Solid Tumor or Lymphoma
Conditions
Keywords
Resistant and refractory solid tumors, lymphomas, hodgkins disease, non-hodgkins lymphoma, neoplasms
Brief summary
The purpose of this study is to determine the maximum tolerated dose (MTD) of lenvatinib in patients with solid tumors or lymphomas.
Detailed description
This is an open-label, non-randomized, dose escalation study. Patients will be treated with lenvatinib once daily. Each four-week treatment period will be considered to be one treatment cycle. The selection of subsequent dose levels will be performed according to an accelerated design: Although initially 3 patients per dose level will be entered, the next dose level can be opened for patient accrual after only the first patient in the previous cohort completes Cycle 1 with no drug-related toxicity greater than grade 1 (except alopecia, lymphopenia and anemia).
Interventions
DRUGLenvatinib
Lenvatinib tablets taken orally, once daily.
Sponsors
Eisai Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the inclusion criteria outlined below in order to be eligible to participate in the study: 1. Patients with histologically and/or cytologically confirmed solid tumor or lymphoma who are resistant/refractory to approved therapies or for whom no appropriate therapies are available. 2. All previous treatment (including surgery and radiotherapy) must have been completed at least four weeks prior to study entry and any acute toxicities must have resolved. 3. Aged greater than or equal to 18 years. 4. Karnofsky performance status greater than or equal 70%. 5. Written informed consent to participate in the study.
Exclusion criteria
Patients with the following characteristics will not be eligible for the study: 1. Brain tumors or brain or leptomeningeal metastases. 2. Any of the following laboratory parameters: 1. hemoglobin less than 9 g/dl (5.6 mmol/L) 2. neutrophils less than 1.5 x 10\^9/L 3. platelets less than 100 x 10\^9/L 4. serum bilirubin greater than 25 micro-mol/l (1.5 mg/dl) 5. other liver parameters greater than 3 x the upper limit of normal (ULN) 6. serum creatinine greater than 1.5 x ULN or creatinine clearance less than 60 ml/minute 3. Uncontrolled infections. 4. Clinically significant cardiac impairment or unstable ischemic heart disease including a myocardial infarction within six months of study start. 5. Any treatment with investigational drugs within 30 days before the start of the study. 6. Pregnancy or lactation (all women of childbearing potential must have a negative pregnancy test before inclusion in the study; post-menopausal women must be amenorrheic for at least 12 months). Female patients of childbearing potential must use adequate contraceptive protection, defined as two forms of contraception, one of which must be a barrier method. 7. Fertile males not willing to use contraception or whose female partners are not using adequate contraceptive protection. 8. History of alcoholism, drug addiction, or any psychiatric or psychological condition which, in the opinion of the investigator, would impair study compliance. 9. Legal incapacity. 10. Centrally located or squamous cell carcinoma of the lung. 11. Proteinuria greater than 1+ on bedside testing. 12. History of gastrointestinal malabsorption. 13. Surgery involving gastro- and/or intestinal anastomosis within four weeks of study start. 14. Patients with bleeding or thrombotic disorders. 15. Patients using therapeutic dosages of anticoagulants. 16. Poorly controlled hypertension (defined as a change in hypertensive therapy within three months of study start) or patients diagnosed with hypertension (defined as a repeat blood pressure measurement of 160/90 mmHg or higher) at screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | Cycle 1 (4 weeks) | The MTD was defined as the highest dose level at which no more than one out of six participants experienced dose-limiting toxicity (DLT). DLT was assessed during the first 4 weeks of therapy (Cycle 1) for dose escalation purposes. Participants enrolled into the MTD cohort were given the option to also participate in the food-effect pilot study. The food-effect pilot study was initiated once the MTD had been established. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | First date of study treatment to date of last dose of study treatment, up to approximately 13 years and 8 months | All AEs were graded on a 5-point scale according to the National Cancer Institute's Common Toxicity Criteria (NCI CTC) grading system, version 3.0. Safety was assessed using the occurrence of DLTs, AEs, SAEs, clinical laboratory test results, vital signs measurements, physical examination findings, and electrocardiograms (ECGs) readings. An AE was defined as any untoward medical occurrence in a participant administered lenvatinib and did not necessarily have a causal relationship to lenvatinib. An SAE was defined as any untoward medical occurrence which results in death, was life-threatening, required hospitalization or prolonged hospitalization, resulted in persistent or significant disability/incapacity, or caused a congenital anomaly/birth defect. Treatment-related AEs and SAEs are AEs considered probably or possibly related to lenvatinib. |
| Dose-limiting Toxicities (DLTs) | Cycle 1 (4 weeks) of each dose level | A DLT was defined as any grade 3 or higher hematological or non-hematological toxicity directly related to lenvatinib, any repeated National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 2 hematological or non-hematological toxicity considered to be directly related to lenvatinib and required dose reduction, or failure to administer greater than or equal to 75% of the planned dosage of lenvatinib during Cycle 1 as a result of treatment-related failure. |
| Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | First date of study treatment to date of withdrawal from study or last dose of study treatment, up to approximately 13 years and 8 months | Treatment-related AEs were untoward medical events that were considered by the investigator to be possibly or probably related to lenvatinib. |
| Best Overall Response (BOR) | Baseline to first date of documented CR, PR, SD, or PD, assessed up to approximately 4 years | BOR was the best confirmed response of complete response (CR), partial response (PR), progressive disease (PD), stable disease (SD), or not evaluable (NE), recorded from the start of lenvatinib until disease progression/recurrence or death. CR; disappearance of all target lesions for at least 1 month. PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD; a 20% or greater increase in the sum of the longest diameter of measured lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions. SD; PR failed to be achieved in the overall response assessment and there was no PD observed at 7 weeks or later after starting lenvatinib. |
| Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Apparent Volume of Distribution (Vz/F) | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Renal Clearance (CLr) of Lenvatinib | Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days) | — |
| Effect of Food on the Area Under the Curve From Zero to 24 Hours (AUC(0-24)) | Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days) | — |
| Effect of Food on the Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days) | — |
| Effect of Food on Time to Maximum Concentration (Tmax) of Lenvatinib | Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days) | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacodynamic (PD) Biomarkers of Lenvatinib in Peripheral Blood Mononuclear Cells (PBMCs) and Tumor Samples | Blood: Cycle 1 Day 1, Day 15, or Day 22, Cycle 2 Day 1 Tumor tissue: Screening and after at least one 28-day Cycle of study treatment | Based on the data in assay development stage before PD biomarker analysis in study E7080-E044-101 we did not find the appropriate PD biomarker in PBMC, therefore we did not have any biomarker analysis for PK/PD analysis. |
Countries
Netherlands, United Kingdom
Participant flow
Recruitment details
Participants took part in the study at 1 site in United Kingdom and 1 site in Netherlands from 01 July 2005 to 01 March 2019.
