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.

STUDY ACTIVITIES AND POPULATION GROUP:

This is an open-label, non-randomized, single center phase 2 trial. A treatment cycle will consist of 4 weeks of therapy.

Sorafenib will be administered at a set dose of 400 mg (2 x 200 mg tablets) twice daily, without food (at least 1 hour before or 2 hours after eating). Temozolomide will be administered at a set dose of 50 mg/m2 once daily without food (at least 1 hour before or 2 hours after eating).

Thirty-two (32) patients will be enrolled in this single-stage study.

DATA ANALYSIS AND RISK/SAFETY ISSUES:

After 16 patients with recurrent GBM are treated, an interim analysis will be conducted. If 6 or more patients have experienced unacceptable toxicity, accrual of patients in this patient group will be terminated. Otherwise, patient accrual will continue. If 9 or more of the total 32 patients experience unacceptable toxicity, the treatment regimen will be considered to have an unacceptable toxicity profile. The type I and II error rates associated with this testing are 0.053 and 0.053, respectively.

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).

16 months

The adverse events were gathered in Common Terminology Criteria for Adverse Events v.3.0, and have been converted to v.4.0 for entry into ClinicalTrials.gov