Bevacizumab and Temozolomide in Treating Older Patients With Newly-Diagnosed Glioblastoma Multiforme or Gliosarcoma

PRIMARY OBJECTIVES:

I. To estimate overall survival in elderly subjects treated with bevacizumab and temozolomide
for newly diagnosed glioblastoma multiforme.

SECONDARY OBJECTIVES:

I. To estimate 12-months survival. II. To estimate progression free survival for 2 years or
until progression is detected.

III. To investigate the safety and tolerability of bevacizumab/temozolomide in elderly
patient with glioblastoma.

IV. To isolate DNA, RNA, and protein isolated from frozen and paraffinized 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 molecule features of treatment response and especially age-related molecular
expression.

OUTLINE:

Patients receive bevacizumab IV over 30-90 minutes every 2 weeks and oral temozolomide on
days 1-5. Treatment repeats every 28 days for 24 courses in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at least every 4 months.

Inclusion Criteria:

- Patients will have histologically proven intracranial glioblastoma multiforme (GBM) or
gliosarcoma (GS); this includes treatment-naive patients with prior tissue diagnosis
of lower grade gliomas that have been upgraded after repeat resection

- Cranial MRI or contrast CT must have been performed within 21 days of study entry; the
use of MRI rather than CT is preferred; the same type of scan, i.e., MRI or CT, must
be used throughout the period of protocol treatment for tumor measurement; if the
surgical procedure was a resection, cranial MRI or contrast CT performed within 96
hours of resection is preferred, but not required; patients without measureable or
assessable disease are eligible

- Patients must begin temozolomide chemotherapy no sooner than 2 weeks and no later than
6 weeks from the diagnostic surgery; patients must begin bevacizumab no sooner than 4
weeks and no later than 6 weeks from the surgery

- Patients must be willing to forego other drug therapy against the tumor while being
treated with bevacizumab and temozolomide

- All patients must sign and informed consent approved by the Institutional Review Board
indicating that they are aware of the investigational nature of this study; patients
must also sign an authorization for the release of their protected heath information

- Life expectancy > 8 weeks

- Patients must have a Karnofsky performance status of >= 60

- WBC >= 3,000/ul

- ANC >= 1,500/mm^3

- Platelet count of >= 100,000/mm^3

- Hemoglobin >= 10 gm/dl

- SGOT < 2.5 times ULN

- Bilirubin < 2.5 ULN

- Patients must have adequate renal function (creatinine < 1.5 mg/dL) before starting
therapy and the test must be performed within 14 days prior to registration

Exclusion Criteria:

- Glioblastoma disease-specific concerns: Patients must not have received previous or
concurrent radiotherapy to the brain

- Glioblastoma disease-specific concerns: Patients must have received cytotoxic drug
therapy, non-cytotoxic drug therapy, or experimental drug therapy directed against the
brain tumor; patients who received Gliadel wafers will be excluded; patients may have
received or be receiving corticosteroids, AED's, analgesics, and other drugs to treat
symptoms or prevent complications

- Patients must not have any significant medical illnesses that in the investigator's
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patient's ability to tolerate this therapy

- Patients with a history of any other cancer (except non-melanoma skin cancer,
carcinoma in-situ of the cervix, or low-risk prostate cancer after curative therapy),
unless in complete remission and off of all therapy for that disease for a minimum of
3 years are ineligible

- Patients receiving current, ongoing treatment with full-dose warfarin or its
equivalent (i.e., unfractionated and/or low molecular weight heparin) are NOT excluded

- Patients must not have any disease that will obscure toxicity or dangerously alter
drug metabolism

- Patients must not have serious uncontrolled inter-current medical illness including,
but not limited to, ongoing or active infection requiring IV antibiotics, psychiatric
illness/social situations that would limit compliance with study requirements, or
disorders associated with significant immunocompromised state (HIV, SLE, etc.)

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study

- Blood pressure of > 150/100 mmHg, history of hypertensive crisis or hypertensive
encephalopathy

- Unstable angina

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- History of myocardial infarction within 6 months prior to day 1

- History of stroke within 6 months prior to day 1

- International normalized ratio (INR) > 1.5 and activated partial thromboplastin time
(aPTT) > 1.5 x the ULN (except for subjects receiving anticoagulation therapy) in the
absence of therapeutic intent to anticoagulate the subject; therapeutic
anticoagulation is permitted

- Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to Day 1

- History of hemoptysis ( >= 1/2 teaspoon of bright red blood per episode) within 1
month prior to Day 1

- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
therapeutic anticoagulation)

- Major surgical procedure, open biopsy, or significant traumatic injury other than
craniotomy within 28 days prior to Day 1, anticipation of need for major surgical
procedure during the course of the study

- Minor surgical procedures such as placement of Port-a-Cath, stereotactic biopsy, fine
needle aspirations, or core biopsies within 7 days prior to Day 1

- History of intracerebral abscess within 6 months prior to Day 1

- Urine protein: creatinine ratio >= 1.0 at screening

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to Day 1

- Serious, non-healing wound, ulcer, or bone fracture; patients with any wound requiring
surgical intervention (including scalp wounds requiring cranioplasty) will be allowed
to resume the study if the wound is clean and without further infection post-surgical
intervention

- Known hypersensitivity to any component of bevacizumab

- Inability to comply with study and/or follow-up procedures