Back to resultsA Study in Subjects With Recurrent Malignant Glioma
Primary Purpose
Glioma
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Lenvatinib
Bevacizumab
Sponsored by
About this trial
This is an interventional treatment trial for Glioma
Eligibility Criteria
Inclusion Criteria
- Histologically confirmed diagnosis of Grade 3 or 4 malignant glioma.
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.
- Karnofsky score of 70% or greater.
- 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.
- Adequate renal function, adequate bone marrow function, adequate blood coagulation function and adequate liver function, as defined in protocol.
- No evidence of hemorrhage on the baseline magnetic resonance imaging (MRI) scan other than in those subjects who are stable grade 1.
Exclusion criteria:
- Females who are pregnant or breastfeeding.
- 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).
- Active infection requiring intravenous antibiotics.
- Therapeutic anti-coagulation with warfarin, aspirin, nonsteroidal anti-inflammatory drugs or clopidogrel (low molecular weight heparin is acceptable).
- Subjects with 24-hour urine protein greater than or equal to 1 gm.
- Prior surgical resection within 4 weeks, or prior stereotactic biopsy within 2 weeks, of Screening Visit.
- 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.
- 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.
- 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.
- Prolongation of QTc interval to greater than 480 msec.
- Active hemoptysis (bright red blood of at least 1/2 teaspoon) within 3 weeks prior to the first dose of study drug.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm Type
Experimental
Experimental
Experimental
Arm Label
Cohort 1
Cohort 2
Cohort 3
Arm Description
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
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.
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.
Outcomes
Primary Outcome Measures
Progression Free Survival (PFS) Rate at Month 6
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)
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
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)
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)
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)
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
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01137604
Brief Title
A Study in Subjects With Recurrent Malignant Glioma
Official Title
An Open-Label, Three-Cohort, Phase 2 Study of E7080 (Lenvatinib) in Subjects With Recurrent Malignant Glioma
Study Type
Interventional
2. Study Status
Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
November 9, 2010 (Actual)
Primary Completion Date
March 19, 2013 (Actual)
Study Completion Date
October 28, 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eisai Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
5. Study Description
Brief Summary
An open-label phase 2, multicenter study in participants with recurrent malignant glioma.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioma
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
151 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cohort 1
Arm Type
Experimental
Arm Description
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
Arm Title
Cohort 2
Arm Type
Experimental
Arm Description
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.
Arm Title
Cohort 3
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Lenvatinib
Other Intervention Name(s)
E7080
Intervention Description
24 mg lenvatinib capsules orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Intervention Type
Drug
Intervention Name(s)
Bevacizumab
Intervention Description
Bevacizumab 10 mg/kg administered intravenously every 2 weeks in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Primary Outcome Measure Information:
Title
Progression Free Survival (PFS) Rate at Month 6
Description
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.
Time Frame
At Month 6 from randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3)
Secondary Outcome Measure Information:
Title
Objective Response Rate (ORR)
Description
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.
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)
Title
Progression Free Survival
Description
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.
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)
Title
Overall Survival (OS)
Description
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.
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)
Title
Disease Control Rate (DCR)
Description
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.
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)
Title
Clinical Benefit Rate (CBR)
Description
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.
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)
Title
Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety
Description
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.
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)
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
99 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria
Histologically confirmed diagnosis of Grade 3 or 4 malignant glioma.
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.
Karnofsky score of 70% or greater.
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.
Adequate renal function, adequate bone marrow function, adequate blood coagulation function and adequate liver function, as defined in protocol.
No evidence of hemorrhage on the baseline magnetic resonance imaging (MRI) scan other than in those subjects who are stable grade 1.
Exclusion criteria:
Females who are pregnant or breastfeeding.
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).
Active infection requiring intravenous antibiotics.
Therapeutic anti-coagulation with warfarin, aspirin, nonsteroidal anti-inflammatory drugs or clopidogrel (low molecular weight heparin is acceptable).
Subjects with 24-hour urine protein greater than or equal to 1 gm.
Prior surgical resection within 4 weeks, or prior stereotactic biopsy within 2 weeks, of Screening Visit.
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.
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.
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.
Prolongation of QTc interval to greater than 480 msec.
Active hemoptysis (bright red blood of at least 1/2 teaspoon) within 3 weeks prior to the first dose of study drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Eisai Medical Services
Organizational Affiliation
Eisai Inc.
Official's Role
Study Director
Facility Information:
City
Tampa
State/Province
Florida
Country
United States
City
Boston
State/Province
Massachusetts
Country
United States
City
Durham
State/Province
North Carolina
Country
United States
City
Calgary
Country
Canada
City
Toronto
Country
Canada
12. IPD Sharing Statement
Learn more about this trial
A Study in Subjects With Recurrent Malignant Glioma
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