Phase II Study of Patients With Recurrent Glioblastoma Multiforme Treated With Maximal Safe Neurosurgical Resection and Intra-Operative Radiation Therapy (IORT) Using the Xoft Axxent Electronic Brachytherapy System and Bevacizumab

• Subject has the ability to provide written informed consent

• Subject has the willingness to comply with all study procedures for the duration of the study

• Subject has histopathologically proven diagnosis of GBM or variants (gliosarcoma, giant cell glioblastoma etc.). Subjects will be also eligible if the original histology was lower-grade glioma and a subsequent diagnosis of glioblastoma or gliosarcoma is made.

• Subjects must have shown unequivocal radiographic evidence for tumor progression by contrast-enhanced MRI within 21 days prior to enrollment

• Subjects must have passed an interval of 6 months or greater between completion of prior radiotherapy and enrollment. If subjects 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, 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 enrollment

• The recurrent GBM must be potentially-resectable with the intent to resect such that residual tumor rim is less than 1 cm enhancing disease

• The recurrent GBM must have the appropriate dimensions to allow a Xoft applicator balloon to fit into the tumor cavity

• Subject has prior history of standard dose CNS radiation of 60 Gy in 30 fractions or 59.4 Gy in 1.8 Gy fractions, or equivalent of lower doses. Patients who have received prior treatment with non-standard RT dose and fractionation, interstitial brachytherapy, stereotactic radiosurgery, etc. are eligible as long as the criterion in 5. is met or approved by principal investigator.

• Subjects who have undergone CNS related core or needle biopsies, a minimum of 7 days must have elapsed prior to registration

⁃ History/physical examination, including neurologic examination, within 14 days prior to enrollment (i.e. date the informed consent was signed by the patient)

⁃ Subject must be ≥ 18 years of age

⁃ Subject must have a Karnofsky Performance Score ≥ 60%

⁃ Subject will have had a CBC/differential obtained within 14 days prior to enrollment , with adequate bone marrow function, i.e.:

⁃ d) Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3 e) Platelets ≥ 75,000 cells/mm3 f) Hemoglobin ≥ 9.0 g/dl (The use of transfusion or other intervention to achieve Hgb ≥ 9.0 g/dl is acceptable.)

⁃ Subjects liver and renal function test should reflect adequate hepatic and renal function 14 days prior to enrollment, i.e.:

• Total bilirubin ≤ 2.0 mg/dL, and SGOT or AST ≤ 2.5 times the upper limit of normal

∙ Serum creatinine ≤ 1.8 mg/dL) within 14 days prior to enrollment

⁃ Subject urine protein level must reflect the following requirements within 14 days before enrollment:

• Urine protein: creatinine (UPC ) ratio \< 1.0 OR

∙ Urine dipstick for proteinuria ≤ 2+ (patients who have \> 2+ proteinuria on dipstick urinalysis at baseline, must have an UPC ratio \<1.0 to be eligible. If the UPC ratio is ≥ 1.0, subsequent 24 hrs urine collection must be ≤ 1 g protein in 24 hrs)

⁃ Patients on full-dose anticoagulants (e.g., warfarin or 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 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 enrollment.

⁃ Women of child-bearing potential must have a negative pregnancy test within 7 days of treatment

⁃ Subjects of child-bearing potential must agree to use adequate contraceptive precautions and not to breastfeed (if applicable) until six months after the end of the treatment with Bevacizumab.

⁃ Patient is planned to have surgery for recurrent Glioblastoma