Pre-assignment details
A total of 82 participants with solid tumors or lymphomas were enrolled and received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Lenvatinib 0.2 mg Two 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced dose-limiting toxicity (DLT) during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the maximum tolerated dose (MTD) was determined. An additional 12 participants were treated at the MTD level. | 4 |
| Lenvatinib 0.4 mg Four 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 4 |
| Lenvatinib 0.8 mg Eight 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 4 |
| Lenvatinib 1.6 mg One 1.0 mg lenvatinib tablet and six 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 3 |
| Lenvatinib 3.2 mg Three 1.0 mg lenvatinib tablets and two 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 3 |
| Lenvatinib 6.4 mg Six 1.0 mg lenvatinib tablets and four 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 3 |
| Lenvatinib 12 mg One 10 mg lenvatinib tablet and two 1.0 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 12 |
| Lenvatinib 12.5 mg One 10 mg lenvatinib tablet, two 1.0 mg lenvatinib tablets, and five 0.1 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 9 |
| Lenvatinib 16 mg One 10 mg lenvatinib tablet and six 1.0 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 6 |
| Lenvatinib 20 mg Two 10 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 3 |
| Lenvatinib (MTD Cohort) 25 mg Participants in this cohort had the option of participating in the food-effect pilot study. Two 10 mg lenvatinib tablets and five 1.0 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 24 |
| Lenvatinib 32 mg Three 10 mg lenvatinib tablets and two 1.0 mg lenvatinib tablets were taken orally, once daily. Lenvatinib was to be taken on an empty stomach shortly after waking. Participants were fasted for 2 hours following administration of lenvatinib and could drink only clear fluids during this time (grapefruit juice was to be avoided). If 1 of 3 participants experienced DLT during Cycle 1 (4 weeks) an additional 3 participants were to be treated at this dose level. If 5 of the 6 participants in the expanded dose level did not experience DLT during the first 4 weeks of therapy, no additional DLT was observed, the next dose level was opened for enrollment. If more than 1 participant experienced DLT during the first 4 weeks of therapy, dose escalation was stopped and the MTD was determined. An additional 12 participants were treated at the MTD level. | 7 |
| Total | 82 |
Baseline characteristics
| Characteristic | Lenvatinib 0.2 mg | Lenvatinib 0.4 mg | Lenvatinib 0.8 mg | Lenvatinib 1.6 mg | Lenvatinib 3.2 mg | Lenvatinib 6.4 mg | Lenvatinib 12 mg | Lenvatinib 12.5 mg | Lenvatinib 16 mg | Lenvatinib 20 mg | Lenvatinib (MTD Cohort) 25 mg | Lenvatinib 32 mg | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 64.5 Years STANDARD_DEVIATION 7.94 | 47.8 Years STANDARD_DEVIATION 6.45 | 64.0 Years STANDARD_DEVIATION 6.48 | 60.0 Years STANDARD_DEVIATION 11.53 | 65.0 Years STANDARD_DEVIATION 19 | 51.0 Years STANDARD_DEVIATION 22.72 | 46.3 Years STANDARD_DEVIATION 13.25 | 52.6 Years STANDARD_DEVIATION 13.28 | 55.7 Years STANDARD_DEVIATION 13.32 | 51.7 Years STANDARD_DEVIATION 12.34 | 52.2 Years STANDARD_DEVIATION 9.65 | 53.9 Years STANDARD_DEVIATION 11.84 | 53.4 Years STANDARD_DEVIATION 12.32 |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 2 Participants | 1 Participants | 2 Participants | 0 Participants | 8 Participants | 3 Participants | 3 Participants | 0 Participants | 14 Participants | 1 Participants | 39 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 4 Participants | 6 Participants | 3 Participants | 3 Participants | 10 Participants | 6 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 1 / 4 | 1 / 4 | 1 / 3 | 0 / 3 | 2 / 3 | 1 / 12 | 1 / 9 | 1 / 6 | 3 / 3 | 0 / 6 | 0 / 5 | 3 / 24 | 2 / 7 |
| other Total, other adverse events | 4 / 4 | 4 / 4 | 4 / 4 | 3 / 3 | 3 / 3 | 3 / 3 | 12 / 12 | 9 / 9 | 6 / 6 | 3 / 3 | 6 / 6 | 5 / 5 | 24 / 24 | 6 / 7 |
| serious Total, serious adverse events | 2 / 4 | 2 / 4 | 1 / 4 | 1 / 3 | 0 / 3 | 3 / 3 | 5 / 12 | 4 / 9 | 2 / 6 | 3 / 3 | 2 / 6 | 2 / 5 | 15 / 24 | 3 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
The MTD was defined as the highest dose level at which no more than one out of six participants experienced dose-limiting toxicity (DLT). DLT was assessed during the first 4 weeks of therapy (Cycle 1) for dose escalation purposes. Participants enrolled into the MTD cohort were given the option to also participate in the food-effect pilot study. The food-effect pilot study was initiated once the MTD had been established.
