Glioblastoma Multiforme
Conditions
Brief summary
This is a Phase II, national, multicenter, open-label, non-comparative study to investigate the efficacy and safety of bevacizumab and temozolomide in patients with recurrent glioblastoma multiforme (GBM) after a first treatment failure. Patients will receive bevacizumab 10 mg/kg intravenously every two weeks until disease progression, consent withdrawal, or unacceptable toxicity. Anticipated time on study treatment is 12-24 months.
Interventions
DRUGbevacizumab [Avastin]
Bevacizumab 10 mg/kg body weight will be administered intravenously every two weeks
DRUGtemozolomide
Daily by the oral route (dose, 150 mg/m2) on days 1 to 7 and 15 to 21 of each cycle
Sponsors
Hoffmann-La Roche
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \>= 18 years * Histological diagnosis of glioblastoma multiforme (GBM) documented by surgical resection or biopsy. * They should be patients in a first relapse treated with radiotherapy and chemotherapy and chemotherapy based on temozolomide 150-200 mg/m2 on days 1 to 5 every 28 days (Stupp regimen) for at least three cycles. At least 4 weeks must have lapsed since previous chemotherapy and 3 months since the last dose of radiotherapy. * Use of an effective contraceptive method by patients and their partners. * Stable or decreasing corticosteroid dose for the five days prior to study entry * Adequate hematological function * Adequate liver function * Adequate kidney function
Exclusion criteria
* Signs of recent bleeding at the MRI of the brain. However, patients with clinically asymptomatic presence of hemosiderin, resolving bleeding changes related to surgery, and presence of punctate hemorrhage in the tumor will be allowed to participate in the study. * Prior treatment with bevacizumab * Poorly controlled arterial hypertension * History of hypertensive crises or hypertensive encephalopathy * New York Health Association (NYHA) Class II or higher congestive heart failure * History of myocardial infarction or unstable angina pectoris within six months of study entry * History of stroke or TIA within six months of study entry * Significant vascular disease within six months of study entry * History of hemoptysis \> grade 2 according to the NCI CTC criteria within one month of study entry * Evidence of bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation) * Major surgery, open biopsy, intracranial biopsy, ventriculoperitoneal shunt, or major traumatic lesion within 28 days of study entry. * Core needle biopsy (excluding intracranial biopsy) or other minor surgery within seven days of randomization. Placement of a central vascular access device (CVAD) if performed in the two days prior to bevacizumab administration * History of abdominal fistula or gastrointestinal perforation within six months of study entry * History of intracranial abscess within six months of randomization * Any prior malignant neoplasm treated with curative intent in the five years prior to study entry, except for adequately controlled limited basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix * Patients with any other metabolic or psychological disease * Hypersensitivity to products derived from Chinese hamster ovary cells or to other humanized or recombinant human antibodies
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) - Percentage of Participants With an Event | Baseline (BL), every 28 days, until progression, death or end-of-study, an average of 32 weeks | PFS was defined as the time, in weeks, from the date of inclusion in the study to the date of the first documentation of disease progression or death of the participant due to any cause. Participants that did not have an event at the time the analysis was performed were censored at the date of last contact. Participants that began a treatment other than those planned in this study (bevacizumab or temozolomide) were censored on the start date of the new treatment. |
| PFS - Time to Event | BL, every 28 days, until progression, death or end-of-study, an average of 32 weeks | PFS was defined as the time, in weeks, from the date of inclusion in the study to the date of the first documentation of disease progression or death of the participant due to any cause. Participants that did not have an event at the time the analysis was performed were censored at the date of last contact. Participants that began a treatment other than those planned in this study (bevacizumab or temozolomide) were censored on the start date of the new treatment. PFS was estimated using the Kaplan-Meier method. |
| PFS: Probability of Remaining Progression Free at 24 Weeks After Beginning the Study | BL, 24 weeks (after 6th cycle) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival - Percentage of Participants With an Event | BL, every 28 days, until death or end-of-study, an average of 32 weeks | Overall survival was defined as the time transpired (in weeks) between the date of the participant's inclusion in the trial until the date of his/her death by any cause. Participants that were alive at the time the analysis was performed were censored on the date of last contact. |
| Overall Survival - Time to Event | BL, every 28 days, until death or end-of-study, an average of 32 weeks | Overall survival was defined as the time transpired (in weeks) between the date of the participant's inclusion in the trial until the date of his/her death by any cause. Participants that were alive at the time the analysis was performed were censored on the date of last contact. Median overall survival was estimated using the Kaplan-Meier method. |
| Percentage of Participants Achieving an Overall Response of Complete Response (CR) or Partial Response (PR) | BL, every 28 days, until progression, death or end-of-study, an average of 32 weeks | Overall response was defined as the percentage of participants who obtained CR or PR using adapted MacDonald criteria. CR: disappearance of all index and non-index lesions, confirmed no less than 4 weeks after assessment, no evidence of disease progression; corticosteroid dosage at or below 20 mg hydrocortisone daily; no neurological changes or an improvement as compared to last disease assessment. PR was defined as: Fifty percent or greater decrease in the sum of products of the larger diameter and the larger perpendicular diameter of all index lesions confirmed no less than 4 weeks after assessment, no evidence of disease progression and the absence of progressive, or non-evaluable disease status for non-index legions; unchanged, or decreased corticosteroid dose as compared to the last disease assessment; no neurological changes or an improvement as compared to the neurological examination at last disease assessment. |
Countries
Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab + Temozolomide Cycles 1-12 (4-week cycles): Participants received bevacizumab 10 mg/kg IV on Days 1 and 15 (followed by 2 weeks off); temozolomide 150 mg/m\^2, PO, on Days 1 through 7 and on Days 15 through 21 (followed by 1 week off). Cycle was repeated for a maximum of 12 cycles.
