An Open Label Phase I Dose Escalation Study Of E7080

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT00121719
First received: July 15, 2005
Last updated: April 19, 2016
Last verified: April 2016
  Purpose
The purpose of this study is to determine the maximum tolerated dose (MTD) of lenvatinib in patients with solid tumors or lymphomas.

Condition Intervention Phase
Solid Tumor or Lymphoma
Drug: Lenvatinib
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open Label Phase I Dose Escalation Study Of E7080

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) [ Time Frame: Cycle 1 (4 weeks) ] [ Designated as safety issue: Yes ]
    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 Outcome Measures:
  • Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: First date of study treatment to date of last dose of study treatment, up to approximately 4 years ] [ Designated as safety issue: Yes ]
    AEs were collected from the signing of the informed consent form until the date the participant was withdrawn from the study. 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) [ Time Frame: Cycle 1 (4 weeks) of each dose level ] [ Designated as safety issue: Yes ]
    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% [ Time Frame: First date of study treatment to date of withdrawal from study or last dose of study treatment, up to approximately 4 years ] [ Designated as safety issue: Yes ]
    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) [ Time Frame: Baseline to first date of documented CR, PR, SD, or PD, assessed up to approximately 4 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. Plasma pharmacokinetics (PK) data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Cmax, which was then summarized as the mean and standard deviation for all participants and expressed as nanograms/milliliter (ng/mL).

  • Time to Maximum Plasma Concentration (Tmax) of Lenvatinib [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Tmax, which was then summarized as the mean and standard deviation for all participants and expressed in hours.

  • Apparent Plasma Half-life (t1/2) of Lenvatinib [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. The apparent plasma half-life was calculated as t1/2 = 0.693/λz where the apparent first order elimination rate constant (λz) was determined by the slope of the terminal log-linear phase of the plasma concentration-time curve. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of t1/2, which was then summarized as the mean and standard deviation for all participants and expressed in hours.

  • Area Under the Plasma Concentration Curve From Time 0 to Infinity (AUC(0-inf)) [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. The area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf) was calculated as AUC(0-t) + Ct / λz where Ct is the last measurable concentration. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of AUC(0-inf), which was then summarized as the mean and standard deviation for all participants and expressed in nanograms*hours/milliliter (ng*hr/mL).

  • Area Under the Plasma Concentration Curve From Time 0 to 24 Hours (AUC(0-24)) [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. The area under the plasma concentration-time curve from time 0 to 24 hours, was calculated using the linear trapezoidal rule. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of AUC(0-24), which was then summarized as the mean and standard deviation for all participants and expressed in ng*hr/mL.

  • Clearance Corrected for the Fraction of Lenvatinib Absorbed (CL/F) [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. CL/F is the clearance for parent lenvatinib only and was calculated as Dose/[AUC0-inf]. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of CL/F, which was then summarized as the mean and standard deviation for all participants and expressed in liters/hour (L/hr).

  • Apparent Volume of Distribution (Vz/F) [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. The apparent volume of distribution gives information about the amount of lenvatinib distributed in body tissue rather than the blood/plasma. Vz/F for parent lenvatinib only was calculated as Dose /[( λz)*( AUC0-inf)]. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Vz/F, which was then summarized as the mean and standard deviation for all participants and expressed in liters (L).

  • Fraction of Unchanged Lenvatinib Excreted in the Urine (fe) [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Urine aliquots were collected at 0 to 8, 8 to 16, and 16 to 24 hour intervals after administration of lenvatinib on Day 1 of Cycle 1 and Cycle 2, and then analyzed for the amount of lenvatinib using approved standardized methods. The samples were analyzed for the amount of lenvatinib in the urine using liquid chromatography-tandem mass spectrometry method of analysis. Urine PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of fe, which was then summarized as the mean and standard deviation for all participants and expressed in percentage of lenvatinib.

