Summary

This randomized phase II trial studies how well bevacizumab with or without radiation therapy works in treating patients with glioblastoma that has returned after a period of improvement. Monoclonal antibodies, such as bevacizumab, may block tumor growth by targeting certain cells. Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. It is not yet known whether bevacizumab is more effective with or without radiation therapy in treating patients with recurrent glioblastoma.

Objectives

PRIMARY OBJECTIVES:
I. To establish an improvement in overall survival in recurrent glioblastoma multiforme (GBM) patients receiving bevacizumab and re-irradiation compared with patients receiving bevacizumab alone.

SECONDARY OBJECTIVES:
I. To estimate and compare the rate of objective response in patients with measurable disease.
II. To estimate and compare the 6-month progression-free survival rate.
III. To estimate and compare progression-free survival.
IV. To estimate and compare the rate of treatment adverse events.
V. To estimate and compare the rate of >= grade 3 acute or delayed central nervous system (CNS) toxicity.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive bevacizumab intravenously (IV) over 30-90 minutes every 2 weeks.

ARM II: Patients receive bevacizumab as in Arm I and undergo radiation therapy using intensity-modulated radiation therapy (IMRT), 3-dimensional conformal radiation therapy (3D-CRT), or proton beam radiation therapy (RT) 5 days a week for 2 weeks.

In both arms, courses with bevacizumab repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year, every 6 months for 1 year, and then annually thereafter.

Eligibility

1. Histopathologically proven diagnosis of glioblastoma or variants (gliosarcoma, giant cell glioblastoma etc); patients will be eligible if the original histology was lower-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made * Patients who did not have recent surgery for their glioblastoma must have shown unequivocal radiographic evidence for tumor progression by contrast-enhanced MRI scan (or CT scan for patients with non-compatible devices) within 21 days prior to registration; Note: patients who did have surgery with a post-operative contrast-enhanced scan falling outside the 5-week window prior to registration, per definition of recent surgery, must have a repeat magnetic resonance imaging (MRI) scan (or computed tomography [CT] scan for patients with non-compatible devices) within 21 days prior to registration * Patients must have passed an interval of 6 months or greater between completion of prior radiotherapy and registration; if patients have not passed an interval of at least 6 months, they may still be eligible if they meet one or more of the following criteria: ** New areas of tumor outside the original radiotherapy fields as determined by the investigator, or ** Histologic confirmation of tumor through biopsy or resection, or ** Nuclear medicine imaging, magnetic resonance (MR) spectroscopy, or MR perfusion imaging consistent with true progressive disease, rather than radiation necrosis obtained within 28 days of registration AND an interval of at least 90 days between completion of radiotherapy and registration * Patients unable to undergo MR imaging because of non-compatible devices can be enrolled provided CT scans are obtained and are of sufficient quality; patients without non-compatible devices may not use CT scans performed to meet this requirement
2. Prior history of standard dose CNS radiation of 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent or lower doses * Patients who have received prior treatment with non-standard radiation therapy (RT) dose and fractionation, interstitial brachytherapy, stereotactic radiosurgery, etc. are eligible as long as the criterion is met or approved by a principal investigator
3. Patients must have recovered from the toxic effects of prior therapy, and there must be a minimum time of 28 days prior to registration from the administration of any investigational agent or prior cytotoxic therapy with the following exceptions: * 14 days from administration of vincristine * 42 days from administration of nitrosoureas * 21 days from administration of procarbazine
4. Patients having undergone recent resection of their glioblastoma (within 5 weeks prior to registration) must have recovered from the effects of surgery; for CNS related core or needle biopsies, a minimum of 7 days must have elapsed prior to registration * Residual disease following resection of recurrent glioblastoma is not mandated for eligibility into the study; to best assess the extent of residual disease post-operatively, a post-operative or intra-operative MRI scan (or CT scan for patients with non-compatible devices) must be performed prior to registration and should be within 96 hours post surgery (although 24 hours would be optimum)
5. History/physical examination, including neurologic examination, within 14 days prior to registration
6. Karnofsky performance status >= 60 within 14 days prior to registration
7. Complete blood count (CBC)/differential obtained within 14 days prior to registration, with adequate bone marrow function
8. Absolute neutrophil count (ANC) >= 1,500 cells/mm^3
9. Platelets >= 75,000 cells/mm^3
10. Hemoglobin >= 9.0 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 9.0 g/dl is acceptable)
11. Total bilirubin =< 2.0 mg/dL
12. Serum glutamic oxaloacetic transaminase (SGOT) or aspartate aminotransferase (AST) =< 2.5 times the upper limit of normal
13. Serum creatinine =< 1.8 mg/dL
14. Urine protein: creatinine (UPC) ratio < 1.0 within 14 days prior to registration OR urine dipstick for proteinuria =< 2 positive (+) (patients discovered to have > 2+ proteinuria on dipstick urinalysis at baseline must have a UPC ratio done that is < 1.0 to be eligible; if the UPC ratio is >= 1.0 then the patients should undergo a 24-hour urine collection and must demonstrate =< 1g of protein in 24 hours to be eligible) * Note: UPC ratio of spot urine is an estimation of the 24-hour urine protein excretion; a UPC ratio of 1 is roughly equivalent to a 24-hour urine protein of 1 gm
15. Patients must not be pregnant (positive pregnancy test) or breast feeding; pregnancy test must be done within 7 days prior to registration; effective contraception (men and women) must be used in patients of child-bearing potential while on study treatment and for 6 months after
16. Patients on full-dose anticoagulants (e.g., warfarin or low molecular weight [LMW] heparin) must meet both of the following criteria: * No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices) * In-range international normalized ratio (INR) (usually between 2 and 3) on a stable dose of oral anticoagulant or on a stable dose of low molecular weight heparin, within 14 days prior to registration
17. Patient must be able to provide study-specific informed consent prior to study entry

Treatment Sites in Georgia