Glioma
Conditions
Brief summary
An open-label phase 2, multicenter study in participants with recurrent malignant glioma.
Interventions
DRUGLenvatinib
24 mg lenvatinib capsules orally, once daily continuously in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
DRUGBevacizumab
Bevacizumab 10 mg/kg administered intravenously every 2 weeks in 28-day cycles until disease progression, development of unacceptable toxicity or withdrawal of consent.
Sponsors
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Rate at Month 6 | At Month 6 from randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3) | 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
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival | 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) | 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) | 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) | 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. |
| Objective Response Rate (ORR) | 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) | 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. |
| Clinical Benefit Rate (CBR) | 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) | 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 | 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) | 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. |
| Disease Control Rate (DCR) | 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) | 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. |
Countries
Canada, United States
Participant flow
Recruitment details
A total of 173 participants were screened and of those, 152 participants were deemed eligible, and 151 received study treatment.
Pre-assignment details
The protocol definition of study completion was that the participant had disease progression. Protocol defined reasons for not completing were adverse event, participant choice, lost to follow-up, administrative/other (including withdrawal of consent, pregnancy, study terminated by sponsor or other). Death was not a protocol defined reason for non-completion. Participants were followed for survival until death, except where they withdrew consent, or the Sponsor stopped the survival follow-up.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 - Bevacizumab Participants with recurrent Grade 4 malignant glioma (ie, glioblastoma \[GBM\]) who were bevacizumab-naive; received bevacizumab 10 mg/kg administered intravenously every 2 weeks in 28-day cycles | 38 |
| Cohort 1 - Lenvatinib Participants with recurrent Grade 4 malignant glioma (ie, glioblastoma \[GBM\]) who were bevacizumab-naive; received lenvatinib capsules 24 mg taken orally, once daily continuously in 28-day cycles | 42 |
| Cohort 2 - Lenvatinib Participants with recurrent Grade 3 malignant glioma who were bevacizumab-naive; received lenvatinib capsules 24 mg taken orally, once daily continuously in 28-day cycles | 39 |
| Cohort 3 - Lenvatinib Participants with recurrent GBM who had disease progression following prior bevacizumab treatment; received lenvatinib capsules 24 mg taken orally, once daily continuously in 28-day cycles | 32 |
| Total | 151 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 6 | 9 | 9 |
| Overall Study | Clinical progression/deterioration | 1 | 2 | 2 | 0 |
| Overall Study | Participant Choice | 0 | 2 | 2 | 0 |
| Overall Study | Withdrawal of consent | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Cohort 1 - Bevacizumab | Cohort 1 - Lenvatinib | Cohort 2 - Lenvatinib | Cohort 3 - Lenvatinib | Total |
|---|---|---|---|---|---|
| Age, Continuous | 55.1 Years STANDARD_DEVIATION 10.61 | 55.5 Years STANDARD_DEVIATION 11.96 | 49.2 Years STANDARD_DEVIATION 11.35 | 53.0 Years STANDARD_DEVIATION 11.15 | 52.6 Years STANDARD_DEVIATION 11.74 |
| Sex: Female, Male Female | 13 Participants | 13 Participants | 10 Participants | 14 Participants | 50 Participants |
| Sex: Female, Male Male | 25 Participants | 29 Participants | 29 Participants | 18 Participants | 101 Participants |
| World Health Organization Grading for Gliomas Grade 3 | 0 Participants | 0 Participants | 39 Participants | 0 Participants | 39 Participants |
| World Health Organization Grading for Gliomas Grade 4 | 38 Participants | 42 Participants | 0 Participants | 32 Participants | 112 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 36 / 38 | 38 / 42 | 27 / 39 | 30 / 32 |
| other Total, other adverse events | 38 / 38 | 40 / 42 | 39 / 39 | 31 / 32 |
| serious Total, serious adverse events | 10 / 38 | 22 / 42 | 12 / 39 | 15 / 32 |
Outcome results
Primary
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.
