnormal High | 5 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Leukocytes: Markedly Abnormal Low | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Leukocytes: Markedly Abnormal High | 0 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Lymphocytes: Markedly Abnormal Low | 4 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Aspartate aminotransferase: Markedly Abnormal High | 6 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Alanine aminotransferase: Markedly Abnormal High | 1 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Gamma-glutamyl transferase: Markedly Abnormal High | 6 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Number of Participants With Treatment-Emergent Markedly Abnormal Laboratory Values (TEMAVs) | Bilirubin: Markedly Abnormal High | 3 Participants |
Primary
Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
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).
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 6 Participants |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 3 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | SAEs | 12 Participants |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1 and Part 2: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | TEAEs | 24 Participants |
Primary
Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs)
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1: Number of Participants With Dose-Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Part 1 and Part 2: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Assessed by Investigator Review
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 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 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1 and Part 2: Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors (mRECIST) Assessed by Investigator Review | 79.2 percentage of participants |
Secondary
Part 1, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 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 6.1 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, AUC(0-Inf): Area Under the Plasma Concentration-time Curve From Zero to Infinity for Lenvatinib | 1630 ng*h/mL | — |
Secondary
Part 1, AUC(0-t): Area Under the Plasma Concentration-time Curve From Zero Time to the Last Measurable Point for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 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 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 0.0801 |
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 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 15 | 1410 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 16.7 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 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 | 1380 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 36 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 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 15 | 1920 nanogram*hour per milliliter (ng*h/mL) | Geometric Coefficient of Variation 17.2 |
Secondary
Part 1, CL/F: Apparent Total Clearance for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, CL/F: Apparent Total Clearance for Lenvatinib | 8.09 liter per hour (L/h) | Geometric Coefficient of Variation 6.3 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, CL/F: Apparent Total Clearance for Lenvatinib | 7.37 liter per hour (L/h) | — |
Secondary
Part 1, Cmax: Maximum Observed Plasma Concentration for Lenvatinib
Cmax was defined as the maximum plasma concentration for lenvatinib. Cmax was derived by non-compartmental analysis using lenvatinib plasma concentrations.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | 93.3 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 16.8 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Cmax: Maximum Observed Plasma Concentration for Lenvatinib | 122 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 46.3 |
Secondary
Part 1, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib
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.
Time frame: Cycle 1 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, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 139 ng/mL | Geometric Coefficient of Variation 29.5 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Css,Max: Maximum Observed Plasma Concentration at Steady State for Lenvatinib | 164 ng/mL | Geometric Coefficient of Variation 9.93 |
Secondary
Part 1, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib
Css,min is the minimum plasma concentration at steady state for lenvatinib. Css,min was derived by non-compartmental analysis using lenvatinib plasma concentrations.
Time frame: Cycle 1 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, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 13.5 ng/mL | Geometric Coefficient of Variation 15.8 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Css,Min: Minimum Observed Plasma Concentration at Steady State for Lenvatinib | 28.2 ng/mL | Geometric Coefficient of Variation 48.7 |
Secondary
Part 1, MRT: Mean Residence Time for Lenvatinib
MRT was derived by non-compartmental analysis using lenvatinib plasma concentrations.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, MRT: Mean Residence Time for Lenvatinib | 10.9 hours |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, MRT: Mean Residence Time for Lenvatinib | 13.7 hours |
Secondary
Part 1, Rac (AUC0-t): Accumulation Ratio of AUC(0-t) for Lenvatinib
Rac(AUC) was calculated as AUC(0-t) at Cycle 1 Day 15/AUC(0-t) at Cycle 1 Day 1.
Time frame: 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, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Rac (AUC0-t): Accumulation Ratio of AUC(0-t) for Lenvatinib | 1.59 ratio | Geometric Coefficient of Variation 17 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Rac (AUC0-t): Accumulation Ratio of AUC(0-t) for Lenvatinib | 1.38 ratio | Geometric Coefficient of Variation 47.1 |
Secondary
Part 1, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib
Rac(Cmax) was calculated as Css,max at Cycle 1 Day 15/Cmax at Cycle 1 Day 1.
Time frame: 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, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 1.48 ratio | Geometric Coefficient of Variation 12.4 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Rac (Cmax): Accumulation Ratio of Cmax for Lenvatinib | 1.28 ratio | Geometric Coefficient of Variation 62.4 |
Secondary
Part 1, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | 6.77 hours | Geometric Coefficient of Variation 27.1 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, t1/2: Terminal Elimination Phase Half-Life for Lenvatinib | 8.95 hours | — |
Secondary
Part 1, Tmax: Time to Reach the Cmax for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Tmax: Time to Reach the Cmax for Lenvatinib | 1.45 hours |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Tmax: Time to Reach the Cmax for Lenvatinib | 3.97 hours |
Secondary
Part 1, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib
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.
Time frame: Cycle 1 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, Overall number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 3.94 hours |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Tss,Max: Time to Maximum Observed Concentration at Steady State For Lenvatinib | 3.93 hours |
Secondary
Part 1, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib
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.
Time frame: 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.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 79.0 liter | Geometric Coefficient of Variation 20.4 |
| Part 2: Lenvatinib 12 mg or 8 mg + Nivolumab 240 mg | Part 1, Vz/F: Apparent Terminal Volume of Distribution for Lenvatinib | 95.1 liter | — |