PRIMARY OBJECTIVES:
I. Establish a maximum tolerable dose of temsirolimus in combination with sorafenib in patients with recurrent glioblastoma not receiving enzyme-inducing anticonvulsants (EIACs). (Phase I [closed to accrual as of 11/21/07]) II. Define the safety profile of temsirolimus and sorafenib in these patients. (Phase I [closed to accrual as of 11/21/07]) III. Assess the evidence of antitumor activity. (Phase I [closed to accrual as of 11/21/07])Assess the efficacy, as measured by progression-free survival, of temsirolimus and sorafenib in patients with recurrent glioblastoma not receiving EIACs. (Phase II) IV. Assess the safety and toxicities of this regimen in these patients. (Phase II)
SECONDARY OBJECTIVES:
I. Correlate tumor and blood biomarkers with clinical outcome of patients treated with temsirolimus and sorafenib.
II. Evaluate tumor tissue specimens for evidence of bioactivity of these agents.
OUTLINE: This is a multicenter, phase I (closed to accrual as of 11/21/07), dose-escalation study of temsirolimus followed by a phase II open-label study.
PHASE I: Patients receive oral sorafenib twice daily on days 1-28 and temsirolimus IV over 30 minutes on days 1, 8, 15, and 22. (closed to accrual as of 11/21/07) Treatment repeats 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 are assigned to 1 of 3 treatment groups.
GROUP 1: Patients receive sorafenib and temsirolimus as in phase I (closed to accrual as of 11/21/07) at the MTD. (patients not undergoing surgery)
GROUP 2: Patients receive oral sorafenib twice daily on days 1-8 (15 doses) and temsirolimus IV at the MTD on day 1. Patients undergo surgery on day 8. (patients undergoing surgery) After recovering from surgery, patients receive sorafenib and temsirolimus as in phase I (closed to accrual as of 11/21/07) at the MTD.
GROUP 3: Patient receive sorafenib and temsirolimus as in phase I (closed to accrual as of 11/21/07) at the MTD. (patients who have received prior anti-VEGF therapy and are not undergoing surgery)
Biopsy or resected tissue and blood are collected prior to treatment (usually at diagnosis) and analyzed for biomarkers. After completion of study treatment, patients are followed every 6 months for 5 years and then annually thereafter.
Inclusion Criteria:
- Histologically confirmed grade IV astrocytoma (glioblastoma) or gliosarcoma
- Evidence of tumor progression by MRI or CT scan after prior radiotherapy or most recent antitumor therapy
- Bidimensionally measurable or evaluable disease by MRI or CT scan
- ECOG performance status 0-2
- WBC ≥ 3,000/mm^3
- Absolute neutrophil count ≥ 1,500/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 10 g/dL
- Bilirubin ≤ 1.5 times ULN
- AST ≤ 2.5 times ULN
- Creatinine ≤ 2.0 times ULN
- Cholesterol ≤ 350 mg/dL
- Triglycerides ≤ 400 mg/dL
- INR ≤ 1.5 (unless on full-dose warfarin)
- Not pregnant or nursing
- Fertile patients must use effective contraception during and for 6 months after completion of study therapy
- No HIV positivity
- No evidence of bleeding diathesis or coagulopathy
- No condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication, requirement for IV alimentation, or active peptic ulcer disease) that would impair the ability to swallow pills
- No uncontrolled hypertension with systolic blood pressure (BP) > 140 mm Hg or diastolic BP pressure> 90 mm Hg
- No uncontrolled infection
- No known hypersensitivity to any of the components of temsirolimus or sorafenib
- No immunocompromised patients (other than that related to the use of corticosteroids)
- No other active malignancy
- No uncontrolled intercurrent illness, including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Psychiatric illness or social situation that would preclude study compliance
- No significant intratumoral, intracerebral, or subarachnoid hemorrhage on baseline MRI or CT scan
- No other history of significant intratumoral, intracerebral, or subarachnoid hemorrhage
- Concurrent full-dose anticoagulants (e.g., warfarin) allowed provided all of the following criteria are met:
- In-range INR(between 2 and 3) on a stable dose of oral anticoagulant or on a stabledose of low molecular weight heparin
- No active bleedingor pathological condition that carries a high risk of bleeding (e.g., tumorinvolving major vessels or known varices)
- At least 12 weeks since prior radiotherapy
- At least 4 weeks since prior temsirolimus, sorafenib, or other agents specifically targeting mTOR, raf, or vascular endothelial growth factor (VEGF)/VEGF receptors and recovered
- At least 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas)
- At least 2 weeks since prior cytostatic chemotherapy (e.g., tamoxifen, isotretinoin, or thalidomide)
- At least 1 week since prior fixed or decreasing dose of corticosteroids (or no corticosteroids)
- At least 1 week since prior minor surgery other than venous line placement (3 weeks for major surgery)
- No more than 2 prior systemic chemotherapy regimens
- No prior surgical procedures affecting absorption
- No prior intratumoral chemotherapy (e.g., polifeprosan 20 with carmustine implant or cintredekin besudotox), stereotactic radiosurgery, or interstitial brachytherapy unless there is a separate lesion on MRI that is not part of the previous treatment field or there is proof of recurrent disease based on biopsy, MRI spectroscopy, or positron emission tomography scan
- No concurrent enzyme-inducing antiepileptic drugs (e.g., phenytoin,fosphenytoin, carbamazepine, phenobarbital, or primidone) or any other potent CYP3A4 inducer, such as rifampin or Hypericum perforatum (St. John's wort)
- No other concurrent investigational agents
- No concurrent prophylactic hematopoietic colony-stimulating factors
- No other concurrent anticancer agents or therapies
- Concurrent prophylactic anticoagulation therapy (e.g., low-dosewarfarin) allowed provided coagulation parameter levels (prothrombin time [INR]) < 1.1 times upper limit of normal (ULN)
Last updated: 03/26/2013
NCT ID: NCT00329719
IRB Number:06-002299
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