Time frame: Cycle 1 (4 weeks)
Population: ITT population included all participants who received at least one dose of lenvatinib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Lenvatinib | Maximum Tolerated Dose (MTD) | 25 milligram (mg) |
Secondary
Apparent Plasma Half-life (t1/2) of Lenvatinib
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 29.540 Hours | Standard Deviation 8.2731 |
| Lenvatinib 0.4 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 26.380 Hours | Standard Deviation 8.0427 |
| Lenvatinib 0.8 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 20.840 Hours | — |
| Lenvatinib 0.8 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 18.180 Hours | Standard Deviation 11.342 |
| Lenvatinib 1.6 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 10.695 Hours | Standard Deviation 8.789 |
| Lenvatinib 1.6 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 10.827 Hours | Standard Deviation 5.555 |
| Lenvatinib 3.2 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 12.805 Hours | Standard Deviation 3.118 |
| Lenvatinib 3.2 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 9.973 Hours | Standard Deviation 1.288 |
| Lenvatinib 6.4 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 8.330 Hours | Standard Deviation 0.517 |
| Lenvatinib 6.4 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 8.077 Hours | Standard Deviation 0.749 |
| Lenvatinib 12 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 6.935 Hours | Standard Deviation 1.1681 |
| Lenvatinib 12 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 5.981 Hours | Standard Deviation 0.484 |
| Lenvatinib 12.5 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 6.567 Hours | Standard Deviation 0.9553 |
| Lenvatinib 12.5 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 6.829 Hours | Standard Deviation 1.019 |
| Lenvatinib 16 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 7.115 Hours | Standard Deviation 1.0866 |
| Lenvatinib 16 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 6.935 Hours | Standard Deviation 0.9313 |
| Lenvatinib 20 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 6.960 Hours | Standard Deviation 1.23 |
| Lenvatinib 20 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 8.090 Hours | — |
| Lenvatinib Fasted/Fed 25 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 6.025 Hours | Standard Deviation 0.704 |
| Lenvatinib Fasted/Fed 25 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 5.848 Hours | Standard Deviation 1.018 |
| Lenvatinib Fed/Fasted 25 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 2 Day 1 | 6.675 Hours | Standard Deviation 0.5216 |
| Lenvatinib Fed/Fasted 25 mg | Apparent Plasma Half-life (t1/2) of Lenvatinib | Cycle 1 Day 1 | 5.550 Hours | Standard Deviation 0.599 |
Secondary
Apparent Volume of Distribution (Vz/F)
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 206.360 Liter (L) | Standard Deviation 96.068 |
| Lenvatinib 0.4 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 208.937 Liter (L) | Standard Deviation 114.969 |
| Lenvatinib 0.8 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 162.975 Liter (L) | Standard Deviation 78.383 |
| Lenvatinib 0.8 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 120.810 Liter (L) | — |
| Lenvatinib 1.6 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 65.437 Liter (L) | Standard Deviation 24.894 |
| Lenvatinib 1.6 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 65.795 Liter (L) | Standard Deviation 0.6435 |
| Lenvatinib 3.2 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 80.365 Liter (L) | Standard Deviation 37.922 |
| Lenvatinib 3.2 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 51.487 Liter (L) | Standard Deviation 16.805 |
| Lenvatinib 6.4 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 97.190 Liter (L) | Standard Deviation 95.442 |
| Lenvatinib 6.4 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 67.747 Liter (L) | Standard Deviation 51.897 |
| Lenvatinib 12 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 57.039 Liter (L) | Standard Deviation 11.887 |
| Lenvatinib 12 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 70.881 Liter (L) | Standard Deviation 40.419 |
| Lenvatinib 12.5 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 99.960 Liter (L) | Standard Deviation 37.787 |
| Lenvatinib 12.5 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 88.069 Liter (L) | Standard Deviation 38.174 |
| Lenvatinib 16 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 60.683 Liter (L) | Standard Deviation 26.763 |
| Lenvatinib 16 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 58.408 Liter (L) | Standard Deviation 32.346 |
| Lenvatinib 20 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 120.730 Liter (L) | — |
| Lenvatinib 20 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 56.350 Liter (L) | Standard Deviation 22.932 |
| Lenvatinib Fasted/Fed 25 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 55.263 Liter (L) | Standard Deviation 22.411 |
| Lenvatinib Fasted/Fed 25 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 57.143 Liter (L) | Standard Deviation 28.55 |
| Lenvatinib Fed/Fasted 25 mg | Apparent Volume of Distribution (Vz/F) | Cycle 1 Day 1 | 68.073 Liter (L) | Standard Deviation 32.456 |
| Lenvatinib Fed/Fasted 25 mg | Apparent Volume of Distribution (Vz/F) | Cycle 2 Day 1 | 76.610 Liter (L) | Standard Deviation 25.967 |
Secondary
Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24))
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 14.348 ng*hr/mL | Standard Deviation 4.5 |
| Lenvatinib | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 43.305 ng*hr/mL | Standard Deviation 8.5913 |
| Lenvatinib 0.4 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 30.207 ng*hr/mL | Standard Deviation 14.521 |
| Lenvatinib 0.4 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 85.477 ng*hr/mL | Standard Deviation 37.054 |
| Lenvatinib 0.8 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 61.915 ng*hr/mL | Standard Deviation 17.164 |
| Lenvatinib 0.8 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 199.100 ng*hr/mL | — |
| Lenvatinib 1.6 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 422.873 ng*hr/mL | Standard Deviation 270.528 |
| Lenvatinib 1.6 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 220.910 ng*hr/mL | Standard Deviation 129.838 |
| Lenvatinib 3.2 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 931.307 ng*hr/mL | Standard Deviation 179.514 |
| Lenvatinib 3.2 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 659.553 ng*hr/mL | Standard Deviation 209.129 |
| Lenvatinib 6.4 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 1168.257 ng*hr/mL | Standard Deviation 799.169 |
| Lenvatinib 6.4 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 1691.160 ng*hr/mL | Standard Deviation 1167.75 |
| Lenvatinib 12 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 2052.965 ng*hr/mL | Standard Deviation 789.504 |
| Lenvatinib 12 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 1655.035 ng*hr/mL | Standard Deviation 555.479 |
| Lenvatinib 12.5 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 1422.584 ng*hr/mL | Standard Deviation 697.699 |
| Lenvatinib 12.5 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 1537.476 ng*hr/mL | Standard Deviation 876.6805 |
| Lenvatinib 16 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 2947.920 ng*hr/mL | Standard Deviation 1286.805 |
| Lenvatinib 16 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 3250.843 ng*hr/mL | Standard Deviation 1826.8789 |
| Lenvatinib 20 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 1934.500 ng*hr/mL | — |
| Lenvatinib 20 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 3709.550 ng*hr/mL | Standard Deviation 2059.6379 |
| Lenvatinib Fasted/Fed 25 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 4224.095 ng*hr/mL | Standard Deviation 1120.837 |
| Lenvatinib Fasted/Fed 25 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 4074.803 ng*hr/mL | Standard Deviation 1666.278 |
| Lenvatinib Fed/Fasted 25 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 1 Day 1 | 4601.014 ng*hr/mL | Standard Deviation 1887.3642 |
| Lenvatinib Fed/Fasted 25 mg | Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) | Cycle 2 Day 1 | 4020.185 ng*hr/mL | Standard Deviation 899.182 |
