A Phase I Study of Temozolomide and RAD001C in Patients With Malignant Glioblastoma Multiforme
- 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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Safety and tolerability of everolimus as measured by NCI CTCAE v3.0
from the time of the first treatment
Warren P. Mason, MD
Princess Margaret Hospital, Canada
Canada: Health Canada