Radiation Therapy and Temozolomide Followed by Temozolomide Plus Sorafenib for Glioblastoma Multiforme
Condition: Glioblastoma Multiforme
MeSH terms: Glioblastoma
Intervention: Radiation Therapy; Temozolomide; Sorafenib
Intervention description: 2 Gy/fraction, single daily fractions M-F, to 60 Gy total; In Combined Modality Therapy, administered as 75 mg/m2 by mouth once daily
In follow-up systemic therapy, administered as 150 mg/m2 by mouth on days 1-5 every 28 days for 6 cycles; In follow-up systemic therapy, administered as 400 mg by mouth twice daily for 6 months
Intervention MeSH terms: Temozolomide; Sorafenib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 47.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Concurrent Radiation Therapy; Temozolomide; Sorafenib; First-line; Glioblastoma Multiforme; Phase II

Summary:

      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.
    

Eligibility criteria:

        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