PRIMARY OBJECTIVES:~Phase 1~1. 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 multiforme or gliosarcoma who are not taking enzyme-inducing antiepileptic drugs.~SECONDARY OBJECTIVES:~Phase 1 and 2~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.~Characterize the pharmacokinetics of these doublet combinations, evaluating single-agent pharmacokinetics of each agent and the combination pharmacokinetics to determine drug-drug interactions.~Phase 2~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.~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.~TERTIARY OBJECTIVES:~Phase 2~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.~Determine the relationship between tumor and blood biomarkers and clinical outcome of patients treated with the combination of targeted agents.~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, Receptor tyrosine-protein kinase (HER-2), Protein kinase B (AKT), S6 ribosomal protein, and Receptor-linked tyrosine kinases (Erk).~After completion of study treatment, patients are followed every 3 months.
This phase I/II trial is studying the side effects and best dose of erlotinib, tipifarnib, and temsirolimus when given together with sorafenib and to see how well they work in treating patients with recurrent glioblastoma multiforme or gliosarcoma. Sorafenib, erlotinib, tipifarnib, and temsirolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Sorafenib and tipifarnib may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving sorafenib together with erlotinib, tipifarnib, or temsirolimus may kill more tumor cells.