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 VEGF-dependent
angiogenic pathways, gene expression microarray, and 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

- WBC ≥ 3,000/mm³

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Hemoglobin ≥ 10 g/dL (transfusion allowed)

- SGOT < 2.5 times upper limit of normal (ULN)

- Bilirubin < 2.5 times ULN

- INR ≤ 1.5 times ULN (except if on therapeutic anticoagulation therapy)

- aPTT ≤ 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,
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

- 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

- concurrent stereotactic radiosurgery or brachytherapy

- concurrent major surgical procedure

- other concurrent anticancer therapy, including chemotherapy, hormonal therapy,
radiotherapy, or immunotherapy