Temozolomide and Everolimus in Treating Patients With Newly Diagnosed, Recurrent, or Progressive Malignant Glioblastoma Multiforme
RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving temozolomide together with everolimus may kill more tumor cells.
PURPOSE: This phase I trial is studying the side effects and best dose of everolimus when given together with temozolomide in treating patients with newly diagnosed, recurrent, or progressive malignant glioblastoma multiforme.
|Brain and Central Nervous System Tumors||Drug: everolimus Drug: temozolomide Genetic: microarray analysis Other: immunohistochemistry staining method||Phase 1|
|Study Design:||Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme|
- Safety and tolerability of everolimus as measured by NCI CTCAE v3.0 [ Time Frame: from the time of the first treatment ]
- Response as measured by CT scan and/or brain MRI at baseline and after every other course and clinical neurologic assessment at baseline and after every course [ Time Frame: after every other course ]
- Correlation of clinical outcome with pretreatment tumor tissue molecular markers as measured by molecular studies of paraffin-embedded tumor samples [ Time Frame: 4 years ]Assessed at study completion
- Pharmacokinetics of everolimus during course 1 [ Time Frame: during course 1 ]
|Study Start Date:||July 2006|
|Study Completion Date:||January 2012|
|Primary Completion Date:||January 2012 (Final data collection date for primary outcome measure)|
- Determine the maximum tolerated dose(s) and the recommended phase II dose(s) of everolimus when administered with standard-dose temozolomide in patients with newly diagnosed, recurrent, or progressive glioblastoma multiforme.
- Determine the toxicity of this regimen in these patients.
- Determine the efficacy of this regimen in patients with measurable disease at baseline.
- Identify correlates of activity by molecular study of paraffin-embedded tumor samples from these patients.
- Determine the pharmacokinetics of this regimen in these patients.
OUTLINE: This is a nonrandomized, nonblinded, parallel-group, multicenter, dose-escalation study of everolimus. Patients are stratified according to concurrent use of enzyme-inducing antiepileptic drugs (yes vs no).
Patients receive oral temozolomide once daily on days 2-5 in course 1 and on days 1-5 in all subsequent courses. Patients also receive oral everolimus once daily on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity. Patients with newly diagnosed disease receive up to 6 courses of treatment. Patients with recurrent disease who achieve a response (partial or complete response) or stable disease may continue treatment until disease progression or unacceptable toxicity.
Cohorts of 3-6 patients per stratum receive escalating doses of everolimus until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity during the first course of therapy. Once the MTD is determined, an additional 6 patients are treated at the MTD.
Patients' archival diagnostic tumor tissue is evaluated during study for correlative molecular studies (by immunohistochemical staining) of mammalian target of rapamycin inhibition status (mTOR activity) and pretreatment molecular markers. Blood samples are taken periodically during course 1 for pharmacokinetic studies.
After completion of study therapy, patients are followed at 4 weeks. Patients with stable or responding disease are then followed every 3 months until relapse or progression.
PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00387400
|Tom Baker Cancer Centre|
|Calgary, Alberta, Canada, T2N 4N2|
|Cross Cancer Institute|
|Edmonton, Alberta, Canada, T6G 1Z2|
|Canada, British Columbia|
|BCCA - Cancer Centre for the Southern Interior|
|Kelowna, British Columbia, Canada, V1Y 5L3|
|BCCA - Vancouver Cancer Centre|
|Vancouver, British Columbia, Canada, V5Z 4E6|
|Canada, Nova Scotia|
|QEII Health Sciences Center|
|Halifax, Nova Scotia, Canada, B3H 1V7|
|London Regional Cancer Program|
|London, Ontario, Canada, N6A 4L6|
|Univ. Health Network-Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|CHUM - Hopital Notre-Dame|
|Montreal, Quebec, Canada, H2L 4M1|
|McGill University - Dept. Oncology|
|Montreal, Quebec, Canada, H2W 1S6|
|Study Chair:||Warren P. Mason, MD||Princess Margaret Hospital, Canada|