  • Renal Clearance (CLr) of Lenvatinib [ Time Frame: Cycle 1 Day 1 (C1D1), Cycle 2 Day 1 (C2D1) ] [ Designated as safety issue: No ]
    Blood samples were drawn immediately prior to the first dose of study drug, and at 15 and 30 minutes and at 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib. For participants who were not enrolled in the food-effect part of the study, the collection of blood samples was repeated following administration of lenvatinib on Day 29 (Cycle 2 Day 1). The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. Renal clearance was calculated as: Ae(0-24)/AUC(0-24) where Ae(0-24) is amount of unchanged lenvatinib recovered in 24 hours. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of CLr, which was then summarized as the mean and standard deviation for all participants and expressed in liters/hour (L/hr).

  • 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 ] [ Designated as safety issue: No ]
    Blood samples for PK analysis were collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib and 24 hours after the first dose of lenvatinib on Day 15 and Day 22 of Cycle 1. Blood samples were not collected on Day 29, except for the pre-dose sample. The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of AUC(0-24), which was then summarized as the mean and standard deviation for all participants and expressed in nanograms*hours/milliliter (ng*hr/mL).

  • Effect of Food on the Maximum Plasma Concentration (Cmax) of Lenvatinib [ Time Frame: Cycle 1 Day 1, Day 15 and Day 22 ] [ Designated as safety issue: No ]
    Blood samples for PK analysis were collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib and 24 hours after the first dose of lenvatinib on Day 15 and Day 22 of Cycle 1. Blood samples were not collected on Day 29, except for the pre-dose sample. The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Cmax, which was then summarized as the mean and standard deviation for all participants and expressed in nanograms/milliliter (ng/mL).

  • Effect of Food on Time to Maximum Concentration (Tmax) of Lenvatinib [ Time Frame: Cycle 1 Day 1, Day 15, and Day 22 ] [ Designated as safety issue: No ]
    Blood samples for PK analysis were collected at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 5, 8, and 24 hours after the first dose of lenvatinib and 24 hours after the first dose of lenvatinib on Day 15 and Day 22 of Cycle 1. Blood samples were not collected on Day 29, except for the pre-dose sample. The samples were analyzed for the amount of lenvatinib in the plasma using liquid chromatography-tandem mass spectrometry method of analysis. Plasma PK data were analyzed using a noncompartmental analysis approach to obtain individual participant estimates of Tmax, which was then summarized as the mean and standard deviation for all participants and expressed in hours.


Other Outcome Measures:
  • Pharmacodynamic (PD) Biomarkers of Lenvatinib in Peripheral Blood Mononuclear Cells (PBMCs) and Tumor Samples [ 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 ] [ Designated as safety issue: No ]
    Blood samples were collected for isolation of Peripheral Blood Mononuclear Cells (PBMCs) immediately prior to the first dose and at 3 and 24 hours following the first dose of lenvatinib. The same collection schedule was repeated following the administration of lenvatinib on Day 29 (Cycle 2 Day 1). For participants in the food-effect pilot study blood samples were collected pre-dose, plus 3 hour and 24 hours PD samples were collected on Day 15 or Day 22. These participants were not required to give PD samples on Cycle 2 Day 1. Tumor tissue samples were collected from participants with tumors accessible to biopsy (optional study). Tissue samples were formalin-fixed then paraffin embedded according to a standard protocol. Once preclinical studies have identified possible PD biomarkers for the biological effect of lenvatinib in vivo, the samples taken from participants in this study are planned to be analyzed. No data was provided at this time.


Enrollment: 87
Study Start Date: July 2005
Estimated Study Completion Date: December 2016
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: Lenvatinib
Lenvatinib tablets taken orally, once daily.
Other Name: E7080

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).
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00121719

Locations
Netherlands
Amsterdam, Netherlands
United Kingdom
Glasgow, United Kingdom
Sponsors and Collaborators
Eisai Inc.
Investigators
Study Director: Jantien Wanders, M.D. Eisai Limited
  More Information

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT00121719     History of Changes
Other Study ID Numbers: E7080-E044-101 
Study First Received: July 15, 2005
Results First Received: April 19, 2016
Last Updated: April 19, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Eisai Inc.:
Resistant and refractory solid tumors
lymphomas
hodgkins disease
non-hodgkins lymphoma
neoplasms

Additional relevant MeSH terms:
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 25, 2016