Secondary
Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf))
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 99.325 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 0.1202 |
| Lenvatinib 0.4 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 174.310 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 46.259 |
| Lenvatinib 0.8 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 123.745 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 20.81 |
| Lenvatinib 0.8 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 370.390 nanogram*hour per milliliter (ng*hr/mL) | — |
| Lenvatinib 1.6 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 585.247 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 397.909 |
| Lenvatinib 1.6 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 376.645 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 312.124 |
| Lenvatinib 3.2 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 780.275 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 189.116 |
| Lenvatinib 3.2 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 1150.393 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 192.365 |
| Lenvatinib 6.4 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 1335.493 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 894.562 |
| Lenvatinib 6.4 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 1952.430 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1323.783 |
| Lenvatinib 12 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 1895.454 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 467.145 |
| Lenvatinib 12 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 2278.016 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 851.258 |
| Lenvatinib 12.5 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 1558.101 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 760.687 |
| Lenvatinib 12.5 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 1693.298 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1011.7941 |
| Lenvatinib 16 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 3310.673 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1544.708 |
| Lenvatinib 16 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 3683.590 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 2210.4521 |
| Lenvatinib 20 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 2260.040 nanogram*hour per milliliter (ng*hr/mL) | — |
| Lenvatinib 20 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 4238.680 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 2602.9271 |
| Lenvatinib Fasted/Fed 25 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 4413.263 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1946.571 |
| Lenvatinib Fasted/Fed 25 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 4549.825 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1161.045 |
| Lenvatinib Fed/Fasted 25 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 1 Day 1 | 4383.678 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 1697.248 |
| Lenvatinib Fed/Fasted 25 mg | Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) | Cycle 2 Day 1 | 4391.160 nanogram*hour per milliliter (ng*hr/mL) | Standard Deviation 997.486 |
Secondary
Best Overall Response (BOR)
BOR was the best confirmed response of complete response (CR), partial response (PR), progressive disease (PD), stable disease (SD), or not evaluable (NE), recorded from the start of lenvatinib until disease progression/recurrence or death. CR; disappearance of all target lesions for at least 1 month. PR; at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD; a 20% or greater increase in the sum of the longest diameter of measured lesions, taking as reference the smallest sum longest diameter recorded since treatment started or the appearance of one or more new lesions. SD; PR failed to be achieved in the overall response assessment and there was no PD observed at 7 weeks or later after starting lenvatinib.
Time frame: Baseline to first date of documented CR, PR, SD, or PD, assessed up to approximately 4 years
Population: ITT population included all participants who received at least one dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib | Best Overall Response (BOR) | Stable disease | 0 Percentage of participants |
| Lenvatinib | Best Overall Response (BOR) | Not evaluable | 25.0 Percentage of participants |
| Lenvatinib | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib | Best Overall Response (BOR) | Progressive disease | 50.0 Percentage of participants |
| Lenvatinib 0.4 mg | Best Overall Response (BOR) | Progressive disease | 50.0 Percentage of participants |
| Lenvatinib 0.4 mg | Best Overall Response (BOR) | Stable disease | 0 Percentage of participants |
| Lenvatinib 0.4 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 0.4 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 0.8 mg | Best Overall Response (BOR) | Stable disease | 25.0 Percentage of participants |
| Lenvatinib 0.8 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 0.8 mg | Best Overall Response (BOR) | Progressive disease | 0 Percentage of participants |
| Lenvatinib 0.8 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 1.6 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 1.6 mg | Best Overall Response (BOR) | Stable disease | 33.3 Percentage of participants |
| Lenvatinib 1.6 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 1.6 mg | Best Overall Response (BOR) | Progressive disease | 0 Percentage of participants |
| Lenvatinib 3.2 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 3.2 mg | Best Overall Response (BOR) | Stable disease | 66.7 Percentage of participants |
| Lenvatinib 3.2 mg | Best Overall Response (BOR) | Progressive disease | 0 Percentage of participants |
| Lenvatinib 3.2 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 6.4 mg | Best Overall Response (BOR) | Progressive disease | 33.3 Percentage of participants |
| Lenvatinib 6.4 mg | Best Overall Response (BOR) | Stable disease | 0 Percentage of participants |
| Lenvatinib 6.4 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 6.4 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 12 mg | Best Overall Response (BOR) | Not evaluable | 8.3 Percentage of participants |
| Lenvatinib 12 mg | Best Overall Response (BOR) | Stable disease | 33.3 Percentage of participants |
| Lenvatinib 12 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 12 mg | Best Overall Response (BOR) | Progressive disease | 41.7 Percentage of participants |
| Lenvatinib 12.5 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 12.5 mg | Best Overall Response (BOR) | Progressive disease | 11.1 Percentage of participants |
| Lenvatinib 12.5 mg | Best Overall Response (BOR) | Stable disease | 55.6 Percentage of participants |
| Lenvatinib 12.5 mg | Best Overall Response (BOR) | Partial response | 11.1 Percentage of participants |
| Lenvatinib 16 mg | Best Overall Response (BOR) | Stable disease | 83.3 Percentage of participants |
| Lenvatinib 16 mg | Best Overall Response (BOR) | Partial response | 0 Percentage of participants |
| Lenvatinib 16 mg | Best Overall Response (BOR) | Progressive disease | 16.7 Percentage of participants |
| Lenvatinib 16 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib 20 mg | Best Overall Response (BOR) | Stable disease | 33.3 Percentage of participants |
| Lenvatinib 20 mg | Best Overall Response (BOR) | Partial response | 33.3 Percentage of participants |
| Lenvatinib 20 mg | Best Overall Response (BOR) | Progressive disease | 0 Percentage of participants |
| Lenvatinib 20 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Best Overall Response (BOR) | Stable disease | 66.7 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Best Overall Response (BOR) | Progressive disease | 8.3 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Best Overall Response (BOR) | Partial response | 12.5 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Best Overall Response (BOR) | Progressive disease | 0 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Best Overall Response (BOR) | Stable disease | 42.9 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Best Overall Response (BOR) | Partial response | 28.6 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Best Overall Response (BOR) | Not evaluable | 0 Percentage of participants |
