The purpose of this study is to determine the maximum tolerated dose (MTD) of lenvatinib in patients with solid tumors or lymphomas.
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).
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
82
Lenvatinib tablets taken orally, once daily.
Netherlands Cancer Institute- Antoni Van Leeuwenhoek Hospital
Amsterdam, Netherlands
Gartnavel General Hospital
Glasgow, United Kingdom
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)
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
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
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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
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
Maximum Plasma Concentration (Cmax) of Lenvatinib
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Time to Maximum Plasma Concentration (Tmax) of Lenvatinib
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
Apparent Plasma Half-life (t1/2) of Lenvatinib
Time frame: 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))
Time frame: 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))
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
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)
Apparent Volume of Distribution (Vz/F)
Time frame: Cycles 1 and 2 Day 1: 0-24 hours postdose (Cycle length = 28 days)
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)
Renal Clearance (CLr) of Lenvatinib
Time frame: 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))
Time frame: 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
Time frame: 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
Time frame: Cycle 1 Day 15 and Day 22: 0-24 hours postdose (Cycle length = 28 days)