Erlotinib and temsirolimus and may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This phase I/II trial is studying the side effects and best dose of temsirolimus when given together with erlotinib and to see how well they work in treating patients with recurrent malignant glioma.
PRIMARY OBJECTIVES: I. To define the maximum tolerated dose (MTD) of OSI-774 (erlotinib; Tarceva) in combination with CCI-779 (temsirolimus) in patients with recurrent malignant glioma who are not taking enzyme-inducing anti-epileptic drugs (EIAEDs). (Phase I) II. To characterize the safety profile of OSI-774 (erlotinib) and CCI-779 (temsirolimus). (Phase I) III. To characterize the pharmacokinetics of OSI-774 (erlotinib) and CCI-779 (temsirolimus). (Phase I) IV. To determine the efficacy of OSI-774 (erlotinib) and CCI-779 (temsirolimus) in patients with recurrent malignant glioma as measured by 6-month progression-free survival. (Phase II) SECONDARY OBJECTIVES: I. Overall progression-free survival. (Phase II) II. Response. (Phase II) TERTIARY OBJECTIVES: I. To explore the association of response to treatment to the molecular phenotype of the tumor. (Phase II) II. Determine whether OSI-774 (erlotinib) and CCI-779 (temsirolimus) inhibits EGFR and mTOR and the PI3K-AKT-mTOR and RAS-ERK signaling pathways in tumor specimens taken from malignant glioma patients undergoing surgery. (Phase II) III. Tumor concentration of OSI-774 (erlotinib) and CCI-779 (temsirolimus). (Phase II) OUTLINE: This is a multicenter, phase I, dose-escalation study of temsirolimus followed by a phase II study. Patients are stratified according to study phase (I vs II), histology at study enrollment (glioblastoma multiforme or gliosarcoma vs anaplastic glioma), preoperative candidacy (yes vs no), and presence of measurable or evaluable disease (yes vs no). PHASE I: Patients receive oral erlotinib once daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of temsirolimus 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. PHASE II: Patients receive temsirolimus at the MTD and erlotinib as in phase I. PHASE II (preoperative component): Patients who are surgical candidates may opt to undergo surgical resection of the tumor. Beginning 5-7 days before surgery, these patients receive oral erlotinib once daily until surgery. Patients also receive temsirolimus IV over 30 minutes at the MTD and then undergo surgical resection of the tumor 3-24 hours later. Beginning 2-4 weeks after surgery, patients receive temsirolimus at the MTD and erlotinib as in phase I. PROJECTED ACCRUAL: A total of 3-24 patients will be accrued for the phase I portion of the study within 1-8 months. A total of 50 patients (32 patients with glioblastoma multiforme and 18 with anaplastic glioma) will be accrued for the phase II portion of the study within 8-12 months.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
69
Given orally
Given IV
Undergo surgical resection
Correlative studies
Correlative studies
University of California Los Angeles
Los Angeles, California, United States
University of California San Francisco
San Francisco, California, United States
National Cancer Institute Neuro-Oncology Branch
Bethesda, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
University of Pittsburgh
Pittsburgh, Pennsylvania, United States
M D Anderson Cancer Center
Houston, Texas, United States
University of Texas Health Science Center
San Antonio, Texas, United States
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States
Maximum Tolerated Dose (Phase I)
Oral erlotinab at 150mg constant dose, 3 pts will be treated with temsirolimus IV with escalating doses, starting at 50mg. Doses will increase or decrease based on toxicity observed. 3 pts will be treated at each dose level - 3 dose levels were observed: 50mg, 25mg, and 15mg
Time frame: based on first 4 weeks of treatment - cycle 1
Safety/Dose Limiting Toxities Phase I
Dose limiting toxities defined as: grade 3 thrombocytopenia, grade 4 anemia and neutropenia, grade \>/= nonhematologic toxicity, and failure to recover from toxicites to be eligible for retreatment in 2 weeks of the last dose of either drug. Also grade 3 nonhematologic toxicities only if they wre refractory to maxiaml medical therapy. MTD defined as dose at which fewer than one-third of patients experienced a DLT Outcome measure defines number of participants who had a defined dose limiting toxicity.
Time frame: first 4 weeks of treatment
Efficacy - Response Phase 1
pt must have at least 8 weeks of treatment to receive MRI scan, scans are every other cycle (every 2 months). Response measured by a bidimensionally measured leison and clearly defined margins by CT or MRI scan. Complete Response (CR): complete disappearance of all measurable and evaluable disease. No new lesions, not on any steroids Partial Response (PR): \>= 50% decrease under baseline in the sum of products of perpendicular diameters of all measurable lesions. No progression of evaluable disease. No new lesions. Steriod dose must be no greater than max used in 1st 8wks of therapy Stable: not qualify for CR, PR, or progression. Steriod dose must be no greater than max used in 1st 8wks of therapy Progression (PD): 25% increase in the sum of products of all measurable lesions over smallest sum observed, OR clear worsening or failure to return for evalution due to death or deteriorating condition (unless clearly unrelated to brain cancer).
Time frame: at least 8 weeks of treatment
Pharmacokinetics (Phase I)
Tersirolimus Cmax (ng/mL) for cycle 1 is presented in the outcome measure table below for the 3 dose levels blood samples (5ml) was collected in EDTA containing tubes on days 1 and 2 of cycle 1 Collection time points: prior to dosing of both drugs, at end of temsirolimus infusion and at 1,2,4,6, and 24 hr after erlotinib administration
Time frame: Days 1, 2 of cycle 1, prior to dosing of both drugs, at end of temsirolimus infusion and at 1,2,4,6, and 24 hr after erlotinib administration
Progression-free Survival at 6 Months (Phase II)
Progression (PD): 25% increase in the sum of products of all measurable lesions over smallest sum observed, OR clear worsening or failure to return for evalution due to death or deteriorating condition (unless clearly unrelated to brain cancer). Responses had to be present on 2 consecutive scans and were centrally reviewed.
Time frame: Evaluated at baseline and every other cycle, till Month 6
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