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Study of Lenvatinib in Subjects With Advanced Endometrial Cancer and Disease Progression

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01111461
First received: April 16, 2010
Last updated: November 23, 2016
Last verified: November 2016
  Purpose
To assess the objective response rate (ORR: complete response + partial response [CR+ PR]) of E7080 in subjects with unresectable endometrial cancer and disease progression following platinum-based, first-line chemotherapy. .

Condition Intervention Phase
Endometrial Cancer
Drug: Lenvatinib
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Single-Arm, Multicenter Phase II Study of E7080 (Lenvatinib) in Subjects With Advanced Endometrial Cancer and Disease Progression Following First-Line Chemotherapy

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Objective Response Rate (ORR) [ Time Frame: From the date of first administration of study treatment until all participants completed a minimum of 6 cycles (28-day cycles) or discontinued treatment prior to the end of Cycle 6 (as of 21 May 2012 data cut-off) ]
    ORR was defined as the percentage of participants with best overall response (BOR) of complete response (CR) or partial response (PR) based on Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for target lesions assessed by magnetic resonance imaging/computed tomography (MRI/CT) scans, as determined by independent radiologic review. BOR of CR was confirmed by a subsequent CR assessment at least 4 weeks later. BOR of PR was confirmed by a subsequent CR or PR assessment at least 4 weeks later. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (target or non-target) had to be reduced in short axis to <10 mm. PR was defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum of diameters. The null hypothesis ORR was ≤10% was tested using 1-sided exact test of a single proportion, at 1-sided 0.05 level. ORR was presented with corresponding 2-sided, 95% confidence interval (CI). ORR=CR+PR


Secondary Outcome Measures:
  • Progression Free Survival (PFS) [ Time Frame: From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression or up to approximately 26 months (as of 21 May 2012 data cut-off) ]
    PFS was measured as the time from the date of first administration of study treatment until the date of first documentation of disease progression or date of death (whichever occurred first), as determined by independent radiologic review (IRR) and Investigator based on RECIST 1.1. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) recorded since the treatment started or the appearance of 1 or more new lesions.

  • Overall Survival (OS) [ Time Frame: From date of first administration of study treatment until the date of death, or up to approximately 32 months (as of 26 Nov 2012 data cut-off) ]
    OS was the length time in months from the date of first treatment until the date of death from any cause. If death was not observed, OS was censored at the last known alive date or data cut-off. Additional survival follow-up data was collected for all participants who had not withdrawn consent and were alive at the time of the initial survival follow-up as of 26 Nov 2012 data cut-off. Participants who were lost to follow-up at the time of the initial assessment may have been contacted again at the investigator's discretion. Updated survival (based on 26 Nov 2012 cut-off) was derived for these participants if the contact was made successfully.

  • Disease Control Rate (DCR) [ Time Frame: From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off) ]
    DCR was defined as the percentage of participants with BOR of CR or PR or stable disease (SD) based on RECIST 1.1 and SD lasting greater than or equal to 7 weeks, as determined by IRR and Investigator.

  • Clinical Benefit Rate (CBR) [ Time Frame: From date of first administration of study treatment until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, or up to approximately 26 months (as of 21 May 2012 data cut-off) ]
    CBR was defined as the percentage of participants with BOR of CR or PR or durable stable disease (dSD) [CR + PR + dSD] based on RECIST 1.1. The dSD rate was defined as the percentage of participants with dSD (based on RECIST 1.1 and defined as SD lasting greater than or equal to 23 weeks), as determined by the IRR and Investigator.

  • Number of Participants With Adverse Events (AEs) /Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib Tolerability of Lenvatinib [ Time Frame: From the administration of first dose up to 30 days after the last dose, or up to data cut-off (21 May 2012), or up to approximately 26 months. ]
    Safety was assessed by monitoring and recording all AEs and SAEs, regular monitoring of hematology, clinical chemistry, and urine values, regular measurement of vital signs, electrocardiograms (ECGs), and echocardiograms.


Other Outcome Measures:
  • Summary of Plasma Concentration of Lenvatinib [ Time Frame: Predose and 2 hours postdose on Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1 ]
    A total of 6 blood samples for pharmacokinetic (PK) analysis were collected from each participant who received lenvatinib once daily.

  • Percentage Change From Baseline for the Imaging Biomarker Parameter of the Area Under the Plasma Concentration Curve Blood Normalized (90) (AUCBN (90)) Median for Total Volume [ Time Frame: Cycle 1 Day 5 ]
    The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of 2 dynamic contrast-enhanced magnetic resonance imaging/diffusion-weighted magnetic resonance imaging (DCE-MRI/DWI MRI) scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included percentage change in initial area under the gadolinium contrast agent time-concentration curve (first 90 seconds, blood normalized) from baseline.