Cycle 13 and beyond (4-week cycles): If the first 12 cycles were tolerated with no disease progression, participants then received bevacizumab 10 mg/kg IV on Days 1 and 15 (followed by 2 weeks off). This cycle was repeated every 28 days until disease progression. | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 3 |
| Overall Study | Death | 22 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Bevacizumab + Temozolomide |
|---|---|
| Age, Continuous | 56.19 years STANDARD_DEVIATION 10.58 |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 32 / 32 |
| serious Total, serious adverse events | 8 / 32 |
Outcome results
Primary
PFS: Probability of Remaining Progression Free at 24 Weeks After Beginning the Study
Time frame: BL, 24 weeks (after 6th cycle)
Population: ITT population
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Bevacizumab + Temozolomide | PFS: Probability of Remaining Progression Free at 24 Weeks After Beginning the Study | 0.30000 survival probability | 0.0819 |
Primary
PFS - Time to Event
PFS was defined as the time, in weeks, from the date of inclusion in the study to the date of the first documentation of disease progression or death of the participant due to any cause. Participants that did not have an event at the time the analysis was performed were censored at the date of last contact. Participants that began a treatment other than those planned in this study (bevacizumab or temozolomide) were censored on the start date of the new treatment. PFS was estimated using the Kaplan-Meier method.
Time frame: BL, every 28 days, until progression, death or end-of-study, an average of 32 weeks
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Temozolomide | PFS - Time to Event | 18.29 weeks |
Primary
Progression-Free Survival (PFS) - Percentage of Participants With an Event
PFS was defined as the time, in weeks, from the date of inclusion in the study to the date of the first documentation of disease progression or death of the participant due to any cause. Participants that did not have an event at the time the analysis was performed were censored at the date of last contact. Participants that began a treatment other than those planned in this study (bevacizumab or temozolomide) were censored on the start date of the new treatment.
Time frame: Baseline (BL), every 28 days, until progression, death or end-of-study, an average of 32 weeks
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Temozolomide | Progression-Free Survival (PFS) - Percentage of Participants With an Event | 96.88 percentage of participants |
Secondary
Overall Survival - Percentage of Participants With an Event
Overall survival was defined as the time transpired (in weeks) between the date of the participant's inclusion in the trial until the date of his/her death by any cause. Participants that were alive at the time the analysis was performed were censored on the date of last contact.
Time frame: BL, every 28 days, until death or end-of-study, an average of 32 weeks
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Temozolomide | Overall Survival - Percentage of Participants With an Event | 75.00 percentage of participants |
Secondary
Overall Survival - Time to Event
Overall survival was defined as the time transpired (in weeks) between the date of the participant's inclusion in the trial until the date of his/her death by any cause. Participants that were alive at the time the analysis was performed were censored on the date of last contact. Median overall survival was estimated using the Kaplan-Meier method.
Time frame: BL, every 28 days, until death or end-of-study, an average of 32 weeks
Population: ITT population
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Bevacizumab + Temozolomide | Overall Survival - Time to Event | 31.43 weeks |
Secondary
Percentage of Participants Achieving an Overall Response of Complete Response (CR) or Partial Response (PR)
Overall response was defined as the percentage of participants who obtained CR or PR using adapted MacDonald criteria. CR: disappearance of all index and non-index lesions, confirmed no less than 4 weeks after assessment, no evidence of disease progression; corticosteroid dosage at or below 20 mg hydrocortisone daily; no neurological changes or an improvement as compared to last disease assessment. PR was defined as: Fifty percent or greater decrease in the sum of products of the larger diameter and the larger perpendicular diameter of all index lesions confirmed no less than 4 weeks after assessment, no evidence of disease progression and the absence of progressive, or non-evaluable disease status for non-index legions; unchanged, or decreased corticosteroid dose as compared to the last disease assessment; no neurological changes or an improvement as compared to the neurological examination at last disease assessment.
Time frame: BL, every 28 days, until progression, death or end-of-study, an average of 32 weeks
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab + Temozolomide | Percentage of Participants Achieving an Overall Response of Complete Response (CR) or Partial Response (PR) | 40.6 percentage of participants |