An Open Label Dose Escalation Study Of E7080

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose (MTD) of lenvatinib in patients with solid tumors or lymphomas.

Detailed Description
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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).

Official Title
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An Open Label Phase I Dose Escalation Study Of E7080

Conditions
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Solid Tumor or Lymphoma

Intervention / Treatment
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* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Patients must meet all of the inclusion criteria outlined below in order to be eligible to participate in the study: 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. 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. Aged greater than or equal to 18 years. Karnofsky performance status greater than or equal 70%. Written informed consent to participate in the study. EXCLUSION CRITERIA: Patients with the following characteristics will not be eligible for the study: Brain tumors or brain or leptomeningeal metastases. Any of the following laboratory parameters: hemoglobin less than 9 g/dl (5.6 mmol/L) neutrophils less than 1.5 x 10^9/L platelets less than 100 x 10^9/L serum bilirubin greater than 25 micro-mol/l (1.5 mg/dl) other liver parameters greater than 3 x the upper limit of normal (ULN) serum creatinine greater than 1.5 x ULN or creatinine clearance less than 60 ml/minute Uncontrolled infections. Clinically significant cardiac impairment or unstable ischemic heart disease including a myocardial infarction within six months of study start. Any treatment with investigational drugs within 30 days before the start of the study. 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. Fertile males not willing to use contraception or whose female partners are not using adequate contraceptive protection. History of alcoholism, drug addiction, or any psychiatric or psychological condition which, in the opinion of the investigator, would impair study compliance. Legal incapacity. Centrally located or squamous cell carcinoma of the lung. Proteinuria greater than 1+ on bedside testing. History of gastrointestinal malabsorption. Surgery involving gastro- and/or intestinal anastomosis within four weeks of study start. Patients with bleeding or thrombotic disorders. Patients using therapeutic dosages of anticoagulants. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: Lenvatinib<br>* Lenvatinib tablets taken orally, once daily.<br>* Other names: E7080;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Cycle 1 (4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | Cycle 1 (4 weeks) of each dose level | 
| 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. | 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. | Baseline to first date of documented CR, PR, SD, or PD, assessed up to approximately 4 years | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Resistant and refractory solid tumors, lymphomas, hodgkins disease, non-hodgkins lymphoma, neoplasms