A Phase II Study of Concurrent Radiation Therapy, Temozolomide, and Bevacizumab Followed by Bevacizumab/Everolimus in the First-line of Treatment of Patients With Glioblastoma Multiforme

Inclusion Criteria:

- Age >=18 years.

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

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

- No previous treatment with radiotherapy or systemic therapy. Local therapy with a
Gliadel wafer placed at the time of surgical debulking is permitted.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- Adequate bone marrow function

- Adequate liver function:

- Serum creatinine <=1.5 x institutional ULN.

- Ability to swallow whole pills.

- Women of child-bearing potential must have a negative serum pregnancy test performed
within 7 days prior to start of treatment. Women of child-bearing potential and men
must agree to use adequate contraception (barrier method of birth control) while
receiving study treatment and for 6 months after the last study treatment. Hormonal
contraceptives are not acceptable as a sole method of contraception. Female patients
must not breast feed.

- INR <1.3 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 everolimus and monitored at least weekly, or as defined by the
local standard of care, until INR is stable.

- Fasting serum cholesterol <=300 mg/dL OR <=7.75 mmol/L AND fasting triglycerides <=
2.5 x institutional ULN.

Exclusion Criteria:

- New York Heart Association (NYHA) grade II or greater congestive heart failure (see
Appendix B) or symptomatic congestive heart failure.

- Inadequately controlled hypertension (defined as systolic blood pressure >150 mmHg
and/or diastolic blood pressure >100 mmHg).

- History of myocardial infarction or unstable angina within 6 months prior to
beginning study treatment.

- History of stroke or transient ischemic attack within 6 months prior to beginning
study treatment.

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

- Prior history of hypertensive crisis or hypertensive encephalopathy.

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

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

- History of abdominal fistula or gastrointestinal perforation within 6 months prior to
Day 1.

- Serious, non-healing wound, active ulcer, or untreated bone fracture.

- Proteinuria as demonstrated by urine dipstick for proteinuria >=2+. For patients
with >=2+ proteinuria on dipstick urinalysis, a urine protein: creatinine (UPC) ratio
will be determined or a 24-hour urine collection will be done. Patients with a UPC
ratio <1 or a 24-hour urine protein <1 gram are eligible.

- Minor surgical procedures (excluding placement of a vascular access device),
fine-needle aspirations, or core biopsies within 7 days prior to starting treatment.

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to starting protocol treatment or anticipation of need for major surgical
procedure during the course of study treatment. Patients who have not recovered from
the side effects of any major surgery are not eligible.

- Treatment with any investigational agents within 4 weeks of study entry.

- Chronic, systemic treatment with corticosteroids or other immunosuppressive agents.
Topical or inhaled steroids are allowed.

- Other malignancies within the past 3 years except for adequately treated carcinoma in
situ of the cervix or basal cell or superficial squamous (skin cell) carcinomas.