Glioblastoma Multiforme
Conditions
Keywords
Glioblastoma Multiforme, Brain and Central Nervous System Tumors, Recurrent Malignant Glioma, Recurrent Glioblastoma Multiforme, Avastin, Bevacizumab, Temodar, Temozolomide
Brief summary
This is a phase II study of the combination of Avastin and metronomic temozolomide in recurrent malignant glioma patients. The primary objective will be to determine the efficacy of Avastin (bevacizumab) and metronomic temozolomide in malignant glioma patients. The secondary objective will be to determine the safety of Avastin, 10 mg/kg every other week, in combination with metronomic temozolomide in terms of progression-free survival.
Detailed description
This is a phase II trial of the combination of Avastin and metronomic temozolomide in recurrent WHO grade IV malignant glioma patients. Patients will receive up to 12 cycles of Avastin and temozolomide and cycles are continuous 28 days. Patients will receive daily temozolomide at a dose of 50mg/m2 and will receive Avastin every other week at a dose of 10mg/kg. Patients will be required to have a baseline MRI within 2 weeks of starting treatment and a repeat MRI every 8 weeks. A total of 32 patients will be enrolled at Duke. Patients with recurrent malignant gliomas have a very poor prognosis, so new therapies are needed. Given the activity of metronomic temozolomide and the safety and activity of Avastin against malignant glioma, it is reasonable to study the combination in recurrent malignant glioma patients.
Interventions
DRUGBevacizumab
Bevacizumab administered intravenously 10mg/kg every other week.
DRUGMetronomic Temozolomide
Temozolomide 50mg/m2 given orally on a daily basis.
Sponsors
Genentech, Inc.
Schering-Plough
Duke University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed diagnosis of WHO grade IV primary malignant glioma * Karnofsy Performance Status (KPS) \>/= 60% * Evidence of measurable primary CNS neoplasm on contrast-enhanced MRI. * An interval of at least 4 weeks between prior surgical resection or 1 week from a biopsy and enrollment on this protocol * An interval of at least 4 weeks from the end of prior radiotherapy or one week from the end of a cycle of chemotherapy and enrollment on this protocol. * No evidence of CNS hemorrhage on the baseline MRI or CT scans
Exclusion criteria
* Life expectancy \< 8 weeks * Pregnancy or breast feeding * Progression to metronomic temozolomide, defined as tumor progression while taking daily temozolomide or progression within 4 weeks of stopping metronomic temozolomide * Inadequately controlled hypertension (defined as systolic blood pressure \>150 and/or diastolic blood pressure \> 100 mmHg on antihypertensive medications)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 6-Month Progression-free Survival | 6 months | Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. \[Optional: Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator).\] |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Response Rate | 27 months | The number of participants with complete or partial response as determined by a modification of the Macdonald criteria. Complete response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. |
| Incidence and Severity of CNS Hemorrhage and Systemic Hemorrhage | 27 months | Number of participants experiencing a Central Nervous System (CNS) hemorrhage or systemic hemorrhage |
| Incidence of Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity | 27 months | Number of participants experiencing a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bevacizumab and Temozolomide Patients will receive up to 12 cycles of Avastin and temozolomide, and each cycle is 28 days. Avastin will be administered at 10 mg/kg every other week beginning a minimum of 7 days after a biopsy or 28 days after a craniotomy. Temozolomide will be dosed at 50 mg/m2 daily in a 28-day cycle. | 32 |
| Total | 32 |
Baseline characteristics
| Characteristic | Bevacizumab and Temozolomide |
|---|---|
| Age Continuous | 54.4 years STANDARD_DEVIATION 12.8 |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 32 |
| serious Total, serious adverse events | 8 / 32 |
Outcome results
Primary
6-Month Progression-free Survival
Percentage of participants surviving six months from the start of study treatment without progression of disease. PFS was defined as the time from the date of study treatment initiation to the date of the first documented progression according to the Macdonald criteria, or to death due to any cause. \[Optional: Macdonald criteria are standard criteria in neuro-oncology. Tumor assessment was made according to the adapted MacDonald criteria based on the combined evaluation of: 1) assessment of the MRI scan for measurable, evaluable, and new lesions (made by the independent external expert too), 2) overall assessment of neurological performance (made by the investigator), 3) concomitant steroid use (as reported by the investigator).\]
Time frame: 6 months
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab and Metronomic Temozolomide | 6-Month Progression-free Survival | 18.8 percentage of participants |
Secondary
Incidence and Severity of CNS Hemorrhage and Systemic Hemorrhage
Number of participants experiencing a Central Nervous System (CNS) hemorrhage or systemic hemorrhage
Time frame: 27 months
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab and Metronomic Temozolomide | Incidence and Severity of CNS Hemorrhage and Systemic Hemorrhage | CNS Hemorrhage | 0 participants |
| Bevacizumab and Metronomic Temozolomide | Incidence and Severity of CNS Hemorrhage and Systemic Hemorrhage | Systemic Hemorrhage | 0 participants |
Secondary
Incidence of Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity
Number of participants experiencing a grade ≥4 hematologic or grade ≥3 non-hematologic toxicity
Time frame: 27 months
Population: Intent to treat
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bevacizumab and Metronomic Temozolomide | Incidence of Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity | Grade ≥ 4 hematologic toxicities | 0 participants |
| Bevacizumab and Metronomic Temozolomide | Incidence of Grade ≥ 4 Hematologic or Grade ≥ 3 Non-hematologic Toxicity | Grade ≥ 3 non-hematologic toxicities | 14 participants |
Secondary
Response Rate
The number of participants with complete or partial response as determined by a modification of the Macdonald criteria. Complete response was defined as complete disappearance on MR/CT of all enhancing tumor and mass effect, off all corticosteroids (or receiving only adrenal replacement doses), accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks. Partial Response was defined as greater than or equal to 50% reduction in tumor size on MR/CT by bi-dimensional measurement, on a stable or decreasing dose of corticosteroids, accompanied by a stable or improving neurologic examination, and maintained for at least 4 weeks.
Time frame: 27 months
Population: Intent to treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Bevacizumab and Metronomic Temozolomide | Response Rate | 9 Number of participants |