NCT00387400

Temozolomide + Everolimus in Newly Diagnosed, Recurrent, or Progressive Malignant Glioblastoma Multiforme

A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme

• Status: Completed
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 32 (actual)
• Sponsor: NCIC Clinical Trials Group · Network
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

OBJECTIVES: Primary * 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. Secondary * 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.

Conditions

• Brain and Central Nervous System Tumors

Interventions

Type	Name	Description
DRUG	everolimus	150 mg/m2/day PO Daily x 5, q 4 weeks
DRUG	temozolomide	2.5 mg PO Daily, beginning day 2 of cycle 1, q 4 weeks
GENETIC	microarray analysis	Tissue sections will be stained by immunohisto-chemistry using the following antibodies: EGFRvIII, PTEN, phospho-specific PKB/Akt Ser473; phosphor-mTORSer2448, p70S6K Thr389; S6 ribosomal protein Ser235/236. These antibodies are selected on the basis of providing a readout of upstream and downstream signaling through mTOR, and availability of antibodies that reliably stain paraffinembedded tissue.
OTHER	immunohistochemistry staining method	Tissue sections will be stained by immunohisto-chemistry using the following antibodies: EGFRvIII, PTEN, phospho-specific PKB/Akt Ser473; phosphor-mTORSer2448, p70S6K Thr389; S6 ribosomal protein Ser235/236. These antibodies are selected on the basis of providing a readout of upstream and downstream signaling through mTOR, and availability of antibodies that reliably stain paraffinembedded tissue.

Timeline

• Start date: 2007-03-20
• Primary completion: 2010-09-24
• Completion: 2012-01-06
• First posted: 2006-10-13
• Last updated: 2023-08-04

Locations

9 sites across 1 country: Canada