A Study in Subjects With Recurrent Malignant Glioma

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.
ClinicalTrials.gov Identifier:
NCT01137604
First received: June 2, 2010
Last updated: May 20, 2016
Last verified: May 2016
  Purpose
An open-label phase 2, multicenter study in participants with recurrent malignant glioma.

Condition Intervention Phase
Glioma
Drug: Lenvatinib
Drug: Bevacizumab
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Three-Cohort, Phase 2 Study of E7080 (Lenvatinib) in Subjects With Recurrent Malignant Glioma

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Progression Free Survival (PFS) Rate at Month 6 [ Time Frame: At Month 6 from randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) ] [ Designated as safety issue: No ]
    PFS at Month 6 was defined as the percentage of participants who remained alive and progression-free at Month 6, based on investigator's assessment. Progression was defined using Response Assessment in Neuro-Oncology (RANO) criteria, as a greater than 25% increase in enhancing lesions despite stable or increasing steroid dose, an increase (significant) in non-enhancing T2-weighted-Fluid-Attenuated Inversion Recovery (T2/FLAIR) lesions that are not attributable to other non-tumor causes, and any new lesions. PFS rate at Month 6 was estimated from Kaplan-Meier (K-M) product-limit estimate of PFS.


Secondary Outcome Measures:
  • Objective Response Rate (ORR) [ Time Frame: From date of randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) until disease progression, development of unacceptable toxicity, withdrawal of consent or up to data cutoff date of 19 March 2013 (i.e., 2.4 years) ] [ Designated as safety issue: No ]
    ORR was the percentage of participants with best overall response (BOR) of complete response (CR) and partial response (PR) based on RANO criteria and investigator's assessment. CR was defined as the disappearance of all enhancing disease (measurable and non-measurable) sustained for at least 4 weeks, no new lesions, and stable or improved non-enhancing (T2/FLAIR) lesions. PR was defined as greater than or equal to 50% decrease, compared to baseline, in the sum of products of perpendicular diameters of all measureable enhancing lesions sustained for at least 4 weeks. No progression of non-measurable disease, no new lesions, stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared to baseline. For both CR and PR, in the absence of a confirming scan 4 weeks later, this scan was considered only stable disease. Only participants with measureable disease at baseline were included in evaluation of ORR.

  • Progression Free Survival [ Time Frame: From date of randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) until disease progression, development of unacceptable toxicity, withdrawal of consent or up to data cutoff date of 19 March 2013 (ie, 2.4 years) ] [ Designated as safety issue: No ]
    PFS was measured as the time from randomization (Cohort 1) or the first day of treatment (Cohorts 2 and 3) until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, based on investigator's assessment.

  • Overall Survival (OS) [ Time Frame: From date of randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) until death due to any cause or up to data cutoff date of 19 March 2013 (ie, 2.4 years) ] [ Designated as safety issue: No ]
    OS was measured as the time from the randomization date (Cohort 1) or the first day of treatment (Cohort 2 and 3) to the date of death from any cause.

  • Disease Control Rate (DCR) [ Time Frame: From date of randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) until disease progression, development of unacceptable toxicity, withdrawal of consent or up to data cutoff date of 19 March 2013 (ie, 2.4 years) ] [ Designated as safety issue: No ]
    DCR was the percentage of the participants who had BOR of CR, PR, and stable disease (SD) with the minimum duration of SD lasting greater than or equal to 7 weeks. Only participants with measurable disease at baseline were included in evaluation of DCR, based on investigator's assessment.

  • Clinical Benefit Rate (CBR) [ Time Frame: From date of randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) until disease progression, development of unacceptable toxicity, withdrawal of consent or up to data cutoff date of 19 March 2013 (ie, 2.4 years) ] [ Designated as safety issue: No ]
    CBR was the percentage of the participants who had BOR of CR, PR, and SD with the minimum duration of SD lasting greater than or equal to 23 weeks. Only participants with measurable disease at baseline were included in evaluation of CBR, based on investigator's assessment.

  • Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety [ Time Frame: For each participant, from the first patient first dose till 30 days after the last dose or the cut-off date of 19 March 2013 (ie, 2.4 years) ] [ Designated as safety issue: Yes ]
    Safety was assessed by monitoring and recording all AEs including all Common Terminology Criteria for Adverse Events (CTCAE) grades (for both increasing and decreasing severity) and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; results of physical examinations, regular measurement of vital signs, and electrocardiograms (ECGs), as detailed in the Schedule of Visits and Procedures. The relationship of AEs to treatment was based on investigator judgment. Details of AEs and SAEs are provided in the reported adverse event section.