Secondary
Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F)
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 4.710 Liter per hour (L/hr) | Standard Deviation 0.9334 |
| Lenvatinib 0.4 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 5.200 Liter per hour (L/hr) | Standard Deviation 1.802 |
| Lenvatinib 0.8 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 4.020 Liter per hour (L/hr) | — |
| Lenvatinib 0.8 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 6.560 Liter per hour (L/hr) | Standard Deviation 1.103 |
| Lenvatinib 1.6 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 6.470 Liter per hour (L/hr) | Standard Deviation 5.36 |
| Lenvatinib 1.6 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 5.347 Liter per hour (L/hr) | Standard Deviation 3.942 |
| Lenvatinib 3.2 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 4.225 Liter per hour (L/hr) | Standard Deviation 1.0253 |
| Lenvatinib 3.2 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 3.533 Liter per hour (L/hr) | Standard Deviation 0.747 |
| Lenvatinib 6.4 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 5.557 Liter per hour (L/hr) | Standard Deviation 4.2 |
| Lenvatinib 6.4 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 8.190 Liter per hour (L/hr) | Standard Deviation 7.923 |
| Lenvatinib 12 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 6.896 Liter per hour (L/hr) | Standard Deviation 3.36 |
| Lenvatinib 12 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 6.614 Liter per hour (L/hr) | Standard Deviation 1.336 |
| Lenvatinib 12.5 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 9.534 Liter per hour (L/hr) | Standard Deviation 4.307 |
| Lenvatinib 12.5 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 10.110 Liter per hour (L/hr) | Standard Deviation 3.321 |
| Lenvatinib 16 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 6.437 Liter per hour (L/hr) | Standard Deviation 3.668 |
| Lenvatinib 16 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 6.157 Liter per hour (L/hr) | Standard Deviation 4.24 |
| Lenvatinib 20 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 5.980 Liter per hour (L/hr) | Standard Deviation 3.236 |
| Lenvatinib 20 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 10.340 Liter per hour (L/hr) | — |
| Lenvatinib Fasted/Fed 25 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 6.863 Liter per hour (L/hr) | Standard Deviation 3.354 |
| Lenvatinib Fasted/Fed 25 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 6.378 Liter per hour (L/hr) | Standard Deviation 2.302 |
| Lenvatinib Fed/Fasted 25 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 2 Day 1 | 7.978 Liter per hour (L/hr) | Standard Deviation 2.763 |
| Lenvatinib Fed/Fasted 25 mg | Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) | Cycle 1 Day 1 | 8.827 Liter per hour (L/hr) | Standard Deviation 5.058 |
Secondary
Dose-limiting Toxicities (DLTs)
A DLT was defined as any grade 3 or higher hematological or non-hematological toxicity directly related to lenvatinib, any repeated National Cancer Institute Common Toxicity Criteria (NCI CTC) grade 2 hematological or non-hematological toxicity considered to be directly related to lenvatinib and required dose reduction, or failure to administer greater than or equal to 75% of the planned dosage of lenvatinib during Cycle 1 as a result of treatment-related failure.
Time frame: Cycle 1 (4 weeks) of each dose level
Population: ITT/ safety population included all participants who received at least one dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 0.4 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 0.4 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 0.4 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 0.4 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 0.4 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 0.8 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 0.8 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 0.8 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 0.8 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 0.8 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 1.6 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 1.6 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 1.6 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 1.6 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 1.6 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 3.2 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 3.2 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 3.2 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 3.2 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 3.2 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 6.4 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 6.4 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 1 Participants |
| Lenvatinib 6.4 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 6.4 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 6.4 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 12 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 12 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 12 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 12 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 12 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 12.5 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib 12.5 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 1 Participants |
| Lenvatinib 12.5 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 12.5 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 12.5 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 1 Participants |
| Lenvatinib 16 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 1 Participants |
| Lenvatinib 16 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 16 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 1 Participants |
| Lenvatinib 16 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 16 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 20 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib 20 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib 20 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib 20 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib 20 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib Fasted/Fed 25 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
| Lenvatinib Fasted/Fed 25 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib Fasted/Fed 25 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 0 Participants |
| Lenvatinib Fasted/Fed 25 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib Fasted/Fed 25 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib Fed/Fasted 25 mg | Dose-limiting Toxicities (DLTs) | Proteinuria | 2 Participants |
| Lenvatinib Fed/Fasted 25 mg | Dose-limiting Toxicities (DLTs) | Fatigue | 0 Participants |
| Lenvatinib Fed/Fasted 25 mg | Dose-limiting Toxicities (DLTs) | Febrile neutropenia | 0 Participants |
| Lenvatinib Fed/Fasted 25 mg | Dose-limiting Toxicities (DLTs) | Thrombocytopenia | 0 Participants |
| Lenvatinib Fed/Fasted 25 mg | Dose-limiting Toxicities (DLTs) | Hypertension | 0 Participants |
Secondary
Effect of Food on the Area Under the Curve From Zero to 24 Hours (AUC(0-24))
Time frame: Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days)
Population: The Food Effect Population consisted of all participants who agreed to participate in this part of the study, have received both the Day 15 and Day 22 doses, with PK sampling during 24 hours following those doses and consumed at least half (approximately) of the high fat breakfast when in the fed period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lenvatinib | Effect of Food on the Area Under the Curve From Zero to 24 Hours (AUC(0-24)) | 3851.773 ng*hr/mL | Standard Deviation 993.1449 |
| Lenvatinib 0.4 mg | Effect of Food on the Area Under the Curve From Zero to 24 Hours (AUC(0-24)) | 4039.681 ng*hr/mL | Standard Deviation 1567.4169 |
Secondary
Effect of Food on the Maximum Plasma Concentration (Cmax) of Lenvatinib
Time frame: Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days)