  • Percentage Change From Baseline in the Contrast Volume Transfer Coefficient (Ktrans) Median [ Time Frame: Cycle 1 Day 5 ]
    The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in Ktrans for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline.

  • Percentage Change From Baseline in the Apparent Diffusion Coefficient (ADC) Median [ Time Frame: Cycle 1 Day 5 ]
    The antiangiogenic and direct antitumor effects of lenvatinib were assessed by analyses of two DCE-MRI/DWI MRI scans obtained on evaluable participants at Baseline and Cycle 1 Day 5. The scans were obtained using standardized acquisition across sites. DWI sequences totaling approximately 30 seconds were acquired during the DCE-MRI scans. Centralized analysis metrics for DCE-MRI included the percentage change in ADC for gadolinium chelate movement from the vasculature into the tissue extracellular space from baseline.


Enrollment: 133
Study Start Date: March 2010
Study Completion Date: October 2015
Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Lenvatinib 24 mg
Participants with advanced endometrial cancer and disease progression following platinum-based, first line chemotherapy.
Drug: Lenvatinib
Lenvatinib 24 mg administered orally, once daily continuously in 28-day cycles to participants with advanced endometrial cancer and disease progression following first-line chemotherapy. Participants continued to receive study drug until disease progression, development of unacceptable toxicity or withdrawal of consent. 'Treatment interruption and subsequent dose reduction' was allowed for participants who experienced lenvatinib-related toxicity.
Other Name: E7080, Lenvima

  Eligibility

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

Inclusion criteria:

  1. Histologically confirmed diagnosis of endometrial carcinoma.
  2. Radiographic evidence of disease progression according to modified RECIST 1.1 after 1 prior systemic, platinum-based chemotherapy regimen for recurrent metastatic or primary unresectable endometrial carcinoma for which no surgical or radiotherapy treatment option exists.
  3. Measureable disease meeting the following criteria:

    • At least 1 lesion of greater than 1.0 cm in the longest diameter for a non-lymph node or greater than 1.5 cm in the short-axis diameter for a lymph node which is serially measureable according to modified RECIST 1.1 using computerized tomography / magnetic resonance imaging.
    • Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency ablation must show evidence of progressive disease based on modified RECIST 1.1 to be deemed a target lesion.
  4. Eastern Cooperative Oncology Group (ECOG) performance status less than 2.
  5. Adequate controlled blood pressure (BP) with or without antihypertensive medications, defined as BP less than 150/90 mmHg at screening and no change in antihypertensive medications within 1 week prior to the Screening Visit.
  6. Adequate renal function defined as calculated creatinine clearance greater than 30 mL/min per the Cockcroft and Gault formula.
  7. Adequate bone marrow, blood coagulation, and liver functions, as defined in the study protocol.
  8. Negative serum or urine pregnancy test for women of reproductive potential.

Exclusion criteria:

  1. Brain or leptomeningeal metastases, including stable metastases.
  2. More than 1 prior systemic chemotherapy regimen for recurrent metastatic or primary unresectable endometrial carcinoma or any treatment targeting vascular endothelial growth factor (VEGF)-directed angiogenesis. No restriction regarding prior adjuvant chemotherapy or hormonal therapy.
  3. Prior systemic anti-tumor therapy within 3 weeks.
  4. Not fully recovered from prior radiotherapy based on investigator judgement.
  5. Participants with greater than 1+ proteinuria on urine dipstick testing to undergo 24-hour urine collection for quantitative assessment of proteinuria. Participants with greater than 1 gm will be ineligible.
  6. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association Class II; unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; cardiac arrhythmia requiring medical treatment.
  7. Prolongation of QTc interval greater than 480 msec.
  8. Bleeding disorder or thrombotic disorders requiring anticoagulant therapy, such as warfarin, or similar agents requiring therapeutic INR monitoring (treatment with low molecular weight heparin [LMWH] allowed).
  9. Active hemoptysis within 3 weeks prior to the first dose of study drug.
  10. Females who are pregnant or breast feeding.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01111461

  Show 79 Study Locations
Sponsors and Collaborators
Eisai Inc.
Investigators
Study Director: Eisai Medical Services Eisai Limited
  More Information

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01111461     History of Changes
Other Study ID Numbers: E7080-G000-204
Study First Received: April 16, 2010
Results First Received: March 13, 2015
Last Updated: November 23, 2016

Keywords provided by Eisai Inc.:
Advanced Endometrial Cancer

Additional relevant MeSH terms:
Endometrial Neoplasms
Disease Progression
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Uterine Diseases
Genital Diseases, Female
Disease Attributes
Pathologic Processes
Lenvatinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 24, 2017