Ph. 2 Sorafenib + Protracted Temozolomide in Recurrent GBM
Condition: Recurrent Glioblastoma Multiforme
MeSH terms: Glioblastoma; Recurrence
Intervention: Sorafenib and Temozolomide
Intervention description: Temozolomide (50 mg per meter-squared of body surface area)every day by mouth in combination with sorafenib. Sorafenib will be taken by mouth twice every day. The dose of sorafenib will be 400 mg (2 x 200mg tablets).
Intervention MeSH terms: Temozolomide; Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Recurrent Glioblastoma Multiforme; GBM; Glioblastoma; Sorafenib; Temozolomide; Brain Tumor; Recurrent GBM; Temodar; Gliosarcoma; Glioma; Nexavar

Summary:

      PURPOSE AND OBJECTIVES:

      Primary Objective To evaluate the activity of Sorafenib plus protracted, daily temozolomide
      in patients with recurrent glioblastoma multiforme (GBM) as measured by 6-month PFS.

      Secondary Objectives To evaluate the safety and toxicity of combination therapy using
      Sorafenib plus temozolomide; To determine the pharmacokinetics of Sorafenib when combined
      with temozolomide in patients on and not on concurrent EIAC medications.
    

Eligibility criteria:

        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 < 1.5 x ULN

               -  ALT & AST < 2.5 x ULN ( < 5 x ULN for pts with liver involvement)

               -  INR < 1.5 or PT/PTT within normal limits (unless on therapeutic
                  anti-coagulation). Pts receiving anti-coagulation treatment with agent such as
                  warfarin or heparin may be allowed to participate. For pts on warfarin, INR
                  should be measured prior to initiation of sorafenib and monitored at least
                  weekly, or as defined by local standard of care, until INR is stable.

               -  Creatinine < 1.5 x ULN

          -  An interval of at least 2 weeks between prior surgical resection (1 week for biopsy)&
             initiation of study regimen;

          -  An interval of at least 12 weeks from completion of standard, daily XRT, unless 1 of
             the following occurs: 1) new area of enhancement on MRI imaging that is outside XRT
             field; 2) biopsy proven recurrent tumor; 3) radiographic evidence of progressive tumor
             on 2 consecutive scans at least 4 weeks apart.

          -  An interval of at least 4 weeks from prior chemotherapy (except nitrosoureas which
             require 6 weeks) unless there is unequivocal evidence of tumor progression and pts has
             recovered from all anticipated toxicities from prior therapy.

          -  Karnofsky performance score > 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).