Population: The Food Effect Population consisted of all participants who agreed to participate in this part of the study, have received both the Day 15 and Day 22 doses, with PK sampling during 24 hours following those doses and consumed at least half (approximately) of the high fat breakfast when in the fed period.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lenvatinib | Effect of Food on the Maximum Plasma Concentration (Cmax) of Lenvatinib | 508.558 ng/mL | Standard Deviation 165.7591 |
| Lenvatinib 0.4 mg | Effect of Food on the Maximum Plasma Concentration (Cmax) of Lenvatinib | 544.058 ng/mL | Standard Deviation 248.5409 |
Secondary
Effect of Food on Time to Maximum Concentration (Tmax) of Lenvatinib
Time frame: Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days)
Population: The Food Effect Population consisted of all participants who agreed to participate in this part of the study, have received both the Day 15 and Day 22 doses, with PK sampling during 24 hours following those doses and consumed at least half (approximately) of the high fat breakfast when in the fed period.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Lenvatinib | Effect of Food on Time to Maximum Concentration (Tmax) of Lenvatinib | 4.980 Hours |
| Lenvatinib 0.4 mg | Effect of Food on Time to Maximum Concentration (Tmax) of Lenvatinib | 2.030 Hours |
Comparison: This was a pilot study and a statistical sample size calculation was not performed.p-value: 0.0146Wilcoxon signed-rank test
Secondary
Fraction of Unchanged Lenvatinib Excreted in the Urine (fe)
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.530 Percentage of lenvatinib | Standard Deviation 0.0141 |
| Lenvatinib | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 1.240 Percentage of lenvatinib | — |
| Lenvatinib 0.4 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.253 Percentage of lenvatinib | Standard Deviation 0.0457 |
| Lenvatinib 0.4 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.715 Percentage of lenvatinib | Standard Deviation 0.1626 |
| Lenvatinib 0.8 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.217 Percentage of lenvatinib | Standard Deviation 0.0896 |
| Lenvatinib 0.8 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.605 Percentage of lenvatinib | Standard Deviation 0.0636 |
| Lenvatinib 1.6 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.363 Percentage of lenvatinib | Standard Deviation 0.129 |
| Lenvatinib 1.6 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.535 Percentage of lenvatinib | Standard Deviation 0.3748 |
| Lenvatinib 3.2 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.355 Percentage of lenvatinib | Standard Deviation 0.0354 |
| Lenvatinib 3.2 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 1.050 Percentage of lenvatinib | — |
| Lenvatinib 6.4 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.390 Percentage of lenvatinib | Standard Deviation 0.0849 |
| Lenvatinib 6.4 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.557 Percentage of lenvatinib | Standard Deviation 0.2212 |
| Lenvatinib 12 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.689 Percentage of lenvatinib | Standard Deviation 0.4208 |
| Lenvatinib 12 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.487 Percentage of lenvatinib | Standard Deviation 0.3137 |
| Lenvatinib 12.5 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.783 Percentage of lenvatinib | Standard Deviation 0.7928 |
| Lenvatinib 12.5 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.663 Percentage of lenvatinib | Standard Deviation 0.2873 |
| Lenvatinib 16 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.825 Percentage of lenvatinib | Standard Deviation 0.2786 |
| Lenvatinib 16 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.348 Percentage of lenvatinib | Standard Deviation 0.191 |
| Lenvatinib 20 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.690 Percentage of lenvatinib | Standard Deviation 0.4851 |
| Lenvatinib 20 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.630 Percentage of lenvatinib | — |
| Lenvatinib Fasted/Fed 25 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.576 Percentage of lenvatinib | Standard Deviation 0.3042 |
| Lenvatinib Fasted/Fed 25 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.778 Percentage of lenvatinib | Standard Deviation 0.3801 |
| Lenvatinib Fed/Fasted 25 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 1 Day 1 | 0.503 Percentage of lenvatinib | Standard Deviation 0.3004 |
| Lenvatinib Fed/Fasted 25 mg | Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) | Cycle 2 Day 1 | 0.527 Percentage of lenvatinib | Standard Deviation 0.1595 |
Secondary
Maximum Plasma Concentration (Cmax) of Lenvatinib
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: Pharmacokinetic (PK) population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 0.753 Nanogram per milliliter (ng/mL) | Standard Deviation 0.2176 |
| Lenvatinib | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 2.385 Nanogram per milliliter (ng/mL) | Standard Deviation 0.5162 |
| Lenvatinib 0.4 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 5.477 Nanogram per milliliter (ng/mL) | Standard Deviation 1.5988 |
| Lenvatinib 0.4 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 1.740 Nanogram per milliliter (ng/mL) | Standard Deviation 0.6921 |
| Lenvatinib 0.8 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 9.610 Nanogram per milliliter (ng/mL) | Standard Deviation 2.3193 |
| Lenvatinib 0.8 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 4.255 Nanogram per milliliter (ng/mL) | Standard Deviation 1.7474 |
| Lenvatinib 1.6 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 20.967 Nanogram per milliliter (ng/mL) | Standard Deviation 11.6741 |
| Lenvatinib 1.6 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 36.483 Nanogram per milliliter (ng/mL) | Standard Deviation 10.9339 |
| Lenvatinib 3.2 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 92.137 Nanogram per milliliter (ng/mL) | Standard Deviation 29.0365 |
| Lenvatinib 3.2 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 49.883 Nanogram per milliliter (ng/mL) | Standard Deviation 15.9952 |
| Lenvatinib 6.4 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 197.217 Nanogram per milliliter (ng/mL) | Standard Deviation 136.7307 |
| Lenvatinib 6.4 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 127.067 Nanogram per milliliter (ng/mL) | Standard Deviation 91.332 |
| Lenvatinib 12 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 259.990 Nanogram per milliliter (ng/mL) | Standard Deviation 108.1789 |
| Lenvatinib 12 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 291.414 Nanogram per milliliter (ng/mL) | Standard Deviation 146.1972 |
| Lenvatinib 12.5 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 209.004 Nanogram per milliliter (ng/mL) | Standard Deviation 112.009 |
| Lenvatinib 12.5 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 187.467 Nanogram per milliliter (ng/mL) | Standard Deviation 86.3962 |
| Lenvatinib 16 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 368.937 Nanogram per milliliter (ng/mL) | Standard Deviation 148.816 |
| Lenvatinib 16 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 375.077 Nanogram per milliliter (ng/mL) | Standard Deviation 158.1811 |
| Lenvatinib 20 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 408.797 Nanogram per milliliter (ng/mL) | Standard Deviation 105.6923 |
| Lenvatinib 20 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 238.670 Nanogram per milliliter (ng/mL) | — |
| Lenvatinib Fasted/Fed 25 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 630.589 Nanogram per milliliter (ng/mL) | Standard Deviation 234.1659 |
| Lenvatinib Fasted/Fed 25 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 544.718 Nanogram per milliliter (ng/mL) | Standard Deviation 183.1259 |
| Lenvatinib Fed/Fasted 25 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 1 Day 1 | 649.927 Nanogram per milliliter (ng/mL) | Standard Deviation 237.7462 |
| Lenvatinib Fed/Fasted 25 mg | Maximum Plasma Concentration (Cmax) of Lenvatinib | Cycle 2 Day 1 | 562.416 Nanogram per milliliter (ng/mL) | Standard Deviation 121.4056 |
Secondary
Renal Clearance (CLr) of Lenvatinib
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.060 L/hour | Standard Deviation 0.0064 |