  • Pharmacokinetic (PK) Profile and Pharmacodynamics (PD) of Lenvatinib [ Time Frame: Blood samples collected at Cycle 1 on Days 1 and 15 and in Cycle 2 on Day 1 ] [ Designated as safety issue: No ]
    Due to the sparse PK sampling in this study, the data were pooled with data from other Phase 1 studies conducted in participants with solid tumors.


Enrollment: 151
Study Start Date: November 2010
Study Completion Date: May 2014
Primary Completion Date: March 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1

Cohort 1 assessed participants with recurrent Grade 4 malignant glioma (ie, glioblastoma [GBM]) who were bevacizumab-naive. Participants were planned to be accrued in Cohort 1 and randomized in a 1:1 ratio to receive lenvatinib (experimental) or bevacizumab (active comparator).

Cohort 1 - Bevacizumab

Cohort 1 - Lenvatinib

Drug: Lenvatinib
24 mg lenvatinib capsules orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Other Name: E7080
Drug: Bevacizumab
Bevacizumab 10 mg/kg administered intravenously every 2 weeks in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Experimental: Cohort 2
Cohort 2 assessed participants with recurrent Grade 3 malignant glioma who were bevacizumab-naive. Participants in Cohort 2 were planned to be treated with lenvatinib.
Drug: Lenvatinib
24 mg lenvatinib capsules orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Other Name: E7080
Experimental: Cohort 3
Cohort 3 assessed participants with recurrent GBM who had disease progression following prior bevacizumab treatment. Participants in Cohort 3 were planned to be treated with lenvatinib.
Drug: Lenvatinib
24 mg lenvatinib capsules orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Other Name: E7080

  Eligibility

Ages Eligible for Study:   18 Years to 99 Years   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Histologically confirmed diagnosis of Grade 3 or 4 malignant glioma.
  2. All subjects who have a first or second recurrence following primary management with surgical resection or biopsy, radiotherapy and up to 2 prior systemic treatments with addition of:

    • No prior bevacizumab treatment is allowed for Cohort 1 and Cohort 2.
    • Subjects must have disease progression following prior bevacizumab treatment for Cohort 3.
    • For all cohorts, no prior anti-vascular endothelial growth factor (VEGF/VEGFR) therapy except for bevacizumab as specified above.
  3. Karnofsky score of 70% or greater.
  4. Adequately 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.
  5. Adequate renal function, adequate bone marrow function, adequate blood coagulation function and adequate liver function, as defined in protocol.
  6. No evidence of hemorrhage on the baseline magnetic resonance imaging (MRI) scan other than in those subjects who are stable grade 1.

Exclusion criteria:

  1. Females who are pregnant or breastfeeding.
  2. Subjects who received enzyme-inducing anti-epileptic agents within 14 days before the first dose of study drug (eg, carbamazepine, phenytoin, phenobarbital, primidone, or oxcarbazepine).
  3. Active infection requiring intravenous antibiotics.
  4. Therapeutic anti-coagulation with warfarin, aspirin, nonsteroidal anti-inflammatory drugs or clopidogrel (low molecular weight heparin is acceptable).
  5. Subjects with 24-hour urine protein greater than or equal to 1 gm.
  6. Prior surgical resection within 4 weeks, or prior stereotactic biopsy within 2 weeks, of Screening Visit.
  7. Prior radiotherapy within 12 weeks unless there is a new area of enhancement consistent with recurrent tumor outside of the radiation field, or there is biopsy-proven unequivocal viable tumor on histopathologic sampling.
  8. Prior chemotherapy (6 weeks for nitrosoureas), or any investigational agent within 4 weeks unless the subject has recovered from all anticipated toxicities associated with that therapy; prior bevacizumab therapy (Cohorts 1 and 2); for Cohort 3, prior bevacizumab therapy within 3 weeks.
  9. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II ; unstable angina; myocardial infarction or stroke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment.
  10. Prolongation of QTc interval to greater than 480 msec.
  11. Active hemoptysis (bright red blood of at least 1/2 teaspoon) within 3 weeks prior to the first dose of study drug.
  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: NCT01137604

Locations
United States, Florida
Tampa, Florida, United States
United States, Massachusetts
Boston, Massachusetts, United States
United States, North Carolina
Durham, North Carolina, United States
Canada
Calgary, Canada
Toronto, Canada
Sponsors and Collaborators
Eisai Inc.
Investigators
Study Director: Eisai Medical Services Eisai Inc.
  More Information

Responsible Party: Eisai Inc.
ClinicalTrials.gov Identifier: NCT01137604     History of Changes
Other Study ID Numbers: E7080-G000-203 
Study First Received: June 2, 2010
Results First Received: March 13, 2015
Last Updated: May 20, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Bevacizumab
Lenvatinib
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 22, 2016