Bevacizumab, Temozolomide, and External Beam Radiation Therapy as First-Line Therapy in Treating Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma

OBJECTIVES:

Primary

• To investigate the safety and tolerability of bevacizumab in combination with temozolomide and external beam fractionated regional radiotherapy as first-line treatment in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. (Pilot phase)
• To estimate the overall survival of patients treated with this regimen. (Expansion phase)

Secondary

• To further investigate the safety and tolerability of this regimen in these patients. (Expansion phase)
• To isolate DNA, RNA, and protein from frozen and paraffin-embedded archival tumor samples for evaluations, such as immunohistochemical pathway profiling of vascular endothelial growth factor (VEGF)-dependent angiogenic pathways, gene expression microarray, and O-6 methylguanine DNA methyltransferase (MGMT) promoter methylation status to define important molecular features of treatment response.

OUTLINE: This is a multicenter study.

Patients undergo external beam fractionated regional radiotherapy once daily 5 days a week for 6 weeks and receive concurrent oral temozolomide once daily for 6 weeks. Patients also receive bevacizumab IV over 30-90 minutes every 2 weeks beginning on the first day of radiotherapy and continuing in the absence of disease progression or unacceptable toxicity. Beginning 2-5 weeks after completion of radiotherapy, patients receive oral temozolomide on days 1-5. Treatment with temozolomide repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Blood and frozen and paraffin-embedded tumor tissue samples are collected for biomarker and genetic analysis.

After completion of study treatment, patients are followed up periodically.

Inclusion criteria

• Histologically confirmed intracranial glioblastoma multiforme (GBM) or gliosarcoma.
• Prior histologic diagnosis of low-grade glioma allowed provided it has been upgraded to GBM after repeat resection
• Has undergone surgery to collect tumor tissue 3-6 weeks ago
• Measurable or assessable disease is not required
• Karnofsky performance status 60-100%
• Life expectancy > 8 weeks
• White Blood Cell (WBC) ≥ 3,000/mm³
• Absolute Neutrophil Count (ANC) ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 10 g/dL (transfusion allowed)
• Serum Glutamate Oxaloacetate Transaminase (SGOT) < 2.5 times upper limit of normal (ULN)
• Bilirubin < 2.5 times ULN
• INR (international normalized ratio) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy)
• aPTT (activated partial thromboplastin time) ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy)
• Creatinine < 1.5 mg/dL
• Urine protein:creatinine ratio < 1.0
• Negative pregnancy test
• Fertile patients must use effective contraception
• More than 28 days since prior major surgical procedures or open biopsy (other than craniotomy)
• More than 7 days since prior minor surgical procedures (e.g., placement of PortoCath (port-a-cath - a port placed under the subjects skin), stereotactic biopsy, fine-needle aspirations, or core biopsies)
• More than 4 weeks since prior and no concurrent participation in another experimental drug study.
• Prior or concurrent corticosteroids, anti-epileptic drugs, analgesics, or other drugs to treat symptoms or prevent complications are allowed
• Concurrent full-dose warfarin or its equivalent (i.e., unfractionated and/or low molecular weight heparin) allowed

Exclusion criteria

• unstable angina
• BP > 150/100 mm Hg
• New York Heart Association (NYHA) class II-IV congestive heart failure
• myocardial infarction within the past 6 months
• stroke within the past 6 months
• clinically significant peripheral vascular disease
• evidence of bleeding diathesis or coagulopathy
• intracerebral abscess within past 6 months
• abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
• serious, non-healing wound, ulcer, or bone fracture
• Any wound requiring surgical intervention (including scalp wounds requiring cranioplasty) allowed provided the wound is clean and without further infection post-surgical intervention
• significant traumatic injury within the past 28 days
• concurrent serious uncontrolled medical illness including, but not limited to, the following:
• Ongoing or active infection requiring IV antibiotics
• Psychiatric illness/social situation that would limit compliance with study requirements
• Disorders associated with significant immunocompromised state (e.g., HIV, systemic lupus erythematosus)
• other cancer within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the cervix
• disease that would obscure toxicity or dangerously alter drug metabolism
• significant medical illness that, in the investigator's opinion, cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate study therapy
• prior radiotherapy to the brain
• prior cytotoxic or non-cytotoxic drug therapy or experimental drug therapy for the brain tumor
• prior Gliadel wafers
• concurrent participation in any other clinical trial
• concurrent GM-CSF (granulocyte-macrophage colony-stimulating factor)
• concurrent stereotactic radiosurgery or brachytherapy
• concurrent major surgical procedure
• other concurrent anticancer therapy, including chemotherapy, hormonal therapy, radiotherapy, or immunotherapy