| Lenvatinib | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.050 L/hour | — |
| Lenvatinib 0.4 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.037 L/hour | Standard Deviation 0.0167 |
| Lenvatinib 0.4 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.045 L/hour | Standard Deviation 0.011 |
| Lenvatinib 0.8 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.027 L/hour | Standard Deviation 0.0042 |
| Lenvatinib 0.8 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.022 L/hour | — |
| Lenvatinib 1.6 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.035 L/hour | Standard Deviation 0.0233 |
| Lenvatinib 1.6 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.029 L/hour | Standard Deviation 0.0042 |
| Lenvatinib 3.2 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.034 L/hour | — |
| Lenvatinib 3.2 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.021 L/hour | Standard Deviation 0.0113 |
| Lenvatinib 6.4 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.017 L/hour | Standard Deviation 0.0078 |
| Lenvatinib 6.4 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.025 L/hour | Standard Deviation 0.0097 |
| Lenvatinib 12 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.050 L/hour | Standard Deviation 0.0304 |
| Lenvatinib 12 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.039 L/hour | Standard Deviation 0.0243 |
| Lenvatinib 12.5 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.064 L/hour | Standard Deviation 0.0534 |
| Lenvatinib 12.5 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.069 L/hour | Standard Deviation 0.021 |
| Lenvatinib 16 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.020 L/hour | Standard Deviation 0.0095 |
| Lenvatinib 16 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.048 L/hour | Standard Deviation 0.36 |
| Lenvatinib 20 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.046 L/hour | Standard Deviation 0.0466 |
| Lenvatinib 20 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.065 L/hour | — |
| Lenvatinib Fasted/Fed 25 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.52 L/hour | Standard Deviation 0.019 |
| Lenvatinib Fasted/Fed 25 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.041 L/hour | Standard Deviation 0.0233 |
| Lenvatinib Fed/Fasted 25 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 2 Day 1 | 0.045 L/hour | Standard Deviation 0.0247 |
| Lenvatinib Fed/Fasted 25 mg | Renal Clearance (CLr) of Lenvatinib | Cycle 1 Day 1 | 0.035 L/hour | Standard Deviation 0.0144 |
Secondary
Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs)
All AEs were graded on a 5-point scale according to the National Cancer Institute's Common Toxicity Criteria (NCI CTC) grading system, version 3.0. Safety was assessed using the occurrence of DLTs, AEs, SAEs, clinical laboratory test results, vital signs measurements, physical examination findings, and electrocardiograms (ECGs) readings. An AE was defined as any untoward medical occurrence in a participant administered lenvatinib and did not necessarily have a causal relationship to lenvatinib. An SAE was defined as any untoward medical occurrence which results in death, was life-threatening, required hospitalization or prolonged hospitalization, resulted in persistent or significant disability/incapacity, or caused a congenital anomaly/birth defect. Treatment-related AEs and SAEs are AEs considered probably or possibly related to lenvatinib.
Time frame: First date of study treatment to date of last dose of study treatment, up to approximately 13 years and 8 months
Population: Safety population (ITT population) included all participants who received at least one dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 50.0 Percentage of participants |
| Lenvatinib | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 75.0 Percentage of participants |
| Lenvatinib | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 25.0 Percentage of participants |
| Lenvatinib 0.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 0 Percentage of participants |
| Lenvatinib 0.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 75.0 Percentage of participants |
| Lenvatinib 0.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 50.0 Percentage of participants |
| Lenvatinib 0.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 0.8 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 0.8 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 50.0 Percentage of participants |
| Lenvatinib 0.8 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 25.0 Percentage of participants |
| Lenvatinib 0.8 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 25.0 Percentage of participants |
| Lenvatinib 1.6 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 0 Percentage of participants |
| Lenvatinib 1.6 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 33.3 Percentage of participants |
| Lenvatinib 1.6 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 1.6 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 66.7 Percentage of participants |
| Lenvatinib 3.2 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 3.2 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib 3.2 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 0 Percentage of participants |
| Lenvatinib 3.2 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 0 Percentage of participants |
| Lenvatinib 6.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 33.3 Percentage of participants |
| Lenvatinib 6.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 100.0 Percentage of participants |
| Lenvatinib 6.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 6.4 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib 12 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 12 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 8.3 Percentage of participants |
| Lenvatinib 12 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 91.7 Percentage of participants |
| Lenvatinib 12 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 41.7 Percentage of participants |
| Lenvatinib 12.5 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib 12.5 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 44.4 Percentage of participants |
| Lenvatinib 12.5 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 12.5 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 11.1 Percentage of participants |
| Lenvatinib 16 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 33.3 Percentage of participants |
| Lenvatinib 16 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 16 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib 16 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 33.3 Percentage of participants |
| Lenvatinib 20 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 100.0 Percentage of participants |
| Lenvatinib 20 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 66.7 Percentage of participants |
| Lenvatinib 20 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib 20 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 33.3 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 16.7 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib Fasted/Fed 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 20.0 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 40.0 Percentage of participants |
| Lenvatinib Fed/Fasted 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib (MTD Cohort) 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 62.5 Percentage of participants |
| Lenvatinib (MTD Cohort) 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib (MTD Cohort) 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 33.3 Percentage of participants |
| Lenvatinib (MTD Cohort) 25 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 100.0 Percentage of participants |
| Lenvatinib 32 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related adverse events | 85.7 Percentage of participants |
| Lenvatinib 32 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Adverse events | 100.0 Percentage of participants |
| Lenvatinib 32 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Treatment-related serious adverse events | 14.3 Percentage of participants |
| Lenvatinib 32 mg | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) | Serious adverse events | 42.9 Percentage of participants |
