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.
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 1. 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. 2. 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 1. 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. 2. 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 1. 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. 2. 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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
92
University of California at Los Angeles
Los Angeles, California, United States
University of California San Francisco
San Francisco, California, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Memorial Sloan-Kettering Cancer Center
New York, New York, United States
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
M D Anderson Cancer Center
Houston, Texas, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
Maximum Tolerated Dose (MTD) of the Each Combination Agent Combined With a Fixed Dose of BAY 43-9006 Determined by Dose-limiting Toxicities (DLT) (Phase I)
DLT defined as: any grade 4 hematologic toxicity; grade 3 thrombocytopenia \> 7 days, any grade 3/4 non-hematologic toxicity (despite maximal medical therapy), any intolerable grade 2 non-hematological, ro grade 3 hematological toxicity requiring deduction during first 28 days of treatment, any toxicity resulting in delay of \>1week during first 28 days of treatment
Time frame: 28 days
Pharmacokinetic Max Concentration (Cmax) of Group 2 Sorafenib and Temsirolimus (Phase I)
Group 2: 13 patients received temsirolimus 25mg IV and 7 patients treated with 200mg Sorafenib and 6 patients treated with 400mg Sorafenib
Time frame: cycle 1 ((Day1, Day15, Day28)
Pharmacokinetic cMax Group 1 Sorafenib and Erlotinib (Phase I)
8 samples collected over 24 hours on Day 1, day 15 and day 28 13 total patients treated 100mg Erlotinib and either 200mg or 400mg of Sorafenib
Time frame: 28days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration)
Pharmacokinetic AUC 0-12 Group 1 Sorafenib and Erlotinib (Phase I)
8 samples collected over 24 hours on Day 1, day 15 and day 28 16 patients Note that although 16 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference AUC - Area Under Curve
Time frame: 28Days (D1, D15, D28) (0,1,2,4,6,8,12,24hr post administration) AUC 0-12
Trough Concentration Group 2 Sorafenib and Temsirolimus (Phase I)
Group 2: 12 patients were analyzed for Day 1 (1 patient not evaluable), 5 patients were analyzed for Day 15 (8 patients not evaluable)
Time frame: 15 days
Plasma Time Curve (AUC) of Group 2 Sorafenib and Temsirolimus (Phase I)
Day 1 = 12 patients (1 sample not evaluable) Day 15 = 5 patients (8 samples not evaluable) AUC - Area Under Curve 8 samples collected over 24 hours - 28 day PKs
Time frame: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)
Pharmacokinetic Cpmax Group 3 Sorafenib and Tipifarnib (Phase I) 100 mg QD (Level -1)
Group 3: Only PKs for Dose level 1 and -1 were collected.
Time frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Pharmacokinetic CpMax Concentration of Group 3 Sorafenib and Tipifarnib (Phase I) 100mg BID
Group 3: patients were studied for their day 1 Cmax, and day 15 Cmax Tipifanib and Day 15 and Day 28 sorafenib Group 3: Only PKs for Dose level 1 and -1 were collected.
Time frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg QD (Level -1)
Group 3: PKs for Dose level -1 100mg QD Note that although 9 patients were accrued/analyzed some samples were incomplete or inevaluable or missing hence number analyzed difference
Time frame: Cycle 1 (D1, D15, D28) (0,1,2,4,6,8,12,24hr post drug administration)
Plasma Time Curve (AUC) of Group 3 Phase I Sorafenib and Tipifarnib 100mg BID (Level 1)
Group 3: PKs for Dose level 1 Tipifarnib 100mg BID
Time frame: Cycle 1 = 28 day PKs D1, D15,D28 (0,1,2,4,6,8,12,24hr post drug administration)
12 Month Survival Rate (Phase II)
number of patients alive at 12 months
Time frame: 12 months
Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase I)
CTCAE 3.0
Time frame: 28 days
Number of High Grade (3 and 4) Related Adverse Events of Each Combination Agent Combined With BAY 43-9006 (Phase 2)
Time frame: 1 year
Progression-free Survival at 6 Months (Phase II)
Patients with a scan at 6 months without progressive disease Progressive disease defined as Progressive neurological abnormalities not explained by other causes or greater than 25% increase in size of tumor or if new lesion.
Time frame: 6 months
Objective Response Rate in Patients With Measurable Disease (Phase II)
Measurable: Bidimensionally measurable lesions w/ clearly defined margins by MRI Evaluable: Unidimensionally measurable lesions, masses w/margins not clearly defined. Complete Response (CR): Complete disappearance of all measurable/evaluable disease. No new lesions. No evidence of non-evaluable disease. Patients on minimal/no steroids. Partial Response (PR): \>/= to 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. Responders must be on same/decreasing doses of dexamethasone. Stable/No Response: Does not qualify for CR, PR, or progression. Progression: 25% increase in the sum of products of all measurable lesions over smallest sum observed (over BL if no decrease), OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer).
Time frame: Up to 5 years
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