Ph. 2 Sorafenib + Protracted Temozolomide in Recurrent GBM

Inclusion Criteria

• Patients must have histologically confirmed diagnosis of recurrent/progressive GBM. Recurrence will be distinguished from "pseudoprogression" following XRT/Temodar as outlined in inclusion criteria 4.6 (below). Pts with recurrent disease whose diagnostic pathology confirmed glioblastoma multiforme will not need re-biopsy. Pts with prior low-grade glioma or WHO grade III malignant glioma are eligible if histologic assessment demonstrates transformation to GBM.
• Age > 18 years.
• Pts must be presenting in 1st, 2nd or 3rd relapse. Prior therapy must have included external beam radiotherapy.
• Adequate bone marrow, liver and renal function as assessed by following:
• Hemoglobin > 9.0 g/dl
• Absolute neutrophil ct (ANC) > 1,500/mm3
• Platelet ct > 100,000/mm3
• Total bilirubin 60%.
• Ability to understand and willingness to sign written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
• If sexually active, patients will take contraceptive measures (barrier method of birth control) for duration of treatments and for 3 months following discontinuation of sorafenib & temozolomide.
• Pts who have had prior bevacizumab are eligible however interval of at least 6 weeks must have elapsed since their last dose.

Exclusion Criteria

• Prior treatment with sorafenib.
• Significant cardiac disease including any of following: a) congestive heart failure > class II NYHA; b) unstable angina (anginal symptoms at rest); c) new onset angina (within last 3 months); d) myocardial infarction within past 6 months; e) cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Known severe hypersensitivity to sorafenib or any of excipients or temozolomide.
• Excessive risk of bleeding as defined by stroke within prior 6 months, history of CNS or intraocular bleed, or septic endocarditis.
• Female pts who are pregnant/breast feeding, or adults of reproductive potential not employing effective method of birth control.
• Concurrent severe and/or uncontrolled medical disease that could compromise participation in study such as uncontrolled diabetes, uncontrolled hypertension, active clinically serious infection > CTCAE Grade 2, history of bleeding diathesis or coagulopathy, impairment of GI function or GI disease that may significantly alter absorption of the study regimen (i.e. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to swallow tablets).
• Thrombolic or embolic events such as cerebrovascular accident including transient ischemic attacks within past 6 months
• Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of 1st dose of study drug.
• Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of 1st dose of study drug.
• Serious non-healing wound, ulcer, or bone fracture.
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of 1st study drug.
• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.
• Pt is < 3 years free of another primary malignancy except: if other primary malignancy is not currently clinically significant or requiring active intervention, or if other primary malignancy is basal cell skin cancer or cervical carcinoma in situ. Existence of any other malignant disease is not allowed.
• Pts unwilling or unable to comply with protocol including ability to swallow whole pills or presence of any malabsorption syndrome.
• Concurrent administration of St. John's Wort.
• Clinically serious infection requiring active intervention (CTCAE grade 2 or greater).