Secondary
Time to Maximum Plasma Concentration (Tmax) of Lenvatinib
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Population: PK population included all participants in the ITT/Safety population that had evaluable PK data in at least one treatment cycle. The PK analysis set where data at specified timepoints was available.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lenvatinib | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 4.280 Hours | Standard Deviation 1.44 |
| Lenvatinib | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.225 Hours | Standard Deviation 0.3889 |
| Lenvatinib 0.4 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 5.785 Hours | Standard Deviation 2.569 |
| Lenvatinib 0.4 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.680 Hours | Standard Deviation 0.589 |
| Lenvatinib 0.8 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 3.263 Hours | Standard Deviation 1.194 |
| Lenvatinib 0.8 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 13.475 Hours | Standard Deviation 14.814 |
| Lenvatinib 1.6 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 3.973 Hours | Standard Deviation 3.494 |
| Lenvatinib 1.6 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.360 Hours | Standard Deviation 1.179 |
| Lenvatinib 3.2 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.173 Hours | Standard Deviation 0.583 |
| Lenvatinib 3.2 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 9.557 Hours | Standard Deviation 12.658 |
| Lenvatinib 6.4 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 2.023 Hours | Standard Deviation 1.035 |
| Lenvatinib 6.4 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.103 Hours | Standard Deviation 0.405 |
| Lenvatinib 12 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.021 Hours | Standard Deviation 1.295 |
| Lenvatinib 12 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 2.348 Hours | Standard Deviation 1.144 |
| Lenvatinib 12.5 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 1.897 Hours | Standard Deviation 0.7768 |
| Lenvatinib 12.5 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 1.944 Hours | Standard Deviation 0.604 |
| Lenvatinib 16 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 2.287 Hours | Standard Deviation 0.3881 |
| Lenvatinib 16 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.352 Hours | Standard Deviation 0.705 |
| Lenvatinib 20 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 2.533 Hours | Standard Deviation 0.826 |
| Lenvatinib 20 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 3.000 Hours | — |
| Lenvatinib Fasted/Fed 25 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 2.983 Hours | Standard Deviation 1.481 |
| Lenvatinib Fasted/Fed 25 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 1.770 Hours | Standard Deviation 0.715 |
| Lenvatinib Fed/Fasted 25 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 2 Day 1 | 1.500 Hours | Standard Deviation 0.408 |
| Lenvatinib Fed/Fasted 25 mg | Time to Maximum Plasma Concentration (Tmax) of Lenvatinib | Cycle 1 Day 1 | 2.674 Hours | Standard Deviation 2.038 |
Secondary
Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10%
Treatment-related AEs were untoward medical events that were considered by the investigator to be possibly or probably related to lenvatinib.
Time frame: First date of study treatment to date of withdrawal from study or last dose of study treatment, up to approximately 13 years and 8 months
Population: Safety population (ITT population) included all participants who took at least one dose of lenvatinib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dysphonia | 0 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Stomatitis | 5 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Vomiting | 33 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Anorexia | 10 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Headache | 0 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Proteinuria | 14 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Fatigue | 10 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Abdominal pain | 0 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Diarrhoea | 19 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dry skin | 5 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Constipation | 10 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Lethargy | 14 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Hypertension | 10 Percentage of participants |
| Lenvatinib | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Nausea | 38 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Headache | 7 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dysphonia | 13 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Nausea | 17 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dry skin | 10 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Fatigue | 23 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Diarrhoea | 27 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Anorexia | 17 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Stomatitis | 20 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Hypertension | 40 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Proteinuria | 27 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Vomiting | 10 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Constipation | 10 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Abdominal pain | 7 Percentage of participants |
| Lenvatinib 0.4 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Lethargy | 17 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Abdominal pain | 29 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Hypertension | 63 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Nausea | 58 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Diarrhoea | 50 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Stomatitis | 63 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Proteinuria | 29 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Vomiting | 33 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Lethargy | 38 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dysphonia | 46 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dry skin | 46 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Fatigue | 21 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Anorexia | 21 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Constipation | 33 Percentage of participants |
| Lenvatinib 0.8 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Headache | 29 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Lethargy | 29 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Nausea | 43 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Anorexia | 29 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Vomiting | 14 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Proteinuria | 43 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Hypertension | 57 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Constipation | 14 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Stomatitis | 57 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Diarrhoea | 57 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Abdominal pain | 0 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dry skin | 14 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Headache | 29 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Fatigue | 14 Percentage of participants |
| Lenvatinib 1.6 mg | Treatment-Related Adverse Events (All Grades) With an Overall Incidence Greater Than or Equal to 10% | Dysphonia | 43 Percentage of participants |
Other Pre-specified
Pharmacodynamic (PD) Biomarkers of Lenvatinib in Peripheral Blood Mononuclear Cells (PBMCs) and Tumor Samples
Based on the data in assay development stage before PD biomarker analysis in study E7080-E044-101 we did not find the appropriate PD biomarker in PBMC, therefore we did not have any biomarker analysis for PK/PD analysis.
Time frame: Blood: Cycle 1 Day 1, Day 15, or Day 22, Cycle 2 Day 1 Tumor tissue: Screening and after at least one 28-day Cycle of study treatment
Population: No appropriate PD biomarker in PBMC, therefore we did not have any biomarker analysis for PK/PD analysis.