The mechanism of action of sorafenib makes it an interesting drug to investigate in the treatment of patients with glioblastoma multiforme. Efficacy of agents with anti-angiogenic activity has already been demonstrated and the PDGF receptor target may also be pertinent in glioblastoma. The combination of temozolomide plus sorafenib has been investigated previously in the treatment of patients with advanced melanoma. The combination was generally well tolerated; in previously untreated patients, a standard dose of sorafenib (400mg PO bid) was administered with temozolomide 150mg/m2 PO daily for 5 days, repeated every 28 days (23).

In this multicenter phase II study, patients with newly diagnosed glioblastoma will receive standard treatment, including initial debulking surgical resection (if feasible) followed by high-dose radiation therapy with concurrent temozolomide. After completion of radiation therapy, patients will continue treatment with temozolomide (150mg/m2 days 1-5) and sorafenib (400mg PO bid daily), repeated at 28-day intervals for 6 cycles.

All patients entering this study will initially undergo combined modality treatment with concurrent radiation therapy + temozolomide. Four weeks after completing radiation therapy, patients will begin 6 months of follow-up treatment with oral temozolomide plus sorafenib.

Combined Modality Therapy - Radiation Therapy Radiotherapy must begin within ≤ 6 weeks of surgery. One treatment of 2.0Gy will be given daily 5 days per week for a total of 60.0Gy over 6 weeks. Temozolomide 75mg/m2 PO will be given daily, beginning on the first day of radiation therapy and continuing through the last day of radiation therapy.

After completion of combined modality therapy, patients will have 4 weeks without any therapy.

Systemic Therapy Beginning 4 weeks after the completion of radiation therapy, patients will receive 6 months of treatment with temozolomide and sorafenib. Temozolomide 150mg/m2 orally will be administered days 1-5, and repeated every 28 days for 6 courses. Sorafenib 400mg PO bid will be administered on days 1-28, repeated for 6 courses concurrently with temozolomide

Inclusion Criteria:

1. Histologically confirmed intracranial glioblastoma multiforme (WHO grade 4).

2. Patients who have had partial or complete surgical debulking are eligible, as are those with inoperable glioblastoma.

3. No previous treatment for glioblastoma except for previous surgical debulking (i.e. no previous radiotherapy, local chemotherapy, or systemic therapy).

4. ECOG performance status 0 or 1 (See Appendix C)

5. Age ≥ 18 years

6. Adequate bone marrow function: hemoglobin ≥ 9.0g/dL; ANC ≥ 1500/μL; platelet count ≥ 100,000/μL.

7. Adequate liver function

   • Total bilirubin ≤ 1.5 x ULN
   • ALT and AST ≤ 2.5 x ULN

8. Serum creatinine < 1.5 x ULN

9. Women of child-bearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment. Women must agree to not breast feed while receiving study treatment.

10. Women of child-bearing potential and men must agree to use adequate contraception (barrier method of birth control) while receiving study treatment. Women should use adequate birth control for at least 3 months after the last administration of sorafenib.

11. INR < 1.5 or PT/PTT within normal limits in patients not receiving anticoagulation. However, patients receiving anticoagulation treatment with an agent such as warfarin or heparin are also eligible. For patients on warfarin, the INR should be measured prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable.

12. Patients must have the ability to understand and the willingness to sign written informed consent. A signed informed consent must be obtained prior to any study-specific procedures.

Exclusion Criteria:

1. Patients must have the ability to swallow whole pills.
2. Active cardiac disease: congestive heart failure > class 2 NYHA (Appendix D); unstable angina or new onset angina within the last 3 months; myocardial infarction within the last 6 months.
3. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
4. Uncontrolled hypertension defined as systolic blood pressure > 150mm Hg or diastolic pressure > 90mm Hg, despite optimal medical management
5. Known human immunodeficiency virus (HIV) infection or chronic hepatitis B or C infection
6. Active clinically serious infection > grade 2
7. Thrombotic or embolic events including cerebral vascular accident or TIAs within the past 6 months
8. Pulmonary hemorrhage/bleeding event ≥ grade 2 within 4 weeks of the first dose of sorafenib
9. Any other hemorrhage/bleeding event ≥ grade 3 within 4 weeks of the first dose of sorafenib
10. Serious non-healing wound, ulcer, or bone fracture
11. Evidence or history of bleeding diathesis or coagulopathy
12. Major surgery, open biopsy, or significant traumatic injury within 4 weeks of beginning treatment with sorafenib
13. Use of St. John's Wort or rifampicin
14. Known or suspected allergy to sorafenib or temozolomide
15. Any malabsorption problem
16. Other active malignancies, or treatment for invasive cancer within the last 2 years