Clinical Trial DesignApproximately 28 patients with recurrent high-grade glioma that has progressed following both combined modality treatment with radiation and temozolomide chemotherapy, as well as therapy with bevacizumab, will be enrolled in the clinical trial at Cancer Therapy & Research Center at The University of Texas Health Science Center at San Antonio. It is anticipated that the dose escalation phase of the trial will enroll up to 24 patients. The study will determine the extent to which TH-302 is able to penetrate the tumor tissue, as well as assess the safety of TH-302 in patients undergoing surgery. The study will also test TH-302 in combination with bevacizumab in order to establish the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) for patients with high grade glioma. Ten patients will be enrolled at the MTD. The primary efficacy endpoint will be progression-free survival after a debulking craniotomy for patients treated with TH-302 in combination with bevacizumab following recurrence on bevacizumab. The study will also explore the extent of tumor hypoxia in recurrent high-grade glioma and its association with TH-302 activity as measured by the DNA damage induced by TH-302. The study will incorporate both a preoperative dose of TH-302 prior to the debulking craniotomy and a post-operative therapeutic component of TH-302 in combination with bevacizumab. The preoperative component will also incorporate the use of pimonidazole to characterize the extent of tumor hypoxia prior to surgery. The extent of hypoxia will then be correlated with the activity of TH-302 as measured by double strand DNA breaks, a known mechanism of activity for TH-302. Clinical Rationale Tumor hypoxia occurs when a cancerous tumor rapidly outgrows its blood supply, leaving portions of the tumor with regions where the oxygen concentration is significantly lower than in healthy tissues. Numerous studies have shown that higher levels of tumor hypoxia correlate with poor treatment outcomes for patients with a variety of solid tumors. TH-302 is the most advanced drug candidate in current clinical development that selectively treats tumor cells within hypoxic regions that can evade traditional therapies and ultimately contribute to relapse and treatment failure. Translational results in preclinical models have demonstrated that TH-302 enhances the antitumor activity of anti-angiogenics, providing a strong rationale for the combination of-TH-302 with agents like Avastin ®, Sutent ®, Votrient ®, and Sorafanib ® among others. Translational studies in glioblastoma models have shown that anti-angiogenic treatment leads to a loss of large-sized vessels with associated reduced perfusion and increase in tumor hypoxia. High-grade Glioma The American Cancer Society estimates that in 2011 there will be more than 22,340 new cases of cancer of the brain or other nervous system and over 13,000 deaths from the disease in the United States. Approximately 80% of all primary brain tumors originate from astrocytes, which are non-neural glial cells, and are referred to as astrocytomas. Astrocytomas are graded on the basis of cell growth and severity and grade 3 and grade 4 astrocytomas are collectively referred to as high-grade astrocytomas. Grade 4 astrocytomas are called glioblastomas and are the most common and most aggressive of the primary brain tumors in adults. Every year, there are approximately 13,000 new cases of glioblastoma in the United States.