Time frame: At Month 6 from randomization (Cohort 1) or first day of treatment (Cohorts 2 and 3)
Population: Full Analysis Set included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Bevacizumab | Progression Free Survival (PFS) Rate at Month 6 | 11.0 Percentage of participants |
| Cohort 1 - Lenvatinib | Progression Free Survival (PFS) Rate at Month 6 | 21.2 Percentage of participants |
| Cohort 2 - Lenvatinib | Progression Free Survival (PFS) Rate at Month 6 | 8.0 Percentage of participants |
| Cohort 3 - Lenvatinib | Progression Free Survival (PFS) Rate at Month 6 | 7.6 Percentage of participants |
Secondary
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.
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)
Population: Full Analysis Set - all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Bevacizumab | Clinical Benefit Rate (CBR) | 15.8 Percentage of participants |
| Cohort 1 - Lenvatinib | Clinical Benefit Rate (CBR) | 26.2 Percentage of participants |
| Cohort 2 - Lenvatinib | Clinical Benefit Rate (CBR) | 17.9 Percentage of participants |
| Cohort 3 - Lenvatinib | Clinical Benefit Rate (CBR) | 6.3 Percentage of participants |
Secondary
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.
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)
Population: Full Analysis Set - all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Bevacizumab | Disease Control Rate (DCR) | 57.9 Percentage of participants |
| Cohort 1 - Lenvatinib | Disease Control Rate (DCR) | 50.0 Percentage of participants |
| Cohort 2 - Lenvatinib | Disease Control Rate (DCR) | 48.7 Percentage of participants |
| Cohort 3 - Lenvatinib | Disease Control Rate (DCR) | 28.1 Percentage of participants |
Secondary
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.
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)
Population: Full Analysis Set - all participants who received at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 - Bevacizumab | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | AEs | 38 Participants |
| Cohort 1 - Bevacizumab | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | SAEs | 9 Participants |
| Cohort 1 - Lenvatinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | SAEs | 20 Participants |
| Cohort 1 - Lenvatinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | AEs | 40 Participants |
| Cohort 2 - Lenvatinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | AEs | 39 Participants |
| Cohort 2 - Lenvatinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | SAEs | 12 Participants |
| Cohort 3 - Lenvatinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | AEs | 32 Participants |
| Cohort 3 - Lenvatinib | Number of Participants With Adverse Events (AEs)/Serious Adverse Events (SAEs) as a Measure of Safety | SAEs | 15 Participants |
Secondary
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.
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)
Population: Full Analysis Set included all participants who received at least one dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 - Bevacizumab | Objective Response Rate (ORR) | 15.8 Percentage of participants |
| Cohort 1 - Lenvatinib | Objective Response Rate (ORR) | 21.4 Percentage of participants |
| Cohort 2 - Lenvatinib | Objective Response Rate (ORR) | 7.7 Percentage of participants |
| Cohort 3 - Lenvatinib | Objective Response Rate (ORR) | 0.0 Percentage of participants |
Secondary
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.
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)
Population: Full Analysis Set - all participants who received at least one dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Bevacizumab | Overall Survival (OS) | 6.0 Months |
| Cohort 1 - Lenvatinib | Overall Survival (OS) | 7.5 Months |
| Cohort 2 - Lenvatinib | Overall Survival (OS) | 12.0 Months |
| Cohort 3 - Lenvatinib | Overall Survival (OS) | 4.1 Months |
Secondary
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.
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)
Population: Full Analysis Set - all participants who received at least one dose of study drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 - Bevacizumab | Progression Free Survival | 2.8 Months |
| Cohort 1 - Lenvatinib | Progression Free Survival | 2.4 Months |
| Cohort 2 - Lenvatinib | Progression Free Survival | 2.8 Months |
| Cohort 3 - Lenvatinib | Progression Free Survival | 1.8 Months |