Phase I/II Studies of BAY 43-9006 (Sorafenib) in Combination With OSI-774 (Erlotinib), R115777 (Tipifarnib) or CCI-779 (Temsirolimus) in Patients With Recurrent Glioblastoma Multiforme or Gliosarcoma
I Determine the maximum tolerated dose (MTD) of tipifarnib, erlotinib hydrochloride, or
temsirolimus in combination with a fixed dose of sorafenib in patients with recurrent
glioblastoma mutiforme or gliosarcoma who are not taking enzyme-inducing antiepileptic
drugs. (Phase I)
I. Characterize the safety profile of the doublet combinations of tipifarnib-sorafenib,
erlotinib hydrochloride-sorafenib, and temsirolimus-sorafenib in patients with recurrent
glioblastoma multiforme or gliosarcoma. (Phase I and II) II. Characterize the
pharmacokinetics of these doublet combinations, evaluating single-agent pharmacokinetics of
each agent and the combination pharmacokinetics to determine drug-drug interactions. (Phase
I and II) III. Determine the efficacy of each of the doublet combinations, in terms of
6-month progression-free survival, in patients with recurrent glioblastoma multiforme or
gliosarcoma. (Phase II) IV. Determine the efficacy of each of the doublet combinations, in
terms of 12-month survival and objective tumor response, in patients with recurrent
glioblastoma multiforme or gliosarcoma. (Phase II)
I. Perform exploratory correlative laboratory studies by examining tissue markers of signal
transduction pathways by immunohistochemical analysis using tissue blocks obtained prior to
initiation of protocol therapy, either from the time of diagnosis or subsequent tumor
resection. (Phase II) II. Determine the relationship between tumor and blood biomarkers and
clinical outcome of patients treated with the combination of targeted agents. (Phase II)
OUTLINE: This is a multicenter, phase I, dose-escalation study of tipifarnib, erlotinib
hydrochloride, and temsirolimus followed by a phase II open-label study.
PHASE I: Patients are sequentially assigned to 1 of 3 treatment groups.
GROUP 1: Patients receive oral sorafenib twice daily and oral erlotinib hydrochloride once
daily on days 1-28.
GROUP 2: Patients receive sorafenib as in group 1. Patients also receive temsirolimus IV
over 30 minutes on days 1, 8, 15, and 22.
GROUP 3: Patients receive sorafenib as in group 1. Patients also receive oral tipifarnib
twice daily on days 1-21.
In all groups, treatment repeats every 28 days for up to 24 courses in the absence of
disease progression or unacceptable toxicity.
In each treatment group, cohorts of 3-6 patients receive escalating doses of erlotinib
hydrochloride (group 1), temsirolimus (group 2), or tipifarnib (group 3) sequentially until
the maximum tolerated dose (MTD) is determined for each group. 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.
PHASE II: Patients receive sorafenib as in phase I. Patients also receive erlotinib
hydrochloride, temsirolimus, or tipifarnib as in phase I at the MTD determined in phase I.
Tissue that was collected during a prior surgery is examined for biomarkers by
immunohistochemistry (in patients enrolled in the phase II portion of the study). Biomarkers
examined include epidermal growth factor receptor, HER-2, AKT, S6 ribosomal protein, and
After completion of study treatment, patients are followed every 3 months.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximally tolerated dose of the each combination agent combined with a fixed dose of BAY 43-9006 determined by dose-limiting toxicities (Phase I)
National Cancer Institute (NCI)
United States: Food and Drug Administration
|M D Anderson Cancer Center||Houston, Texas 77030|
|Adult Brain Tumor Consortium||Baltimore, Maryland 21231-1000|